I recently picked up volume 1, number 1 of The Hospitalist, which was edited by John Nelson and Win Whitcomb and published in spring 1997. The Hospitalist was six pages long and had five articles and three job advertisements. The articles included one by Bob Wachter about how hospitalists represent “without a doubt … a bona fide new specialty in American medicine,” and one by Richard Slataper about how hospitalists improve quality of care.

As I compare volume 1, number 1 with the current volume, I marvel at how much things have changed—and how much they have stayed the same. The change is obvious just by looking at The Hospitalist. The similarities are evident by reading the content. We still talk about how hospital medicine is emerging as a new specialty and is taking important strides in that direction. Quality is still the key metric by which we measure our practice.

With this volume, we enter a new, exciting era for The Hospitalist with a new format, new editorial staff leadership, and a new publisher—but the same commitment to excellence and dedication to addressing key issues in the field of hospital medicine. I thank Jim Pile for his outstanding job as the previous editor of The Hospitalist. Jamie Newman assumes the role of physician editor with this issue, and I am excited to have his energy and creative ideas to lead the new phase of this important publication.

It has been said that half of what you learn in medical school is obsolete five years after you graduate. The trouble is you can’t know which half that will be until five years later. I remember being warned as an intern never to give a beta-blocker to a patient with heart failure. We now know that beta-blockers are lifesaving for people with heart failure. We are fortunate to practice in a world where scientific discoveries enhance our ability to help our patients and where the pace of discovery is growing by leaps and bounds. I wish I could list everything we do today that will be obsolete in five years, but my crystal ball is not that clear. Because I cannot predict what will change in medicine, I have instead thought about what does not change. As we celebrate the new with this volume of The Hospitalist I want to remember what is timeless in our profession.

Cornerstones of Diagnosis

With so much technology it is easy to believe that technology makes the diagnosis and heals the patient. But despite all of the new and amazing tests at our disposal, the patient history and physical examination remain the cornerstones of diagnosis.

It has been said that in more than 90% of cases the correct diagnosis appears on the differential after the history and physical. The tests merely help to confirm or rule out diagnoses. As technology races ahead the importance of sitting at the bedside, talking with the patient, and hearing her story stays constant.

One of my mentors says, “Don’t just do something, sit there.” When I’m confused about what is going on with a patient, my best aid in figuring things out is to pull up a chair and have the patient tell me his story from the beginning. What I like so much about being a hospitalist is that I have the ability to spend that kind of time when I need to. Unlike the outpatient setting where patients are scheduled every 15 minutes regardless of the reason for the visit, in the hospital I can be more flexible about how I allocate my time. I can spend time sitting and listening.

There is an apocryphal story I like that says that if you sit down in the patient’s room the patient will experience your visit as having lasted longer than if you stand for the same amount of time. I say apocryphal because I have searched for this study but have never found it; however, I believe it. Patients also like telling their story. There is healing in the telling and in knowing that you have been heard. As so much of medicine changes, sitting with the patient and hearing her story remains timeless.

Reach Out and Touch

Another part of medicine that has not changed over the millennia is the power of touch. During my second year of residency I realized that in many situations the physical examination just didn’t add much to my care of the patient. Perhaps this fact reflected my physical examination skills, but I believe it was more a function of realizing that in the absence of complaints in the chest I was unlikely to discover something on lung exam.

The great symbolism and importance of touching and examining the patient goes beyond discovering the unexpected finding. The laying on of hands creates a physical connection to the patient and can heal. I now make it a point to physically examine every patient every day. I examine patients not just to support billing and not just because there just may be a new finding, but because there is power and healing in touch. I want the patient to benefit from this power and I want to connect to it for myself. As a hospitalist I feel privileged to be able to be at the bedside with patients.

Identify with the Patient

Another timeless part of patient care is empathy. Many patients simply want someone to walk alongside them and understand their experience of illness. Empathy makes this possible.

As I talk with patients I use myself as a guide for understanding the patient’s emotional experience and try to reflect that back. More than simply taking the history or laying my hands on the patient, I try to understand what the patient is feeling and going through. The fear and loneliness of illness can be greatly relieved by knowing that another person understands your experience and is walking with you. Our patients’ need and desire for empathy has not changed despite all of our technological innovations.

As hospitalists we meet people at their sickest and most vulnerable. They enter the foreign world of the hospital where they are often alone and where they have little to no control over what happens to them. Patients typically can’t even dictate the basics of life in the hospital like when or what they can eat. Even if we imagine the ideal hospital of the future built around the patient and that affords maximum control to the patient, the hospital will still be foreign. The power of empathy and the human interaction it represents will remain as important in this ideal hospital as it is today and as it always has been.

Education Never Ends

The other certainty in medicine is that science and technology will advance, bringing new and better ways to diagnose and treat illness. Thus the final constant in medicine is the need to always be learning. As an attending I had to learn that beta-blockers were good for people with heart failure and saved lives. I have learned many more new things since residency and understand the need to continue to learn.

Another wonderful aspect of being a hospitalist is the continuous progress of medical care and the ability to apply it to help patients. Advances in diagnosis and treatment, changes to systems that ensure that all patients receive this care, and attention to patient safety, quality, and palliative care all help ensure that patients receive the best possible care. Hospitalists are at the forefront of all of these activities.

In Conclusion

I delight in the new and celebrate progress that this era for The Hospitalist represents. I’m proud of the The Hospitalist and look forward to it continuing the tradition of quality while it expands and grows in new ways. In the same way I’m excited about medical advances but try always to remember what is timeless. Sitting with patients, listening to them, touching them, and being empathic reap great rewards for patients and for us.

As hospitalists we care for people at their most vulnerable moments. At those times our humanity, our gentle, caring touch, and our empathy matter most. In addition to bringing to bear the best that modern medicine has to offer in medications, diagnostic tests, and interventions let us remember the power to heal that we bring to the bedside when we bring ourselves—open to being with the patient and not just doing something but sitting there. TH

Dr. Pantilat is an associate professor of clinical medicine at the University of California at San Francisco.

I recently picked up volume 1, number 1 of The Hospitalist, which was edited by John Nelson and Win Whitcomb and published in spring 1997. The Hospitalist was six pages long and had five articles and three job advertisements. The articles included one by Bob Wachter about how hospitalists represent “without a doubt … a bona fide new specialty in American medicine,” and one by Richard Slataper about how hospitalists improve quality of care.

As I compare volume 1, number 1 with the current volume, I marvel at how much things have changed—and how much they have stayed the same. The change is obvious just by looking at The Hospitalist. The similarities are evident by reading the content. We still talk about how hospital medicine is emerging as a new specialty and is taking important strides in that direction. Quality is still the key metric by which we measure our practice.

With this volume, we enter a new, exciting era for The Hospitalist with a new format, new editorial staff leadership, and a new publisher—but the same commitment to excellence and dedication to addressing key issues in the field of hospital medicine. I thank Jim Pile for his outstanding job as the previous editor of The Hospitalist. Jamie Newman assumes the role of physician editor with this issue, and I am excited to have his energy and creative ideas to lead the new phase of this important publication.

It has been said that half of what you learn in medical school is obsolete five years after you graduate. The trouble is you can’t know which half that will be until five years later. I remember being warned as an intern never to give a beta-blocker to a patient with heart failure. We now know that beta-blockers are lifesaving for people with heart failure. We are fortunate to practice in a world where scientific discoveries enhance our ability to help our patients and where the pace of discovery is growing by leaps and bounds. I wish I could list everything we do today that will be obsolete in five years, but my crystal ball is not that clear. Because I cannot predict what will change in medicine, I have instead thought about what does not change. As we celebrate the new with this volume of The Hospitalist I want to remember what is timeless in our profession.

Cornerstones of Diagnosis

With so much technology it is easy to believe that technology makes the diagnosis and heals the patient. But despite all of the new and amazing tests at our disposal, the patient history and physical examination remain the cornerstones of diagnosis.

It has been said that in more than 90% of cases the correct diagnosis appears on the differential after the history and physical. The tests merely help to confirm or rule out diagnoses. As technology races ahead the importance of sitting at the bedside, talking with the patient, and hearing her story stays constant.

One of my mentors says, “Don’t just do something, sit there.” When I’m confused about what is going on with a patient, my best aid in figuring things out is to pull up a chair and have the patient tell me his story from the beginning. What I like so much about being a hospitalist is that I have the ability to spend that kind of time when I need to. Unlike the outpatient setting where patients are scheduled every 15 minutes regardless of the reason for the visit, in the hospital I can be more flexible about how I allocate my time. I can spend time sitting and listening.

There is an apocryphal story I like that says that if you sit down in the patient’s room the patient will experience your visit as having lasted longer than if you stand for the same amount of time. I say apocryphal because I have searched for this study but have never found it; however, I believe it. Patients also like telling their story. There is healing in the telling and in knowing that you have been heard. As so much of medicine changes, sitting with the patient and hearing her story remains timeless.

Reach Out and Touch

Another part of medicine that has not changed over the millennia is the power of touch. During my second year of residency I realized that in many situations the physical examination just didn’t add much to my care of the patient. Perhaps this fact reflected my physical examination skills, but I believe it was more a function of realizing that in the absence of complaints in the chest I was unlikely to discover something on lung exam.

The great symbolism and importance of touching and examining the patient goes beyond discovering the unexpected finding. The laying on of hands creates a physical connection to the patient and can heal. I now make it a point to physically examine every patient every day. I examine patients not just to support billing and not just because there just may be a new finding, but because there is power and healing in touch. I want the patient to benefit from this power and I want to connect to it for myself. As a hospitalist I feel privileged to be able to be at the bedside with patients.

Identify with the Patient

Another timeless part of patient care is empathy. Many patients simply want someone to walk alongside them and understand their experience of illness. Empathy makes this possible.

As I talk with patients I use myself as a guide for understanding the patient’s emotional experience and try to reflect that back. More than simply taking the history or laying my hands on the patient, I try to understand what the patient is feeling and going through. The fear and loneliness of illness can be greatly relieved by knowing that another person understands your experience and is walking with you. Our patients’ need and desire for empathy has not changed despite all of our technological innovations.

As hospitalists we meet people at their sickest and most vulnerable. They enter the foreign world of the hospital where they are often alone and where they have little to no control over what happens to them. Patients typically can’t even dictate the basics of life in the hospital like when or what they can eat. Even if we imagine the ideal hospital of the future built around the patient and that affords maximum control to the patient, the hospital will still be foreign. The power of empathy and the human interaction it represents will remain as important in this ideal hospital as it is today and as it always has been.

Education Never Ends

The other certainty in medicine is that science and technology will advance, bringing new and better ways to diagnose and treat illness. Thus the final constant in medicine is the need to always be learning. As an attending I had to learn that beta-blockers were good for people with heart failure and saved lives. I have learned many more new things since residency and understand the need to continue to learn.

Another wonderful aspect of being a hospitalist is the continuous progress of medical care and the ability to apply it to help patients. Advances in diagnosis and treatment, changes to systems that ensure that all patients receive this care, and attention to patient safety, quality, and palliative care all help ensure that patients receive the best possible care. Hospitalists are at the forefront of all of these activities.

In Conclusion

I delight in the new and celebrate progress that this era for The Hospitalist represents. I’m proud of the The Hospitalist and look forward to it continuing the tradition of quality while it expands and grows in new ways. In the same way I’m excited about medical advances but try always to remember what is timeless. Sitting with patients, listening to them, touching them, and being empathic reap great rewards for patients and for us.

As hospitalists we care for people at their most vulnerable moments. At those times our humanity, our gentle, caring touch, and our empathy matter most. In addition to bringing to bear the best that modern medicine has to offer in medications, diagnostic tests, and interventions let us remember the power to heal that we bring to the bedside when we bring ourselves—open to being with the patient and not just doing something but sitting there. TH

Dr. Pantilat is an associate professor of clinical medicine at the University of California at San Francisco.

I recently picked up volume 1, number 1 of The Hospitalist, which was edited by John Nelson and Win Whitcomb and published in spring 1997. The Hospitalist was six pages long and had five articles and three job advertisements. The articles included one by Bob Wachter about how hospitalists represent “without a doubt … a bona fide new specialty in American medicine,” and one by Richard Slataper about how hospitalists improve quality of care.

As I compare volume 1, number 1 with the current volume, I marvel at how much things have changed—and how much they have stayed the same. The change is obvious just by looking at The Hospitalist. The similarities are evident by reading the content. We still talk about how hospital medicine is emerging as a new specialty and is taking important strides in that direction. Quality is still the key metric by which we measure our practice.

With this volume, we enter a new, exciting era for The Hospitalist with a new format, new editorial staff leadership, and a new publisher—but the same commitment to excellence and dedication to addressing key issues in the field of hospital medicine. I thank Jim Pile for his outstanding job as the previous editor of The Hospitalist. Jamie Newman assumes the role of physician editor with this issue, and I am excited to have his energy and creative ideas to lead the new phase of this important publication.

It has been said that half of what you learn in medical school is obsolete five years after you graduate. The trouble is you can’t know which half that will be until five years later. I remember being warned as an intern never to give a beta-blocker to a patient with heart failure. We now know that beta-blockers are lifesaving for people with heart failure. We are fortunate to practice in a world where scientific discoveries enhance our ability to help our patients and where the pace of discovery is growing by leaps and bounds. I wish I could list everything we do today that will be obsolete in five years, but my crystal ball is not that clear. Because I cannot predict what will change in medicine, I have instead thought about what does not change. As we celebrate the new with this volume of The Hospitalist I want to remember what is timeless in our profession.

Cornerstones of Diagnosis

With so much technology it is easy to believe that technology makes the diagnosis and heals the patient. But despite all of the new and amazing tests at our disposal, the patient history and physical examination remain the cornerstones of diagnosis.

It has been said that in more than 90% of cases the correct diagnosis appears on the differential after the history and physical. The tests merely help to confirm or rule out diagnoses. As technology races ahead the importance of sitting at the bedside, talking with the patient, and hearing her story stays constant.

One of my mentors says, “Don’t just do something, sit there.” When I’m confused about what is going on with a patient, my best aid in figuring things out is to pull up a chair and have the patient tell me his story from the beginning. What I like so much about being a hospitalist is that I have the ability to spend that kind of time when I need to. Unlike the outpatient setting where patients are scheduled every 15 minutes regardless of the reason for the visit, in the hospital I can be more flexible about how I allocate my time. I can spend time sitting and listening.

There is an apocryphal story I like that says that if you sit down in the patient’s room the patient will experience your visit as having lasted longer than if you stand for the same amount of time. I say apocryphal because I have searched for this study but have never found it; however, I believe it. Patients also like telling their story. There is healing in the telling and in knowing that you have been heard. As so much of medicine changes, sitting with the patient and hearing her story remains timeless.

Reach Out and Touch

Another part of medicine that has not changed over the millennia is the power of touch. During my second year of residency I realized that in many situations the physical examination just didn’t add much to my care of the patient. Perhaps this fact reflected my physical examination skills, but I believe it was more a function of realizing that in the absence of complaints in the chest I was unlikely to discover something on lung exam.

The great symbolism and importance of touching and examining the patient goes beyond discovering the unexpected finding. The laying on of hands creates a physical connection to the patient and can heal. I now make it a point to physically examine every patient every day. I examine patients not just to support billing and not just because there just may be a new finding, but because there is power and healing in touch. I want the patient to benefit from this power and I want to connect to it for myself. As a hospitalist I feel privileged to be able to be at the bedside with patients.

Identify with the Patient

Another timeless part of patient care is empathy. Many patients simply want someone to walk alongside them and understand their experience of illness. Empathy makes this possible.

As I talk with patients I use myself as a guide for understanding the patient’s emotional experience and try to reflect that back. More than simply taking the history or laying my hands on the patient, I try to understand what the patient is feeling and going through. The fear and loneliness of illness can be greatly relieved by knowing that another person understands your experience and is walking with you. Our patients’ need and desire for empathy has not changed despite all of our technological innovations.

As hospitalists we meet people at their sickest and most vulnerable. They enter the foreign world of the hospital where they are often alone and where they have little to no control over what happens to them. Patients typically can’t even dictate the basics of life in the hospital like when or what they can eat. Even if we imagine the ideal hospital of the future built around the patient and that affords maximum control to the patient, the hospital will still be foreign. The power of empathy and the human interaction it represents will remain as important in this ideal hospital as it is today and as it always has been.

Education Never Ends

The other certainty in medicine is that science and technology will advance, bringing new and better ways to diagnose and treat illness. Thus the final constant in medicine is the need to always be learning. As an attending I had to learn that beta-blockers were good for people with heart failure and saved lives. I have learned many more new things since residency and understand the need to continue to learn.

Another wonderful aspect of being a hospitalist is the continuous progress of medical care and the ability to apply it to help patients. Advances in diagnosis and treatment, changes to systems that ensure that all patients receive this care, and attention to patient safety, quality, and palliative care all help ensure that patients receive the best possible care. Hospitalists are at the forefront of all of these activities.

In Conclusion

I delight in the new and celebrate progress that this era for The Hospitalist represents. I’m proud of the The Hospitalist and look forward to it continuing the tradition of quality while it expands and grows in new ways. In the same way I’m excited about medical advances but try always to remember what is timeless. Sitting with patients, listening to them, touching them, and being empathic reap great rewards for patients and for us.

As hospitalists we care for people at their most vulnerable moments. At those times our humanity, our gentle, caring touch, and our empathy matter most. In addition to bringing to bear the best that modern medicine has to offer in medications, diagnostic tests, and interventions let us remember the power to heal that we bring to the bedside when we bring ourselves—open to being with the patient and not just doing something but sitting there. TH

Dr. Pantilat is an associate professor of clinical medicine at the University of California at San Francisco.

As the diversity of the U.S. population increases, so do the challenges for hospitalists, as they seek to deliver truly patient-centered care in the 21st century. The March 2002 Institute of Medicine report, “Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care,” concluded that, while some care inequities can be attributed to access and linguistic barriers, healthcare providers themselves may contribute to disparities in care for their minority patients.1

How can hospitalists ensure that they bridge the cultural divide between themselves and their patients from different racial, ethnic, and cultural backgrounds and avoid potential missteps in care delivery?

An Open Mind

Experts in cultural competency interviewed for this article explained that hospitalists can readily acquire the knowledge and skills necessary to effectively provide patient-centered care for all their patients. (See “Resource List,” p. 27.) But the most critical element in culturally competent healthcare delivery is the attitude with which the provider approaches his or her patients.

“I don’t think we can teach attitude,” says Alicia Fernandez, MD, assistant clinical professor of medicine, Division of General Internal Medicine, University of California, San Francisco, a nationally known researcher on language barriers and former full-time hospitalist. “But I think that any doctor who’s trying to do the best he or she can by their individual patients has the right attitude, which is to remain open to practicing patient-centered care.”

Hospitalists face more difficulty with some cultural issues than primary care providers because we’re thrust into a situation of an acute illness, whereas the primary care provider at least gets an opportunity to establish a relationship.

—Jack Percelay, MD

Physicians must be able to approach each patient on his or her own terms, and to acknowledge that members of different racial and ethnic groups hold beliefs about health and illness that diverge from those of Western medicine.

“You really need to have the capacity to empathize, and turn off all of your own belief systems, in some cases, to listen,” says Stacy Goldsholl, MD, a hospitalist based in Wilmington, N.C., and an SHM Board member.

Dr. Goldsholl recalls one situation involving a patient who was a Jehovah’s Witness who entered the hospital with a gastrointestinal bleed. Because of religious proscriptions, the patient refused a blood transfusion.

“It was extremely difficult as a scientist-trained physician, to watch someone bleed to a hemoglobin of 5, knowing that a simple transfusion would save this patient,” recalls Dr. Goldsholl.

The patient later underwent surgery without a transfusion and survived, but Dr. Goldsholl believes this case illustrates that delivering patient-centered care requires the practice not just of the science—but the art—of medicine.

“I think the real message is, you have to think outside of your own box,” she offers. “In addition, the cultural issues become much more pronounced when you start to approach end-of-life issues that take on more of a cultural, ethnic. and spiritual dimension.”

Awareness and Knowledge

Mitchell D. Wilson, MD, believes “the average American tends to be very ethnocentric. We are not taught cultural awareness in recognizing our own inherent biases, so we are unable to take the next step and recognize that there is a gap between our culture and another person’s culture that would require us to take a different approach.”

Dr. Wilson is associate professor of medicine, medical director and physician advisor, Department of Clinical Care Management, University of North Carolina (UNC) Hospitals, and section chief of hospital medicine and medical director, FirstHealth of the Carolinas Hospitalist Services, UNC School of Medicine, Chapel Hill. He is also an SHM Board member.

Dr. Wilson says that his own cultural awareness emanated from participation in a spirituality and medicine program for student doctors and nurses at the medical school where he trained and was later on faculty.

“I was able to function both as a small group facilitator and a large group panelist, and we used a case-based format for creating awareness of spirituality in medicine,” he explains.

Dr. Wilson notes that he later drew on these experiences when, as a hospitalist at a regional medical center, he was called to admit a woman to the hospital from the emergency department. She was dressed in traditional Muslim clothing and spoke no English. Knowing that it is offensive for traditional Islamic women to be examined by a man, Dr. Wilson asked through the woman’s friends who had accompanied the woman whether she would prefer a woman doctor and whether she would be comfortable at least with his taking her history. She answered “yes” to both questions.

Dr. Wilson prevailed upon a female doctor in a competing practice to perform the examination and also made a special effort to admit the patient to the female physician in his own group who would be working the next day.

“It’s not that I’ve been trained in cultural awareness,” he says, “but this case points out the importance of recognizing other traditions, so that you can deliver care that is effective and culturally sensitive.”

Earning Trust

Maren Grainger-Monsen, MD, senior research scholar and director of the Biomedical Ethics in Film Program at the Stanford University Center for Biomedical Ethics (Calif.), has produced several award-winning films about patients from different racial and ethnic groups and their interface with the healthcare delivery system. In the process of filming patients with their families, she has realized that as a physician she often mistook respect for trust.

Patients, she says, “would be respectful and polite and seeming to agree with me, but as I have worked on these films and spent time with families, I realize that they approach the physician and the hospital system with more caution and they wait to see if the people are trustworthy.”

Jack Percelay, MD, chair, American Academy of Pediatrics Section on Hospital Medicine and SHM Board member, notes that “hospitalists face more difficulty with some cultural issues than primary care providers because we’re thrust into a situation of an acute illness, whereas the primary care provider at least gets an opportunity to establish a relationship. In pediatric hospital medicine, we need to be very careful and cognizant of this, make sure we employ translation resources and social workers, and be hesitant to judge someone else’s value system, while still advocating for the patient.”

While it can be important to acquire a baseline of knowledge about dominant cultural and religious groups (especially if a group comprises a sizable percentage of patients seen at one’s institution), Dr. Fernandez cautions against using a laundry list approach to cultural competency.

“It’s helpful to know, for instance, that many Vietnamese here came as a result of the Vietnam War,” she says. “On the other hand, it is not that helpful to say [something like], ‘Don’t shake hands with Vietnamese.’ Our patients are forgiving of whether we shake hands or don’t shake hands. They are less forgiving when we appear not to listen to them.”

Lost in Translation

Nearly 14% of people who live in the United States speak a language other than English in their homes, according to the U.S. Census Bureau’s Census 2000 estimates.2 When a person with limited English proficiency (LEP) enters the healthcare system, the potential for medical error increases if language barriers are not addressed. Indeed, healthcare institutions that receive federal healthcare dollars (Medicare, Medicaid) are obligated under Title VI of the Civil Rights Act of 1964 to provide access to interpreter services—free of charge—to LEP patients.

Those interviewed for this article advised that physicians should avail themselves of trained medical interpreters whenever possible. These professionals are trained to translate providers’ and patients’ communications verbatim—without editing—and are conversant with medical terminology.

However, such resources may not be available in rural hospitals. Such is the case for William D. Atchley, Jr., MD, medical director of the Hospitalist Service at Sentara Careplex Hospital in Hampton, Va., who recently used a cafeteria staff person to translate while he examined and admitted a Mexico-born patient with rhabdomyolysis that resulted from heat exhaustion. Dr. Atchley, an SHM Board member, has also used family members as translators. He notes, though, that “trying to get an understanding of what is going on can be difficult at times because the one family member who may act as a translator may not have as good a command of English [as a trained medical interpreter]. You are always fearful that something could get lost in translation.”

Even large institutions that have medical interpreters on staff may not have 24-hour coverage. In that case, telephone interpreters through AT&T’s Language Line service can be another option (www.languageline.com). Physicians can also work with ad-hoc interpreters, defined as family members or friends who act as interpreters, but are not professionally trained, says Dr. Fernandez.

“It can pay off to first take a few minutes to explain to these interpreters that you want them to repeat everything they hear as much word for word as they can,” she explains. “Tell them that you will give them time to participate in the conversation—as a family member—later on. First, you want them to play this narrow role as interpreter, and later you will let them add information as the family member because their contribution is also valuable.”

Young people, including teenage children, should not be used to interpret unless the situation is immediately life-threatening. “There has been a lot of research,” says Dr. Fernandez, “showing that [using children as interpreters] distorts family roles and makes the children uncomfortable.”

For example, says Dr. Grainger-Monsen, it would be completely inappropriate for a child to translate while a physician asks his mother about her past sexual history or vaginal bleeding.

The Time It Takes

At San Francisco General Hospital, where Dr. Fernandez is an attending physician, there are 140 languages spoken each month. She says the variety of patient backgrounds presents a challenge even for someone like herself, who has conducted extensive research on barriers to minority healthcare. She admits that she sometimes experiences an “internal groan” when she notices that the next patient in her busy clinic day is someone who speaks a language that she doesn’t. Like many of the hospitalists interviewed for this article, Dr. Fernandez notes that because using medical interpreters is time-consuming, she experiences initial resistance to the process.

A 2004 Canadian study examined the relationship between length of stay and LEP in the ambulatory care setting. It found that LEP patients stayed in the hospital longer for conditions, such as unstable coronary syndromes and chest pain, stroke, diabetes, and elective hip replacement.3

Issues about cultural competency are “fairly complex,” notes Alpesh Amin, MD, MBA, FACP, executive director Hospitalist Program and vice chair for clinical affairs, Department of Medicine at the University of California, Irvine, and SHM Board member. Sorting through issues surrounding patients’ beliefs toward healthcare, as well as their family values and dynamics, “takes time to resolve, and if I really want to understand your personal beliefs, I’ve got to be willing to sit down and talk about it. But, I’m not going to get paid for that time. This is not a reimbursable expense for the physician.”

Still, taking time to explore a patient’s preferences could also shorten length of stay if, for instance, the patient indicated that prescribed management indicated after an expensive test would not be his choice of care, says Dr. Amin.

Understanding what beliefs and experiences patients bring to the table, as well as their past health behaviors, does involve a time investment, agrees Minn.-based Russell Holman, MD, national medical director for Cogent Healthcare, Inc. and SHM Board member. But that investment “can only help efficiency,” he maintains. “We’ve invested ourselves tremendously in terms of identifying what are best practices for a patient with heart failure, or pneumonia, or heart attack, but the cultural competency dimension of healthcare has been largely overlooked.”

Training in cultural competency is piecemeal at best, notes Dr. Holman, and often acquired on the job. He recalls a situation in which he learned first-hand the profound effect that culture has on health. While working with a Hmong man who was in a coma and on a ventilator, Dr. Holman initially attempted to seek decision-making from the patient’s wife.

“I found out that was not the appropriate decision-making process for their culture,” says Dr. Holman. The discussion was initiated in the patient’s room, and was moved to a lecture-style classroom to accommodate the 37 members of the man’s clan who came to discuss his condition.

“The fascinating thing to me was that the patient’s wife and the other women sat in the back of the classroom and did not speak the entire time,” explains Dr. Holman. “The decisions were largely conducted by the clan elders. I also found out that my patient was the clan leader, and the elders had very clear goals in mind. The goal was to keep this individual alive, because he was so important as a figure in the clan. I learned that their culture had a profound impact on their expectations of me as a physician and a provider—how I conducted myself in terms of family and clan communications, what resources I brought to bear to try and stabilize and improve his health, and how I worked with specialists. I also learned that although some clan and family members were fluent in English, even modest miscommunications, if I were to use them as translators, could result in significant setbacks.”

Prior to his current position with Cogent Healthcare, Dr. Holman managed a group of 30 hospitalists at HealthPartners Medical Group in Minnesota and in partnership with the Center for International Health developed a cultural competency curriculum for their group and for the University of Minnesota residents in training at Regions Hospital in St. Paul.

“When you are busy working in the hospital, you need to be able to quickly access some resources to be able to give you a ‘just in time’ amount of information and awareness” with which to approach your patient, he says.

Agents for Change?

In addition to Title VI compliance, hospitals are now surveyed by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) and are evaluated on their ability to provide language services.

“This is a changing area,” notes Dr. Fernandez, “and I think it is important for hospitalists to be on the forefront of that change, part of the process that says, ‘Yes, we need to be able to provide more efficient, more patient-centered, and safer care.’ Language barriers, as one example, are inefficient, are dangerous, and are clearly associated with increased medical error.”

Dr. Percelay believes that dealing with patients from different backgrounds involves using “common sense, being respectful and legitimately curious, and avoiding shortcuts in terms of translation issues. I think if people have an inherent respect for diversity, and are open to it, it can enrich your practice.”

Dr. Fernandez agrees. “Practicing medicine in a patient-centered way is ultimately a more rewarding way to work and live,” she says. “There also needs to be reform at a national level that allows physicians and hospitalists to be appropriately compensated for much of the conversation and bedside work that we do.” TH

Writer Gretchen Henkel lives in California and writes regularly about healthcare.

References

1. Unequal Treatment: Understanding Racial and Ethnic Disparities in Health Care. Institute of Medicine, National Academy of Sciences. 2002. Available from the National Academy Press Available at http://books.nap.edu/catalog/11036.html. Last accessed July 27, 2005; and Unequal Treatment: What Healthcare Providers Need to Know about Racial and Ethnic Disparities in Healthcare. Institute of Medicine, National Academy of Sciences. Available at www.nap.edu/catalog/10260.html. Last accessed July 27, 2005.
2. Shin HB, Bruno R. Language use and English-speaking ability: a Census 2000 brief. U.S. Census Bureau, 2003. Available online at www.census.gov/population/www/cen2000/briefs.html. Last accessed July 27, 2005.
3. John-Baptiste A, Naglie G, Tomlinson G, et al. The effect of English language proficiency on length of stay and in-hospital mortality. J Gen Intern Med. March 2004;19(3):221-228.

As the diversity of the U.S. population increases, so do the challenges for hospitalists, as they seek to deliver truly patient-centered care in the 21st century. The March 2002 Institute of Medicine report, “Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care,” concluded that, while some care inequities can be attributed to access and linguistic barriers, healthcare providers themselves may contribute to disparities in care for their minority patients.1

How can hospitalists ensure that they bridge the cultural divide between themselves and their patients from different racial, ethnic, and cultural backgrounds and avoid potential missteps in care delivery?

An Open Mind

Experts in cultural competency interviewed for this article explained that hospitalists can readily acquire the knowledge and skills necessary to effectively provide patient-centered care for all their patients. (See “Resource List,” p. 27.) But the most critical element in culturally competent healthcare delivery is the attitude with which the provider approaches his or her patients.

“I don’t think we can teach attitude,” says Alicia Fernandez, MD, assistant clinical professor of medicine, Division of General Internal Medicine, University of California, San Francisco, a nationally known researcher on language barriers and former full-time hospitalist. “But I think that any doctor who’s trying to do the best he or she can by their individual patients has the right attitude, which is to remain open to practicing patient-centered care.”

Hospitalists face more difficulty with some cultural issues than primary care providers because we’re thrust into a situation of an acute illness, whereas the primary care provider at least gets an opportunity to establish a relationship.

—Jack Percelay, MD

Physicians must be able to approach each patient on his or her own terms, and to acknowledge that members of different racial and ethnic groups hold beliefs about health and illness that diverge from those of Western medicine.

“You really need to have the capacity to empathize, and turn off all of your own belief systems, in some cases, to listen,” says Stacy Goldsholl, MD, a hospitalist based in Wilmington, N.C., and an SHM Board member.

Dr. Goldsholl recalls one situation involving a patient who was a Jehovah’s Witness who entered the hospital with a gastrointestinal bleed. Because of religious proscriptions, the patient refused a blood transfusion.

“It was extremely difficult as a scientist-trained physician, to watch someone bleed to a hemoglobin of 5, knowing that a simple transfusion would save this patient,” recalls Dr. Goldsholl.

The patient later underwent surgery without a transfusion and survived, but Dr. Goldsholl believes this case illustrates that delivering patient-centered care requires the practice not just of the science—but the art—of medicine.

“I think the real message is, you have to think outside of your own box,” she offers. “In addition, the cultural issues become much more pronounced when you start to approach end-of-life issues that take on more of a cultural, ethnic. and spiritual dimension.”

Awareness and Knowledge

Mitchell D. Wilson, MD, believes “the average American tends to be very ethnocentric. We are not taught cultural awareness in recognizing our own inherent biases, so we are unable to take the next step and recognize that there is a gap between our culture and another person’s culture that would require us to take a different approach.”

Dr. Wilson is associate professor of medicine, medical director and physician advisor, Department of Clinical Care Management, University of North Carolina (UNC) Hospitals, and section chief of hospital medicine and medical director, FirstHealth of the Carolinas Hospitalist Services, UNC School of Medicine, Chapel Hill. He is also an SHM Board member.

Dr. Wilson says that his own cultural awareness emanated from participation in a spirituality and medicine program for student doctors and nurses at the medical school where he trained and was later on faculty.

“I was able to function both as a small group facilitator and a large group panelist, and we used a case-based format for creating awareness of spirituality in medicine,” he explains.

Dr. Wilson notes that he later drew on these experiences when, as a hospitalist at a regional medical center, he was called to admit a woman to the hospital from the emergency department. She was dressed in traditional Muslim clothing and spoke no English. Knowing that it is offensive for traditional Islamic women to be examined by a man, Dr. Wilson asked through the woman’s friends who had accompanied the woman whether she would prefer a woman doctor and whether she would be comfortable at least with his taking her history. She answered “yes” to both questions.

Dr. Wilson prevailed upon a female doctor in a competing practice to perform the examination and also made a special effort to admit the patient to the female physician in his own group who would be working the next day.

“It’s not that I’ve been trained in cultural awareness,” he says, “but this case points out the importance of recognizing other traditions, so that you can deliver care that is effective and culturally sensitive.”

Earning Trust

Maren Grainger-Monsen, MD, senior research scholar and director of the Biomedical Ethics in Film Program at the Stanford University Center for Biomedical Ethics (Calif.), has produced several award-winning films about patients from different racial and ethnic groups and their interface with the healthcare delivery system. In the process of filming patients with their families, she has realized that as a physician she often mistook respect for trust.

Patients, she says, “would be respectful and polite and seeming to agree with me, but as I have worked on these films and spent time with families, I realize that they approach the physician and the hospital system with more caution and they wait to see if the people are trustworthy.”

Jack Percelay, MD, chair, American Academy of Pediatrics Section on Hospital Medicine and SHM Board member, notes that “hospitalists face more difficulty with some cultural issues than primary care providers because we’re thrust into a situation of an acute illness, whereas the primary care provider at least gets an opportunity to establish a relationship. In pediatric hospital medicine, we need to be very careful and cognizant of this, make sure we employ translation resources and social workers, and be hesitant to judge someone else’s value system, while still advocating for the patient.”

While it can be important to acquire a baseline of knowledge about dominant cultural and religious groups (especially if a group comprises a sizable percentage of patients seen at one’s institution), Dr. Fernandez cautions against using a laundry list approach to cultural competency.

“It’s helpful to know, for instance, that many Vietnamese here came as a result of the Vietnam War,” she says. “On the other hand, it is not that helpful to say [something like], ‘Don’t shake hands with Vietnamese.’ Our patients are forgiving of whether we shake hands or don’t shake hands. They are less forgiving when we appear not to listen to them.”

Lost in Translation

Nearly 14% of people who live in the United States speak a language other than English in their homes, according to the U.S. Census Bureau’s Census 2000 estimates.2 When a person with limited English proficiency (LEP) enters the healthcare system, the potential for medical error increases if language barriers are not addressed. Indeed, healthcare institutions that receive federal healthcare dollars (Medicare, Medicaid) are obligated under Title VI of the Civil Rights Act of 1964 to provide access to interpreter services—free of charge—to LEP patients.

Those interviewed for this article advised that physicians should avail themselves of trained medical interpreters whenever possible. These professionals are trained to translate providers’ and patients’ communications verbatim—without editing—and are conversant with medical terminology.

However, such resources may not be available in rural hospitals. Such is the case for William D. Atchley, Jr., MD, medical director of the Hospitalist Service at Sentara Careplex Hospital in Hampton, Va., who recently used a cafeteria staff person to translate while he examined and admitted a Mexico-born patient with rhabdomyolysis that resulted from heat exhaustion. Dr. Atchley, an SHM Board member, has also used family members as translators. He notes, though, that “trying to get an understanding of what is going on can be difficult at times because the one family member who may act as a translator may not have as good a command of English [as a trained medical interpreter]. You are always fearful that something could get lost in translation.”

Even large institutions that have medical interpreters on staff may not have 24-hour coverage. In that case, telephone interpreters through AT&T’s Language Line service can be another option (www.languageline.com). Physicians can also work with ad-hoc interpreters, defined as family members or friends who act as interpreters, but are not professionally trained, says Dr. Fernandez.

“It can pay off to first take a few minutes to explain to these interpreters that you want them to repeat everything they hear as much word for word as they can,” she explains. “Tell them that you will give them time to participate in the conversation—as a family member—later on. First, you want them to play this narrow role as interpreter, and later you will let them add information as the family member because their contribution is also valuable.”

Young people, including teenage children, should not be used to interpret unless the situation is immediately life-threatening. “There has been a lot of research,” says Dr. Fernandez, “showing that [using children as interpreters] distorts family roles and makes the children uncomfortable.”

For example, says Dr. Grainger-Monsen, it would be completely inappropriate for a child to translate while a physician asks his mother about her past sexual history or vaginal bleeding.

The Time It Takes

At San Francisco General Hospital, where Dr. Fernandez is an attending physician, there are 140 languages spoken each month. She says the variety of patient backgrounds presents a challenge even for someone like herself, who has conducted extensive research on barriers to minority healthcare. She admits that she sometimes experiences an “internal groan” when she notices that the next patient in her busy clinic day is someone who speaks a language that she doesn’t. Like many of the hospitalists interviewed for this article, Dr. Fernandez notes that because using medical interpreters is time-consuming, she experiences initial resistance to the process.

A 2004 Canadian study examined the relationship between length of stay and LEP in the ambulatory care setting. It found that LEP patients stayed in the hospital longer for conditions, such as unstable coronary syndromes and chest pain, stroke, diabetes, and elective hip replacement.3

Issues about cultural competency are “fairly complex,” notes Alpesh Amin, MD, MBA, FACP, executive director Hospitalist Program and vice chair for clinical affairs, Department of Medicine at the University of California, Irvine, and SHM Board member. Sorting through issues surrounding patients’ beliefs toward healthcare, as well as their family values and dynamics, “takes time to resolve, and if I really want to understand your personal beliefs, I’ve got to be willing to sit down and talk about it. But, I’m not going to get paid for that time. This is not a reimbursable expense for the physician.”

Still, taking time to explore a patient’s preferences could also shorten length of stay if, for instance, the patient indicated that prescribed management indicated after an expensive test would not be his choice of care, says Dr. Amin.

Understanding what beliefs and experiences patients bring to the table, as well as their past health behaviors, does involve a time investment, agrees Minn.-based Russell Holman, MD, national medical director for Cogent Healthcare, Inc. and SHM Board member. But that investment “can only help efficiency,” he maintains. “We’ve invested ourselves tremendously in terms of identifying what are best practices for a patient with heart failure, or pneumonia, or heart attack, but the cultural competency dimension of healthcare has been largely overlooked.”

Training in cultural competency is piecemeal at best, notes Dr. Holman, and often acquired on the job. He recalls a situation in which he learned first-hand the profound effect that culture has on health. While working with a Hmong man who was in a coma and on a ventilator, Dr. Holman initially attempted to seek decision-making from the patient’s wife.

“I found out that was not the appropriate decision-making process for their culture,” says Dr. Holman. The discussion was initiated in the patient’s room, and was moved to a lecture-style classroom to accommodate the 37 members of the man’s clan who came to discuss his condition.

“The fascinating thing to me was that the patient’s wife and the other women sat in the back of the classroom and did not speak the entire time,” explains Dr. Holman. “The decisions were largely conducted by the clan elders. I also found out that my patient was the clan leader, and the elders had very clear goals in mind. The goal was to keep this individual alive, because he was so important as a figure in the clan. I learned that their culture had a profound impact on their expectations of me as a physician and a provider—how I conducted myself in terms of family and clan communications, what resources I brought to bear to try and stabilize and improve his health, and how I worked with specialists. I also learned that although some clan and family members were fluent in English, even modest miscommunications, if I were to use them as translators, could result in significant setbacks.”

Prior to his current position with Cogent Healthcare, Dr. Holman managed a group of 30 hospitalists at HealthPartners Medical Group in Minnesota and in partnership with the Center for International Health developed a cultural competency curriculum for their group and for the University of Minnesota residents in training at Regions Hospital in St. Paul.

“When you are busy working in the hospital, you need to be able to quickly access some resources to be able to give you a ‘just in time’ amount of information and awareness” with which to approach your patient, he says.

Agents for Change?

In addition to Title VI compliance, hospitals are now surveyed by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) and are evaluated on their ability to provide language services.

“This is a changing area,” notes Dr. Fernandez, “and I think it is important for hospitalists to be on the forefront of that change, part of the process that says, ‘Yes, we need to be able to provide more efficient, more patient-centered, and safer care.’ Language barriers, as one example, are inefficient, are dangerous, and are clearly associated with increased medical error.”

Dr. Percelay believes that dealing with patients from different backgrounds involves using “common sense, being respectful and legitimately curious, and avoiding shortcuts in terms of translation issues. I think if people have an inherent respect for diversity, and are open to it, it can enrich your practice.”

Dr. Fernandez agrees. “Practicing medicine in a patient-centered way is ultimately a more rewarding way to work and live,” she says. “There also needs to be reform at a national level that allows physicians and hospitalists to be appropriately compensated for much of the conversation and bedside work that we do.” TH

Writer Gretchen Henkel lives in California and writes regularly about healthcare.

References

1. Unequal Treatment: Understanding Racial and Ethnic Disparities in Health Care. Institute of Medicine, National Academy of Sciences. 2002. Available from the National Academy Press Available at http://books.nap.edu/catalog/11036.html. Last accessed July 27, 2005; and Unequal Treatment: What Healthcare Providers Need to Know about Racial and Ethnic Disparities in Healthcare. Institute of Medicine, National Academy of Sciences. Available at www.nap.edu/catalog/10260.html. Last accessed July 27, 2005.
2. Shin HB, Bruno R. Language use and English-speaking ability: a Census 2000 brief. U.S. Census Bureau, 2003. Available online at www.census.gov/population/www/cen2000/briefs.html. Last accessed July 27, 2005.
3. John-Baptiste A, Naglie G, Tomlinson G, et al. The effect of English language proficiency on length of stay and in-hospital mortality. J Gen Intern Med. March 2004;19(3):221-228.

As the diversity of the U.S. population increases, so do the challenges for hospitalists, as they seek to deliver truly patient-centered care in the 21st century. The March 2002 Institute of Medicine report, “Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care,” concluded that, while some care inequities can be attributed to access and linguistic barriers, healthcare providers themselves may contribute to disparities in care for their minority patients.1

How can hospitalists ensure that they bridge the cultural divide between themselves and their patients from different racial, ethnic, and cultural backgrounds and avoid potential missteps in care delivery?

An Open Mind

Experts in cultural competency interviewed for this article explained that hospitalists can readily acquire the knowledge and skills necessary to effectively provide patient-centered care for all their patients. (See “Resource List,” p. 27.) But the most critical element in culturally competent healthcare delivery is the attitude with which the provider approaches his or her patients.

“I don’t think we can teach attitude,” says Alicia Fernandez, MD, assistant clinical professor of medicine, Division of General Internal Medicine, University of California, San Francisco, a nationally known researcher on language barriers and former full-time hospitalist. “But I think that any doctor who’s trying to do the best he or she can by their individual patients has the right attitude, which is to remain open to practicing patient-centered care.”

Hospitalists face more difficulty with some cultural issues than primary care providers because we’re thrust into a situation of an acute illness, whereas the primary care provider at least gets an opportunity to establish a relationship.

—Jack Percelay, MD

Physicians must be able to approach each patient on his or her own terms, and to acknowledge that members of different racial and ethnic groups hold beliefs about health and illness that diverge from those of Western medicine.

“You really need to have the capacity to empathize, and turn off all of your own belief systems, in some cases, to listen,” says Stacy Goldsholl, MD, a hospitalist based in Wilmington, N.C., and an SHM Board member.

Dr. Goldsholl recalls one situation involving a patient who was a Jehovah’s Witness who entered the hospital with a gastrointestinal bleed. Because of religious proscriptions, the patient refused a blood transfusion.

“It was extremely difficult as a scientist-trained physician, to watch someone bleed to a hemoglobin of 5, knowing that a simple transfusion would save this patient,” recalls Dr. Goldsholl.

The patient later underwent surgery without a transfusion and survived, but Dr. Goldsholl believes this case illustrates that delivering patient-centered care requires the practice not just of the science—but the art—of medicine.

“I think the real message is, you have to think outside of your own box,” she offers. “In addition, the cultural issues become much more pronounced when you start to approach end-of-life issues that take on more of a cultural, ethnic. and spiritual dimension.”

Awareness and Knowledge

Mitchell D. Wilson, MD, believes “the average American tends to be very ethnocentric. We are not taught cultural awareness in recognizing our own inherent biases, so we are unable to take the next step and recognize that there is a gap between our culture and another person’s culture that would require us to take a different approach.”

Dr. Wilson is associate professor of medicine, medical director and physician advisor, Department of Clinical Care Management, University of North Carolina (UNC) Hospitals, and section chief of hospital medicine and medical director, FirstHealth of the Carolinas Hospitalist Services, UNC School of Medicine, Chapel Hill. He is also an SHM Board member.

Dr. Wilson says that his own cultural awareness emanated from participation in a spirituality and medicine program for student doctors and nurses at the medical school where he trained and was later on faculty.

“I was able to function both as a small group facilitator and a large group panelist, and we used a case-based format for creating awareness of spirituality in medicine,” he explains.

Dr. Wilson notes that he later drew on these experiences when, as a hospitalist at a regional medical center, he was called to admit a woman to the hospital from the emergency department. She was dressed in traditional Muslim clothing and spoke no English. Knowing that it is offensive for traditional Islamic women to be examined by a man, Dr. Wilson asked through the woman’s friends who had accompanied the woman whether she would prefer a woman doctor and whether she would be comfortable at least with his taking her history. She answered “yes” to both questions.

Dr. Wilson prevailed upon a female doctor in a competing practice to perform the examination and also made a special effort to admit the patient to the female physician in his own group who would be working the next day.

“It’s not that I’ve been trained in cultural awareness,” he says, “but this case points out the importance of recognizing other traditions, so that you can deliver care that is effective and culturally sensitive.”

Earning Trust

Maren Grainger-Monsen, MD, senior research scholar and director of the Biomedical Ethics in Film Program at the Stanford University Center for Biomedical Ethics (Calif.), has produced several award-winning films about patients from different racial and ethnic groups and their interface with the healthcare delivery system. In the process of filming patients with their families, she has realized that as a physician she often mistook respect for trust.

Patients, she says, “would be respectful and polite and seeming to agree with me, but as I have worked on these films and spent time with families, I realize that they approach the physician and the hospital system with more caution and they wait to see if the people are trustworthy.”

Jack Percelay, MD, chair, American Academy of Pediatrics Section on Hospital Medicine and SHM Board member, notes that “hospitalists face more difficulty with some cultural issues than primary care providers because we’re thrust into a situation of an acute illness, whereas the primary care provider at least gets an opportunity to establish a relationship. In pediatric hospital medicine, we need to be very careful and cognizant of this, make sure we employ translation resources and social workers, and be hesitant to judge someone else’s value system, while still advocating for the patient.”

While it can be important to acquire a baseline of knowledge about dominant cultural and religious groups (especially if a group comprises a sizable percentage of patients seen at one’s institution), Dr. Fernandez cautions against using a laundry list approach to cultural competency.

“It’s helpful to know, for instance, that many Vietnamese here came as a result of the Vietnam War,” she says. “On the other hand, it is not that helpful to say [something like], ‘Don’t shake hands with Vietnamese.’ Our patients are forgiving of whether we shake hands or don’t shake hands. They are less forgiving when we appear not to listen to them.”

Lost in Translation

Nearly 14% of people who live in the United States speak a language other than English in their homes, according to the U.S. Census Bureau’s Census 2000 estimates.2 When a person with limited English proficiency (LEP) enters the healthcare system, the potential for medical error increases if language barriers are not addressed. Indeed, healthcare institutions that receive federal healthcare dollars (Medicare, Medicaid) are obligated under Title VI of the Civil Rights Act of 1964 to provide access to interpreter services—free of charge—to LEP patients.

Those interviewed for this article advised that physicians should avail themselves of trained medical interpreters whenever possible. These professionals are trained to translate providers’ and patients’ communications verbatim—without editing—and are conversant with medical terminology.

However, such resources may not be available in rural hospitals. Such is the case for William D. Atchley, Jr., MD, medical director of the Hospitalist Service at Sentara Careplex Hospital in Hampton, Va., who recently used a cafeteria staff person to translate while he examined and admitted a Mexico-born patient with rhabdomyolysis that resulted from heat exhaustion. Dr. Atchley, an SHM Board member, has also used family members as translators. He notes, though, that “trying to get an understanding of what is going on can be difficult at times because the one family member who may act as a translator may not have as good a command of English [as a trained medical interpreter]. You are always fearful that something could get lost in translation.”

Even large institutions that have medical interpreters on staff may not have 24-hour coverage. In that case, telephone interpreters through AT&T’s Language Line service can be another option (www.languageline.com). Physicians can also work with ad-hoc interpreters, defined as family members or friends who act as interpreters, but are not professionally trained, says Dr. Fernandez.

“It can pay off to first take a few minutes to explain to these interpreters that you want them to repeat everything they hear as much word for word as they can,” she explains. “Tell them that you will give them time to participate in the conversation—as a family member—later on. First, you want them to play this narrow role as interpreter, and later you will let them add information as the family member because their contribution is also valuable.”

Young people, including teenage children, should not be used to interpret unless the situation is immediately life-threatening. “There has been a lot of research,” says Dr. Fernandez, “showing that [using children as interpreters] distorts family roles and makes the children uncomfortable.”

For example, says Dr. Grainger-Monsen, it would be completely inappropriate for a child to translate while a physician asks his mother about her past sexual history or vaginal bleeding.

The Time It Takes

At San Francisco General Hospital, where Dr. Fernandez is an attending physician, there are 140 languages spoken each month. She says the variety of patient backgrounds presents a challenge even for someone like herself, who has conducted extensive research on barriers to minority healthcare. She admits that she sometimes experiences an “internal groan” when she notices that the next patient in her busy clinic day is someone who speaks a language that she doesn’t. Like many of the hospitalists interviewed for this article, Dr. Fernandez notes that because using medical interpreters is time-consuming, she experiences initial resistance to the process.

A 2004 Canadian study examined the relationship between length of stay and LEP in the ambulatory care setting. It found that LEP patients stayed in the hospital longer for conditions, such as unstable coronary syndromes and chest pain, stroke, diabetes, and elective hip replacement.3

Issues about cultural competency are “fairly complex,” notes Alpesh Amin, MD, MBA, FACP, executive director Hospitalist Program and vice chair for clinical affairs, Department of Medicine at the University of California, Irvine, and SHM Board member. Sorting through issues surrounding patients’ beliefs toward healthcare, as well as their family values and dynamics, “takes time to resolve, and if I really want to understand your personal beliefs, I’ve got to be willing to sit down and talk about it. But, I’m not going to get paid for that time. This is not a reimbursable expense for the physician.”

Still, taking time to explore a patient’s preferences could also shorten length of stay if, for instance, the patient indicated that prescribed management indicated after an expensive test would not be his choice of care, says Dr. Amin.

Understanding what beliefs and experiences patients bring to the table, as well as their past health behaviors, does involve a time investment, agrees Minn.-based Russell Holman, MD, national medical director for Cogent Healthcare, Inc. and SHM Board member. But that investment “can only help efficiency,” he maintains. “We’ve invested ourselves tremendously in terms of identifying what are best practices for a patient with heart failure, or pneumonia, or heart attack, but the cultural competency dimension of healthcare has been largely overlooked.”

Training in cultural competency is piecemeal at best, notes Dr. Holman, and often acquired on the job. He recalls a situation in which he learned first-hand the profound effect that culture has on health. While working with a Hmong man who was in a coma and on a ventilator, Dr. Holman initially attempted to seek decision-making from the patient’s wife.

“I found out that was not the appropriate decision-making process for their culture,” says Dr. Holman. The discussion was initiated in the patient’s room, and was moved to a lecture-style classroom to accommodate the 37 members of the man’s clan who came to discuss his condition.

“The fascinating thing to me was that the patient’s wife and the other women sat in the back of the classroom and did not speak the entire time,” explains Dr. Holman. “The decisions were largely conducted by the clan elders. I also found out that my patient was the clan leader, and the elders had very clear goals in mind. The goal was to keep this individual alive, because he was so important as a figure in the clan. I learned that their culture had a profound impact on their expectations of me as a physician and a provider—how I conducted myself in terms of family and clan communications, what resources I brought to bear to try and stabilize and improve his health, and how I worked with specialists. I also learned that although some clan and family members were fluent in English, even modest miscommunications, if I were to use them as translators, could result in significant setbacks.”

Prior to his current position with Cogent Healthcare, Dr. Holman managed a group of 30 hospitalists at HealthPartners Medical Group in Minnesota and in partnership with the Center for International Health developed a cultural competency curriculum for their group and for the University of Minnesota residents in training at Regions Hospital in St. Paul.

“When you are busy working in the hospital, you need to be able to quickly access some resources to be able to give you a ‘just in time’ amount of information and awareness” with which to approach your patient, he says.

Agents for Change?

In addition to Title VI compliance, hospitals are now surveyed by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) and are evaluated on their ability to provide language services.

“This is a changing area,” notes Dr. Fernandez, “and I think it is important for hospitalists to be on the forefront of that change, part of the process that says, ‘Yes, we need to be able to provide more efficient, more patient-centered, and safer care.’ Language barriers, as one example, are inefficient, are dangerous, and are clearly associated with increased medical error.”

Dr. Percelay believes that dealing with patients from different backgrounds involves using “common sense, being respectful and legitimately curious, and avoiding shortcuts in terms of translation issues. I think if people have an inherent respect for diversity, and are open to it, it can enrich your practice.”

Dr. Fernandez agrees. “Practicing medicine in a patient-centered way is ultimately a more rewarding way to work and live,” she says. “There also needs to be reform at a national level that allows physicians and hospitalists to be appropriately compensated for much of the conversation and bedside work that we do.” TH

Writer Gretchen Henkel lives in California and writes regularly about healthcare.

References

1. Unequal Treatment: Understanding Racial and Ethnic Disparities in Health Care. Institute of Medicine, National Academy of Sciences. 2002. Available from the National Academy Press Available at http://books.nap.edu/catalog/11036.html. Last accessed July 27, 2005; and Unequal Treatment: What Healthcare Providers Need to Know about Racial and Ethnic Disparities in Healthcare. Institute of Medicine, National Academy of Sciences. Available at www.nap.edu/catalog/10260.html. Last accessed July 27, 2005.
2. Shin HB, Bruno R. Language use and English-speaking ability: a Census 2000 brief. U.S. Census Bureau, 2003. Available online at www.census.gov/population/www/cen2000/briefs.html. Last accessed July 27, 2005.
3. John-Baptiste A, Naglie G, Tomlinson G, et al. The effect of English language proficiency on length of stay and in-hospital mortality. J Gen Intern Med. March 2004;19(3):221-228.

Pneumonia is associated with as many as 2 million annual deaths among children globally and 19% of all deaths in children less than 5 years of age (1). It is one of the most common diagnoses made in the acutely ill child, with an annual incidence of 34 to 40 cases per 1,000 children in Europe and North America.

In the past, viral pathogens were estimated to cause as many as 80% of cases. Streptococcus pneumoniae was generally regarded as the most frequent bacterial cause of community-acquired pneumonia (CAP), especially in cases with complicated parapneumonic effusions. Infectious etiologies are age specific, with bacterial etiologies predominating in the very young infant and viral pathogens in the older infant and adult (Table 1). Knowledge of the most likely pathogen, the prevailing susceptibilities of these infecting pathogens, and the severity of the illness will help guide antibiotic and other treatment decision making.

click for large version

Most children do not require hospital admission, and mildly ill children who likely have a viral illness do not need antibiotics. The following guideline will attempt to help the practitioner identify those who do require hospitalization and provide an approach to management of those with complicated infection.

Recognition of the Patient with CAP

The first obstacle is to identify the patient with pneumonia. In managing the child with CAP, it is important to distinguish those with other underlying pathology, including asthma, RSV, or other confirmed viral etiology. It is important to remember that pathogens in the compromised host, cystic fibrosis patient, or patient with other chronic pulmonary pathology are different from typical CAP pathogens and include a wide differential. Most patients with CAP have an acute illness associated with fever (>38°C), cough, and evidence of lower respiratory tract symptoms/signs. Chest radiograph typically shows pulmonary infiltrate. Whether this is patchy infiltrate or lobar in appearance can assist the practitioner in treatment decision making in that the latter is much more likely to be associated with a bacterial etiology.

Once the diagnosis is considered, further assessment should focus on hydration status, hemodynamic parameters, and oxygenation. A careful assessment should identify other associated foci (i.e., meningitis or bacteremia) on examination and laboratory evaluation.

click for large version

Identification of the Patient Requiring Hospitalization

Consider hospital admission for the toxic patient, those with altered mental status, significant dehydration, hypoxemia, dyspnea, grunting respirations, or retractions, and any patient with hemodynamic instability. Chest radiograph showing a significant pleural effusion should also be considered an indicator for hospital admission.

Bacterial pathogens are more likely in the severely ill patient, patients with a rapidly progressive process, and those with radiographic evidence of lobar consolidation or pleural effusion. Some children with viral processes may require admission for supportive care.

Prompt Recognition of the Patient with Empyema

For the patient with pneumonia and parapneumonic effusion, distinction between a free-flowing effusion and pleural empyema is critical. Standard plain film can identify pulmonary infiltrate and often effusion and lateral decubitus films can help identify free flowing effusion (Figure 1). While CT scan more effectively identifies pleural fibrinous adhesions that may entrap lung, ultrasound most effectively identifies complex fluid collections with loculation and septation, and it can be utilized to guide thoracentesis.

Empyema is defined as pus in the pleural space and is estimated to occur in 10–40% of patients with pneumonia. Empyema may also result from causes other than a complication of bacterial pneumonia, such as thoracic trauma or postsurgical complication, rupture of lung abscess, esophageal tear, or complication of indwelling catheter. It generally occurs in stages including acute (early-cloudy fluid), fibrino-purulent (thicker, multiloculated fluid), and organized (late with thick pleural peel and entrapment of lung).

Pleural fluid evaluation is important both in diagnosis and in guiding treatment in such cases. Pleural fluid collections are defined as transudative or exudative based on biochemical evaluation. Evaluation includes cell type and differential, pH, glucose, protein and LDH. Gram-stained smear needs to be performed on all specimens at the time of culture. Empyema is exudative, typically with low glucose and high LDH (Table 2 on page 64) (2).

click for large version

Changing Epidemiology and Antibiotic Decision Making

Data presented by Finland and Barnes in 1978 confirmed that S. pneumoniae, group A streptococcus (GAS), and Staphylococcus aureus were the most commonly identified pathogens in empyema cases in 1935, with S. aureus emerging in the 1950s (3). Most literature from the 1960–1980s detailing etiology of pneumonia with pleural empyema continued to emphasize the role of S. aureus in such cases. In all reviews, staphylococcal pneumonia is noted primarily to be a disease of infants. In 1 review of 100 cases of staphylococcal pneumonia, the median age was 5 months, 78 patients being below 1 year of age (4). Chartrand and McCracken analyzed 79 cases of staphylococcal pneumonia and noted that in about 75% of cases, staphylococcal pneumonia was a primary pneumonia in infants with a median age of 6 months. In this study, older children were more likely to have pulmonary involvement as a secondary finding in the setting of disseminated staphylococcal disease. A pleural effusion was found in 80% of infants with primary pneumonia and in 61% of those with secondary disease, thus providing the tip-off of a more serious process to the clinician (5). A high index of suspicion for S. aureus in the young infant with pneumonia is important, as physicians need to expect a rapidly progressive clinical course. Those infants frequently require ventilatory support, alteration in antibiotic choice, and the prompt recognition of pleural complications including pneumothoraces and pneumatoceles.

Data in the 1990s emphasized the role of multidrug resistant pneumococcus as a pathogen in empyema. In a recent review of cases in the postpneumococcal conjugate disease era, pneumococcus remained the most commonly confirmed etiologic agent, with other gram-positive pathogens, including GAS and S. aureus, also documented (6). Despite widespread implementation of pneumococcal conjugate vaccine (PCV), and a population based surveillance study in the US that suggested that adding PCV to the childhood immunization schedule was associated with a 10-fold greater reduction in pneumonia (7), serious pneumonia caused by S. pneumoniae continued to be reported. The prevalence of serotype 1 and 3 as the etiologies of such infections may limit the utility of the current vaccine. One study from Greece demonstrated that the most common serotypes causing bacteremic pneumonia were 14, 6B, 1 and 19F (8). Childhood empyema in the UK is noted to be increasing, and a recent study of 47 empyema cases confirmed pneumococcus as the major pathogen, with over half caused by serotype 1 (9).

More recent data suggest yet another change to the epidemiology of empyema. Schultz et al. from Houston, TX, reviewed a decade of experience from 1993–2002, and while they identified a decrease in total cases of empyema, the emergence of methicillin-resistant S. aureus (MRSA) infection was noted (10).

While MRSA has long been considered an important pathogen in the etiology of healthcare-associated infection, experience in our institution also confirms the appearance of an increasing number of cases of community-acquired MRSA disease. Vancomycin is clearly part of the treatment regimen in the child at risk for staphylococcal pneumonia, though many have utilized clindamycin for the non–critically ill patient. The increase in such cases clearly has important implications for treatment decisions, as MRSA with inducible clindamycin resistance is not yet recognized in every facility. Data are not available to confirm the utility of trimethoprim-sulfamethoxazole in serious community-aquired MRSA infections, and the role for newer antibiotics, such as linezolid, has not been clearly defined.

(Courtesy of George W. Holcomb, MD)

Management: Antibiotics and the Role of Pleural Drainage Procedures

Figure 2 on page 58 shows an algorithm that guides clinical management of the empyema patient. Once a diagnosis is made, attention should be directed to fluid and electrolyte correction, hemodynamic stabilization, and respiratory support (i.e., oxygenation and ventilation). Antibiotics should be initiated and the choice is based on severity of illness and age of the child.

Drainage of the pleural pus has long been recognized as integral to the success in treatment of pneumonia with empyema. Recently, there has been much debate concerning which modality to use and when.

Intrapleural fibrinolytic therapy has been shown in multiple studies to decrease length of stay without increased risk. Data compiled in the Cochrane database comparing fibrinolytic therapy vs. more conservative management suggests that intrapleural fibrinolytic therapy confers significant benefit when compared with normal saline control; however, a definitive statement was not made, given that the trial numbers were too small (11). More recent data from the Cochrane database and a systematic review suggest that video-assisted thoracostomy (VATS) performed early in the disease course is associated with better outcome than chest tube drainage with streptokinase with regard to duration of chest tube placement and hospital stay. However there are questions about validity, and this study is also too small to draw conclusions (12,13). Figure 3 shows the typical findings encountered at VATS in a child with empyema.

A retrospective chart review from our institution from December 2000 to March 2004, excluding immunocompromised hosts, found 96 cases of radiographic pneumonia with pleural effusion. Thirty-four met criteria for empyema, including ultrasound and/or chest CT showing pleural fluid loculation and septation, or purulent fluid/positive culture. Average age was 5 years, and pathogens were defined in 38% of patients. Length of stay averaged 9 days, with a range of 5–23 days. Two had no intervention and had a stay of 8 days, 14 had tube thoracostomy and had an average stay of 11.5 days with 6 failures, 10 had thoracostomy and fibrinolytic therapy with an average stay of 7 days, 3 had early VATS with an average stay of 7 days, and 5 had late VATS with an average stay of 10.4 days. In our institution, among invasive interventions, tube thoracostomy alone had longer LOS and more failures. Early VATS and intrapleural fibrinolysis have shorter stays and are on the lower end of the cost scale: $25,549 vs. $21,062 respectively (Figure 4).

click for large version

The decision for interventional management of empyema will likely be institutionally variable in the absence of large randomized controlled studies. Institutions with aggressive interventional radiologists may favor thoracostomy tube with fibrinolysis. Those with surgeons skilled in video-scopic surgery may provide early VATS. Data on interventions clearly show benefit beyond that provided by routine chest tube placement. The key becomes prompt diagnosis of empyema with early use of ultrasound, knowledge of local antibiotic susceptibilities, and clear guidelines set up by each institution to guide interventional management.

The Future

Increasing the accuracy of diagnostic testing for children with CAP would likely lead to decreased morbidity, mortality, and total cost of care. The use of PCR is becoming more widespread and could be utilized to more rapidly confirm the diagnosis of both chlamydophila pneumoniae, mycoplasma pneumoniae, and Influenza A virus (14). Influenza A is well known to cause serious morbidity and mortality and may be the most common virus causing CAP, with a comparable clinical burden to viruses such as respiratory syneytial virus. This is further evidence supporting universal childhood influenza immunization. Expansion of the serotypes included in pneumococcal conjugate vaccines (PCV) is to include serotypes 1 and 3, both currently non-PCV strains in the U.S. vaccine, is underway.

click for large version

As the epidemiology of CAP continues to evolve, practitioners need to be aware of the prevalent pathogens in their region. In the age of continuing antimicrobial resistance of bacterial pathogens, it is important to know the local antimicrobial susceptibility patterns to appropriately choose empiric therapy when a bacterial process is suspected. Local laboratories can commonly provide this data.

Whatever the future holds, we continue to need the collaboration and expertise of the inpatient practitioner, the infectious disease specialist, and the surgeon/interventionalist. All are necessary to ensure the prompt recognition of empyema and the need for timely medical and surgical intervention for these patients.

References

1. Bryce J, Boschi-Pinto C, Shibuya K, Black RE; WHO Child Health Epidemiology Reference Group. WHO estimates of the causes of death in children. Lancet. 2005;365:1147-52.
2. Wheeler JG, Jacobs RF. Pleural effusions and empyema. In: Feigin RD, Cherry JD, Demmler GJ, Kaplan SL, eds. Textbook of Pediatric Infectious Diseases. 5th ed. Philadelphia, Pa: Saunders;2004:320-30.
3. Finland M, Barnes MW. Changing ecology of acute bacterial empyema: occurrence and mortality at Boston City Hospital during 12 selected years from 1935 to 1972. J Infect Dis. 1978;137:274-91.
4. Goel A, Bamford L, Hanslo D, Hussey G. Primary staphylococcal pneumonia in young children: a review of 100 cases. J Trop Pediatr. 1999;45:233-6.
5. Chartrand SA, McCracken GH Jr. Staphylococcal pneumonia in infants and children Pediatr Infect Dis. 1982;1:19-23.
6. Buckingham SC, King MD, Miller ML. Incidence and etiologies of complicated parapneumonic effusions in children, 1996 to 2001. Pediatr Infect Dis J. 2003;22:499-504.
7. Poehling KA, Lafleur BJ, Szilagyi PG, et al. Populationbased impact of pneumococcal conjugate vaccine in young children. Pediatrics. 2004;114:755-61.
8. Syriopoulou V, Daikos GL, Soulis K, et al. Epidemiology of invasive childhood pneumococcal infections in Greece. Acta Paediatr Suppl. 2000;89:30-4.
9. Eastham KM, Freeman R, Kearns AM, et al. Clinical features, aetiology and outcome of empyema in children in the north east of England. Thorax. 2004;59:522-5.
10. Schultz KD, Fan LL, Pinsky J, et al. The changing face of pleural empyemas in children: epidemiology and management. Pediatrics. 2004;113:1735-40.
11. Cameron R, Davies HR. Intra-pleural fibrinolytic therapy versus conservative management in the treatment of para-pneumonic effusions and empyema. Cochrane Database Syst Rev. 2004:CD002312. Review.
12. Coote N. Surgical versus non-surgical management of pleural empyema. Cochrane Database Syst Rev. 2002:CD001956. Review.
13. Gates RL, Caniano DA, Hayes JR, Arca MJ. Does VATS provide optimal treatment of empyema in children? A systematic review. J Pediatr Surg. 2004;39:381-6. Review.
14. Laundy M, Ajayi-Obe E, Hawrami K, Aitken C, Breuer J, Booy R. Influenza A community-acquired pneumonia in East London infants and young children. Pediatr Infect Dis J. 2003;22(Suppl):S223-7.

Pneumonia is associated with as many as 2 million annual deaths among children globally and 19% of all deaths in children less than 5 years of age (1). It is one of the most common diagnoses made in the acutely ill child, with an annual incidence of 34 to 40 cases per 1,000 children in Europe and North America.

In the past, viral pathogens were estimated to cause as many as 80% of cases. Streptococcus pneumoniae was generally regarded as the most frequent bacterial cause of community-acquired pneumonia (CAP), especially in cases with complicated parapneumonic effusions. Infectious etiologies are age specific, with bacterial etiologies predominating in the very young infant and viral pathogens in the older infant and adult (Table 1). Knowledge of the most likely pathogen, the prevailing susceptibilities of these infecting pathogens, and the severity of the illness will help guide antibiotic and other treatment decision making.

click for large version

Most children do not require hospital admission, and mildly ill children who likely have a viral illness do not need antibiotics. The following guideline will attempt to help the practitioner identify those who do require hospitalization and provide an approach to management of those with complicated infection.

Recognition of the Patient with CAP

The first obstacle is to identify the patient with pneumonia. In managing the child with CAP, it is important to distinguish those with other underlying pathology, including asthma, RSV, or other confirmed viral etiology. It is important to remember that pathogens in the compromised host, cystic fibrosis patient, or patient with other chronic pulmonary pathology are different from typical CAP pathogens and include a wide differential. Most patients with CAP have an acute illness associated with fever (>38°C), cough, and evidence of lower respiratory tract symptoms/signs. Chest radiograph typically shows pulmonary infiltrate. Whether this is patchy infiltrate or lobar in appearance can assist the practitioner in treatment decision making in that the latter is much more likely to be associated with a bacterial etiology.

Once the diagnosis is considered, further assessment should focus on hydration status, hemodynamic parameters, and oxygenation. A careful assessment should identify other associated foci (i.e., meningitis or bacteremia) on examination and laboratory evaluation.

click for large version

Identification of the Patient Requiring Hospitalization

Consider hospital admission for the toxic patient, those with altered mental status, significant dehydration, hypoxemia, dyspnea, grunting respirations, or retractions, and any patient with hemodynamic instability. Chest radiograph showing a significant pleural effusion should also be considered an indicator for hospital admission.

Bacterial pathogens are more likely in the severely ill patient, patients with a rapidly progressive process, and those with radiographic evidence of lobar consolidation or pleural effusion. Some children with viral processes may require admission for supportive care.

Prompt Recognition of the Patient with Empyema

For the patient with pneumonia and parapneumonic effusion, distinction between a free-flowing effusion and pleural empyema is critical. Standard plain film can identify pulmonary infiltrate and often effusion and lateral decubitus films can help identify free flowing effusion (Figure 1). While CT scan more effectively identifies pleural fibrinous adhesions that may entrap lung, ultrasound most effectively identifies complex fluid collections with loculation and septation, and it can be utilized to guide thoracentesis.

Empyema is defined as pus in the pleural space and is estimated to occur in 10–40% of patients with pneumonia. Empyema may also result from causes other than a complication of bacterial pneumonia, such as thoracic trauma or postsurgical complication, rupture of lung abscess, esophageal tear, or complication of indwelling catheter. It generally occurs in stages including acute (early-cloudy fluid), fibrino-purulent (thicker, multiloculated fluid), and organized (late with thick pleural peel and entrapment of lung).

Pleural fluid evaluation is important both in diagnosis and in guiding treatment in such cases. Pleural fluid collections are defined as transudative or exudative based on biochemical evaluation. Evaluation includes cell type and differential, pH, glucose, protein and LDH. Gram-stained smear needs to be performed on all specimens at the time of culture. Empyema is exudative, typically with low glucose and high LDH (Table 2 on page 64) (2).

click for large version

Changing Epidemiology and Antibiotic Decision Making

Data presented by Finland and Barnes in 1978 confirmed that S. pneumoniae, group A streptococcus (GAS), and Staphylococcus aureus were the most commonly identified pathogens in empyema cases in 1935, with S. aureus emerging in the 1950s (3). Most literature from the 1960–1980s detailing etiology of pneumonia with pleural empyema continued to emphasize the role of S. aureus in such cases. In all reviews, staphylococcal pneumonia is noted primarily to be a disease of infants. In 1 review of 100 cases of staphylococcal pneumonia, the median age was 5 months, 78 patients being below 1 year of age (4). Chartrand and McCracken analyzed 79 cases of staphylococcal pneumonia and noted that in about 75% of cases, staphylococcal pneumonia was a primary pneumonia in infants with a median age of 6 months. In this study, older children were more likely to have pulmonary involvement as a secondary finding in the setting of disseminated staphylococcal disease. A pleural effusion was found in 80% of infants with primary pneumonia and in 61% of those with secondary disease, thus providing the tip-off of a more serious process to the clinician (5). A high index of suspicion for S. aureus in the young infant with pneumonia is important, as physicians need to expect a rapidly progressive clinical course. Those infants frequently require ventilatory support, alteration in antibiotic choice, and the prompt recognition of pleural complications including pneumothoraces and pneumatoceles.

Data in the 1990s emphasized the role of multidrug resistant pneumococcus as a pathogen in empyema. In a recent review of cases in the postpneumococcal conjugate disease era, pneumococcus remained the most commonly confirmed etiologic agent, with other gram-positive pathogens, including GAS and S. aureus, also documented (6). Despite widespread implementation of pneumococcal conjugate vaccine (PCV), and a population based surveillance study in the US that suggested that adding PCV to the childhood immunization schedule was associated with a 10-fold greater reduction in pneumonia (7), serious pneumonia caused by S. pneumoniae continued to be reported. The prevalence of serotype 1 and 3 as the etiologies of such infections may limit the utility of the current vaccine. One study from Greece demonstrated that the most common serotypes causing bacteremic pneumonia were 14, 6B, 1 and 19F (8). Childhood empyema in the UK is noted to be increasing, and a recent study of 47 empyema cases confirmed pneumococcus as the major pathogen, with over half caused by serotype 1 (9).

More recent data suggest yet another change to the epidemiology of empyema. Schultz et al. from Houston, TX, reviewed a decade of experience from 1993–2002, and while they identified a decrease in total cases of empyema, the emergence of methicillin-resistant S. aureus (MRSA) infection was noted (10).

While MRSA has long been considered an important pathogen in the etiology of healthcare-associated infection, experience in our institution also confirms the appearance of an increasing number of cases of community-acquired MRSA disease. Vancomycin is clearly part of the treatment regimen in the child at risk for staphylococcal pneumonia, though many have utilized clindamycin for the non–critically ill patient. The increase in such cases clearly has important implications for treatment decisions, as MRSA with inducible clindamycin resistance is not yet recognized in every facility. Data are not available to confirm the utility of trimethoprim-sulfamethoxazole in serious community-aquired MRSA infections, and the role for newer antibiotics, such as linezolid, has not been clearly defined.

(Courtesy of George W. Holcomb, MD)

Management: Antibiotics and the Role of Pleural Drainage Procedures

Figure 2 on page 58 shows an algorithm that guides clinical management of the empyema patient. Once a diagnosis is made, attention should be directed to fluid and electrolyte correction, hemodynamic stabilization, and respiratory support (i.e., oxygenation and ventilation). Antibiotics should be initiated and the choice is based on severity of illness and age of the child.

Drainage of the pleural pus has long been recognized as integral to the success in treatment of pneumonia with empyema. Recently, there has been much debate concerning which modality to use and when.

Intrapleural fibrinolytic therapy has been shown in multiple studies to decrease length of stay without increased risk. Data compiled in the Cochrane database comparing fibrinolytic therapy vs. more conservative management suggests that intrapleural fibrinolytic therapy confers significant benefit when compared with normal saline control; however, a definitive statement was not made, given that the trial numbers were too small (11). More recent data from the Cochrane database and a systematic review suggest that video-assisted thoracostomy (VATS) performed early in the disease course is associated with better outcome than chest tube drainage with streptokinase with regard to duration of chest tube placement and hospital stay. However there are questions about validity, and this study is also too small to draw conclusions (12,13). Figure 3 shows the typical findings encountered at VATS in a child with empyema.

A retrospective chart review from our institution from December 2000 to March 2004, excluding immunocompromised hosts, found 96 cases of radiographic pneumonia with pleural effusion. Thirty-four met criteria for empyema, including ultrasound and/or chest CT showing pleural fluid loculation and septation, or purulent fluid/positive culture. Average age was 5 years, and pathogens were defined in 38% of patients. Length of stay averaged 9 days, with a range of 5–23 days. Two had no intervention and had a stay of 8 days, 14 had tube thoracostomy and had an average stay of 11.5 days with 6 failures, 10 had thoracostomy and fibrinolytic therapy with an average stay of 7 days, 3 had early VATS with an average stay of 7 days, and 5 had late VATS with an average stay of 10.4 days. In our institution, among invasive interventions, tube thoracostomy alone had longer LOS and more failures. Early VATS and intrapleural fibrinolysis have shorter stays and are on the lower end of the cost scale: $25,549 vs. $21,062 respectively (Figure 4).

click for large version

The decision for interventional management of empyema will likely be institutionally variable in the absence of large randomized controlled studies. Institutions with aggressive interventional radiologists may favor thoracostomy tube with fibrinolysis. Those with surgeons skilled in video-scopic surgery may provide early VATS. Data on interventions clearly show benefit beyond that provided by routine chest tube placement. The key becomes prompt diagnosis of empyema with early use of ultrasound, knowledge of local antibiotic susceptibilities, and clear guidelines set up by each institution to guide interventional management.

The Future

Increasing the accuracy of diagnostic testing for children with CAP would likely lead to decreased morbidity, mortality, and total cost of care. The use of PCR is becoming more widespread and could be utilized to more rapidly confirm the diagnosis of both chlamydophila pneumoniae, mycoplasma pneumoniae, and Influenza A virus (14). Influenza A is well known to cause serious morbidity and mortality and may be the most common virus causing CAP, with a comparable clinical burden to viruses such as respiratory syneytial virus. This is further evidence supporting universal childhood influenza immunization. Expansion of the serotypes included in pneumococcal conjugate vaccines (PCV) is to include serotypes 1 and 3, both currently non-PCV strains in the U.S. vaccine, is underway.

click for large version

As the epidemiology of CAP continues to evolve, practitioners need to be aware of the prevalent pathogens in their region. In the age of continuing antimicrobial resistance of bacterial pathogens, it is important to know the local antimicrobial susceptibility patterns to appropriately choose empiric therapy when a bacterial process is suspected. Local laboratories can commonly provide this data.

Whatever the future holds, we continue to need the collaboration and expertise of the inpatient practitioner, the infectious disease specialist, and the surgeon/interventionalist. All are necessary to ensure the prompt recognition of empyema and the need for timely medical and surgical intervention for these patients.

References

1. Bryce J, Boschi-Pinto C, Shibuya K, Black RE; WHO Child Health Epidemiology Reference Group. WHO estimates of the causes of death in children. Lancet. 2005;365:1147-52.
2. Wheeler JG, Jacobs RF. Pleural effusions and empyema. In: Feigin RD, Cherry JD, Demmler GJ, Kaplan SL, eds. Textbook of Pediatric Infectious Diseases. 5th ed. Philadelphia, Pa: Saunders;2004:320-30.
3. Finland M, Barnes MW. Changing ecology of acute bacterial empyema: occurrence and mortality at Boston City Hospital during 12 selected years from 1935 to 1972. J Infect Dis. 1978;137:274-91.
4. Goel A, Bamford L, Hanslo D, Hussey G. Primary staphylococcal pneumonia in young children: a review of 100 cases. J Trop Pediatr. 1999;45:233-6.
5. Chartrand SA, McCracken GH Jr. Staphylococcal pneumonia in infants and children Pediatr Infect Dis. 1982;1:19-23.
6. Buckingham SC, King MD, Miller ML. Incidence and etiologies of complicated parapneumonic effusions in children, 1996 to 2001. Pediatr Infect Dis J. 2003;22:499-504.
7. Poehling KA, Lafleur BJ, Szilagyi PG, et al. Populationbased impact of pneumococcal conjugate vaccine in young children. Pediatrics. 2004;114:755-61.
8. Syriopoulou V, Daikos GL, Soulis K, et al. Epidemiology of invasive childhood pneumococcal infections in Greece. Acta Paediatr Suppl. 2000;89:30-4.
9. Eastham KM, Freeman R, Kearns AM, et al. Clinical features, aetiology and outcome of empyema in children in the north east of England. Thorax. 2004;59:522-5.
10. Schultz KD, Fan LL, Pinsky J, et al. The changing face of pleural empyemas in children: epidemiology and management. Pediatrics. 2004;113:1735-40.
11. Cameron R, Davies HR. Intra-pleural fibrinolytic therapy versus conservative management in the treatment of para-pneumonic effusions and empyema. Cochrane Database Syst Rev. 2004:CD002312. Review.
12. Coote N. Surgical versus non-surgical management of pleural empyema. Cochrane Database Syst Rev. 2002:CD001956. Review.
13. Gates RL, Caniano DA, Hayes JR, Arca MJ. Does VATS provide optimal treatment of empyema in children? A systematic review. J Pediatr Surg. 2004;39:381-6. Review.
14. Laundy M, Ajayi-Obe E, Hawrami K, Aitken C, Breuer J, Booy R. Influenza A community-acquired pneumonia in East London infants and young children. Pediatr Infect Dis J. 2003;22(Suppl):S223-7.

Pneumonia is associated with as many as 2 million annual deaths among children globally and 19% of all deaths in children less than 5 years of age (1). It is one of the most common diagnoses made in the acutely ill child, with an annual incidence of 34 to 40 cases per 1,000 children in Europe and North America.

In the past, viral pathogens were estimated to cause as many as 80% of cases. Streptococcus pneumoniae was generally regarded as the most frequent bacterial cause of community-acquired pneumonia (CAP), especially in cases with complicated parapneumonic effusions. Infectious etiologies are age specific, with bacterial etiologies predominating in the very young infant and viral pathogens in the older infant and adult (Table 1). Knowledge of the most likely pathogen, the prevailing susceptibilities of these infecting pathogens, and the severity of the illness will help guide antibiotic and other treatment decision making.

click for large version

Most children do not require hospital admission, and mildly ill children who likely have a viral illness do not need antibiotics. The following guideline will attempt to help the practitioner identify those who do require hospitalization and provide an approach to management of those with complicated infection.

Recognition of the Patient with CAP

The first obstacle is to identify the patient with pneumonia. In managing the child with CAP, it is important to distinguish those with other underlying pathology, including asthma, RSV, or other confirmed viral etiology. It is important to remember that pathogens in the compromised host, cystic fibrosis patient, or patient with other chronic pulmonary pathology are different from typical CAP pathogens and include a wide differential. Most patients with CAP have an acute illness associated with fever (>38°C), cough, and evidence of lower respiratory tract symptoms/signs. Chest radiograph typically shows pulmonary infiltrate. Whether this is patchy infiltrate or lobar in appearance can assist the practitioner in treatment decision making in that the latter is much more likely to be associated with a bacterial etiology.

Once the diagnosis is considered, further assessment should focus on hydration status, hemodynamic parameters, and oxygenation. A careful assessment should identify other associated foci (i.e., meningitis or bacteremia) on examination and laboratory evaluation.

click for large version

Identification of the Patient Requiring Hospitalization

Consider hospital admission for the toxic patient, those with altered mental status, significant dehydration, hypoxemia, dyspnea, grunting respirations, or retractions, and any patient with hemodynamic instability. Chest radiograph showing a significant pleural effusion should also be considered an indicator for hospital admission.

Bacterial pathogens are more likely in the severely ill patient, patients with a rapidly progressive process, and those with radiographic evidence of lobar consolidation or pleural effusion. Some children with viral processes may require admission for supportive care.

Prompt Recognition of the Patient with Empyema

For the patient with pneumonia and parapneumonic effusion, distinction between a free-flowing effusion and pleural empyema is critical. Standard plain film can identify pulmonary infiltrate and often effusion and lateral decubitus films can help identify free flowing effusion (Figure 1). While CT scan more effectively identifies pleural fibrinous adhesions that may entrap lung, ultrasound most effectively identifies complex fluid collections with loculation and septation, and it can be utilized to guide thoracentesis.

Empyema is defined as pus in the pleural space and is estimated to occur in 10–40% of patients with pneumonia. Empyema may also result from causes other than a complication of bacterial pneumonia, such as thoracic trauma or postsurgical complication, rupture of lung abscess, esophageal tear, or complication of indwelling catheter. It generally occurs in stages including acute (early-cloudy fluid), fibrino-purulent (thicker, multiloculated fluid), and organized (late with thick pleural peel and entrapment of lung).

Pleural fluid evaluation is important both in diagnosis and in guiding treatment in such cases. Pleural fluid collections are defined as transudative or exudative based on biochemical evaluation. Evaluation includes cell type and differential, pH, glucose, protein and LDH. Gram-stained smear needs to be performed on all specimens at the time of culture. Empyema is exudative, typically with low glucose and high LDH (Table 2 on page 64) (2).

click for large version

Changing Epidemiology and Antibiotic Decision Making

Data presented by Finland and Barnes in 1978 confirmed that S. pneumoniae, group A streptococcus (GAS), and Staphylococcus aureus were the most commonly identified pathogens in empyema cases in 1935, with S. aureus emerging in the 1950s (3). Most literature from the 1960–1980s detailing etiology of pneumonia with pleural empyema continued to emphasize the role of S. aureus in such cases. In all reviews, staphylococcal pneumonia is noted primarily to be a disease of infants. In 1 review of 100 cases of staphylococcal pneumonia, the median age was 5 months, 78 patients being below 1 year of age (4). Chartrand and McCracken analyzed 79 cases of staphylococcal pneumonia and noted that in about 75% of cases, staphylococcal pneumonia was a primary pneumonia in infants with a median age of 6 months. In this study, older children were more likely to have pulmonary involvement as a secondary finding in the setting of disseminated staphylococcal disease. A pleural effusion was found in 80% of infants with primary pneumonia and in 61% of those with secondary disease, thus providing the tip-off of a more serious process to the clinician (5). A high index of suspicion for S. aureus in the young infant with pneumonia is important, as physicians need to expect a rapidly progressive clinical course. Those infants frequently require ventilatory support, alteration in antibiotic choice, and the prompt recognition of pleural complications including pneumothoraces and pneumatoceles.

Data in the 1990s emphasized the role of multidrug resistant pneumococcus as a pathogen in empyema. In a recent review of cases in the postpneumococcal conjugate disease era, pneumococcus remained the most commonly confirmed etiologic agent, with other gram-positive pathogens, including GAS and S. aureus, also documented (6). Despite widespread implementation of pneumococcal conjugate vaccine (PCV), and a population based surveillance study in the US that suggested that adding PCV to the childhood immunization schedule was associated with a 10-fold greater reduction in pneumonia (7), serious pneumonia caused by S. pneumoniae continued to be reported. The prevalence of serotype 1 and 3 as the etiologies of such infections may limit the utility of the current vaccine. One study from Greece demonstrated that the most common serotypes causing bacteremic pneumonia were 14, 6B, 1 and 19F (8). Childhood empyema in the UK is noted to be increasing, and a recent study of 47 empyema cases confirmed pneumococcus as the major pathogen, with over half caused by serotype 1 (9).

More recent data suggest yet another change to the epidemiology of empyema. Schultz et al. from Houston, TX, reviewed a decade of experience from 1993–2002, and while they identified a decrease in total cases of empyema, the emergence of methicillin-resistant S. aureus (MRSA) infection was noted (10).

While MRSA has long been considered an important pathogen in the etiology of healthcare-associated infection, experience in our institution also confirms the appearance of an increasing number of cases of community-acquired MRSA disease. Vancomycin is clearly part of the treatment regimen in the child at risk for staphylococcal pneumonia, though many have utilized clindamycin for the non–critically ill patient. The increase in such cases clearly has important implications for treatment decisions, as MRSA with inducible clindamycin resistance is not yet recognized in every facility. Data are not available to confirm the utility of trimethoprim-sulfamethoxazole in serious community-aquired MRSA infections, and the role for newer antibiotics, such as linezolid, has not been clearly defined.

(Courtesy of George W. Holcomb, MD)

Management: Antibiotics and the Role of Pleural Drainage Procedures

Figure 2 on page 58 shows an algorithm that guides clinical management of the empyema patient. Once a diagnosis is made, attention should be directed to fluid and electrolyte correction, hemodynamic stabilization, and respiratory support (i.e., oxygenation and ventilation). Antibiotics should be initiated and the choice is based on severity of illness and age of the child.

Drainage of the pleural pus has long been recognized as integral to the success in treatment of pneumonia with empyema. Recently, there has been much debate concerning which modality to use and when.

Intrapleural fibrinolytic therapy has been shown in multiple studies to decrease length of stay without increased risk. Data compiled in the Cochrane database comparing fibrinolytic therapy vs. more conservative management suggests that intrapleural fibrinolytic therapy confers significant benefit when compared with normal saline control; however, a definitive statement was not made, given that the trial numbers were too small (11). More recent data from the Cochrane database and a systematic review suggest that video-assisted thoracostomy (VATS) performed early in the disease course is associated with better outcome than chest tube drainage with streptokinase with regard to duration of chest tube placement and hospital stay. However there are questions about validity, and this study is also too small to draw conclusions (12,13). Figure 3 shows the typical findings encountered at VATS in a child with empyema.

A retrospective chart review from our institution from December 2000 to March 2004, excluding immunocompromised hosts, found 96 cases of radiographic pneumonia with pleural effusion. Thirty-four met criteria for empyema, including ultrasound and/or chest CT showing pleural fluid loculation and septation, or purulent fluid/positive culture. Average age was 5 years, and pathogens were defined in 38% of patients. Length of stay averaged 9 days, with a range of 5–23 days. Two had no intervention and had a stay of 8 days, 14 had tube thoracostomy and had an average stay of 11.5 days with 6 failures, 10 had thoracostomy and fibrinolytic therapy with an average stay of 7 days, 3 had early VATS with an average stay of 7 days, and 5 had late VATS with an average stay of 10.4 days. In our institution, among invasive interventions, tube thoracostomy alone had longer LOS and more failures. Early VATS and intrapleural fibrinolysis have shorter stays and are on the lower end of the cost scale: $25,549 vs. $21,062 respectively (Figure 4).

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The decision for interventional management of empyema will likely be institutionally variable in the absence of large randomized controlled studies. Institutions with aggressive interventional radiologists may favor thoracostomy tube with fibrinolysis. Those with surgeons skilled in video-scopic surgery may provide early VATS. Data on interventions clearly show benefit beyond that provided by routine chest tube placement. The key becomes prompt diagnosis of empyema with early use of ultrasound, knowledge of local antibiotic susceptibilities, and clear guidelines set up by each institution to guide interventional management.

The Future

Increasing the accuracy of diagnostic testing for children with CAP would likely lead to decreased morbidity, mortality, and total cost of care. The use of PCR is becoming more widespread and could be utilized to more rapidly confirm the diagnosis of both chlamydophila pneumoniae, mycoplasma pneumoniae, and Influenza A virus (14). Influenza A is well known to cause serious morbidity and mortality and may be the most common virus causing CAP, with a comparable clinical burden to viruses such as respiratory syneytial virus. This is further evidence supporting universal childhood influenza immunization. Expansion of the serotypes included in pneumococcal conjugate vaccines (PCV) is to include serotypes 1 and 3, both currently non-PCV strains in the U.S. vaccine, is underway.

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As the epidemiology of CAP continues to evolve, practitioners need to be aware of the prevalent pathogens in their region. In the age of continuing antimicrobial resistance of bacterial pathogens, it is important to know the local antimicrobial susceptibility patterns to appropriately choose empiric therapy when a bacterial process is suspected. Local laboratories can commonly provide this data.

Whatever the future holds, we continue to need the collaboration and expertise of the inpatient practitioner, the infectious disease specialist, and the surgeon/interventionalist. All are necessary to ensure the prompt recognition of empyema and the need for timely medical and surgical intervention for these patients.

References

1. Bryce J, Boschi-Pinto C, Shibuya K, Black RE; WHO Child Health Epidemiology Reference Group. WHO estimates of the causes of death in children. Lancet. 2005;365:1147-52.
2. Wheeler JG, Jacobs RF. Pleural effusions and empyema. In: Feigin RD, Cherry JD, Demmler GJ, Kaplan SL, eds. Textbook of Pediatric Infectious Diseases. 5th ed. Philadelphia, Pa: Saunders;2004:320-30.
3. Finland M, Barnes MW. Changing ecology of acute bacterial empyema: occurrence and mortality at Boston City Hospital during 12 selected years from 1935 to 1972. J Infect Dis. 1978;137:274-91.
4. Goel A, Bamford L, Hanslo D, Hussey G. Primary staphylococcal pneumonia in young children: a review of 100 cases. J Trop Pediatr. 1999;45:233-6.
5. Chartrand SA, McCracken GH Jr. Staphylococcal pneumonia in infants and children Pediatr Infect Dis. 1982;1:19-23.
6. Buckingham SC, King MD, Miller ML. Incidence and etiologies of complicated parapneumonic effusions in children, 1996 to 2001. Pediatr Infect Dis J. 2003;22:499-504.
7. Poehling KA, Lafleur BJ, Szilagyi PG, et al. Populationbased impact of pneumococcal conjugate vaccine in young children. Pediatrics. 2004;114:755-61.
8. Syriopoulou V, Daikos GL, Soulis K, et al. Epidemiology of invasive childhood pneumococcal infections in Greece. Acta Paediatr Suppl. 2000;89:30-4.
9. Eastham KM, Freeman R, Kearns AM, et al. Clinical features, aetiology and outcome of empyema in children in the north east of England. Thorax. 2004;59:522-5.
10. Schultz KD, Fan LL, Pinsky J, et al. The changing face of pleural empyemas in children: epidemiology and management. Pediatrics. 2004;113:1735-40.
11. Cameron R, Davies HR. Intra-pleural fibrinolytic therapy versus conservative management in the treatment of para-pneumonic effusions and empyema. Cochrane Database Syst Rev. 2004:CD002312. Review.
12. Coote N. Surgical versus non-surgical management of pleural empyema. Cochrane Database Syst Rev. 2002:CD001956. Review.
13. Gates RL, Caniano DA, Hayes JR, Arca MJ. Does VATS provide optimal treatment of empyema in children? A systematic review. J Pediatr Surg. 2004;39:381-6. Review.
14. Laundy M, Ajayi-Obe E, Hawrami K, Aitken C, Breuer J, Booy R. Influenza A community-acquired pneumonia in East London infants and young children. Pediatr Infect Dis J. 2003;22(Suppl):S223-7.

Hospital medicine has arrived at just the right moment for a healthcare delivery system in need of change. Medical errors and cost escalation continue to dominate the headlines. With regard to quality the National Quality Foundation is attempting to define standards and health plans are creating incentives through Pay for Performance programs. With regard to costs, there are expectations that they will rise even higher as the baby boomer population ages.

Providing high-quality, cost-effective care to acutely ill patients in the hospital is becoming more complex. It requires physicians who can focus on inpatient care, allowing primary care physicians, surgeons, and subspecialists to concentrate on what they do best. Providing the best care available to the hospitalized patients can no longer be done by one health professional acting alone, no matter how wise and well meaning. Hospitalists have dedicated their professional careers to providing team-based, patient-centered care that achieves cost-effective, quality outcomes.

As the specialty society for hospital medicine, SHM provides a vehicle to define this new specialty. We are doing this with our surveys of hospitalist productivity and compensation, by articles that appear in the medical and lay press, and by the Core Curriculum for Hospital Medicine that will be published in the coming months.

Hospitalists provide significant value to their healthcare communities and to patients, physicians, other health professionals, and administrators well beyond the benefits of direct patient care. This supplement to The Hospitalist, the official publication of SHM, is a compendium of papers designed to further define the full range of benefits provided by the specialty of hospital medicine.

Physician Methods of Payment Outdated

As the American healthcare system is reshaped, we must recognize that part of the problem is the outdated way in which we pay for medical services. Physicians are rewarded as piece workers by the unit of the visit or the procedure. This has led to a culture of doing more things for one individual patient rather than attempting to make the hospital work better for all patients. In addition, this unit-based payment does not reward efficiency or effectiveness.

Hospitalists are, in many ways, change agents in the inpatient environment. Hospitalists can spend as much as 50% of their professional time improving the entire enterprise by taking on the responsibilities of other physicians, developing plans to improve quality educating hospital staff or medical trainees, addressing efficiencies through earlier discharge or improved throughput in the ED or ICU, creating teams of health professionals, or being available around the clock.

The diverse work that hospitalizes perform is very important and time consuming. However, the traditional payment scheme for physicians does not provide a direct way to compensate the hospitalist for this skill and expertise.

Hospitals have realized that these hospitalist skills bring real value to their health communities. And hospitals have been willing to invest their own funds to grow and support their hospital medicine groups to the tune of $75,000 or more per hospitalist per year. This is not a hand-out or a subsidy. This is true commerce. Hospitals continue to get significant benefits from their hospitalists.

In fact, when confronted with the choice of whether to ask the hospitalists to ''just see patients'' to generate more direct patient fees or to continue to improve the effectiveness and efficiency of their health communities, enlightened hospital executives vote with their money and ask the hospitalists to improve quality, build teams, reduce LOS, improve throughput, educate their staff, and generally build the hospital of the future.

With regard to paying physicians, SHM believes that the Pay for Performance movement is an important step in the right direction. Hospitalists welcome a reimbursement scheme that rewards institutions that follow best practices and achieve superior outcomes.

Audiences for this Supplement

This supplement, How Hospitalists Add Value, has two major audiences. First, hospitalists need to categorize what they can and will do for their hospitals and healthcare communities. They need to understand that this is not voluntary work to be done in their spare time. The provision of these services provides strategic and market benefits to their hospital.

Second, there are hospital administrators and leaders at 1,500 hospitals who have been crucial to growing hospital medicine to more than 12,000 hospitalists. They recognize that hospitalists are core to their future. This supplement will further confirm and document the ways in which hospitalists can help their organizations. The facts put forth in these papers can create a rationale for continued support with dollars and manpower, not as a subsidy but as an intelligent investment for the hospital.

Hospitalists Add Value

• Hospitalists can provide measurable quality improvement through setting standards and compliance.
• Hospitalists can save money and resources by reducing LOS and achieving better utilization.
• Hospitalists can improve the efficiency of the hospital by early discharge, better throughput in the ED, and the opening up of ICU beds.
• Hospitalists can create a seamless continuity from inpatient to outpatient care, from the ED to the floor, and from the ICU to the floor.
• Hospitalists can make other physicians' lives better and help hospitals to recruit and retain PCPs, surgeons, and specialists.
• Hospitalists can do things other physicians have given up by admitting patients without health insurance or by serving on hospital committees.
• Hospitalists can be instrumental in creating teams of healthcare professionals that make better use of the talent at the hospital and create a better working environment for nurses and others.
• Hospitalists can have a leading role in educating nurses, other hospital staff, and physicals in training.
• And hospitalizes can take care of the acutely ill complex hospitalized patients.

Add it all up and it is clear that hospitalists are a resource to hospitals in meeting the complex challenges of their healthcare communities. Hopefully, this set of important papers will define these issues more clearly and assist hospitalists and their hospital leaders in creating a stable and supportive environment for collaboration that can lead to better healthcare for our patients.

Hospital medicine has arrived at just the right moment for a healthcare delivery system in need of change. Medical errors and cost escalation continue to dominate the headlines. With regard to quality the National Quality Foundation is attempting to define standards and health plans are creating incentives through Pay for Performance programs. With regard to costs, there are expectations that they will rise even higher as the baby boomer population ages.

Providing high-quality, cost-effective care to acutely ill patients in the hospital is becoming more complex. It requires physicians who can focus on inpatient care, allowing primary care physicians, surgeons, and subspecialists to concentrate on what they do best. Providing the best care available to the hospitalized patients can no longer be done by one health professional acting alone, no matter how wise and well meaning. Hospitalists have dedicated their professional careers to providing team-based, patient-centered care that achieves cost-effective, quality outcomes.

As the specialty society for hospital medicine, SHM provides a vehicle to define this new specialty. We are doing this with our surveys of hospitalist productivity and compensation, by articles that appear in the medical and lay press, and by the Core Curriculum for Hospital Medicine that will be published in the coming months.

Hospitalists provide significant value to their healthcare communities and to patients, physicians, other health professionals, and administrators well beyond the benefits of direct patient care. This supplement to The Hospitalist, the official publication of SHM, is a compendium of papers designed to further define the full range of benefits provided by the specialty of hospital medicine.

Physician Methods of Payment Outdated

As the American healthcare system is reshaped, we must recognize that part of the problem is the outdated way in which we pay for medical services. Physicians are rewarded as piece workers by the unit of the visit or the procedure. This has led to a culture of doing more things for one individual patient rather than attempting to make the hospital work better for all patients. In addition, this unit-based payment does not reward efficiency or effectiveness.

Hospitalists are, in many ways, change agents in the inpatient environment. Hospitalists can spend as much as 50% of their professional time improving the entire enterprise by taking on the responsibilities of other physicians, developing plans to improve quality educating hospital staff or medical trainees, addressing efficiencies through earlier discharge or improved throughput in the ED or ICU, creating teams of health professionals, or being available around the clock.

The diverse work that hospitalizes perform is very important and time consuming. However, the traditional payment scheme for physicians does not provide a direct way to compensate the hospitalist for this skill and expertise.

Hospitals have realized that these hospitalist skills bring real value to their health communities. And hospitals have been willing to invest their own funds to grow and support their hospital medicine groups to the tune of $75,000 or more per hospitalist per year. This is not a hand-out or a subsidy. This is true commerce. Hospitals continue to get significant benefits from their hospitalists.

In fact, when confronted with the choice of whether to ask the hospitalists to ''just see patients'' to generate more direct patient fees or to continue to improve the effectiveness and efficiency of their health communities, enlightened hospital executives vote with their money and ask the hospitalists to improve quality, build teams, reduce LOS, improve throughput, educate their staff, and generally build the hospital of the future.

With regard to paying physicians, SHM believes that the Pay for Performance movement is an important step in the right direction. Hospitalists welcome a reimbursement scheme that rewards institutions that follow best practices and achieve superior outcomes.

Audiences for this Supplement

This supplement, How Hospitalists Add Value, has two major audiences. First, hospitalists need to categorize what they can and will do for their hospitals and healthcare communities. They need to understand that this is not voluntary work to be done in their spare time. The provision of these services provides strategic and market benefits to their hospital.

Second, there are hospital administrators and leaders at 1,500 hospitals who have been crucial to growing hospital medicine to more than 12,000 hospitalists. They recognize that hospitalists are core to their future. This supplement will further confirm and document the ways in which hospitalists can help their organizations. The facts put forth in these papers can create a rationale for continued support with dollars and manpower, not as a subsidy but as an intelligent investment for the hospital.

Hospitalists Add Value

• Hospitalists can provide measurable quality improvement through setting standards and compliance.
• Hospitalists can save money and resources by reducing LOS and achieving better utilization.
• Hospitalists can improve the efficiency of the hospital by early discharge, better throughput in the ED, and the opening up of ICU beds.
• Hospitalists can create a seamless continuity from inpatient to outpatient care, from the ED to the floor, and from the ICU to the floor.
• Hospitalists can make other physicians' lives better and help hospitals to recruit and retain PCPs, surgeons, and specialists.
• Hospitalists can do things other physicians have given up by admitting patients without health insurance or by serving on hospital committees.
• Hospitalists can be instrumental in creating teams of healthcare professionals that make better use of the talent at the hospital and create a better working environment for nurses and others.
• Hospitalists can have a leading role in educating nurses, other hospital staff, and physicals in training.
• And hospitalizes can take care of the acutely ill complex hospitalized patients.

Add it all up and it is clear that hospitalists are a resource to hospitals in meeting the complex challenges of their healthcare communities. Hopefully, this set of important papers will define these issues more clearly and assist hospitalists and their hospital leaders in creating a stable and supportive environment for collaboration that can lead to better healthcare for our patients.

Hospital medicine has arrived at just the right moment for a healthcare delivery system in need of change. Medical errors and cost escalation continue to dominate the headlines. With regard to quality the National Quality Foundation is attempting to define standards and health plans are creating incentives through Pay for Performance programs. With regard to costs, there are expectations that they will rise even higher as the baby boomer population ages.

Providing high-quality, cost-effective care to acutely ill patients in the hospital is becoming more complex. It requires physicians who can focus on inpatient care, allowing primary care physicians, surgeons, and subspecialists to concentrate on what they do best. Providing the best care available to the hospitalized patients can no longer be done by one health professional acting alone, no matter how wise and well meaning. Hospitalists have dedicated their professional careers to providing team-based, patient-centered care that achieves cost-effective, quality outcomes.

As the specialty society for hospital medicine, SHM provides a vehicle to define this new specialty. We are doing this with our surveys of hospitalist productivity and compensation, by articles that appear in the medical and lay press, and by the Core Curriculum for Hospital Medicine that will be published in the coming months.

Hospitalists provide significant value to their healthcare communities and to patients, physicians, other health professionals, and administrators well beyond the benefits of direct patient care. This supplement to The Hospitalist, the official publication of SHM, is a compendium of papers designed to further define the full range of benefits provided by the specialty of hospital medicine.

Physician Methods of Payment Outdated

As the American healthcare system is reshaped, we must recognize that part of the problem is the outdated way in which we pay for medical services. Physicians are rewarded as piece workers by the unit of the visit or the procedure. This has led to a culture of doing more things for one individual patient rather than attempting to make the hospital work better for all patients. In addition, this unit-based payment does not reward efficiency or effectiveness.

Hospitalists are, in many ways, change agents in the inpatient environment. Hospitalists can spend as much as 50% of their professional time improving the entire enterprise by taking on the responsibilities of other physicians, developing plans to improve quality educating hospital staff or medical trainees, addressing efficiencies through earlier discharge or improved throughput in the ED or ICU, creating teams of health professionals, or being available around the clock.

The diverse work that hospitalizes perform is very important and time consuming. However, the traditional payment scheme for physicians does not provide a direct way to compensate the hospitalist for this skill and expertise.

Hospitals have realized that these hospitalist skills bring real value to their health communities. And hospitals have been willing to invest their own funds to grow and support their hospital medicine groups to the tune of $75,000 or more per hospitalist per year. This is not a hand-out or a subsidy. This is true commerce. Hospitals continue to get significant benefits from their hospitalists.

In fact, when confronted with the choice of whether to ask the hospitalists to ''just see patients'' to generate more direct patient fees or to continue to improve the effectiveness and efficiency of their health communities, enlightened hospital executives vote with their money and ask the hospitalists to improve quality, build teams, reduce LOS, improve throughput, educate their staff, and generally build the hospital of the future.

With regard to paying physicians, SHM believes that the Pay for Performance movement is an important step in the right direction. Hospitalists welcome a reimbursement scheme that rewards institutions that follow best practices and achieve superior outcomes.

Audiences for this Supplement

This supplement, How Hospitalists Add Value, has two major audiences. First, hospitalists need to categorize what they can and will do for their hospitals and healthcare communities. They need to understand that this is not voluntary work to be done in their spare time. The provision of these services provides strategic and market benefits to their hospital.

Second, there are hospital administrators and leaders at 1,500 hospitals who have been crucial to growing hospital medicine to more than 12,000 hospitalists. They recognize that hospitalists are core to their future. This supplement will further confirm and document the ways in which hospitalists can help their organizations. The facts put forth in these papers can create a rationale for continued support with dollars and manpower, not as a subsidy but as an intelligent investment for the hospital.

Hospitalists Add Value

• Hospitalists can provide measurable quality improvement through setting standards and compliance.
• Hospitalists can save money and resources by reducing LOS and achieving better utilization.
• Hospitalists can improve the efficiency of the hospital by early discharge, better throughput in the ED, and the opening up of ICU beds.
• Hospitalists can create a seamless continuity from inpatient to outpatient care, from the ED to the floor, and from the ICU to the floor.
• Hospitalists can make other physicians' lives better and help hospitals to recruit and retain PCPs, surgeons, and specialists.
• Hospitalists can do things other physicians have given up by admitting patients without health insurance or by serving on hospital committees.
• Hospitalists can be instrumental in creating teams of healthcare professionals that make better use of the talent at the hospital and create a better working environment for nurses and others.
• Hospitalists can have a leading role in educating nurses, other hospital staff, and physicals in training.
• And hospitalizes can take care of the acutely ill complex hospitalized patients.

Add it all up and it is clear that hospitalists are a resource to hospitals in meeting the complex challenges of their healthcare communities. Hopefully, this set of important papers will define these issues more clearly and assist hospitalists and their hospital leaders in creating a stable and supportive environment for collaboration that can lead to better healthcare for our patients.

Introduction

Clostridium difficile–associated diarrhea (CDAD) has been recognized with increased frequency as a cause of nosocomial illness. The frequency and incidence of CDAD varies widely, and is influenced by multiple factors including nosocomial outbreaks, patterns of antimicrobial use, and individual susceptibility. There are no reports of prospective studies by hospitals tracking positive toxin A or A/B and the outcomes of CDAD and its complications.

The Centers for Disease Control and Prevention (CDC) has analyzed secular trends in the incidence of CDAD, and it reported a steady increase from 1987 to 2001 (1). In this report, 30% of 440 infectious disease physicians who participated in a Web-based poll reported that they are seeing higher rates of CDAD, more severe CDAD, and more relapsing CDAD than in the past. There is an overall impression that there has been an increase in the proportion of cases with severe and fatal complications, and an increase in the relapse rate among affected patients.

In addition to morbidity and mortality, the economic burden of C. difficile infection in terms of delayed discharge and other hospital costs is considerable.

Epidemiology

The frequency and incidence of CDAD varies between hospitals and within a given institution over time. The risk for disease increases in patients with antibiotic exposure, gastrointestinal surgery, increasing length of stay in healthcare settings, serious underlying illness, immuno-compromising conditions, and advanced age.

C. difficile is shed in feces. Any surface, device, or material (e.g., commode, bathing tub, and electronic rectal thermometer) that becomes contaminated with feces may serve as a reservoir for C. difficile spores. Spores are transferred to patients mainly via the hands of healthcare personnel who have touched a contaminated surface or item (2-6).

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The Organism and Pathophysiology of C. difficile Diarrhea

C. difficile is a gram-positive, anaerobic, spore-forming bacillus that is responsible for the development of antibiotic-associated diarrhea and colitis. C. difficile was first described in 1935 as a component of the fecal flora of healthy newborns and was initially not thought to be pathogenic (7). The bacillus was named difficile because it grows slowly and is difficult to culture. C. difficile is presently responsible for nearly all causes of pseudomembranous colitis and as many as 20% of cases of antibiotic-associated diarrhea without colitis. Although found in the stool of only 5% of the general population, as many as 21% of adults become colonized with this organism while hospitalized (2,6).

An alteration of the normal colonic microflora, usually caused by antibiotic therapy, is the main factor that predisposes to infection with C. difficile. Almost all antibiotics have been associated with C. difficile diarrhea and colitis. The antibiotics most frequently associated include clindamycin, cephalosporins, ampicillin, and amoxicillin (Table 1) (8).

In addition to antibiotic therapy, older age and severity of underlying disease are important risk factors for C. difficile infection. Other risk factors include the presence of a nasogastric tube, gastrointestinal procedures, acid antisecretory medications, intensive care unit stay, and duration of hospitalization (9).

C. difficile diarrhea is caused primarily by the elaboration of toxins A and B produced by bacterial multiplication within the intestinal lumen. These toxins bind to the colonic mucosa and exert their deleterious effects upon it. The organism rarely damages the colon by direct invasion, and diarrhea is caused by the effects of toxins produced within the intestinal lumen that adhere to the mucosal surface. Most toxigenic isolates produce both toxins, and about 5–25% of isolates produce neither toxin A nor B, and do not cause colitis or diarrhea (3-5).

Clinical Manifestations

Infection with C. difficile may produce a wide range of clinical manifestations, including asymptomatic carriage, mild-to-moderate diarrhea, and fulminant disease with pseudomembranous colitis (10). In patients who develop CDAD, symptoms usually begin soon after colonization. Colonization may occur during antibiotic treatment or up to several weeks after a course of antibiotics. CDAD typically is associated with the passage of frequent, loose bowel movements consistent with proctocolitis. Mucus or occult blood may be present, but visible blood is rare.

Diagnosis

The diagnosis of CDAD is based on a history of recent or current antibiotic therapy, development of diarrhea or other evidence of acute colitis, and demonstration of infection by toxigenic C. difficile, usually by detection of toxin A or toxin B in stool sample.

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Practical Guidelines for Diagnosis of C. difficile Diarrheal Syndromes

1. The diagnosis should be suspected in anyone with diarrhea who has received antibiotics within the previous 2 months and/or whose diarrhea begins 72 hours or more after hospitalization.
2. When the diagnosis is suspected, a single stool specimen should be sent to the laboratory for testing for the presence of C. difficile and/or its toxins.
3. When diarrhea persists despite a negative stool toxin result, one or two additional samples may be sent for testing with the same or different tests (4). Endoscopy is reserved for special situations, such as when a rapid diagnosis is needed and test results are delayed or the test is not highly sensitive, when the patient has ileus and stool is not available, or when other colonic diseases are also a consideration.

There is as yet no simple, inexpensive, rapid, sensitive and specific test for diagnosing C. difficile diarrhea and colitis, nor are all the available tests suitable for adoption by every laboratory (Table 2) (11).

Endoscopic Diagnosis of C. difficile Diarrhea and Colitis

Sigmoidoscopy and colonoscopy are not indicated for most patients with CDAD (10,12). Endoscopy is helpful, however, in special situations, such as when the diagnosis is in doubt or the clinical situation demands rapid diagnosis. The results of endoscopic examination may be normal in patients with mild diarrhea or may show nonspecific colitis in moderate cases. The finding of colonic pseudomembranes in a patient with antibiotic-associated diarrhea is virtually pathognomonic for C. difficile colitis. A few patients without any diagnostic features in the rectosigmoid have pseudomembranes in the more proximal areas of the colon (13). Other endoscopic findings include erythema, edema, friability, and nonspecific colitis with small ulcerations or erosions.

Treatment

The first step in the management of C. difficile diarrhea and colitis is to discontinue the precipitating antibiotics if possible (10,12). Diarrhea resolves in approximately 15–25% of patients without specific anti–C. difficile therapy (14,15). Conservative management alone may not be indicated, however, in patients who are systemically ill or who have multiple medical problems, since it is difficult to predict which patients will improve spontaneously. If it is not possible to discontinue the precipitating antibiotic because of other active infections, the patient’s antibiotic regimen should be altered if possible to make use of agents less likely to cause CDAD (e.g., aminoglycosides, trimethoprim, rifampin, or a quinolone).

Antiperistaltic agents, such as diphenoxylate plus atropine (Lomotil), or loperamide (Imodium), and narcotic analgesics should be avoided because they may delay clearance of toxins from the colon and thereby exacerbate toxin-induced colonic injury or precipitate ileus and toxic dilatation (12,16). Specific therapy to eradicate C. difficile should be used in patients with initially severe symptoms and in patients whose symptoms persist despite discontinuation of antibiotic treatment. Although the diagnosis of C. difficile colitis should ideally be established before antimicrobial therapy is implemented, current ACG guidelines recommend that empiric therapy should be initiated in highly suggestive cases of severely ill patients (Table 3 on page 54) (12).

Currently, oral vancomycin or metronidazole, used for 7 to 10 days, are considered first-line therapy by most authors and current guidelines. Metronidazole at a dose of 250 mg 4 times daily is recommended by most authors and ACG guidelines as the drug of choice for the initial treatment of C. difficile colitis (12). These recommendations are largely based on efficacy, lower costs, and concerns about the development of vancomycin-resistant strains. Major disadvantages of metronidazole include a less desirable drug profile and contraindications in children and pregnant women.

Vancomycin, on the other hand, at a dose of 125 mg 4 times daily, is safe and well tolerated and achieves stool levels 20 times the required minimal inhibitory concentration for the treatment of C. difficile. Drawbacks to the use of vancomycin are cost and potential development of vancomycin-resistant strains. The current ACG guidelines consider vancomycin the drug of choice in severely ill patients and in cases in which the use of metronidazole is precluded.

Controlled clinical trials are lacking for patients with fulminant colitis who may not tolerate oral therapy. Administration of metronidazole intravenously or administration of vancomycin by nasogastric tube or rectal enema has been described in small case series (17-20). Intravenous administration of vancomycin is not recommended, because the drug is not excreted in the colon (17).

Management of Recurrent C. difficile Diarrhea

Despite successful initial treatment of CDAD, 15–20% of patients have recurrence of diarrhea in association with a positive stool test for C. difficile toxin. Symptomatic recurrence is rarely due to treatment failure or antimicrobial resistance to metronidazole or vancomycin. Approaches to management include conservative therapy (however, many patients are elderly and infirm and unable to tolerate diarrhea), therapy with specific anti–C. difficile antibiotics, the use of anion-binding resins, therapy with microorganisms (probiotics), and immunoglobulin therapy.

The most common therapy for recurrent C. difficile diarrhea is a second course of the same antibiotic used to treat the initial episode (12). In a large observational study in the United States, 92% of patients with recurrent CDAD responded successfully to a single repeated course of therapy, usually with metronidazole or vancomycin (14). There is evidence to suggest that patients with a history of recurrence have a high risk of further episodes of CDAD after antibiotic therapy is discontinued. There are no data to suggest that sequential episodes become progressively more severe or complicated (21). A variety of treatment schedules have been suggested for patients with multiple recurrences of C. difficile diarrhea. One approach is to give a prolonged course of vancomycin (or metronidazole) using a decreasing dosage schedule followed by pulse therapy (Table 4).

Cholestyramine, an anionexchange resin administered at a dose of 4 grams 3 or 4 times daily for 1 to 2 weeks, binds C. difficile toxins and may be used in conjunction with antibiotics to treat repeated relapses. Because cholestyramine may bind vancomycin as well as toxins, it should be taken at least 2 to 3 hours apart from the vancomycin.

Severe C. difficile Colitis

The incidence of fulminant C. difficile colitis has been reported to be 1.6–3.2% (22). Although recent precise figures from other centers are lacking, it is being recognized as an increasing cause of complications and death. The clinical syndrome of fulminant C. difficile colitis can be recognized with a proper knowledge of the spectrum of disease presentation.

A. Diarrhea: Although diarrhea is the hallmark of C. difficile colitis, it is not invariably present, and its absence may lead to diagnostic confusion. When diarrhea is absent, this appears to be secondary to severe colonic dysmotility. Even when present, diarrhea may be perceived to be a minor component of a nonspecific septic picture.

Reprinted with permission from BUMC Proceedings 1999; 12:249-250

Reprinted with permission from BUMC Proceedings 1999; 12:249-250

Reprinted with permission from BUMC Proceedings 1999; 12:249-250

B. Severe Disease: Fulminant colitis is an unusual form of C. difficile infection, occurring in only 3% of patients but accounting for virtually all serious complications. Patients with more severe forms of the disease may present with or without diarrhea. When patients develop colitis localized to the cecum and right side of the colon, diarrhea may be minimal or absent. In the absence of diarrhea, the only clues to diagnosis may be systemic signs of toxicity (fever, tachycardia, leukocytosis, and/or volume depletion).

An elevated white blood cell count may be an important clue to impending fulminant C. difficile colitis. The rapid elevation of the peripheral white cell count (commonly as high as 30,000 to 50,000) with a significant excess of bands and sometimes more immature forms often precedes hemodynamic instability and the development of organ dysfunction. Even in patients who are mildly symptomatic for an extended period, sudden and unexpected progression to shock may occur. It is difficult to predict those patients who may not respond to medical treatment. Hence, early warning signs such as a leukemoid reaction may be invaluable.

Hypotension is a late finding and can be resistant to vasopressor support. Abdominal signs range from distention to generalized tenderness with guarding. Colonic perforation is usually accompanied by abdominal rigidity, involuntary guarding, rebound tenderness, and absent bowel sounds. Free air may be revealed on abdominal radiographs. Any suspicion of perforation in this setting should prompt immediate surgical consultation. Death generally occurs before free air and perforation can occur. In one study, contrary to most other literature, perforation was found to be rare (22).

Abdominal radiography may reveal a dilated colon (>7 cm in its greatest diameter), consistent with toxic megacolon. Patients with megacolon may have an associated small bowel ileus with dilated small intestine on plain abdominal radiographs, with air-fluid levels mimicking small intestinal obstruction or ischemia. CT without contrast and endoscopy can quickly diagnose or at least strongly suggest fulminant C.difficile colitis. CT scan findings include evidence of ascites, colonic wall thickening and/or dilatation. These findings may prove helpful in categorizing the severity of the colitis.

More aggressive intervention in medically unresponsive patients, including rapid identification of patients failing to respond to medical therapy, is crucial to a positive outcome, and early surgical intervention should be done in this group (Figures 1-3).

It is important that everyone involved with patient care in hospitals, nursing homes, and skilled nursing facilities be educated about the organism and its epidemiology, rational approaches to the treatment and care of patients with C. difficile diarrhea, the importance of hand washing between contact with patients, the use of gloves when caring for a patient with C. difficile diarrhea, and the avoidance of the unnecessary use of antimicrobials.

Conclusion

Recent years have raised concerns over rising incidence and serious complication rates of CDAD in North American hospitals (22,23). The Canadian Medical Association journal published a report in 2004 detailing an outbreak of CDAD involving several hospitals in Montreal. The introduction of new hypervirulent and highly transmissible strains of C. difficile has been postulated as the possible cause for the outbreak (24). A deteriorating infrastructure, inadequate infection control practices, the increasing number of debilitated patients, an aging population, and hypervirulent strains were all felt to be likely contributors to recent outbreaks in Canada (25).

Two epidemiological investigations in the United States and Canada (24,26) independently examined samples of C. difficile and found that a mutated version of the “wild” strain was responsible for outbreaks in Quebec and increased rates of CDAD in hospitals in the United States recently (22,23). Clinical epidemiologists at the CDC investigated C. difficile isolates from hospitals in the United States with recent (i.e., 2001–2004) CDAD outbreaks (22,23). The report indicates the emergence of a new epidemic strain, “BI” (distinct from the “J” strain of 1989–1992), which may be responsible for the recent increase in rates and apparent severity of CDAD (26).

CDAD and colitis in most cases can be treated by the administration of metronidazole or vancomycin. In some patients severe life-threatening toxicity develops despite appropriate and timely medical treatment, and surgical intervention is necessary. Systemic symptoms of infection with C. difficile are reported not to derive from bacteremia, colonic perforation or ischemia, but from toxin-induced inflammatory mediators released from the colon (27-29). Early surgical intervention should be employed in refractory cases of severe disease. Surgical intervention is far from ideal, however, and carries a very high rate of complications and significant risk of mortality (22). The future clinical approach to the treatment of nosocomial C. difficile colitis may eventually involve specific antitoxin hyperimmunoglobulins and inhibitors of the inflammatory cascade (28,30,31).

References

1. Archibald LK, Banerjee SN, Jarvis WR. Secular trend in hospital-acquired Clostridium difficile disease in the United States; 1987-2001. J Infect Dis. 2004;189:1585-9.
2. Fekety R. Antibiotic-associated colitis. In: Mandell G, Bennet JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 4th ed. New York: Churchill Livingston; 1996:978-806.
3. Mitty RD, LaMont T. Clostridium difficile diarrhea: Pathogenesis, epidemiology, and treatment. Gastroenterologist. 1994;2:61-9.
4. Bartlett JG. Clostridium difficile: History of its role as an enteric pathogen and the current state of knowledge about the organism. Clin Infect Dis. 1994;18(Suppl 4):265-72.
5. Johnson S, Gerding D. Clostridium difficile. In: Mayhall CG, ed. Hospital Epidemiology and Infection Control. Baltimore, Md: Williams & Wilkins; 1996:99-408.
6. Mcfarland LV, Mulligan ME, Kwok RY, Stamm WE. Nosocomial acquisition of Clostridium difficile. N Engl J Med. 1989;320:204-10.
7. Hall IC, O Toole E. Intestinal Flora in new-born infants: With a description of a new pathogenic anaerobe, Bacillus difficile. Am J Dis Child. 1935;49:390-402.
8. Kelly CP, LaMont JT. Treatment of Clostridium difficile diarrhea and colitis. In: Wolfe MM, ed. Gastrointestinal Pharmacotherapy. Philadelphia, Pa.: WB Saunders; 1993:199-212.
9. Bignardi GE. Risk factors for Clostridium difficile infection. J Hosp Infect. 1998;40:1-15.
10. Kelly CP, Pothoulakas C, LaMont JT. Clostridium difficile colitis. N Engl J Med. 1994;330:257-62.
11. Linevsky JK, Kelly CP. Clostridium difficile colitis. In: Lamont JT, ed. Gastrointestinal Infections: Diagnosis and Management. New York: Marcel Dekker; 1997:293-325.
12. Fekety R. Guidelines for the diagnosis and management of Clostridium difficile associated diarrhea and colitis. American College of Gastroenetrology, Practice Parameters Committee. Am J Gastroenterol. 1997;92:739-50.
13. Tedesco FJ, Corless JK, Brownstein RE. Rectal sparing in antibiotic-associated pseudomembranous colitis: A prospective study. Gastroenterology. 1982;83:1259-60.
14. Olson MM, Shanholtzer CJ, Lee JT Jr, Gerding DN. Ten years of prospective Clostridium difficile-associated disease surveillance and treatment at the Minneapolis VA Medical Center, 1982-1991. Infect Control Hosp Epidemiol. 1994;15: 371-81.
15. Teasley DG, Gerding DN, Olson MM, et al. Prospective randomized trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis. Lancet. 1983;2:1043-6.
16. Walley T, Milson D. Loperamide-related toxic megacolon in Clostridium difficile colitis. Postgrad Med J. 1990;66:582.
17. Malnick SD, Zimhony O. Treatment of Clostridium difficile associated diarrhea. Ann Pharmacother. 2002;36:1767-75.
18. Sehgal M, Kyne L. Clostridium difficile disease. Curr Treatment Options Infect Dis. 2002;4:201-10.
19. Apisarnthanarak A, Razavi B, Mundy LM. Adjunctive intracolonic vancomycin for severe Clostridium difficile colitis: case series and review of the literature. Clin Infect Dis. 2002;35:690-6.
20. Friendenberg F, Fernandez A, Kaul V, Niami P, Levine GM. Intravenous metronidazole for the treatment of Clostridium difficile colitis. Dis Colon Rectum. 2001;44:1176-80.
21. Fekety R, McFarland LV, Surawicz CMGreenberg, RN, Elmer GW, Mulligan ME. Recurrent Clostridium difficile diarrhea: characteristics of and risk factors for patients enrolled in a prospective, randomized, double-blind trial. Clin Infect Dis. 1997;24:324-33.
22. Dallal RM, Harbrecht BG, Boujoukas AJ, et al. Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications. Ann Surg. 2002;235:363-72.
23. Morris AM, Jobe BA, Sontey, M, Sheppard BC, Deveney CW, Deveney KE. Clostridium difficile colitis: an increasingly aggressive iatrogenic disease? Arch Surg. 2002;137:1096-100.
24. Eggerston L, Sibbald B. Hospitals battling outbreaks of C. difficile. CMAJ. 2004;171:19-21.
25. Valiquette L, Low DE, Pepin J, McGeer A. Clostridium difficile infection in hospitals: a brewing storm. CMAJ. 2004;171:27-9.
26. McDonald LC, Killgore GE, Thompson A, et al. Emergence of an epidemic strain of Clostridium difficile in the United States, 2001-4: Potential role for virulence factors and antimicrobial resistance traits. Infectious Diseases Society of America 42th Annual Meeting. Boston, MA, September 30 – October 3, 2004. Abstract # LB-2.
27. Flegel W, Muller F, Daubener W, Fischer HG, Hadding U, Northoff H. Cytokine response by human monocytes to Clostridium difficile toxin A and toxin B. Infect Immun. 1991;59:3659-66.
28. Castagliuolo I, Keates A, Qiu B, et al. Increased substance P responses in dorsal root ganglia, intestinal macrophages during Clostridium difficile toxin A enteritis in rats. Proc Natl Acad Sci U S A. 1997;94:4788-93.
29. Castagliuolo I, Keates A, Wang C, et al. Clostridium difficile toxin A stimulates macrophage-inflammatory protein-2 production in rat intestinal epithelial cells. J Immunol. 1998;160:6039-45.
30. Kelly C, Chetham S, Keates S, et al. Survival of anti-Clostridium difficile bovine immunoglobulin concentrate in the human gastrointestinal tract. Antimicrob Agents Chemother. 1997;41:236-41.
31. Salcedo J, Keates S, Pothoulakis C, et. al. Intravenous immunoglobulin therapy for severe Clostridium difficile colitis. Gut. 1997;41:366-70.

General References

1. Shea Position Paper Gerding DN,Johnson S, Peterson LR, Mulligan ME Silva J. SHEA Position Paper:Clostridium difficile-associated diarrhea and colitis; Infect Control Hosp Epidemiol 1995, 16:459-77
2. Kyne L, Farrell RJ, Kelly CP. Clostridium difficile. Gastroenterol Clin North Am 2001; 30:753-77.

Introduction

Clostridium difficile–associated diarrhea (CDAD) has been recognized with increased frequency as a cause of nosocomial illness. The frequency and incidence of CDAD varies widely, and is influenced by multiple factors including nosocomial outbreaks, patterns of antimicrobial use, and individual susceptibility. There are no reports of prospective studies by hospitals tracking positive toxin A or A/B and the outcomes of CDAD and its complications.

The Centers for Disease Control and Prevention (CDC) has analyzed secular trends in the incidence of CDAD, and it reported a steady increase from 1987 to 2001 (1). In this report, 30% of 440 infectious disease physicians who participated in a Web-based poll reported that they are seeing higher rates of CDAD, more severe CDAD, and more relapsing CDAD than in the past. There is an overall impression that there has been an increase in the proportion of cases with severe and fatal complications, and an increase in the relapse rate among affected patients.

In addition to morbidity and mortality, the economic burden of C. difficile infection in terms of delayed discharge and other hospital costs is considerable.

Epidemiology

The frequency and incidence of CDAD varies between hospitals and within a given institution over time. The risk for disease increases in patients with antibiotic exposure, gastrointestinal surgery, increasing length of stay in healthcare settings, serious underlying illness, immuno-compromising conditions, and advanced age.

C. difficile is shed in feces. Any surface, device, or material (e.g., commode, bathing tub, and electronic rectal thermometer) that becomes contaminated with feces may serve as a reservoir for C. difficile spores. Spores are transferred to patients mainly via the hands of healthcare personnel who have touched a contaminated surface or item (2-6).

click for large version

The Organism and Pathophysiology of C. difficile Diarrhea

C. difficile is a gram-positive, anaerobic, spore-forming bacillus that is responsible for the development of antibiotic-associated diarrhea and colitis. C. difficile was first described in 1935 as a component of the fecal flora of healthy newborns and was initially not thought to be pathogenic (7). The bacillus was named difficile because it grows slowly and is difficult to culture. C. difficile is presently responsible for nearly all causes of pseudomembranous colitis and as many as 20% of cases of antibiotic-associated diarrhea without colitis. Although found in the stool of only 5% of the general population, as many as 21% of adults become colonized with this organism while hospitalized (2,6).

An alteration of the normal colonic microflora, usually caused by antibiotic therapy, is the main factor that predisposes to infection with C. difficile. Almost all antibiotics have been associated with C. difficile diarrhea and colitis. The antibiotics most frequently associated include clindamycin, cephalosporins, ampicillin, and amoxicillin (Table 1) (8).

In addition to antibiotic therapy, older age and severity of underlying disease are important risk factors for C. difficile infection. Other risk factors include the presence of a nasogastric tube, gastrointestinal procedures, acid antisecretory medications, intensive care unit stay, and duration of hospitalization (9).

C. difficile diarrhea is caused primarily by the elaboration of toxins A and B produced by bacterial multiplication within the intestinal lumen. These toxins bind to the colonic mucosa and exert their deleterious effects upon it. The organism rarely damages the colon by direct invasion, and diarrhea is caused by the effects of toxins produced within the intestinal lumen that adhere to the mucosal surface. Most toxigenic isolates produce both toxins, and about 5–25% of isolates produce neither toxin A nor B, and do not cause colitis or diarrhea (3-5).

Clinical Manifestations

Infection with C. difficile may produce a wide range of clinical manifestations, including asymptomatic carriage, mild-to-moderate diarrhea, and fulminant disease with pseudomembranous colitis (10). In patients who develop CDAD, symptoms usually begin soon after colonization. Colonization may occur during antibiotic treatment or up to several weeks after a course of antibiotics. CDAD typically is associated with the passage of frequent, loose bowel movements consistent with proctocolitis. Mucus or occult blood may be present, but visible blood is rare.

Diagnosis

The diagnosis of CDAD is based on a history of recent or current antibiotic therapy, development of diarrhea or other evidence of acute colitis, and demonstration of infection by toxigenic C. difficile, usually by detection of toxin A or toxin B in stool sample.

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Practical Guidelines for Diagnosis of C. difficile Diarrheal Syndromes

1. The diagnosis should be suspected in anyone with diarrhea who has received antibiotics within the previous 2 months and/or whose diarrhea begins 72 hours or more after hospitalization.
2. When the diagnosis is suspected, a single stool specimen should be sent to the laboratory for testing for the presence of C. difficile and/or its toxins.
3. When diarrhea persists despite a negative stool toxin result, one or two additional samples may be sent for testing with the same or different tests (4). Endoscopy is reserved for special situations, such as when a rapid diagnosis is needed and test results are delayed or the test is not highly sensitive, when the patient has ileus and stool is not available, or when other colonic diseases are also a consideration.

There is as yet no simple, inexpensive, rapid, sensitive and specific test for diagnosing C. difficile diarrhea and colitis, nor are all the available tests suitable for adoption by every laboratory (Table 2) (11).

Endoscopic Diagnosis of C. difficile Diarrhea and Colitis

Sigmoidoscopy and colonoscopy are not indicated for most patients with CDAD (10,12). Endoscopy is helpful, however, in special situations, such as when the diagnosis is in doubt or the clinical situation demands rapid diagnosis. The results of endoscopic examination may be normal in patients with mild diarrhea or may show nonspecific colitis in moderate cases. The finding of colonic pseudomembranes in a patient with antibiotic-associated diarrhea is virtually pathognomonic for C. difficile colitis. A few patients without any diagnostic features in the rectosigmoid have pseudomembranes in the more proximal areas of the colon (13). Other endoscopic findings include erythema, edema, friability, and nonspecific colitis with small ulcerations or erosions.

Treatment

The first step in the management of C. difficile diarrhea and colitis is to discontinue the precipitating antibiotics if possible (10,12). Diarrhea resolves in approximately 15–25% of patients without specific anti–C. difficile therapy (14,15). Conservative management alone may not be indicated, however, in patients who are systemically ill or who have multiple medical problems, since it is difficult to predict which patients will improve spontaneously. If it is not possible to discontinue the precipitating antibiotic because of other active infections, the patient’s antibiotic regimen should be altered if possible to make use of agents less likely to cause CDAD (e.g., aminoglycosides, trimethoprim, rifampin, or a quinolone).

Antiperistaltic agents, such as diphenoxylate plus atropine (Lomotil), or loperamide (Imodium), and narcotic analgesics should be avoided because they may delay clearance of toxins from the colon and thereby exacerbate toxin-induced colonic injury or precipitate ileus and toxic dilatation (12,16). Specific therapy to eradicate C. difficile should be used in patients with initially severe symptoms and in patients whose symptoms persist despite discontinuation of antibiotic treatment. Although the diagnosis of C. difficile colitis should ideally be established before antimicrobial therapy is implemented, current ACG guidelines recommend that empiric therapy should be initiated in highly suggestive cases of severely ill patients (Table 3 on page 54) (12).

Currently, oral vancomycin or metronidazole, used for 7 to 10 days, are considered first-line therapy by most authors and current guidelines. Metronidazole at a dose of 250 mg 4 times daily is recommended by most authors and ACG guidelines as the drug of choice for the initial treatment of C. difficile colitis (12). These recommendations are largely based on efficacy, lower costs, and concerns about the development of vancomycin-resistant strains. Major disadvantages of metronidazole include a less desirable drug profile and contraindications in children and pregnant women.

Vancomycin, on the other hand, at a dose of 125 mg 4 times daily, is safe and well tolerated and achieves stool levels 20 times the required minimal inhibitory concentration for the treatment of C. difficile. Drawbacks to the use of vancomycin are cost and potential development of vancomycin-resistant strains. The current ACG guidelines consider vancomycin the drug of choice in severely ill patients and in cases in which the use of metronidazole is precluded.

Controlled clinical trials are lacking for patients with fulminant colitis who may not tolerate oral therapy. Administration of metronidazole intravenously or administration of vancomycin by nasogastric tube or rectal enema has been described in small case series (17-20). Intravenous administration of vancomycin is not recommended, because the drug is not excreted in the colon (17).

Management of Recurrent C. difficile Diarrhea

Despite successful initial treatment of CDAD, 15–20% of patients have recurrence of diarrhea in association with a positive stool test for C. difficile toxin. Symptomatic recurrence is rarely due to treatment failure or antimicrobial resistance to metronidazole or vancomycin. Approaches to management include conservative therapy (however, many patients are elderly and infirm and unable to tolerate diarrhea), therapy with specific anti–C. difficile antibiotics, the use of anion-binding resins, therapy with microorganisms (probiotics), and immunoglobulin therapy.

The most common therapy for recurrent C. difficile diarrhea is a second course of the same antibiotic used to treat the initial episode (12). In a large observational study in the United States, 92% of patients with recurrent CDAD responded successfully to a single repeated course of therapy, usually with metronidazole or vancomycin (14). There is evidence to suggest that patients with a history of recurrence have a high risk of further episodes of CDAD after antibiotic therapy is discontinued. There are no data to suggest that sequential episodes become progressively more severe or complicated (21). A variety of treatment schedules have been suggested for patients with multiple recurrences of C. difficile diarrhea. One approach is to give a prolonged course of vancomycin (or metronidazole) using a decreasing dosage schedule followed by pulse therapy (Table 4).

Cholestyramine, an anionexchange resin administered at a dose of 4 grams 3 or 4 times daily for 1 to 2 weeks, binds C. difficile toxins and may be used in conjunction with antibiotics to treat repeated relapses. Because cholestyramine may bind vancomycin as well as toxins, it should be taken at least 2 to 3 hours apart from the vancomycin.

Severe C. difficile Colitis

The incidence of fulminant C. difficile colitis has been reported to be 1.6–3.2% (22). Although recent precise figures from other centers are lacking, it is being recognized as an increasing cause of complications and death. The clinical syndrome of fulminant C. difficile colitis can be recognized with a proper knowledge of the spectrum of disease presentation.

A. Diarrhea: Although diarrhea is the hallmark of C. difficile colitis, it is not invariably present, and its absence may lead to diagnostic confusion. When diarrhea is absent, this appears to be secondary to severe colonic dysmotility. Even when present, diarrhea may be perceived to be a minor component of a nonspecific septic picture.

Reprinted with permission from BUMC Proceedings 1999; 12:249-250

Reprinted with permission from BUMC Proceedings 1999; 12:249-250

Reprinted with permission from BUMC Proceedings 1999; 12:249-250

B. Severe Disease: Fulminant colitis is an unusual form of C. difficile infection, occurring in only 3% of patients but accounting for virtually all serious complications. Patients with more severe forms of the disease may present with or without diarrhea. When patients develop colitis localized to the cecum and right side of the colon, diarrhea may be minimal or absent. In the absence of diarrhea, the only clues to diagnosis may be systemic signs of toxicity (fever, tachycardia, leukocytosis, and/or volume depletion).

An elevated white blood cell count may be an important clue to impending fulminant C. difficile colitis. The rapid elevation of the peripheral white cell count (commonly as high as 30,000 to 50,000) with a significant excess of bands and sometimes more immature forms often precedes hemodynamic instability and the development of organ dysfunction. Even in patients who are mildly symptomatic for an extended period, sudden and unexpected progression to shock may occur. It is difficult to predict those patients who may not respond to medical treatment. Hence, early warning signs such as a leukemoid reaction may be invaluable.

Hypotension is a late finding and can be resistant to vasopressor support. Abdominal signs range from distention to generalized tenderness with guarding. Colonic perforation is usually accompanied by abdominal rigidity, involuntary guarding, rebound tenderness, and absent bowel sounds. Free air may be revealed on abdominal radiographs. Any suspicion of perforation in this setting should prompt immediate surgical consultation. Death generally occurs before free air and perforation can occur. In one study, contrary to most other literature, perforation was found to be rare (22).

Abdominal radiography may reveal a dilated colon (>7 cm in its greatest diameter), consistent with toxic megacolon. Patients with megacolon may have an associated small bowel ileus with dilated small intestine on plain abdominal radiographs, with air-fluid levels mimicking small intestinal obstruction or ischemia. CT without contrast and endoscopy can quickly diagnose or at least strongly suggest fulminant C.difficile colitis. CT scan findings include evidence of ascites, colonic wall thickening and/or dilatation. These findings may prove helpful in categorizing the severity of the colitis.

More aggressive intervention in medically unresponsive patients, including rapid identification of patients failing to respond to medical therapy, is crucial to a positive outcome, and early surgical intervention should be done in this group (Figures 1-3).

It is important that everyone involved with patient care in hospitals, nursing homes, and skilled nursing facilities be educated about the organism and its epidemiology, rational approaches to the treatment and care of patients with C. difficile diarrhea, the importance of hand washing between contact with patients, the use of gloves when caring for a patient with C. difficile diarrhea, and the avoidance of the unnecessary use of antimicrobials.

Conclusion

Recent years have raised concerns over rising incidence and serious complication rates of CDAD in North American hospitals (22,23). The Canadian Medical Association journal published a report in 2004 detailing an outbreak of CDAD involving several hospitals in Montreal. The introduction of new hypervirulent and highly transmissible strains of C. difficile has been postulated as the possible cause for the outbreak (24). A deteriorating infrastructure, inadequate infection control practices, the increasing number of debilitated patients, an aging population, and hypervirulent strains were all felt to be likely contributors to recent outbreaks in Canada (25).

Two epidemiological investigations in the United States and Canada (24,26) independently examined samples of C. difficile and found that a mutated version of the “wild” strain was responsible for outbreaks in Quebec and increased rates of CDAD in hospitals in the United States recently (22,23). Clinical epidemiologists at the CDC investigated C. difficile isolates from hospitals in the United States with recent (i.e., 2001–2004) CDAD outbreaks (22,23). The report indicates the emergence of a new epidemic strain, “BI” (distinct from the “J” strain of 1989–1992), which may be responsible for the recent increase in rates and apparent severity of CDAD (26).

CDAD and colitis in most cases can be treated by the administration of metronidazole or vancomycin. In some patients severe life-threatening toxicity develops despite appropriate and timely medical treatment, and surgical intervention is necessary. Systemic symptoms of infection with C. difficile are reported not to derive from bacteremia, colonic perforation or ischemia, but from toxin-induced inflammatory mediators released from the colon (27-29). Early surgical intervention should be employed in refractory cases of severe disease. Surgical intervention is far from ideal, however, and carries a very high rate of complications and significant risk of mortality (22). The future clinical approach to the treatment of nosocomial C. difficile colitis may eventually involve specific antitoxin hyperimmunoglobulins and inhibitors of the inflammatory cascade (28,30,31).

References

1. Archibald LK, Banerjee SN, Jarvis WR. Secular trend in hospital-acquired Clostridium difficile disease in the United States; 1987-2001. J Infect Dis. 2004;189:1585-9.
2. Fekety R. Antibiotic-associated colitis. In: Mandell G, Bennet JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 4th ed. New York: Churchill Livingston; 1996:978-806.
3. Mitty RD, LaMont T. Clostridium difficile diarrhea: Pathogenesis, epidemiology, and treatment. Gastroenterologist. 1994;2:61-9.
4. Bartlett JG. Clostridium difficile: History of its role as an enteric pathogen and the current state of knowledge about the organism. Clin Infect Dis. 1994;18(Suppl 4):265-72.
5. Johnson S, Gerding D. Clostridium difficile. In: Mayhall CG, ed. Hospital Epidemiology and Infection Control. Baltimore, Md: Williams & Wilkins; 1996:99-408.
6. Mcfarland LV, Mulligan ME, Kwok RY, Stamm WE. Nosocomial acquisition of Clostridium difficile. N Engl J Med. 1989;320:204-10.
7. Hall IC, O Toole E. Intestinal Flora in new-born infants: With a description of a new pathogenic anaerobe, Bacillus difficile. Am J Dis Child. 1935;49:390-402.
8. Kelly CP, LaMont JT. Treatment of Clostridium difficile diarrhea and colitis. In: Wolfe MM, ed. Gastrointestinal Pharmacotherapy. Philadelphia, Pa.: WB Saunders; 1993:199-212.
9. Bignardi GE. Risk factors for Clostridium difficile infection. J Hosp Infect. 1998;40:1-15.
10. Kelly CP, Pothoulakas C, LaMont JT. Clostridium difficile colitis. N Engl J Med. 1994;330:257-62.
11. Linevsky JK, Kelly CP. Clostridium difficile colitis. In: Lamont JT, ed. Gastrointestinal Infections: Diagnosis and Management. New York: Marcel Dekker; 1997:293-325.
12. Fekety R. Guidelines for the diagnosis and management of Clostridium difficile associated diarrhea and colitis. American College of Gastroenetrology, Practice Parameters Committee. Am J Gastroenterol. 1997;92:739-50.
13. Tedesco FJ, Corless JK, Brownstein RE. Rectal sparing in antibiotic-associated pseudomembranous colitis: A prospective study. Gastroenterology. 1982;83:1259-60.
14. Olson MM, Shanholtzer CJ, Lee JT Jr, Gerding DN. Ten years of prospective Clostridium difficile-associated disease surveillance and treatment at the Minneapolis VA Medical Center, 1982-1991. Infect Control Hosp Epidemiol. 1994;15: 371-81.
15. Teasley DG, Gerding DN, Olson MM, et al. Prospective randomized trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis. Lancet. 1983;2:1043-6.
16. Walley T, Milson D. Loperamide-related toxic megacolon in Clostridium difficile colitis. Postgrad Med J. 1990;66:582.
17. Malnick SD, Zimhony O. Treatment of Clostridium difficile associated diarrhea. Ann Pharmacother. 2002;36:1767-75.
18. Sehgal M, Kyne L. Clostridium difficile disease. Curr Treatment Options Infect Dis. 2002;4:201-10.
19. Apisarnthanarak A, Razavi B, Mundy LM. Adjunctive intracolonic vancomycin for severe Clostridium difficile colitis: case series and review of the literature. Clin Infect Dis. 2002;35:690-6.
20. Friendenberg F, Fernandez A, Kaul V, Niami P, Levine GM. Intravenous metronidazole for the treatment of Clostridium difficile colitis. Dis Colon Rectum. 2001;44:1176-80.
21. Fekety R, McFarland LV, Surawicz CMGreenberg, RN, Elmer GW, Mulligan ME. Recurrent Clostridium difficile diarrhea: characteristics of and risk factors for patients enrolled in a prospective, randomized, double-blind trial. Clin Infect Dis. 1997;24:324-33.
22. Dallal RM, Harbrecht BG, Boujoukas AJ, et al. Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications. Ann Surg. 2002;235:363-72.
23. Morris AM, Jobe BA, Sontey, M, Sheppard BC, Deveney CW, Deveney KE. Clostridium difficile colitis: an increasingly aggressive iatrogenic disease? Arch Surg. 2002;137:1096-100.
24. Eggerston L, Sibbald B. Hospitals battling outbreaks of C. difficile. CMAJ. 2004;171:19-21.
25. Valiquette L, Low DE, Pepin J, McGeer A. Clostridium difficile infection in hospitals: a brewing storm. CMAJ. 2004;171:27-9.
26. McDonald LC, Killgore GE, Thompson A, et al. Emergence of an epidemic strain of Clostridium difficile in the United States, 2001-4: Potential role for virulence factors and antimicrobial resistance traits. Infectious Diseases Society of America 42th Annual Meeting. Boston, MA, September 30 – October 3, 2004. Abstract # LB-2.
27. Flegel W, Muller F, Daubener W, Fischer HG, Hadding U, Northoff H. Cytokine response by human monocytes to Clostridium difficile toxin A and toxin B. Infect Immun. 1991;59:3659-66.
28. Castagliuolo I, Keates A, Qiu B, et al. Increased substance P responses in dorsal root ganglia, intestinal macrophages during Clostridium difficile toxin A enteritis in rats. Proc Natl Acad Sci U S A. 1997;94:4788-93.
29. Castagliuolo I, Keates A, Wang C, et al. Clostridium difficile toxin A stimulates macrophage-inflammatory protein-2 production in rat intestinal epithelial cells. J Immunol. 1998;160:6039-45.
30. Kelly C, Chetham S, Keates S, et al. Survival of anti-Clostridium difficile bovine immunoglobulin concentrate in the human gastrointestinal tract. Antimicrob Agents Chemother. 1997;41:236-41.
31. Salcedo J, Keates S, Pothoulakis C, et. al. Intravenous immunoglobulin therapy for severe Clostridium difficile colitis. Gut. 1997;41:366-70.

General References

1. Shea Position Paper Gerding DN,Johnson S, Peterson LR, Mulligan ME Silva J. SHEA Position Paper:Clostridium difficile-associated diarrhea and colitis; Infect Control Hosp Epidemiol 1995, 16:459-77
2. Kyne L, Farrell RJ, Kelly CP. Clostridium difficile. Gastroenterol Clin North Am 2001; 30:753-77.

Introduction

Clostridium difficile–associated diarrhea (CDAD) has been recognized with increased frequency as a cause of nosocomial illness. The frequency and incidence of CDAD varies widely, and is influenced by multiple factors including nosocomial outbreaks, patterns of antimicrobial use, and individual susceptibility. There are no reports of prospective studies by hospitals tracking positive toxin A or A/B and the outcomes of CDAD and its complications.

The Centers for Disease Control and Prevention (CDC) has analyzed secular trends in the incidence of CDAD, and it reported a steady increase from 1987 to 2001 (1). In this report, 30% of 440 infectious disease physicians who participated in a Web-based poll reported that they are seeing higher rates of CDAD, more severe CDAD, and more relapsing CDAD than in the past. There is an overall impression that there has been an increase in the proportion of cases with severe and fatal complications, and an increase in the relapse rate among affected patients.

In addition to morbidity and mortality, the economic burden of C. difficile infection in terms of delayed discharge and other hospital costs is considerable.

Epidemiology

The frequency and incidence of CDAD varies between hospitals and within a given institution over time. The risk for disease increases in patients with antibiotic exposure, gastrointestinal surgery, increasing length of stay in healthcare settings, serious underlying illness, immuno-compromising conditions, and advanced age.

C. difficile is shed in feces. Any surface, device, or material (e.g., commode, bathing tub, and electronic rectal thermometer) that becomes contaminated with feces may serve as a reservoir for C. difficile spores. Spores are transferred to patients mainly via the hands of healthcare personnel who have touched a contaminated surface or item (2-6).

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The Organism and Pathophysiology of C. difficile Diarrhea

C. difficile is a gram-positive, anaerobic, spore-forming bacillus that is responsible for the development of antibiotic-associated diarrhea and colitis. C. difficile was first described in 1935 as a component of the fecal flora of healthy newborns and was initially not thought to be pathogenic (7). The bacillus was named difficile because it grows slowly and is difficult to culture. C. difficile is presently responsible for nearly all causes of pseudomembranous colitis and as many as 20% of cases of antibiotic-associated diarrhea without colitis. Although found in the stool of only 5% of the general population, as many as 21% of adults become colonized with this organism while hospitalized (2,6).

An alteration of the normal colonic microflora, usually caused by antibiotic therapy, is the main factor that predisposes to infection with C. difficile. Almost all antibiotics have been associated with C. difficile diarrhea and colitis. The antibiotics most frequently associated include clindamycin, cephalosporins, ampicillin, and amoxicillin (Table 1) (8).

In addition to antibiotic therapy, older age and severity of underlying disease are important risk factors for C. difficile infection. Other risk factors include the presence of a nasogastric tube, gastrointestinal procedures, acid antisecretory medications, intensive care unit stay, and duration of hospitalization (9).

C. difficile diarrhea is caused primarily by the elaboration of toxins A and B produced by bacterial multiplication within the intestinal lumen. These toxins bind to the colonic mucosa and exert their deleterious effects upon it. The organism rarely damages the colon by direct invasion, and diarrhea is caused by the effects of toxins produced within the intestinal lumen that adhere to the mucosal surface. Most toxigenic isolates produce both toxins, and about 5–25% of isolates produce neither toxin A nor B, and do not cause colitis or diarrhea (3-5).

Clinical Manifestations

Infection with C. difficile may produce a wide range of clinical manifestations, including asymptomatic carriage, mild-to-moderate diarrhea, and fulminant disease with pseudomembranous colitis (10). In patients who develop CDAD, symptoms usually begin soon after colonization. Colonization may occur during antibiotic treatment or up to several weeks after a course of antibiotics. CDAD typically is associated with the passage of frequent, loose bowel movements consistent with proctocolitis. Mucus or occult blood may be present, but visible blood is rare.

Diagnosis

The diagnosis of CDAD is based on a history of recent or current antibiotic therapy, development of diarrhea or other evidence of acute colitis, and demonstration of infection by toxigenic C. difficile, usually by detection of toxin A or toxin B in stool sample.

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Practical Guidelines for Diagnosis of C. difficile Diarrheal Syndromes

1. The diagnosis should be suspected in anyone with diarrhea who has received antibiotics within the previous 2 months and/or whose diarrhea begins 72 hours or more after hospitalization.
2. When the diagnosis is suspected, a single stool specimen should be sent to the laboratory for testing for the presence of C. difficile and/or its toxins.
3. When diarrhea persists despite a negative stool toxin result, one or two additional samples may be sent for testing with the same or different tests (4). Endoscopy is reserved for special situations, such as when a rapid diagnosis is needed and test results are delayed or the test is not highly sensitive, when the patient has ileus and stool is not available, or when other colonic diseases are also a consideration.

There is as yet no simple, inexpensive, rapid, sensitive and specific test for diagnosing C. difficile diarrhea and colitis, nor are all the available tests suitable for adoption by every laboratory (Table 2) (11).

Endoscopic Diagnosis of C. difficile Diarrhea and Colitis

Sigmoidoscopy and colonoscopy are not indicated for most patients with CDAD (10,12). Endoscopy is helpful, however, in special situations, such as when the diagnosis is in doubt or the clinical situation demands rapid diagnosis. The results of endoscopic examination may be normal in patients with mild diarrhea or may show nonspecific colitis in moderate cases. The finding of colonic pseudomembranes in a patient with antibiotic-associated diarrhea is virtually pathognomonic for C. difficile colitis. A few patients without any diagnostic features in the rectosigmoid have pseudomembranes in the more proximal areas of the colon (13). Other endoscopic findings include erythema, edema, friability, and nonspecific colitis with small ulcerations or erosions.

Treatment

The first step in the management of C. difficile diarrhea and colitis is to discontinue the precipitating antibiotics if possible (10,12). Diarrhea resolves in approximately 15–25% of patients without specific anti–C. difficile therapy (14,15). Conservative management alone may not be indicated, however, in patients who are systemically ill or who have multiple medical problems, since it is difficult to predict which patients will improve spontaneously. If it is not possible to discontinue the precipitating antibiotic because of other active infections, the patient’s antibiotic regimen should be altered if possible to make use of agents less likely to cause CDAD (e.g., aminoglycosides, trimethoprim, rifampin, or a quinolone).

Antiperistaltic agents, such as diphenoxylate plus atropine (Lomotil), or loperamide (Imodium), and narcotic analgesics should be avoided because they may delay clearance of toxins from the colon and thereby exacerbate toxin-induced colonic injury or precipitate ileus and toxic dilatation (12,16). Specific therapy to eradicate C. difficile should be used in patients with initially severe symptoms and in patients whose symptoms persist despite discontinuation of antibiotic treatment. Although the diagnosis of C. difficile colitis should ideally be established before antimicrobial therapy is implemented, current ACG guidelines recommend that empiric therapy should be initiated in highly suggestive cases of severely ill patients (Table 3 on page 54) (12).

Currently, oral vancomycin or metronidazole, used for 7 to 10 days, are considered first-line therapy by most authors and current guidelines. Metronidazole at a dose of 250 mg 4 times daily is recommended by most authors and ACG guidelines as the drug of choice for the initial treatment of C. difficile colitis (12). These recommendations are largely based on efficacy, lower costs, and concerns about the development of vancomycin-resistant strains. Major disadvantages of metronidazole include a less desirable drug profile and contraindications in children and pregnant women.

Vancomycin, on the other hand, at a dose of 125 mg 4 times daily, is safe and well tolerated and achieves stool levels 20 times the required minimal inhibitory concentration for the treatment of C. difficile. Drawbacks to the use of vancomycin are cost and potential development of vancomycin-resistant strains. The current ACG guidelines consider vancomycin the drug of choice in severely ill patients and in cases in which the use of metronidazole is precluded.

Controlled clinical trials are lacking for patients with fulminant colitis who may not tolerate oral therapy. Administration of metronidazole intravenously or administration of vancomycin by nasogastric tube or rectal enema has been described in small case series (17-20). Intravenous administration of vancomycin is not recommended, because the drug is not excreted in the colon (17).

Management of Recurrent C. difficile Diarrhea

Despite successful initial treatment of CDAD, 15–20% of patients have recurrence of diarrhea in association with a positive stool test for C. difficile toxin. Symptomatic recurrence is rarely due to treatment failure or antimicrobial resistance to metronidazole or vancomycin. Approaches to management include conservative therapy (however, many patients are elderly and infirm and unable to tolerate diarrhea), therapy with specific anti–C. difficile antibiotics, the use of anion-binding resins, therapy with microorganisms (probiotics), and immunoglobulin therapy.

The most common therapy for recurrent C. difficile diarrhea is a second course of the same antibiotic used to treat the initial episode (12). In a large observational study in the United States, 92% of patients with recurrent CDAD responded successfully to a single repeated course of therapy, usually with metronidazole or vancomycin (14). There is evidence to suggest that patients with a history of recurrence have a high risk of further episodes of CDAD after antibiotic therapy is discontinued. There are no data to suggest that sequential episodes become progressively more severe or complicated (21). A variety of treatment schedules have been suggested for patients with multiple recurrences of C. difficile diarrhea. One approach is to give a prolonged course of vancomycin (or metronidazole) using a decreasing dosage schedule followed by pulse therapy (Table 4).

Cholestyramine, an anionexchange resin administered at a dose of 4 grams 3 or 4 times daily for 1 to 2 weeks, binds C. difficile toxins and may be used in conjunction with antibiotics to treat repeated relapses. Because cholestyramine may bind vancomycin as well as toxins, it should be taken at least 2 to 3 hours apart from the vancomycin.

Severe C. difficile Colitis

The incidence of fulminant C. difficile colitis has been reported to be 1.6–3.2% (22). Although recent precise figures from other centers are lacking, it is being recognized as an increasing cause of complications and death. The clinical syndrome of fulminant C. difficile colitis can be recognized with a proper knowledge of the spectrum of disease presentation.

A. Diarrhea: Although diarrhea is the hallmark of C. difficile colitis, it is not invariably present, and its absence may lead to diagnostic confusion. When diarrhea is absent, this appears to be secondary to severe colonic dysmotility. Even when present, diarrhea may be perceived to be a minor component of a nonspecific septic picture.

Reprinted with permission from BUMC Proceedings 1999; 12:249-250

Reprinted with permission from BUMC Proceedings 1999; 12:249-250

Reprinted with permission from BUMC Proceedings 1999; 12:249-250

B. Severe Disease: Fulminant colitis is an unusual form of C. difficile infection, occurring in only 3% of patients but accounting for virtually all serious complications. Patients with more severe forms of the disease may present with or without diarrhea. When patients develop colitis localized to the cecum and right side of the colon, diarrhea may be minimal or absent. In the absence of diarrhea, the only clues to diagnosis may be systemic signs of toxicity (fever, tachycardia, leukocytosis, and/or volume depletion).

An elevated white blood cell count may be an important clue to impending fulminant C. difficile colitis. The rapid elevation of the peripheral white cell count (commonly as high as 30,000 to 50,000) with a significant excess of bands and sometimes more immature forms often precedes hemodynamic instability and the development of organ dysfunction. Even in patients who are mildly symptomatic for an extended period, sudden and unexpected progression to shock may occur. It is difficult to predict those patients who may not respond to medical treatment. Hence, early warning signs such as a leukemoid reaction may be invaluable.

Hypotension is a late finding and can be resistant to vasopressor support. Abdominal signs range from distention to generalized tenderness with guarding. Colonic perforation is usually accompanied by abdominal rigidity, involuntary guarding, rebound tenderness, and absent bowel sounds. Free air may be revealed on abdominal radiographs. Any suspicion of perforation in this setting should prompt immediate surgical consultation. Death generally occurs before free air and perforation can occur. In one study, contrary to most other literature, perforation was found to be rare (22).

Abdominal radiography may reveal a dilated colon (>7 cm in its greatest diameter), consistent with toxic megacolon. Patients with megacolon may have an associated small bowel ileus with dilated small intestine on plain abdominal radiographs, with air-fluid levels mimicking small intestinal obstruction or ischemia. CT without contrast and endoscopy can quickly diagnose or at least strongly suggest fulminant C.difficile colitis. CT scan findings include evidence of ascites, colonic wall thickening and/or dilatation. These findings may prove helpful in categorizing the severity of the colitis.

More aggressive intervention in medically unresponsive patients, including rapid identification of patients failing to respond to medical therapy, is crucial to a positive outcome, and early surgical intervention should be done in this group (Figures 1-3).

It is important that everyone involved with patient care in hospitals, nursing homes, and skilled nursing facilities be educated about the organism and its epidemiology, rational approaches to the treatment and care of patients with C. difficile diarrhea, the importance of hand washing between contact with patients, the use of gloves when caring for a patient with C. difficile diarrhea, and the avoidance of the unnecessary use of antimicrobials.

Conclusion

Recent years have raised concerns over rising incidence and serious complication rates of CDAD in North American hospitals (22,23). The Canadian Medical Association journal published a report in 2004 detailing an outbreak of CDAD involving several hospitals in Montreal. The introduction of new hypervirulent and highly transmissible strains of C. difficile has been postulated as the possible cause for the outbreak (24). A deteriorating infrastructure, inadequate infection control practices, the increasing number of debilitated patients, an aging population, and hypervirulent strains were all felt to be likely contributors to recent outbreaks in Canada (25).

Two epidemiological investigations in the United States and Canada (24,26) independently examined samples of C. difficile and found that a mutated version of the “wild” strain was responsible for outbreaks in Quebec and increased rates of CDAD in hospitals in the United States recently (22,23). Clinical epidemiologists at the CDC investigated C. difficile isolates from hospitals in the United States with recent (i.e., 2001–2004) CDAD outbreaks (22,23). The report indicates the emergence of a new epidemic strain, “BI” (distinct from the “J” strain of 1989–1992), which may be responsible for the recent increase in rates and apparent severity of CDAD (26).

CDAD and colitis in most cases can be treated by the administration of metronidazole or vancomycin. In some patients severe life-threatening toxicity develops despite appropriate and timely medical treatment, and surgical intervention is necessary. Systemic symptoms of infection with C. difficile are reported not to derive from bacteremia, colonic perforation or ischemia, but from toxin-induced inflammatory mediators released from the colon (27-29). Early surgical intervention should be employed in refractory cases of severe disease. Surgical intervention is far from ideal, however, and carries a very high rate of complications and significant risk of mortality (22). The future clinical approach to the treatment of nosocomial C. difficile colitis may eventually involve specific antitoxin hyperimmunoglobulins and inhibitors of the inflammatory cascade (28,30,31).

References

1. Archibald LK, Banerjee SN, Jarvis WR. Secular trend in hospital-acquired Clostridium difficile disease in the United States; 1987-2001. J Infect Dis. 2004;189:1585-9.
2. Fekety R. Antibiotic-associated colitis. In: Mandell G, Bennet JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 4th ed. New York: Churchill Livingston; 1996:978-806.
3. Mitty RD, LaMont T. Clostridium difficile diarrhea: Pathogenesis, epidemiology, and treatment. Gastroenterologist. 1994;2:61-9.
4. Bartlett JG. Clostridium difficile: History of its role as an enteric pathogen and the current state of knowledge about the organism. Clin Infect Dis. 1994;18(Suppl 4):265-72.
5. Johnson S, Gerding D. Clostridium difficile. In: Mayhall CG, ed. Hospital Epidemiology and Infection Control. Baltimore, Md: Williams & Wilkins; 1996:99-408.
6. Mcfarland LV, Mulligan ME, Kwok RY, Stamm WE. Nosocomial acquisition of Clostridium difficile. N Engl J Med. 1989;320:204-10.
7. Hall IC, O Toole E. Intestinal Flora in new-born infants: With a description of a new pathogenic anaerobe, Bacillus difficile. Am J Dis Child. 1935;49:390-402.
8. Kelly CP, LaMont JT. Treatment of Clostridium difficile diarrhea and colitis. In: Wolfe MM, ed. Gastrointestinal Pharmacotherapy. Philadelphia, Pa.: WB Saunders; 1993:199-212.
9. Bignardi GE. Risk factors for Clostridium difficile infection. J Hosp Infect. 1998;40:1-15.
10. Kelly CP, Pothoulakas C, LaMont JT. Clostridium difficile colitis. N Engl J Med. 1994;330:257-62.
11. Linevsky JK, Kelly CP. Clostridium difficile colitis. In: Lamont JT, ed. Gastrointestinal Infections: Diagnosis and Management. New York: Marcel Dekker; 1997:293-325.
12. Fekety R. Guidelines for the diagnosis and management of Clostridium difficile associated diarrhea and colitis. American College of Gastroenetrology, Practice Parameters Committee. Am J Gastroenterol. 1997;92:739-50.
13. Tedesco FJ, Corless JK, Brownstein RE. Rectal sparing in antibiotic-associated pseudomembranous colitis: A prospective study. Gastroenterology. 1982;83:1259-60.
14. Olson MM, Shanholtzer CJ, Lee JT Jr, Gerding DN. Ten years of prospective Clostridium difficile-associated disease surveillance and treatment at the Minneapolis VA Medical Center, 1982-1991. Infect Control Hosp Epidemiol. 1994;15: 371-81.
15. Teasley DG, Gerding DN, Olson MM, et al. Prospective randomized trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis. Lancet. 1983;2:1043-6.
16. Walley T, Milson D. Loperamide-related toxic megacolon in Clostridium difficile colitis. Postgrad Med J. 1990;66:582.
17. Malnick SD, Zimhony O. Treatment of Clostridium difficile associated diarrhea. Ann Pharmacother. 2002;36:1767-75.
18. Sehgal M, Kyne L. Clostridium difficile disease. Curr Treatment Options Infect Dis. 2002;4:201-10.
19. Apisarnthanarak A, Razavi B, Mundy LM. Adjunctive intracolonic vancomycin for severe Clostridium difficile colitis: case series and review of the literature. Clin Infect Dis. 2002;35:690-6.
20. Friendenberg F, Fernandez A, Kaul V, Niami P, Levine GM. Intravenous metronidazole for the treatment of Clostridium difficile colitis. Dis Colon Rectum. 2001;44:1176-80.
21. Fekety R, McFarland LV, Surawicz CMGreenberg, RN, Elmer GW, Mulligan ME. Recurrent Clostridium difficile diarrhea: characteristics of and risk factors for patients enrolled in a prospective, randomized, double-blind trial. Clin Infect Dis. 1997;24:324-33.
22. Dallal RM, Harbrecht BG, Boujoukas AJ, et al. Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications. Ann Surg. 2002;235:363-72.
23. Morris AM, Jobe BA, Sontey, M, Sheppard BC, Deveney CW, Deveney KE. Clostridium difficile colitis: an increasingly aggressive iatrogenic disease? Arch Surg. 2002;137:1096-100.
24. Eggerston L, Sibbald B. Hospitals battling outbreaks of C. difficile. CMAJ. 2004;171:19-21.
25. Valiquette L, Low DE, Pepin J, McGeer A. Clostridium difficile infection in hospitals: a brewing storm. CMAJ. 2004;171:27-9.
26. McDonald LC, Killgore GE, Thompson A, et al. Emergence of an epidemic strain of Clostridium difficile in the United States, 2001-4: Potential role for virulence factors and antimicrobial resistance traits. Infectious Diseases Society of America 42th Annual Meeting. Boston, MA, September 30 – October 3, 2004. Abstract # LB-2.
27. Flegel W, Muller F, Daubener W, Fischer HG, Hadding U, Northoff H. Cytokine response by human monocytes to Clostridium difficile toxin A and toxin B. Infect Immun. 1991;59:3659-66.
28. Castagliuolo I, Keates A, Qiu B, et al. Increased substance P responses in dorsal root ganglia, intestinal macrophages during Clostridium difficile toxin A enteritis in rats. Proc Natl Acad Sci U S A. 1997;94:4788-93.
29. Castagliuolo I, Keates A, Wang C, et al. Clostridium difficile toxin A stimulates macrophage-inflammatory protein-2 production in rat intestinal epithelial cells. J Immunol. 1998;160:6039-45.
30. Kelly C, Chetham S, Keates S, et al. Survival of anti-Clostridium difficile bovine immunoglobulin concentrate in the human gastrointestinal tract. Antimicrob Agents Chemother. 1997;41:236-41.
31. Salcedo J, Keates S, Pothoulakis C, et. al. Intravenous immunoglobulin therapy for severe Clostridium difficile colitis. Gut. 1997;41:366-70.

General References

1. Shea Position Paper Gerding DN,Johnson S, Peterson LR, Mulligan ME Silva J. SHEA Position Paper:Clostridium difficile-associated diarrhea and colitis; Infect Control Hosp Epidemiol 1995, 16:459-77
2. Kyne L, Farrell RJ, Kelly CP. Clostridium difficile. Gastroenterol Clin North Am 2001; 30:753-77.

Introduction

Urinary tract infections (UTIs) are serious bacterial infections and a common cause for hospital admission of infants and young children. The prevalence of UTI in infants younger than 1 year of age ranges from 3.3% to 6.5%, and between 1 and 2 years of age from 1.9% to 8.1%. Females outpace males across all age groups, with the exception of the first 3 months of life (1). Without appropriate treatment and management, UTI can result in dehydration, urosepsis, and long-term medical problems including hypertension, renal scarring, and decreased renal function. This review will focus on the inpatient management of first-episode UTI in infants and young children.

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Diagnosis

Presenting symptoms in older children include urgency, frequency, dysuria, and complaints of back pain. In contrast, symptoms in infants and young children are often nonspecific and include irritability, diarrhea, vomiting, poor feeding, poor weight gain, crying on urination, and foul-smelling urine. The presence of a fever in infants and young children with UTI has been accepted as a marker of pyelonephritis, which occurs when infection has ascended to the upper collecting system of the kidney. Urinalysis (UA) and culture should be collected by suprapubic aspiration or transurethral catheterization, or by appropriately performed clean catch method for children of appropriate age and developmental ability. The use of a bag-collected urine specimen is insufficient and unreliable and should not be used in making the diagnosis of UTI. While suprapubic aspiration is considered the gold standard with a specificity and sensitivity of 100%, there is often resistance from parents and from physicians who are not properly trained to do this procedure.

The most accepted method of obtaining urine is sterile transurethral catheterization, results of which have 95% sensitivity and 99% specificity (2). When interpreting the UA, the most useful components for the diagnosis of a UTI include a positive leukocyte esterase, nitrite test, or gram stain on unspun urine, and microscopy revealing >10 white blood cells per high-powered field of spun urine. However, neonates under 30 days old may have no abnormality noted on initial UA (3,4). The presence of any bacteria on gram-stained urine offers the best sensitivity and specificity (5). Final diagnosis depends upon isolation of >10⁵ of a single organism from a clean-catch specimen, or >10⁴ of a single organism from a catheterized specimen.

Admission Criteria

Guidelines for evaluation of serious bacterial infection and parenteral antibiotic use for febrile infants under 60 days of age should be followed. All febrile neonates less than 30 days of age should be admitted for parenteral antibiotics (6–11). Controversy exists on the need to use corrected or postconceptual age when evaluating and determining need for admission for febrile preterm infants, particularly for those under 35 weeks of gestation. Factors that can be considered by the practitioner include severity of Neonatal ICU course, severity of prematurity, and combined disease burden of UTI with common preterm comorbidities (anemia, apnea of prematurity, chronic lung disease).

Consider admitting and initiating parenteral antibiotic treatment using Table 1 as a guideline. Exercise a lower threshold for admitting infants and toxic-appearing young children due to concern for urosepsis, complications, and the need for appropriate and aggressive initial therapy.

Initial Inpatient Management

The 3 goals of inhospital treatment of UTIs are to effectively treat and eliminate the acute infection, prevent urosepsis in infants and immunocompromised children, and prevent and reduce long-term complications such as renal scarring, hypertension, and decreased renal function. Initial antibiotic treatment should be administered parenterally to ensure optimal antimicrobial levels and aimed at the most common organisms, including Escherichia coli, Klebsiella, Proteus, and Enterobacter spp. Less common organisms to consider include Pseudomonas, Enterococcus, Staphylococcus aureus, and group B Streptococcus. Organisms will differ on many factors, such as age, underlying disease, prior colonization, and antibiotic exposure.

Table 2 outlines the initial choices of antibiotics until culture and sensitivities are known.

The choices and dosage of antibiotics are dependent on the age of the patient and are selected based on the other most likely organisms and their expected sensitivities (12). Ampicillin is added to the less than 2-month age group not only to cover Enterococcus, but also as part of broader neonatal sepsis coverage for Listeria. The third-generation cephalosporins are felt to be adequate initial coverage for most of the common organisms causing UTI. Children with congenital anomalies known to be associated with genitourinary abnormalities may be infected with less common organisms. In these situations, consider tailoring initial antibiotic coverage.

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Complications

The major complication of UTIs in infants is bacteremia. The rate of bacteremia in infants 0–3 months has variably been reported as 10% (13), 21–31% (14), and 36% (15). Infants with and without bacteremia are often clinically indistinguishable, making early determination of bacteremia difficult. A recent comprehensive review of 17 studies by Malik noted both C-reactive protein (CRP) and procalcitonin (PCT) results were highly variable in infants under 90 days old with known positive bacterial cultures (16). These inflammatory markers are therefore currently not useful to predict bacteremia. In addition to blood stream infection, other acute complications include meningitis, renal and perinephric abscess, and infected calculi. Longer-term complications include reflux nephropathy, renal scarring, hypertension, decreased renal function, and renal failure.

Duration of Antibiotic Therapy

While most uncomplicated UTIs are successfully treated with a 10-day treatment course, many experts prefer a 14-day course for neonates, infants, and ill-appearing young children. Despite effectiveness in adults, very-short-course therapy (≤3 days) for pediatric patients is associated with more treatment failures and reinfections (17). Although it may be considered in older children with cystitis, at this time it is not appropriate for treating infants and younger children in whom pyelonephritis cannot be distinguished from isolated lower tract infection (17,18).

Total treatment time and total days of parenteral therapy needed continue to be debated. Hoberman randomized children as young as 1 month of age to either entirely oral treatment or parenteral therapy for 3 days followed by oral treatment (19). In both arms of this study, children received 14 days of total therapy as was the standard at the time. He suggested, however, that a 10-day course of antibiotics should be adequate therapy for noncomplicated acute pyelonephritis. Of the 306 children, only 13 were under 2 months of age. Although only 13 positive blood cultures were reported, 10 of these occurred in children under 6 months of age. Given the limited number of children less than 2 months of age and the prevalence of positive blood cultures noted, conclusions cannot be drawn on the safety of entirely oral treatment for young infants. Parenteral antibiotic therapy should be continued for all hospitalized children until the patient is afebrile and free from signs of toxicity. Most hospitalized pediatric patients defervesce quickly on parenteral therapy—89% within 48 hours and 97% within 72 hours (20). Longer parenteral therapy of at least 10 days should be considered for neonates and infants with urosepsis, because they are immunologically immature, at greater risk of complications, have higher incidence of urinary tract anomalies, and have less reliable absorption of oral antibiotics.

Delayed or lack of response to antibiotic therapy may indicate the presence of urinary tract obstruction, resistant organisms, or renal or perinephric abscess. A repeat urine culture and immediate renal ultrasound or CT should be performed if the patient is not improving within 48 hours.

Radiological Studies

Renal Ultrasound (RUS)

Recent studies have questioned the value of performing routine RUS after a first-time UTI because of the low sensitivity in detecting vesicoureteral reflux (VUR) and a lack of significant influence in altering management (21,22). Patients who have had a normal late (30-32 weeks’ gestation) prenatal ultrasound with a good view of the kidneys may not require a repeat postnatal renal ultrasound (21,22). Further studies are needed to evaluate the costs and value of routine RUS. Until these studies are completed, renal and bladder ultrasound early during hospitalization continues to be recommended for all patients admitted with a first-time UTI to identify hydronephrosis, duplicating collecting systems, ureteral dilatation, calculi, and other structural anomalies.

Voiding Cystourethrogram (VCUG) or Radionuclide Cystography (RNC)

Either a VCUG or RNC should be performed to detect vesico-ureteral reflux in infants and young children. The AAP practice parameter and more recent literature clearly state the need for this evaluation in children under the age of 2 years (2,21). Additional data on incidence of anomalies by age suggest studying children under the age of 6 years (23,24). Recommendations for evaluation of children over age 6 may vary depending on age, patient, and family history, and comorbidities. Alternate methods such as voiding sonogram may also be options for this age group, and is not part of this discussion (25).

RNC exposes the patient to less radiation but does not show urethral or bladder anomalies. RNC is more often used for females with normal RUS and no voiding dysfunction, or to follow the progress of known VUR. The VCUG is often preferred because it provides more anatomic detail and is better for grading VUR and demonstrating posterior urethral vales in males (26). It is suggested that infants with antenatal renal pelvis dilation who have 2 normal renal sonograms in the first month of life are at low risk for abnormalities and may not require a VCUG (27). The rate of detection of VUR with a first episode of UTI does not increase when the VCUG is done early, within the first 7 days of diagnosis (28,29). Performing the VCUG as an inpatient should be considered if outpatient follow-up is of significant concern, or if the RUS suggests bilateral ureteral obstruction. If done as an inpatient procedure, it should be performed preferably during day 3–5 of antibiotic therapy and when the patient is clinically responding to the appropriate antibiotic. The overall value of the VCUG is being reviewed, as its usefulness is most significant only if VUR antimicrobial prophylaxis is effective in reducing reinfections and renal scarring (21,30). Until further studies are performed, the VCUG should continue as part of the initial UTI evaluation for infants and young children.

Renal Cortical Scintigraphy (RCS)

This is the imaging study of choice for the detection of acute pyelonephritis and renal scarring. As children are treated for presumptive upper-tract infection empirically, DMSA scan for diagnosis of pyelonephritis has limited utility (21). Scans have more often been performed at 6 months’ postinfection to document scar formation. Hoberman demonstrated that only 15% of children with abnormal scintigraphy at diagnosis have renal scarring on repeat RCS at 6 months. The importance of these scars is unclear. Association of scars with ultimate development of hypertension, renal insufficiency, and end-stage renal disease is based on studies performed in the 1980s using intravenous pyelogram. RCS is much more sensitive, finding more minor scars of uncertain significance.

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Table 3 may be of value when considering imaging options.

Other Considerations

CRP and PCT use in UTI have been evaluated by Pratt. Values at diagnosis are potentially helpful in ruling out scar formation at 6 months’ postinfection. Values under 1.0 ng/mL for PCT and 20 mg/L for CRP had a negative predictive value of 97.5% and 95%, respectively (31). Further studies are warranted to confirm the usefulness of these inflammatory markers to rule out future scar formation.

Consultations

Consider urology consultation if the RUS, VCUG, voiding history, or examination demonstrated concern for significant genitourinary abnormalities, abnormal voiding function or neurogenic bladder (23,32). Consider infectious disease consultation if the patient is not responding to conventional therapy without obstruction, unusual organisms are identified, or the patient is having recurrent urinary tract infections in the presence of normal urological structure and function.

Discharge Criteria and Processes

Consider discharge under the following conditions:

• The patient is comfortable and tolerating oral fluids well.
• The patient has been afebrile or has significantly decreasing fever for 24 hours.
• Appropriate radiological studies and consultations have been completed or arranged for as an outpatient.
• For patients requiring parenterally administered medications at home, long-term IV access must be obtained to assessment of home care service availability, benefits, family home resources, and caregiver education completed.
• Appropriate prophylactic antibiotic prescription has been given to the caregiver with education on use after completion of acute antibiotic therapy. Prophylactic antibiotics should be administered until imaging studies have been completed and assessed.

Conclusion

UTI is a common bacterial infection requiring hospital admission for infants and young children. Admission decisions should take into consideration goals for inpatient care and special age or clinical circumstances. Treatment mode and duration must address avoidance of both acute and chronic complications. Radiologic studies offer both anatomic view and functional information. Clinical relevance of scars, utility of radiologic studies, and value of inflammatory markers are some of the many areas requiring further study.

References

1. Long SS, Klein J. Bacterial infections of the urinary tract. In: Remington JSand Klein JO(eds.). Infectious Diseases of the Fetus and Newborn Infant. 5th ed. Philadelphia, Pa: WB Saunders; 2001:1035-46.
2. Committee on Quality Improvement, Subcommittee on Urinary Tract Infection. Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatrics. 1999;103:843-52.
3. Dayan PS, Bennett J, Best R, et al. Test characteristics of the urine gram stain in infants ≤60 days of age with fever. Pediatr Emerg Care. 2002;18:12-4.
4. Huicho L, Campos-Sanchez M, Alamo C. Metaanalysis of urine screening tests for determining the risk of urinary tract infection in children. Pediatr Infect Dis J. 2002;21:1-11.
5. Gorelick M, Shaw KN. Screening tests for urinary tract infections in Children: a meta-analysis. Pediatrics. 1999;104:e54.
6. Byington CL, Enriquez F, Hoff C, et al. Serious bacterial infections in febrile infants 1 to 90 days old with and without viral infections. Pediatrics. 2004:113:1662-6.
7. Baraff L. Management of fever without source in infants and children. Ann Emerg Med. 2000;36:602-14.
8. Baraff LJ, Oslund SA, Schriger D, Stephen ML. Probability of bacterial infections in febrile infants less than three months of age: a meta-analysis. Pediatr Infect Dis J. 1992;11:257-64.
9. Klein JO. Management of the febrile child without a focus of infection in the era of universal pneumococcal immunization. Pediatr Infect Dis J. 2002;21:584-8.
10. Syrogiannopoulos G, Grieva I, Anastassiou E, Triga M, Dimitracopoulos G, Beratis N. Sterile cerebrospinal fluid pleocytosis in young infants with urinary tract infections. Pediatr Infect Dis J. 2001;20:927-30.
11. Jaskiewicz JA, Mc Carthy CA, Richardson AC, ET AL. Febrile infants at low risk for serious bacterial infection--an appraisal of the Rochester criteria and implications for management. Febrile Collaborative Study Group. Pediatrics. 1994;94:390-6.
12. AAP Redbook. Report of the committee on infectious diseases, 2003:700.
13. Newman TB, Bernzweig JA, Takayama JI, Finch SA, Wasserman RC, Pantell RH. Urine testing and urinary tract infections in febrile infants seen in the office setting: the Pediatric Research in Office Settings’ Febrile Infant Study Arch Pediatr Adolesc Med. 2002;156:44-54.
14. Ginsberg CM, McCracken GH Jr. Urinary tract infection in young infants. Pediatrics. 1982;69:409-12.
15. Wiswell T, Geschke D. Risks from circumcision during the first month of life compared to uncircumcised boys. Pediatrics. 1989;83:1011-15.
16. Malik A, Hui C, Pennie RA, Kirpalani H. Beyond the complete blood cell count and C-reactive protein: a systematic review of modern diagnostic tests for neonatal sepsis. Arch Pediatr Adolesc Med. 2003;157:511-6.
17. Keren R, Chan E. A meta-analysis of randomized, controlled trials comparing short- and long-course antibiotic therapy for urinary tract infections in children. Pediatrics. 2002;109:e70.
18. Michael M, Hodson EM, Craig JC, Martin S, Moyer VA. Short versus standard duration oral antibiotic therapy for acute urinary tract infection in children. Cochrane Database of Syst Rev.2003.
19. Hoberman A, Wald ER, Hickey RW, et al. Oral versus intravenous therapy for urinary tract infections in young children. Pediatrics. 1999;104:79-86.
20. Bachur R. Nonresponders: prolonged fever among infants with urinary tract infections. Pediatrics. 2000;105:E59.
21. Hoberman A, Charron M, Hickey RW, Baskin M, Kearney DH, Wald ER. Imaging studies after a first febrile urinary tract infection in young children. N Engl J Med. 2003;348:195-202.
22. Zamir G, Sakran W, Horowitz Y, Koren A, Miron D. Urinary tract infection: is there a need for routine renal ultrasonography? Arch Dis Child. 2004;89:466-8.
23. Johnson CE. New advances in childhood urinary tract infections. Pediatr Rev. 1999:20:335-43.
24. Thompson M, Simon S, Sharma V, Alon US. Timing of follow-up voiding cystourethrogram in children with primary vesicoureteral reflux: development and application of a clinical algorithm. Pediatrics. 2005:115:426-34.
25. Darge K, Moeller RT, Trusen A, BuĴer F, Gordjani N, Riedmiller H. Diagnosis of vesicoureteral reflux with low-dose contrast-enhanced harmonic ultrasound imaging. Pediatr Radiol. 2005:35:73-8.
26. Kraus S. Genitourinary imaging in children. Pediatr Clin North Am. 2001;48:1381-1424.
27. Ismaili K, Avni F, Hall M; Brussels Free University Perinatal Nephrology (BFUPN) Study Group. Results of systematic voiding cystourethrography in infants with antenatally diagnosed renal pelvis dilation. J Pediatr. 2002;141: 21-4.
28. Mahant S, To T, Friedman J. Timing of voiding cystourethrogram in the investigation of urinary tract infections in children. J Pediatr. 2001;39:568-71.
29. McDonald A, Scranton M, Gillespie R, Mahajan V, Edwards GA. Voiding cystourethrograms and urinary tract infections: how long to wait? Pediatrics. 2000:105:E50.
30. Williams G, Lee A, Craig J. Antibiotics for the prevention of urinary tract infection in children: a systematic review of randomized controlled trials. J Pediatr. 2001;138:868-74.
31. Prat C, Dominguez J, Rodrigo C, et al. Elevated serum procalcitonin values correlate with renal scarring in children with urinary tract infection. Pediatr Infect Dis J. 2003;22:438-42.
32. Roberts KB. Urinary tract infection treatment and evaluation update. Pediatr Infect Dis J. 2004: 23:1163-4.

Introduction

Urinary tract infections (UTIs) are serious bacterial infections and a common cause for hospital admission of infants and young children. The prevalence of UTI in infants younger than 1 year of age ranges from 3.3% to 6.5%, and between 1 and 2 years of age from 1.9% to 8.1%. Females outpace males across all age groups, with the exception of the first 3 months of life (1). Without appropriate treatment and management, UTI can result in dehydration, urosepsis, and long-term medical problems including hypertension, renal scarring, and decreased renal function. This review will focus on the inpatient management of first-episode UTI in infants and young children.

click for large version

Diagnosis

Presenting symptoms in older children include urgency, frequency, dysuria, and complaints of back pain. In contrast, symptoms in infants and young children are often nonspecific and include irritability, diarrhea, vomiting, poor feeding, poor weight gain, crying on urination, and foul-smelling urine. The presence of a fever in infants and young children with UTI has been accepted as a marker of pyelonephritis, which occurs when infection has ascended to the upper collecting system of the kidney. Urinalysis (UA) and culture should be collected by suprapubic aspiration or transurethral catheterization, or by appropriately performed clean catch method for children of appropriate age and developmental ability. The use of a bag-collected urine specimen is insufficient and unreliable and should not be used in making the diagnosis of UTI. While suprapubic aspiration is considered the gold standard with a specificity and sensitivity of 100%, there is often resistance from parents and from physicians who are not properly trained to do this procedure.

The most accepted method of obtaining urine is sterile transurethral catheterization, results of which have 95% sensitivity and 99% specificity (2). When interpreting the UA, the most useful components for the diagnosis of a UTI include a positive leukocyte esterase, nitrite test, or gram stain on unspun urine, and microscopy revealing >10 white blood cells per high-powered field of spun urine. However, neonates under 30 days old may have no abnormality noted on initial UA (3,4). The presence of any bacteria on gram-stained urine offers the best sensitivity and specificity (5). Final diagnosis depends upon isolation of >10⁵ of a single organism from a clean-catch specimen, or >10⁴ of a single organism from a catheterized specimen.

Admission Criteria

Guidelines for evaluation of serious bacterial infection and parenteral antibiotic use for febrile infants under 60 days of age should be followed. All febrile neonates less than 30 days of age should be admitted for parenteral antibiotics (6–11). Controversy exists on the need to use corrected or postconceptual age when evaluating and determining need for admission for febrile preterm infants, particularly for those under 35 weeks of gestation. Factors that can be considered by the practitioner include severity of Neonatal ICU course, severity of prematurity, and combined disease burden of UTI with common preterm comorbidities (anemia, apnea of prematurity, chronic lung disease).

Consider admitting and initiating parenteral antibiotic treatment using Table 1 as a guideline. Exercise a lower threshold for admitting infants and toxic-appearing young children due to concern for urosepsis, complications, and the need for appropriate and aggressive initial therapy.

Initial Inpatient Management

The 3 goals of inhospital treatment of UTIs are to effectively treat and eliminate the acute infection, prevent urosepsis in infants and immunocompromised children, and prevent and reduce long-term complications such as renal scarring, hypertension, and decreased renal function. Initial antibiotic treatment should be administered parenterally to ensure optimal antimicrobial levels and aimed at the most common organisms, including Escherichia coli, Klebsiella, Proteus, and Enterobacter spp. Less common organisms to consider include Pseudomonas, Enterococcus, Staphylococcus aureus, and group B Streptococcus. Organisms will differ on many factors, such as age, underlying disease, prior colonization, and antibiotic exposure.

Table 2 outlines the initial choices of antibiotics until culture and sensitivities are known.

The choices and dosage of antibiotics are dependent on the age of the patient and are selected based on the other most likely organisms and their expected sensitivities (12). Ampicillin is added to the less than 2-month age group not only to cover Enterococcus, but also as part of broader neonatal sepsis coverage for Listeria. The third-generation cephalosporins are felt to be adequate initial coverage for most of the common organisms causing UTI. Children with congenital anomalies known to be associated with genitourinary abnormalities may be infected with less common organisms. In these situations, consider tailoring initial antibiotic coverage.

click for large version

Complications

The major complication of UTIs in infants is bacteremia. The rate of bacteremia in infants 0–3 months has variably been reported as 10% (13), 21–31% (14), and 36% (15). Infants with and without bacteremia are often clinically indistinguishable, making early determination of bacteremia difficult. A recent comprehensive review of 17 studies by Malik noted both C-reactive protein (CRP) and procalcitonin (PCT) results were highly variable in infants under 90 days old with known positive bacterial cultures (16). These inflammatory markers are therefore currently not useful to predict bacteremia. In addition to blood stream infection, other acute complications include meningitis, renal and perinephric abscess, and infected calculi. Longer-term complications include reflux nephropathy, renal scarring, hypertension, decreased renal function, and renal failure.

Duration of Antibiotic Therapy

While most uncomplicated UTIs are successfully treated with a 10-day treatment course, many experts prefer a 14-day course for neonates, infants, and ill-appearing young children. Despite effectiveness in adults, very-short-course therapy (≤3 days) for pediatric patients is associated with more treatment failures and reinfections (17). Although it may be considered in older children with cystitis, at this time it is not appropriate for treating infants and younger children in whom pyelonephritis cannot be distinguished from isolated lower tract infection (17,18).

Total treatment time and total days of parenteral therapy needed continue to be debated. Hoberman randomized children as young as 1 month of age to either entirely oral treatment or parenteral therapy for 3 days followed by oral treatment (19). In both arms of this study, children received 14 days of total therapy as was the standard at the time. He suggested, however, that a 10-day course of antibiotics should be adequate therapy for noncomplicated acute pyelonephritis. Of the 306 children, only 13 were under 2 months of age. Although only 13 positive blood cultures were reported, 10 of these occurred in children under 6 months of age. Given the limited number of children less than 2 months of age and the prevalence of positive blood cultures noted, conclusions cannot be drawn on the safety of entirely oral treatment for young infants. Parenteral antibiotic therapy should be continued for all hospitalized children until the patient is afebrile and free from signs of toxicity. Most hospitalized pediatric patients defervesce quickly on parenteral therapy—89% within 48 hours and 97% within 72 hours (20). Longer parenteral therapy of at least 10 days should be considered for neonates and infants with urosepsis, because they are immunologically immature, at greater risk of complications, have higher incidence of urinary tract anomalies, and have less reliable absorption of oral antibiotics.

Delayed or lack of response to antibiotic therapy may indicate the presence of urinary tract obstruction, resistant organisms, or renal or perinephric abscess. A repeat urine culture and immediate renal ultrasound or CT should be performed if the patient is not improving within 48 hours.

Radiological Studies

Renal Ultrasound (RUS)

Recent studies have questioned the value of performing routine RUS after a first-time UTI because of the low sensitivity in detecting vesicoureteral reflux (VUR) and a lack of significant influence in altering management (21,22). Patients who have had a normal late (30-32 weeks’ gestation) prenatal ultrasound with a good view of the kidneys may not require a repeat postnatal renal ultrasound (21,22). Further studies are needed to evaluate the costs and value of routine RUS. Until these studies are completed, renal and bladder ultrasound early during hospitalization continues to be recommended for all patients admitted with a first-time UTI to identify hydronephrosis, duplicating collecting systems, ureteral dilatation, calculi, and other structural anomalies.

Voiding Cystourethrogram (VCUG) or Radionuclide Cystography (RNC)

Either a VCUG or RNC should be performed to detect vesico-ureteral reflux in infants and young children. The AAP practice parameter and more recent literature clearly state the need for this evaluation in children under the age of 2 years (2,21). Additional data on incidence of anomalies by age suggest studying children under the age of 6 years (23,24). Recommendations for evaluation of children over age 6 may vary depending on age, patient, and family history, and comorbidities. Alternate methods such as voiding sonogram may also be options for this age group, and is not part of this discussion (25).

RNC exposes the patient to less radiation but does not show urethral or bladder anomalies. RNC is more often used for females with normal RUS and no voiding dysfunction, or to follow the progress of known VUR. The VCUG is often preferred because it provides more anatomic detail and is better for grading VUR and demonstrating posterior urethral vales in males (26). It is suggested that infants with antenatal renal pelvis dilation who have 2 normal renal sonograms in the first month of life are at low risk for abnormalities and may not require a VCUG (27). The rate of detection of VUR with a first episode of UTI does not increase when the VCUG is done early, within the first 7 days of diagnosis (28,29). Performing the VCUG as an inpatient should be considered if outpatient follow-up is of significant concern, or if the RUS suggests bilateral ureteral obstruction. If done as an inpatient procedure, it should be performed preferably during day 3–5 of antibiotic therapy and when the patient is clinically responding to the appropriate antibiotic. The overall value of the VCUG is being reviewed, as its usefulness is most significant only if VUR antimicrobial prophylaxis is effective in reducing reinfections and renal scarring (21,30). Until further studies are performed, the VCUG should continue as part of the initial UTI evaluation for infants and young children.

Renal Cortical Scintigraphy (RCS)

This is the imaging study of choice for the detection of acute pyelonephritis and renal scarring. As children are treated for presumptive upper-tract infection empirically, DMSA scan for diagnosis of pyelonephritis has limited utility (21). Scans have more often been performed at 6 months’ postinfection to document scar formation. Hoberman demonstrated that only 15% of children with abnormal scintigraphy at diagnosis have renal scarring on repeat RCS at 6 months. The importance of these scars is unclear. Association of scars with ultimate development of hypertension, renal insufficiency, and end-stage renal disease is based on studies performed in the 1980s using intravenous pyelogram. RCS is much more sensitive, finding more minor scars of uncertain significance.

click for large version

Table 3 may be of value when considering imaging options.

Other Considerations

CRP and PCT use in UTI have been evaluated by Pratt. Values at diagnosis are potentially helpful in ruling out scar formation at 6 months’ postinfection. Values under 1.0 ng/mL for PCT and 20 mg/L for CRP had a negative predictive value of 97.5% and 95%, respectively (31). Further studies are warranted to confirm the usefulness of these inflammatory markers to rule out future scar formation.

Consultations

Consider urology consultation if the RUS, VCUG, voiding history, or examination demonstrated concern for significant genitourinary abnormalities, abnormal voiding function or neurogenic bladder (23,32). Consider infectious disease consultation if the patient is not responding to conventional therapy without obstruction, unusual organisms are identified, or the patient is having recurrent urinary tract infections in the presence of normal urological structure and function.

Discharge Criteria and Processes

Consider discharge under the following conditions:

• The patient is comfortable and tolerating oral fluids well.
• The patient has been afebrile or has significantly decreasing fever for 24 hours.
• Appropriate radiological studies and consultations have been completed or arranged for as an outpatient.
• For patients requiring parenterally administered medications at home, long-term IV access must be obtained to assessment of home care service availability, benefits, family home resources, and caregiver education completed.
• Appropriate prophylactic antibiotic prescription has been given to the caregiver with education on use after completion of acute antibiotic therapy. Prophylactic antibiotics should be administered until imaging studies have been completed and assessed.

Conclusion

UTI is a common bacterial infection requiring hospital admission for infants and young children. Admission decisions should take into consideration goals for inpatient care and special age or clinical circumstances. Treatment mode and duration must address avoidance of both acute and chronic complications. Radiologic studies offer both anatomic view and functional information. Clinical relevance of scars, utility of radiologic studies, and value of inflammatory markers are some of the many areas requiring further study.

References

1. Long SS, Klein J. Bacterial infections of the urinary tract. In: Remington JSand Klein JO(eds.). Infectious Diseases of the Fetus and Newborn Infant. 5th ed. Philadelphia, Pa: WB Saunders; 2001:1035-46.
2. Committee on Quality Improvement, Subcommittee on Urinary Tract Infection. Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatrics. 1999;103:843-52.
3. Dayan PS, Bennett J, Best R, et al. Test characteristics of the urine gram stain in infants ≤60 days of age with fever. Pediatr Emerg Care. 2002;18:12-4.
4. Huicho L, Campos-Sanchez M, Alamo C. Metaanalysis of urine screening tests for determining the risk of urinary tract infection in children. Pediatr Infect Dis J. 2002;21:1-11.
5. Gorelick M, Shaw KN. Screening tests for urinary tract infections in Children: a meta-analysis. Pediatrics. 1999;104:e54.
6. Byington CL, Enriquez F, Hoff C, et al. Serious bacterial infections in febrile infants 1 to 90 days old with and without viral infections. Pediatrics. 2004:113:1662-6.
7. Baraff L. Management of fever without source in infants and children. Ann Emerg Med. 2000;36:602-14.
8. Baraff LJ, Oslund SA, Schriger D, Stephen ML. Probability of bacterial infections in febrile infants less than three months of age: a meta-analysis. Pediatr Infect Dis J. 1992;11:257-64.
9. Klein JO. Management of the febrile child without a focus of infection in the era of universal pneumococcal immunization. Pediatr Infect Dis J. 2002;21:584-8.
10. Syrogiannopoulos G, Grieva I, Anastassiou E, Triga M, Dimitracopoulos G, Beratis N. Sterile cerebrospinal fluid pleocytosis in young infants with urinary tract infections. Pediatr Infect Dis J. 2001;20:927-30.
11. Jaskiewicz JA, Mc Carthy CA, Richardson AC, ET AL. Febrile infants at low risk for serious bacterial infection--an appraisal of the Rochester criteria and implications for management. Febrile Collaborative Study Group. Pediatrics. 1994;94:390-6.
12. AAP Redbook. Report of the committee on infectious diseases, 2003:700.
13. Newman TB, Bernzweig JA, Takayama JI, Finch SA, Wasserman RC, Pantell RH. Urine testing and urinary tract infections in febrile infants seen in the office setting: the Pediatric Research in Office Settings’ Febrile Infant Study Arch Pediatr Adolesc Med. 2002;156:44-54.
14. Ginsberg CM, McCracken GH Jr. Urinary tract infection in young infants. Pediatrics. 1982;69:409-12.
15. Wiswell T, Geschke D. Risks from circumcision during the first month of life compared to uncircumcised boys. Pediatrics. 1989;83:1011-15.
16. Malik A, Hui C, Pennie RA, Kirpalani H. Beyond the complete blood cell count and C-reactive protein: a systematic review of modern diagnostic tests for neonatal sepsis. Arch Pediatr Adolesc Med. 2003;157:511-6.
17. Keren R, Chan E. A meta-analysis of randomized, controlled trials comparing short- and long-course antibiotic therapy for urinary tract infections in children. Pediatrics. 2002;109:e70.
18. Michael M, Hodson EM, Craig JC, Martin S, Moyer VA. Short versus standard duration oral antibiotic therapy for acute urinary tract infection in children. Cochrane Database of Syst Rev.2003.
19. Hoberman A, Wald ER, Hickey RW, et al. Oral versus intravenous therapy for urinary tract infections in young children. Pediatrics. 1999;104:79-86.
20. Bachur R. Nonresponders: prolonged fever among infants with urinary tract infections. Pediatrics. 2000;105:E59.
21. Hoberman A, Charron M, Hickey RW, Baskin M, Kearney DH, Wald ER. Imaging studies after a first febrile urinary tract infection in young children. N Engl J Med. 2003;348:195-202.
22. Zamir G, Sakran W, Horowitz Y, Koren A, Miron D. Urinary tract infection: is there a need for routine renal ultrasonography? Arch Dis Child. 2004;89:466-8.
23. Johnson CE. New advances in childhood urinary tract infections. Pediatr Rev. 1999:20:335-43.
24. Thompson M, Simon S, Sharma V, Alon US. Timing of follow-up voiding cystourethrogram in children with primary vesicoureteral reflux: development and application of a clinical algorithm. Pediatrics. 2005:115:426-34.
25. Darge K, Moeller RT, Trusen A, BuĴer F, Gordjani N, Riedmiller H. Diagnosis of vesicoureteral reflux with low-dose contrast-enhanced harmonic ultrasound imaging. Pediatr Radiol. 2005:35:73-8.
26. Kraus S. Genitourinary imaging in children. Pediatr Clin North Am. 2001;48:1381-1424.
27. Ismaili K, Avni F, Hall M; Brussels Free University Perinatal Nephrology (BFUPN) Study Group. Results of systematic voiding cystourethrography in infants with antenatally diagnosed renal pelvis dilation. J Pediatr. 2002;141: 21-4.
28. Mahant S, To T, Friedman J. Timing of voiding cystourethrogram in the investigation of urinary tract infections in children. J Pediatr. 2001;39:568-71.
29. McDonald A, Scranton M, Gillespie R, Mahajan V, Edwards GA. Voiding cystourethrograms and urinary tract infections: how long to wait? Pediatrics. 2000:105:E50.
30. Williams G, Lee A, Craig J. Antibiotics for the prevention of urinary tract infection in children: a systematic review of randomized controlled trials. J Pediatr. 2001;138:868-74.
31. Prat C, Dominguez J, Rodrigo C, et al. Elevated serum procalcitonin values correlate with renal scarring in children with urinary tract infection. Pediatr Infect Dis J. 2003;22:438-42.
32. Roberts KB. Urinary tract infection treatment and evaluation update. Pediatr Infect Dis J. 2004: 23:1163-4.

Introduction

Urinary tract infections (UTIs) are serious bacterial infections and a common cause for hospital admission of infants and young children. The prevalence of UTI in infants younger than 1 year of age ranges from 3.3% to 6.5%, and between 1 and 2 years of age from 1.9% to 8.1%. Females outpace males across all age groups, with the exception of the first 3 months of life (1). Without appropriate treatment and management, UTI can result in dehydration, urosepsis, and long-term medical problems including hypertension, renal scarring, and decreased renal function. This review will focus on the inpatient management of first-episode UTI in infants and young children.

click for large version

Diagnosis

Presenting symptoms in older children include urgency, frequency, dysuria, and complaints of back pain. In contrast, symptoms in infants and young children are often nonspecific and include irritability, diarrhea, vomiting, poor feeding, poor weight gain, crying on urination, and foul-smelling urine. The presence of a fever in infants and young children with UTI has been accepted as a marker of pyelonephritis, which occurs when infection has ascended to the upper collecting system of the kidney. Urinalysis (UA) and culture should be collected by suprapubic aspiration or transurethral catheterization, or by appropriately performed clean catch method for children of appropriate age and developmental ability. The use of a bag-collected urine specimen is insufficient and unreliable and should not be used in making the diagnosis of UTI. While suprapubic aspiration is considered the gold standard with a specificity and sensitivity of 100%, there is often resistance from parents and from physicians who are not properly trained to do this procedure.

The most accepted method of obtaining urine is sterile transurethral catheterization, results of which have 95% sensitivity and 99% specificity (2). When interpreting the UA, the most useful components for the diagnosis of a UTI include a positive leukocyte esterase, nitrite test, or gram stain on unspun urine, and microscopy revealing >10 white blood cells per high-powered field of spun urine. However, neonates under 30 days old may have no abnormality noted on initial UA (3,4). The presence of any bacteria on gram-stained urine offers the best sensitivity and specificity (5). Final diagnosis depends upon isolation of >10⁵ of a single organism from a clean-catch specimen, or >10⁴ of a single organism from a catheterized specimen.

Admission Criteria

Guidelines for evaluation of serious bacterial infection and parenteral antibiotic use for febrile infants under 60 days of age should be followed. All febrile neonates less than 30 days of age should be admitted for parenteral antibiotics (6–11). Controversy exists on the need to use corrected or postconceptual age when evaluating and determining need for admission for febrile preterm infants, particularly for those under 35 weeks of gestation. Factors that can be considered by the practitioner include severity of Neonatal ICU course, severity of prematurity, and combined disease burden of UTI with common preterm comorbidities (anemia, apnea of prematurity, chronic lung disease).

Consider admitting and initiating parenteral antibiotic treatment using Table 1 as a guideline. Exercise a lower threshold for admitting infants and toxic-appearing young children due to concern for urosepsis, complications, and the need for appropriate and aggressive initial therapy.

Initial Inpatient Management

The 3 goals of inhospital treatment of UTIs are to effectively treat and eliminate the acute infection, prevent urosepsis in infants and immunocompromised children, and prevent and reduce long-term complications such as renal scarring, hypertension, and decreased renal function. Initial antibiotic treatment should be administered parenterally to ensure optimal antimicrobial levels and aimed at the most common organisms, including Escherichia coli, Klebsiella, Proteus, and Enterobacter spp. Less common organisms to consider include Pseudomonas, Enterococcus, Staphylococcus aureus, and group B Streptococcus. Organisms will differ on many factors, such as age, underlying disease, prior colonization, and antibiotic exposure.

Table 2 outlines the initial choices of antibiotics until culture and sensitivities are known.

The choices and dosage of antibiotics are dependent on the age of the patient and are selected based on the other most likely organisms and their expected sensitivities (12). Ampicillin is added to the less than 2-month age group not only to cover Enterococcus, but also as part of broader neonatal sepsis coverage for Listeria. The third-generation cephalosporins are felt to be adequate initial coverage for most of the common organisms causing UTI. Children with congenital anomalies known to be associated with genitourinary abnormalities may be infected with less common organisms. In these situations, consider tailoring initial antibiotic coverage.

click for large version

Complications

The major complication of UTIs in infants is bacteremia. The rate of bacteremia in infants 0–3 months has variably been reported as 10% (13), 21–31% (14), and 36% (15). Infants with and without bacteremia are often clinically indistinguishable, making early determination of bacteremia difficult. A recent comprehensive review of 17 studies by Malik noted both C-reactive protein (CRP) and procalcitonin (PCT) results were highly variable in infants under 90 days old with known positive bacterial cultures (16). These inflammatory markers are therefore currently not useful to predict bacteremia. In addition to blood stream infection, other acute complications include meningitis, renal and perinephric abscess, and infected calculi. Longer-term complications include reflux nephropathy, renal scarring, hypertension, decreased renal function, and renal failure.

Duration of Antibiotic Therapy

While most uncomplicated UTIs are successfully treated with a 10-day treatment course, many experts prefer a 14-day course for neonates, infants, and ill-appearing young children. Despite effectiveness in adults, very-short-course therapy (≤3 days) for pediatric patients is associated with more treatment failures and reinfections (17). Although it may be considered in older children with cystitis, at this time it is not appropriate for treating infants and younger children in whom pyelonephritis cannot be distinguished from isolated lower tract infection (17,18).

Total treatment time and total days of parenteral therapy needed continue to be debated. Hoberman randomized children as young as 1 month of age to either entirely oral treatment or parenteral therapy for 3 days followed by oral treatment (19). In both arms of this study, children received 14 days of total therapy as was the standard at the time. He suggested, however, that a 10-day course of antibiotics should be adequate therapy for noncomplicated acute pyelonephritis. Of the 306 children, only 13 were under 2 months of age. Although only 13 positive blood cultures were reported, 10 of these occurred in children under 6 months of age. Given the limited number of children less than 2 months of age and the prevalence of positive blood cultures noted, conclusions cannot be drawn on the safety of entirely oral treatment for young infants. Parenteral antibiotic therapy should be continued for all hospitalized children until the patient is afebrile and free from signs of toxicity. Most hospitalized pediatric patients defervesce quickly on parenteral therapy—89% within 48 hours and 97% within 72 hours (20). Longer parenteral therapy of at least 10 days should be considered for neonates and infants with urosepsis, because they are immunologically immature, at greater risk of complications, have higher incidence of urinary tract anomalies, and have less reliable absorption of oral antibiotics.

Delayed or lack of response to antibiotic therapy may indicate the presence of urinary tract obstruction, resistant organisms, or renal or perinephric abscess. A repeat urine culture and immediate renal ultrasound or CT should be performed if the patient is not improving within 48 hours.

Radiological Studies

Renal Ultrasound (RUS)

Recent studies have questioned the value of performing routine RUS after a first-time UTI because of the low sensitivity in detecting vesicoureteral reflux (VUR) and a lack of significant influence in altering management (21,22). Patients who have had a normal late (30-32 weeks’ gestation) prenatal ultrasound with a good view of the kidneys may not require a repeat postnatal renal ultrasound (21,22). Further studies are needed to evaluate the costs and value of routine RUS. Until these studies are completed, renal and bladder ultrasound early during hospitalization continues to be recommended for all patients admitted with a first-time UTI to identify hydronephrosis, duplicating collecting systems, ureteral dilatation, calculi, and other structural anomalies.

Voiding Cystourethrogram (VCUG) or Radionuclide Cystography (RNC)

Either a VCUG or RNC should be performed to detect vesico-ureteral reflux in infants and young children. The AAP practice parameter and more recent literature clearly state the need for this evaluation in children under the age of 2 years (2,21). Additional data on incidence of anomalies by age suggest studying children under the age of 6 years (23,24). Recommendations for evaluation of children over age 6 may vary depending on age, patient, and family history, and comorbidities. Alternate methods such as voiding sonogram may also be options for this age group, and is not part of this discussion (25).

RNC exposes the patient to less radiation but does not show urethral or bladder anomalies. RNC is more often used for females with normal RUS and no voiding dysfunction, or to follow the progress of known VUR. The VCUG is often preferred because it provides more anatomic detail and is better for grading VUR and demonstrating posterior urethral vales in males (26). It is suggested that infants with antenatal renal pelvis dilation who have 2 normal renal sonograms in the first month of life are at low risk for abnormalities and may not require a VCUG (27). The rate of detection of VUR with a first episode of UTI does not increase when the VCUG is done early, within the first 7 days of diagnosis (28,29). Performing the VCUG as an inpatient should be considered if outpatient follow-up is of significant concern, or if the RUS suggests bilateral ureteral obstruction. If done as an inpatient procedure, it should be performed preferably during day 3–5 of antibiotic therapy and when the patient is clinically responding to the appropriate antibiotic. The overall value of the VCUG is being reviewed, as its usefulness is most significant only if VUR antimicrobial prophylaxis is effective in reducing reinfections and renal scarring (21,30). Until further studies are performed, the VCUG should continue as part of the initial UTI evaluation for infants and young children.

Renal Cortical Scintigraphy (RCS)

This is the imaging study of choice for the detection of acute pyelonephritis and renal scarring. As children are treated for presumptive upper-tract infection empirically, DMSA scan for diagnosis of pyelonephritis has limited utility (21). Scans have more often been performed at 6 months’ postinfection to document scar formation. Hoberman demonstrated that only 15% of children with abnormal scintigraphy at diagnosis have renal scarring on repeat RCS at 6 months. The importance of these scars is unclear. Association of scars with ultimate development of hypertension, renal insufficiency, and end-stage renal disease is based on studies performed in the 1980s using intravenous pyelogram. RCS is much more sensitive, finding more minor scars of uncertain significance.

click for large version

Table 3 may be of value when considering imaging options.

Other Considerations

CRP and PCT use in UTI have been evaluated by Pratt. Values at diagnosis are potentially helpful in ruling out scar formation at 6 months’ postinfection. Values under 1.0 ng/mL for PCT and 20 mg/L for CRP had a negative predictive value of 97.5% and 95%, respectively (31). Further studies are warranted to confirm the usefulness of these inflammatory markers to rule out future scar formation.

Consultations

Consider urology consultation if the RUS, VCUG, voiding history, or examination demonstrated concern for significant genitourinary abnormalities, abnormal voiding function or neurogenic bladder (23,32). Consider infectious disease consultation if the patient is not responding to conventional therapy without obstruction, unusual organisms are identified, or the patient is having recurrent urinary tract infections in the presence of normal urological structure and function.

Discharge Criteria and Processes

Consider discharge under the following conditions:

• The patient is comfortable and tolerating oral fluids well.
• The patient has been afebrile or has significantly decreasing fever for 24 hours.
• Appropriate radiological studies and consultations have been completed or arranged for as an outpatient.
• For patients requiring parenterally administered medications at home, long-term IV access must be obtained to assessment of home care service availability, benefits, family home resources, and caregiver education completed.
• Appropriate prophylactic antibiotic prescription has been given to the caregiver with education on use after completion of acute antibiotic therapy. Prophylactic antibiotics should be administered until imaging studies have been completed and assessed.

Conclusion

UTI is a common bacterial infection requiring hospital admission for infants and young children. Admission decisions should take into consideration goals for inpatient care and special age or clinical circumstances. Treatment mode and duration must address avoidance of both acute and chronic complications. Radiologic studies offer both anatomic view and functional information. Clinical relevance of scars, utility of radiologic studies, and value of inflammatory markers are some of the many areas requiring further study.

References

1. Long SS, Klein J. Bacterial infections of the urinary tract. In: Remington JSand Klein JO(eds.). Infectious Diseases of the Fetus and Newborn Infant. 5th ed. Philadelphia, Pa: WB Saunders; 2001:1035-46.
2. Committee on Quality Improvement, Subcommittee on Urinary Tract Infection. Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatrics. 1999;103:843-52.
3. Dayan PS, Bennett J, Best R, et al. Test characteristics of the urine gram stain in infants ≤60 days of age with fever. Pediatr Emerg Care. 2002;18:12-4.
4. Huicho L, Campos-Sanchez M, Alamo C. Metaanalysis of urine screening tests for determining the risk of urinary tract infection in children. Pediatr Infect Dis J. 2002;21:1-11.
5. Gorelick M, Shaw KN. Screening tests for urinary tract infections in Children: a meta-analysis. Pediatrics. 1999;104:e54.
6. Byington CL, Enriquez F, Hoff C, et al. Serious bacterial infections in febrile infants 1 to 90 days old with and without viral infections. Pediatrics. 2004:113:1662-6.
7. Baraff L. Management of fever without source in infants and children. Ann Emerg Med. 2000;36:602-14.
8. Baraff LJ, Oslund SA, Schriger D, Stephen ML. Probability of bacterial infections in febrile infants less than three months of age: a meta-analysis. Pediatr Infect Dis J. 1992;11:257-64.
9. Klein JO. Management of the febrile child without a focus of infection in the era of universal pneumococcal immunization. Pediatr Infect Dis J. 2002;21:584-8.
10. Syrogiannopoulos G, Grieva I, Anastassiou E, Triga M, Dimitracopoulos G, Beratis N. Sterile cerebrospinal fluid pleocytosis in young infants with urinary tract infections. Pediatr Infect Dis J. 2001;20:927-30.
11. Jaskiewicz JA, Mc Carthy CA, Richardson AC, ET AL. Febrile infants at low risk for serious bacterial infection--an appraisal of the Rochester criteria and implications for management. Febrile Collaborative Study Group. Pediatrics. 1994;94:390-6.
12. AAP Redbook. Report of the committee on infectious diseases, 2003:700.
13. Newman TB, Bernzweig JA, Takayama JI, Finch SA, Wasserman RC, Pantell RH. Urine testing and urinary tract infections in febrile infants seen in the office setting: the Pediatric Research in Office Settings’ Febrile Infant Study Arch Pediatr Adolesc Med. 2002;156:44-54.
14. Ginsberg CM, McCracken GH Jr. Urinary tract infection in young infants. Pediatrics. 1982;69:409-12.
15. Wiswell T, Geschke D. Risks from circumcision during the first month of life compared to uncircumcised boys. Pediatrics. 1989;83:1011-15.
16. Malik A, Hui C, Pennie RA, Kirpalani H. Beyond the complete blood cell count and C-reactive protein: a systematic review of modern diagnostic tests for neonatal sepsis. Arch Pediatr Adolesc Med. 2003;157:511-6.
17. Keren R, Chan E. A meta-analysis of randomized, controlled trials comparing short- and long-course antibiotic therapy for urinary tract infections in children. Pediatrics. 2002;109:e70.
18. Michael M, Hodson EM, Craig JC, Martin S, Moyer VA. Short versus standard duration oral antibiotic therapy for acute urinary tract infection in children. Cochrane Database of Syst Rev.2003.
19. Hoberman A, Wald ER, Hickey RW, et al. Oral versus intravenous therapy for urinary tract infections in young children. Pediatrics. 1999;104:79-86.
20. Bachur R. Nonresponders: prolonged fever among infants with urinary tract infections. Pediatrics. 2000;105:E59.
21. Hoberman A, Charron M, Hickey RW, Baskin M, Kearney DH, Wald ER. Imaging studies after a first febrile urinary tract infection in young children. N Engl J Med. 2003;348:195-202.
22. Zamir G, Sakran W, Horowitz Y, Koren A, Miron D. Urinary tract infection: is there a need for routine renal ultrasonography? Arch Dis Child. 2004;89:466-8.
23. Johnson CE. New advances in childhood urinary tract infections. Pediatr Rev. 1999:20:335-43.
24. Thompson M, Simon S, Sharma V, Alon US. Timing of follow-up voiding cystourethrogram in children with primary vesicoureteral reflux: development and application of a clinical algorithm. Pediatrics. 2005:115:426-34.
25. Darge K, Moeller RT, Trusen A, BuĴer F, Gordjani N, Riedmiller H. Diagnosis of vesicoureteral reflux with low-dose contrast-enhanced harmonic ultrasound imaging. Pediatr Radiol. 2005:35:73-8.
26. Kraus S. Genitourinary imaging in children. Pediatr Clin North Am. 2001;48:1381-1424.
27. Ismaili K, Avni F, Hall M; Brussels Free University Perinatal Nephrology (BFUPN) Study Group. Results of systematic voiding cystourethrography in infants with antenatally diagnosed renal pelvis dilation. J Pediatr. 2002;141: 21-4.
28. Mahant S, To T, Friedman J. Timing of voiding cystourethrogram in the investigation of urinary tract infections in children. J Pediatr. 2001;39:568-71.
29. McDonald A, Scranton M, Gillespie R, Mahajan V, Edwards GA. Voiding cystourethrograms and urinary tract infections: how long to wait? Pediatrics. 2000:105:E50.
30. Williams G, Lee A, Craig J. Antibiotics for the prevention of urinary tract infection in children: a systematic review of randomized controlled trials. J Pediatr. 2001;138:868-74.
31. Prat C, Dominguez J, Rodrigo C, et al. Elevated serum procalcitonin values correlate with renal scarring in children with urinary tract infection. Pediatr Infect Dis J. 2003;22:438-42.
32. Roberts KB. Urinary tract infection treatment and evaluation update. Pediatr Infect Dis J. 2004: 23:1163-4.

Introduction

A 55-year-old heroin addict presented to the emergency department, complaining of shaking chills and fevers for 2 weeks. On examination, there was a loud holosystolic murmur, maximally audible in the epigastric space, and a pulsatile liver. Subcutaneous nodular lesions were noted on his palms. Blood cultures grew Pseudomonas aeruginosa. After nearly completing a prolonged course of intravenous antibiotic therapy, the patient died in his washroom from an overdose of heroin. This sad tale, often tragically repeated, represents a continuing challenge to the medical community. The patients’ palm lesions noted were

Osler’s nodes, originally described in 1908 by Sir William Osler, considered by many the father of internal medicine. Osler was born in 1849 and died in 1919. He was an astute clinician and educator, with professorships at McGill University, University of Pennsylvania, Johns Hopkins University, and Oxford University. Osler defined “chronic” infectious endocarditis as an illness lasting longer than 3 months and characterized by low grade fevers. This syndrome was distinct from a “malignant” form, which resulted in early death. Blood cultures usually grew streptococci or, occasionally, staphylococci. Osler made a practice of following his patients to the autopsy table. Vegetations on valves from patients who died of the chronic form looked more like “warts,” and were neither ”ulcerating or very large.” Osler thought anti-streptococcal vaccines might be of some benefit. There was little else to offer. Regardless of the form, nearly all patients died.

In this review, I discuss current methods for the diagnosis and management of infective endocarditis. Cases seen in recent years will illustrate key points.

Case 1 A 39-year-old computer programmer complained of occipital headaches, migratory muscle pains, afternoon fevers, and a 15-pound weight loss for 2 months. He had previously enjoyed excellent health. On examination his temperature was 38.0°C. An apical systolic heart murmur was noted. A transthoracic echocardiogram (TTE) showed mitral regurgitation, with a probable vegetation on the mitral valve. Blood cultures were drawn and the patient was admitted to the hospital. The next day, a transesophageal echocardiogram (TEE) showed perforation of the posterior mitral leaflet. That evening, the patient developed severe right flank pain. CT scan showed infarcts in the right kidney and spleen. The next day the patient underwent urgent mitral valve repair and was dismissed 5 days later to complete a course of intravenous ceftriaxone. All blood cultures grew viridans streptococci, exquisitely susceptible to penicillin.

Comment: This patient represents classic “subacute” bacterial endocarditis with fever, weight loss, and a heart murmur. In most cases, he would be cured with medical therapy alone. However, a TEE showed a lesion that was not appreciated on the initial TTE, and he required urgent surgery to restore a failing mitral valve.

Although the patient had no identified skin or mucosal lesions, when present these suggest the diagnosis. The subconjunctivial sacs and soft palate should be examined for petechiae, the nail beds for splinter hemorrhages, and digits for Janeway lesions.

Osler’s definition of endocarditis included remittent fever, history of valvular heart disease, embolic features, skin lesions, and heart failure. These remain useful bedside observations, and positive blood cultures usually clinch the diagnosis. Perhaps the most important technical advance in recent years for diagnosis is the echocardiogram. The major Duke criteria, published in 1994, include a predictable bacterial organism in blood culture, multiple positive blood cultures with the same organism, or an echocardiogram with definite vegetation, abscess, or valve dehiscence. Any two of the above suffice for diagnosis of probable endocarditis. Accepted minor criteria consist of predisposing lesions, history of intravenous drug abuse, temperature higher than 38°C, vasculitis, skin lesions, or “suggestive” echocardiographic or microbiologic findings. Five of these, or three with one major criterion, support the diagnosis. Transesophageal is superior to transthoracic echocardiography and should be performed if the TTE is equivocal or non-diagnostic.

Case 2 A 31-year-old warehouse manager with progressive dyspnea was transferred from an outside hospital. His illness began 8 months earlier with a dry cough and progressive fatigue. His past history was negative except for an asymptomatic heart murmur. On examination, he was pale and diaphoretic with a temperature of 36°C, pulse 110, and blood pressure of 108/56mm Hg. Neck veins were distended beats/min; loud heart murmurs and diffuse airway crackles were heard. The spleen was palpable. Blood cultures were drawn and antibiotics started.

As the patient was being wheeled for urgent heart surgery, he suffered a huge left-sided stroke. Contrast studies showed a leaking basilar artery aneurysm with subarachnoid hemorrhage. Once his neurologic problem stabilized, urgent mitral and aortic valve replacement was performed. Both valves were severely damaged and rife with vegetations. Admission blood cultures grew viridans streptococci, susceptible to penicillin. After prolonged hospitalization, the patient was transferred for continued care to a rehabilitation unit closer to home.

Comment: Neurologic complications of endocarditis are more common than generally appreciated, and occur in at least one third of patients at the time of diagnosis. Stroke is the most frequent finding, but encephalopathy, retinal embolic lesions, mycotic aneurysm, brain abscess, and meningitis can also occur. Fortunately, most neurologic problems resolve with medical management, but as seen in this patient, some are devastating and have permanent sequelae.

Organisms responsible for the majority of cases of native valve endocarditis are streptococci, as was true in Osler’s time. Staphylococcus aureus is next in frequency, followed by gram-negative bacilli, fungi, coagulase-negative staphylococci, and a poorly-defined category of “culture negative” cases. Therapy for infection caused by penicillin-susceptible streptococci is straightforward. The preferred agent is intravenous penicillin or ampicillin, with ceftraxione or vancomycin as alternatives. Streptococci less susceptible to penicillin, including nutritionally variant organisms, are treated more vigorously with a penicillin and low-dose aminoglycoside.

The HACEK group of gram-negative bacteria (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella species) often produce large vegetations. Embolic lesions to major organs or extremities are a fairly common presenting feature. Treatment with ceftriaxone or ampicillin plus gentamicin is usually successful.

“Culture negative” endocarditis includes infections due to microorganisms difficult to culture on standard media. These uncommon pathogens include Bartonella, Brucella, Chlamydia, Coxiella, Francisella, Legionella, and Tropheryma whippeli.

Bartonella endocarditis has been reported in the homeless population. Blood cultures are usually negative. Serology is helpful. More recently, polymerase drain reactions (PCR) from resected valve tissue have proven useful. Treatment of choice is ampicillin plus gentamicin, but mortality remains approximately 25%.

Patients with endocarditis due to Coxiella burnetii (Q fever) are likewise difficult to diagnose. They may not have fever. However, there is generally underlying valvular heart disease, and frequently patients are immunosuppressed. Vegetations are rarely detected on echocardiogram. Routine blood cultures are negative. Fortunately, serology is quite specific for the diagnosis. A combination of doxycycline and chloroquine is the current treatment of choice.

PCR and special immunohistochemical techniques may be useful in the diagnosis of these unusual etiologies. Unfortunately, the methodology is not currently available at most hospitals. Broad-range PCR on surgical tissue help to identify more typical organisms (staphylococci and streptococci), whose growth may be suppressed by conventional antibiotic therapy. Although promising, PCR technology may lack specificity in these cases.

Case 3 A 61-year-old executive was admitted with a 4 week history of fevers and fatigue. Three months earlier he had undergone a bovine aortic valve replacement with mitral valve repair. Blood cultures drawn by a local physician grew methicillin-resistant Staphylococcus epidermidis (MRSE). Despite antibiotics, the patient’s fatigue persisted and he returned for further evaluation. On examination, he was afebrile, with a resting pulse of 71 beats/min and a blood pressure of 135/63mm Hg. However, he was very pale. Loud systolic and diastolic murmurs were heard throughout the precordium. His spleen was enlarged and very soft.

The patient underwent urgent reoperation. At surgery, partial aortic valve dehiscence as a result of a large subprosthetic abscess was discovered. Both aortic and mitral valve were replaced. Admission and operative cultures were negative on antibiotic therapy.

Comment: This is a classic presentation of early-onset prosthetic valve endocarditis. Usual organisms are S. epidermidis and S. aureus Streptococci, vancomycin-resistant enterococci (VRE), diphtheroids, gram-negative bacilli, and fungi (yeast and molds) are all seen in this setting, albeit less frequently.

S. epidermidis is of special interest because it produces hemolysins, grows very slowly on cell surfaces, and binds to host and foreign proteins. This biofilm creates a barrier to host defenses and appears to neutralize certain antibiotics. In addition there is clonal variability, with some isolates fully susceptible to oxacillin, while other clones are resistant.

Standard therapy for staphylococcal prosthetic valve endocarditis is oxacillin with gentamicin and rifampin. For oxacillin-resistant species, vancomycin is substituted. Prosthetic valve enterococcal endocarditis resistant to both penicillin and vancomycin is a growing concern. Some medical centers report VRE colonization rates as high as 30%. Therapy is daunting. For strains with a minimum inhibitory concentrations (MIC) less than 128 gr/mL to ampicillin, ampicillin/sulbactam plus an aminoglycoside has been recommended. For strains totally resistant to ampicillin, quinupristin/dalfopristin, linezolid, or daptomycin may be tried, but the overall success rate is probably no better than 50%.

Case 4 A 31-year-old automobile mechanic underwent aortic valve and graft replacement for severe aortic regurgitation with a large aneurysm of the ascending aorta. His post-operative course was complicated by massive bleeding at the distal graft anastomosis, and respiratory failure. After prolonged hospitalization, the patient was discharged improved, but 2 days later he complained of blurred vision and fevers. His wife noted a green hue from his right pupil. The patient was readmitted and started on intravenous acyclovir for presumed acute retinal necrosis. However, several days later, vitrectomy fluid grew Pseudoallescheria boydii.

Therapy was switched to intravenous miconazole but, shortly afterward, the patient suffered a cardiac arrest. Although his pulse and blood pressure were restored, he remained comatose and support was withdrawn. At autopsy, invasive prosthetic aortic valve and graft endocarditis was noted. Blood and tissue cultures also grew P. boydii.

Comment: Fungal prosthetic valve endocarditis is a devastating disease. Predisposing factors are prolonged use of central vascular catheters, often for antibiotic therapy or parenteral nutrition, and immunosuppression. Most success has been reported combining surgery with intravenous antifungal therapy. Patients should be continued on oral suppressive therapy afterward to prevent relapse later in life.

“Pacemaker endocarditis,” seen with increasing frequency, applies to pacemakers, defibrillators, or combinations thereof. Usual causes are skin flora microbes (staphylococci and Propionibacterium species) that gain access through a generator pocket wound. An echocardiogram may not show vegetations unless they extend to the tricuspid valve. Removal of all hardware, combined with intravenous antibiotic therapy, is necessary for cure. Some impacted leads require open heart surgery for removal.

Hospital-associated bacteremia from another source may spread to a heart valve or pacemaker lead, causing endocarditis. S. aureus bacteremia from intravenous catheters, hemodialysis fistula, and surgical wounds is most likely to do this. Patients on hemodialysis may be colonized with methicillin-resistant S. aureus (MRSA), a risk factor for infection. While intra-nasal mupirocin ointment may reduce MRSA colonization transiently, it is probably not effective for long-term prophylaxis.

Case 5 A 54-year-old accountant was admitted with chills and palpitations for several days. A bovine aortic valve prosthesis had been implanted 2 years earlier. The patient had complained of intermittent fevers for 6 months. A single blood culture had grown Propionibacterium acnes. Although a TEE was interpreted as normal, he was treated with intravenous vancomycin. Follow-up blood cultures were negative and a TTE was read as normal.

On examination, the patient was acutely ill with distended neck veins. His pulse was 50 beats/min and blood pressure 110/50mm Hg. Systolic and diastolic murmurs were present. Blood cultures were drawn, and antibiotics started.

An electrocardiogram showed heart block. A temporary pacemaker was placed. A TEE revealed a huge atrial septal abscess with a fistula from the right atrium to the aorta. The patient was taken emergently to surgery, where the prosthesis was found to have nearly completely dehisced. The fistula was resected and the aortic valve replaced with a homograft. Postoperatively the patient remained in cardiogenic shock and died. Admission blood and valve cultures subsequently grew P. acnes.

Comment and Conclusions

Continued fevers despite appropriate antibiotic and medical management are cause for alarm. Ring abscesses may develop. This is a clear indication for surgical intervention. Fevers may also be caused by embolic events (arterial or venous), drug reactions, and intravascular catheter-related infections. Close monitoring is necessary to avoid major events. Vigilance should be maintained for widening pulse pressures and rhythm disturbances as these are ominous signs of progressive infection.

Indications for urgent surgery include progressive valvular dysfunction; aortic root, ring or septal abscesses; large vegetations (greater than l cm in diameter); and organisms such as VRE, MRSA, Pseudomonas species, and fungi refractive to antimicrobial therapy. It is important to note that, even with appropriate therapy and a bacteriologic “cure,” about one half of patients will have enough valve damage to require surgery later in life.

Despite our best efforts, the death rate from infective endocarditis remains in the range of 10–20%. Death is more likely with prosthetic valve endocarditis and when the organism is S. aureus. Patients still succumb from congestive heart failure, embolic phenomenon, and ruptured mycotic aneurysms, just as they did during Osler’s time.

It is clear there is room for improvement in the diagnosis and management of endocarditis. First, we must continue to refine microbiologic techniques, to allow diagnosis more quickly and accurately. Second, we must develop more effective antimicrobial therapy, especially for pathogens resistant to conventional antimicrobials. Third, we must learn how to combat biofilms. Perhaps in the future we can avoid removal of foreign materials. Finally, we must follow our patients closely and pursue timely surgical intervention when indicated. In recent years this has become more difficult, because patients, once stabilized, are often discharged home or to a skilled nursing facility to complete antibiotic therapy.

While we have learned more about infective endocarditis over the past quarter century, the challenges we face today are greater than ever before.

References

1. Osler W. Chronic infectious endocarditis. Q J Med. 1909;2: 219-30.
2. Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med. 2001;345:1318-30.
3. Durack DT, Lukes AS, Bright KD, et al: New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Am J Med. 1994;96:200-9.
4. Salgado AV, Furlan AJ, Keys TF. Neurologic complications of endocarditis: a 12 year experience. Neurology. 1989;39:173-8.
5. Wilson WR, Karchmer AW, Dajani AS, et al: Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, staphylococci and HACEK micro organisms. JAMA. 1995;274:1706-13.
6. Lepidi H, Houpikian P, Liang Z, Raoult D. Cardiac valves in patients with Q-fever endocarditis. J Infect Dis. 2003;187: 1097-106.
7. Bosshard PP, Kronenberg A, Zbinden R, et al. Etiologic diagnosis of infective endocarditis by broad-range PCR. Clin Infect Dis. 2003;37:167-72.
8. Keys TF. Early-onset prosthetic valve endocarditis. Cleve Clin J Med. 1993;60:455-9.
9. Proctor RA. Coagulase-negative staphylococcal infection: a diagnostic and therapeutic challenge. Clin Infect Dis. 2000;31:31-3.
10. Melgar GR, Nasser RM, Gordon SM, et al. Fungal prosthetic-valve endocarditis in 16 patients: an 11-year experience in a tertiary care hospital. Medicine. 1997;76:94-103.
11. Fowler VG, Sanders LL, Kong LK, et al. Infective endocarditis due to Staphylococcus aureus. Clin Infect Dis. 1999;28:106-14.
12. Douglas A, Moore-Gillon J, Eykyn S. Fever during treatment of infective endocarditis. Lancet. 1986;1:1341-3.
13. Tornos MP, Permanyer-Miralda G, Olona J, et al. Long term complications of native valve endocarditis in non-addicts: a 15 year follow up study. Ann Intern Med. 1992;117:567-72.
14. Andrews MM, Von Reyn CF. Patients election criteria and management guidelines for outpatient parenteral antibiotic therapy for native valve infective endocarditis. Clin Infect Dis. 2001;32:203-9.

Introduction

A 55-year-old heroin addict presented to the emergency department, complaining of shaking chills and fevers for 2 weeks. On examination, there was a loud holosystolic murmur, maximally audible in the epigastric space, and a pulsatile liver. Subcutaneous nodular lesions were noted on his palms. Blood cultures grew Pseudomonas aeruginosa. After nearly completing a prolonged course of intravenous antibiotic therapy, the patient died in his washroom from an overdose of heroin. This sad tale, often tragically repeated, represents a continuing challenge to the medical community. The patients’ palm lesions noted were

Osler’s nodes, originally described in 1908 by Sir William Osler, considered by many the father of internal medicine. Osler was born in 1849 and died in 1919. He was an astute clinician and educator, with professorships at McGill University, University of Pennsylvania, Johns Hopkins University, and Oxford University. Osler defined “chronic” infectious endocarditis as an illness lasting longer than 3 months and characterized by low grade fevers. This syndrome was distinct from a “malignant” form, which resulted in early death. Blood cultures usually grew streptococci or, occasionally, staphylococci. Osler made a practice of following his patients to the autopsy table. Vegetations on valves from patients who died of the chronic form looked more like “warts,” and were neither ”ulcerating or very large.” Osler thought anti-streptococcal vaccines might be of some benefit. There was little else to offer. Regardless of the form, nearly all patients died.

In this review, I discuss current methods for the diagnosis and management of infective endocarditis. Cases seen in recent years will illustrate key points.

Case 1 A 39-year-old computer programmer complained of occipital headaches, migratory muscle pains, afternoon fevers, and a 15-pound weight loss for 2 months. He had previously enjoyed excellent health. On examination his temperature was 38.0°C. An apical systolic heart murmur was noted. A transthoracic echocardiogram (TTE) showed mitral regurgitation, with a probable vegetation on the mitral valve. Blood cultures were drawn and the patient was admitted to the hospital. The next day, a transesophageal echocardiogram (TEE) showed perforation of the posterior mitral leaflet. That evening, the patient developed severe right flank pain. CT scan showed infarcts in the right kidney and spleen. The next day the patient underwent urgent mitral valve repair and was dismissed 5 days later to complete a course of intravenous ceftriaxone. All blood cultures grew viridans streptococci, exquisitely susceptible to penicillin.

Comment: This patient represents classic “subacute” bacterial endocarditis with fever, weight loss, and a heart murmur. In most cases, he would be cured with medical therapy alone. However, a TEE showed a lesion that was not appreciated on the initial TTE, and he required urgent surgery to restore a failing mitral valve.

Although the patient had no identified skin or mucosal lesions, when present these suggest the diagnosis. The subconjunctivial sacs and soft palate should be examined for petechiae, the nail beds for splinter hemorrhages, and digits for Janeway lesions.

Osler’s definition of endocarditis included remittent fever, history of valvular heart disease, embolic features, skin lesions, and heart failure. These remain useful bedside observations, and positive blood cultures usually clinch the diagnosis. Perhaps the most important technical advance in recent years for diagnosis is the echocardiogram. The major Duke criteria, published in 1994, include a predictable bacterial organism in blood culture, multiple positive blood cultures with the same organism, or an echocardiogram with definite vegetation, abscess, or valve dehiscence. Any two of the above suffice for diagnosis of probable endocarditis. Accepted minor criteria consist of predisposing lesions, history of intravenous drug abuse, temperature higher than 38°C, vasculitis, skin lesions, or “suggestive” echocardiographic or microbiologic findings. Five of these, or three with one major criterion, support the diagnosis. Transesophageal is superior to transthoracic echocardiography and should be performed if the TTE is equivocal or non-diagnostic.

Case 2 A 31-year-old warehouse manager with progressive dyspnea was transferred from an outside hospital. His illness began 8 months earlier with a dry cough and progressive fatigue. His past history was negative except for an asymptomatic heart murmur. On examination, he was pale and diaphoretic with a temperature of 36°C, pulse 110, and blood pressure of 108/56mm Hg. Neck veins were distended beats/min; loud heart murmurs and diffuse airway crackles were heard. The spleen was palpable. Blood cultures were drawn and antibiotics started.

As the patient was being wheeled for urgent heart surgery, he suffered a huge left-sided stroke. Contrast studies showed a leaking basilar artery aneurysm with subarachnoid hemorrhage. Once his neurologic problem stabilized, urgent mitral and aortic valve replacement was performed. Both valves were severely damaged and rife with vegetations. Admission blood cultures grew viridans streptococci, susceptible to penicillin. After prolonged hospitalization, the patient was transferred for continued care to a rehabilitation unit closer to home.

Comment: Neurologic complications of endocarditis are more common than generally appreciated, and occur in at least one third of patients at the time of diagnosis. Stroke is the most frequent finding, but encephalopathy, retinal embolic lesions, mycotic aneurysm, brain abscess, and meningitis can also occur. Fortunately, most neurologic problems resolve with medical management, but as seen in this patient, some are devastating and have permanent sequelae.

Organisms responsible for the majority of cases of native valve endocarditis are streptococci, as was true in Osler’s time. Staphylococcus aureus is next in frequency, followed by gram-negative bacilli, fungi, coagulase-negative staphylococci, and a poorly-defined category of “culture negative” cases. Therapy for infection caused by penicillin-susceptible streptococci is straightforward. The preferred agent is intravenous penicillin or ampicillin, with ceftraxione or vancomycin as alternatives. Streptococci less susceptible to penicillin, including nutritionally variant organisms, are treated more vigorously with a penicillin and low-dose aminoglycoside.

The HACEK group of gram-negative bacteria (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella species) often produce large vegetations. Embolic lesions to major organs or extremities are a fairly common presenting feature. Treatment with ceftriaxone or ampicillin plus gentamicin is usually successful.

“Culture negative” endocarditis includes infections due to microorganisms difficult to culture on standard media. These uncommon pathogens include Bartonella, Brucella, Chlamydia, Coxiella, Francisella, Legionella, and Tropheryma whippeli.

Bartonella endocarditis has been reported in the homeless population. Blood cultures are usually negative. Serology is helpful. More recently, polymerase drain reactions (PCR) from resected valve tissue have proven useful. Treatment of choice is ampicillin plus gentamicin, but mortality remains approximately 25%.

Patients with endocarditis due to Coxiella burnetii (Q fever) are likewise difficult to diagnose. They may not have fever. However, there is generally underlying valvular heart disease, and frequently patients are immunosuppressed. Vegetations are rarely detected on echocardiogram. Routine blood cultures are negative. Fortunately, serology is quite specific for the diagnosis. A combination of doxycycline and chloroquine is the current treatment of choice.

PCR and special immunohistochemical techniques may be useful in the diagnosis of these unusual etiologies. Unfortunately, the methodology is not currently available at most hospitals. Broad-range PCR on surgical tissue help to identify more typical organisms (staphylococci and streptococci), whose growth may be suppressed by conventional antibiotic therapy. Although promising, PCR technology may lack specificity in these cases.

Case 3 A 61-year-old executive was admitted with a 4 week history of fevers and fatigue. Three months earlier he had undergone a bovine aortic valve replacement with mitral valve repair. Blood cultures drawn by a local physician grew methicillin-resistant Staphylococcus epidermidis (MRSE). Despite antibiotics, the patient’s fatigue persisted and he returned for further evaluation. On examination, he was afebrile, with a resting pulse of 71 beats/min and a blood pressure of 135/63mm Hg. However, he was very pale. Loud systolic and diastolic murmurs were heard throughout the precordium. His spleen was enlarged and very soft.

The patient underwent urgent reoperation. At surgery, partial aortic valve dehiscence as a result of a large subprosthetic abscess was discovered. Both aortic and mitral valve were replaced. Admission and operative cultures were negative on antibiotic therapy.

Comment: This is a classic presentation of early-onset prosthetic valve endocarditis. Usual organisms are S. epidermidis and S. aureus Streptococci, vancomycin-resistant enterococci (VRE), diphtheroids, gram-negative bacilli, and fungi (yeast and molds) are all seen in this setting, albeit less frequently.

S. epidermidis is of special interest because it produces hemolysins, grows very slowly on cell surfaces, and binds to host and foreign proteins. This biofilm creates a barrier to host defenses and appears to neutralize certain antibiotics. In addition there is clonal variability, with some isolates fully susceptible to oxacillin, while other clones are resistant.

Standard therapy for staphylococcal prosthetic valve endocarditis is oxacillin with gentamicin and rifampin. For oxacillin-resistant species, vancomycin is substituted. Prosthetic valve enterococcal endocarditis resistant to both penicillin and vancomycin is a growing concern. Some medical centers report VRE colonization rates as high as 30%. Therapy is daunting. For strains with a minimum inhibitory concentrations (MIC) less than 128 gr/mL to ampicillin, ampicillin/sulbactam plus an aminoglycoside has been recommended. For strains totally resistant to ampicillin, quinupristin/dalfopristin, linezolid, or daptomycin may be tried, but the overall success rate is probably no better than 50%.

Case 4 A 31-year-old automobile mechanic underwent aortic valve and graft replacement for severe aortic regurgitation with a large aneurysm of the ascending aorta. His post-operative course was complicated by massive bleeding at the distal graft anastomosis, and respiratory failure. After prolonged hospitalization, the patient was discharged improved, but 2 days later he complained of blurred vision and fevers. His wife noted a green hue from his right pupil. The patient was readmitted and started on intravenous acyclovir for presumed acute retinal necrosis. However, several days later, vitrectomy fluid grew Pseudoallescheria boydii.

Therapy was switched to intravenous miconazole but, shortly afterward, the patient suffered a cardiac arrest. Although his pulse and blood pressure were restored, he remained comatose and support was withdrawn. At autopsy, invasive prosthetic aortic valve and graft endocarditis was noted. Blood and tissue cultures also grew P. boydii.

Comment: Fungal prosthetic valve endocarditis is a devastating disease. Predisposing factors are prolonged use of central vascular catheters, often for antibiotic therapy or parenteral nutrition, and immunosuppression. Most success has been reported combining surgery with intravenous antifungal therapy. Patients should be continued on oral suppressive therapy afterward to prevent relapse later in life.

“Pacemaker endocarditis,” seen with increasing frequency, applies to pacemakers, defibrillators, or combinations thereof. Usual causes are skin flora microbes (staphylococci and Propionibacterium species) that gain access through a generator pocket wound. An echocardiogram may not show vegetations unless they extend to the tricuspid valve. Removal of all hardware, combined with intravenous antibiotic therapy, is necessary for cure. Some impacted leads require open heart surgery for removal.

Hospital-associated bacteremia from another source may spread to a heart valve or pacemaker lead, causing endocarditis. S. aureus bacteremia from intravenous catheters, hemodialysis fistula, and surgical wounds is most likely to do this. Patients on hemodialysis may be colonized with methicillin-resistant S. aureus (MRSA), a risk factor for infection. While intra-nasal mupirocin ointment may reduce MRSA colonization transiently, it is probably not effective for long-term prophylaxis.

Case 5 A 54-year-old accountant was admitted with chills and palpitations for several days. A bovine aortic valve prosthesis had been implanted 2 years earlier. The patient had complained of intermittent fevers for 6 months. A single blood culture had grown Propionibacterium acnes. Although a TEE was interpreted as normal, he was treated with intravenous vancomycin. Follow-up blood cultures were negative and a TTE was read as normal.

On examination, the patient was acutely ill with distended neck veins. His pulse was 50 beats/min and blood pressure 110/50mm Hg. Systolic and diastolic murmurs were present. Blood cultures were drawn, and antibiotics started.

An electrocardiogram showed heart block. A temporary pacemaker was placed. A TEE revealed a huge atrial septal abscess with a fistula from the right atrium to the aorta. The patient was taken emergently to surgery, where the prosthesis was found to have nearly completely dehisced. The fistula was resected and the aortic valve replaced with a homograft. Postoperatively the patient remained in cardiogenic shock and died. Admission blood and valve cultures subsequently grew P. acnes.

Comment and Conclusions

Continued fevers despite appropriate antibiotic and medical management are cause for alarm. Ring abscesses may develop. This is a clear indication for surgical intervention. Fevers may also be caused by embolic events (arterial or venous), drug reactions, and intravascular catheter-related infections. Close monitoring is necessary to avoid major events. Vigilance should be maintained for widening pulse pressures and rhythm disturbances as these are ominous signs of progressive infection.

Indications for urgent surgery include progressive valvular dysfunction; aortic root, ring or septal abscesses; large vegetations (greater than l cm in diameter); and organisms such as VRE, MRSA, Pseudomonas species, and fungi refractive to antimicrobial therapy. It is important to note that, even with appropriate therapy and a bacteriologic “cure,” about one half of patients will have enough valve damage to require surgery later in life.

Despite our best efforts, the death rate from infective endocarditis remains in the range of 10–20%. Death is more likely with prosthetic valve endocarditis and when the organism is S. aureus. Patients still succumb from congestive heart failure, embolic phenomenon, and ruptured mycotic aneurysms, just as they did during Osler’s time.

It is clear there is room for improvement in the diagnosis and management of endocarditis. First, we must continue to refine microbiologic techniques, to allow diagnosis more quickly and accurately. Second, we must develop more effective antimicrobial therapy, especially for pathogens resistant to conventional antimicrobials. Third, we must learn how to combat biofilms. Perhaps in the future we can avoid removal of foreign materials. Finally, we must follow our patients closely and pursue timely surgical intervention when indicated. In recent years this has become more difficult, because patients, once stabilized, are often discharged home or to a skilled nursing facility to complete antibiotic therapy.

While we have learned more about infective endocarditis over the past quarter century, the challenges we face today are greater than ever before.

References

1. Osler W. Chronic infectious endocarditis. Q J Med. 1909;2: 219-30.
2. Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med. 2001;345:1318-30.
3. Durack DT, Lukes AS, Bright KD, et al: New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Am J Med. 1994;96:200-9.
4. Salgado AV, Furlan AJ, Keys TF. Neurologic complications of endocarditis: a 12 year experience. Neurology. 1989;39:173-8.
5. Wilson WR, Karchmer AW, Dajani AS, et al: Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, staphylococci and HACEK micro organisms. JAMA. 1995;274:1706-13.
6. Lepidi H, Houpikian P, Liang Z, Raoult D. Cardiac valves in patients with Q-fever endocarditis. J Infect Dis. 2003;187: 1097-106.
7. Bosshard PP, Kronenberg A, Zbinden R, et al. Etiologic diagnosis of infective endocarditis by broad-range PCR. Clin Infect Dis. 2003;37:167-72.
8. Keys TF. Early-onset prosthetic valve endocarditis. Cleve Clin J Med. 1993;60:455-9.
9. Proctor RA. Coagulase-negative staphylococcal infection: a diagnostic and therapeutic challenge. Clin Infect Dis. 2000;31:31-3.
10. Melgar GR, Nasser RM, Gordon SM, et al. Fungal prosthetic-valve endocarditis in 16 patients: an 11-year experience in a tertiary care hospital. Medicine. 1997;76:94-103.
11. Fowler VG, Sanders LL, Kong LK, et al. Infective endocarditis due to Staphylococcus aureus. Clin Infect Dis. 1999;28:106-14.
12. Douglas A, Moore-Gillon J, Eykyn S. Fever during treatment of infective endocarditis. Lancet. 1986;1:1341-3.
13. Tornos MP, Permanyer-Miralda G, Olona J, et al. Long term complications of native valve endocarditis in non-addicts: a 15 year follow up study. Ann Intern Med. 1992;117:567-72.
14. Andrews MM, Von Reyn CF. Patients election criteria and management guidelines for outpatient parenteral antibiotic therapy for native valve infective endocarditis. Clin Infect Dis. 2001;32:203-9.

Introduction

A 55-year-old heroin addict presented to the emergency department, complaining of shaking chills and fevers for 2 weeks. On examination, there was a loud holosystolic murmur, maximally audible in the epigastric space, and a pulsatile liver. Subcutaneous nodular lesions were noted on his palms. Blood cultures grew Pseudomonas aeruginosa. After nearly completing a prolonged course of intravenous antibiotic therapy, the patient died in his washroom from an overdose of heroin. This sad tale, often tragically repeated, represents a continuing challenge to the medical community. The patients’ palm lesions noted were

Osler’s nodes, originally described in 1908 by Sir William Osler, considered by many the father of internal medicine. Osler was born in 1849 and died in 1919. He was an astute clinician and educator, with professorships at McGill University, University of Pennsylvania, Johns Hopkins University, and Oxford University. Osler defined “chronic” infectious endocarditis as an illness lasting longer than 3 months and characterized by low grade fevers. This syndrome was distinct from a “malignant” form, which resulted in early death. Blood cultures usually grew streptococci or, occasionally, staphylococci. Osler made a practice of following his patients to the autopsy table. Vegetations on valves from patients who died of the chronic form looked more like “warts,” and were neither ”ulcerating or very large.” Osler thought anti-streptococcal vaccines might be of some benefit. There was little else to offer. Regardless of the form, nearly all patients died.

In this review, I discuss current methods for the diagnosis and management of infective endocarditis. Cases seen in recent years will illustrate key points.

Case 1 A 39-year-old computer programmer complained of occipital headaches, migratory muscle pains, afternoon fevers, and a 15-pound weight loss for 2 months. He had previously enjoyed excellent health. On examination his temperature was 38.0°C. An apical systolic heart murmur was noted. A transthoracic echocardiogram (TTE) showed mitral regurgitation, with a probable vegetation on the mitral valve. Blood cultures were drawn and the patient was admitted to the hospital. The next day, a transesophageal echocardiogram (TEE) showed perforation of the posterior mitral leaflet. That evening, the patient developed severe right flank pain. CT scan showed infarcts in the right kidney and spleen. The next day the patient underwent urgent mitral valve repair and was dismissed 5 days later to complete a course of intravenous ceftriaxone. All blood cultures grew viridans streptococci, exquisitely susceptible to penicillin.

Comment: This patient represents classic “subacute” bacterial endocarditis with fever, weight loss, and a heart murmur. In most cases, he would be cured with medical therapy alone. However, a TEE showed a lesion that was not appreciated on the initial TTE, and he required urgent surgery to restore a failing mitral valve.

Although the patient had no identified skin or mucosal lesions, when present these suggest the diagnosis. The subconjunctivial sacs and soft palate should be examined for petechiae, the nail beds for splinter hemorrhages, and digits for Janeway lesions.

Osler’s definition of endocarditis included remittent fever, history of valvular heart disease, embolic features, skin lesions, and heart failure. These remain useful bedside observations, and positive blood cultures usually clinch the diagnosis. Perhaps the most important technical advance in recent years for diagnosis is the echocardiogram. The major Duke criteria, published in 1994, include a predictable bacterial organism in blood culture, multiple positive blood cultures with the same organism, or an echocardiogram with definite vegetation, abscess, or valve dehiscence. Any two of the above suffice for diagnosis of probable endocarditis. Accepted minor criteria consist of predisposing lesions, history of intravenous drug abuse, temperature higher than 38°C, vasculitis, skin lesions, or “suggestive” echocardiographic or microbiologic findings. Five of these, or three with one major criterion, support the diagnosis. Transesophageal is superior to transthoracic echocardiography and should be performed if the TTE is equivocal or non-diagnostic.

Case 2 A 31-year-old warehouse manager with progressive dyspnea was transferred from an outside hospital. His illness began 8 months earlier with a dry cough and progressive fatigue. His past history was negative except for an asymptomatic heart murmur. On examination, he was pale and diaphoretic with a temperature of 36°C, pulse 110, and blood pressure of 108/56mm Hg. Neck veins were distended beats/min; loud heart murmurs and diffuse airway crackles were heard. The spleen was palpable. Blood cultures were drawn and antibiotics started.

As the patient was being wheeled for urgent heart surgery, he suffered a huge left-sided stroke. Contrast studies showed a leaking basilar artery aneurysm with subarachnoid hemorrhage. Once his neurologic problem stabilized, urgent mitral and aortic valve replacement was performed. Both valves were severely damaged and rife with vegetations. Admission blood cultures grew viridans streptococci, susceptible to penicillin. After prolonged hospitalization, the patient was transferred for continued care to a rehabilitation unit closer to home.

Comment: Neurologic complications of endocarditis are more common than generally appreciated, and occur in at least one third of patients at the time of diagnosis. Stroke is the most frequent finding, but encephalopathy, retinal embolic lesions, mycotic aneurysm, brain abscess, and meningitis can also occur. Fortunately, most neurologic problems resolve with medical management, but as seen in this patient, some are devastating and have permanent sequelae.

Organisms responsible for the majority of cases of native valve endocarditis are streptococci, as was true in Osler’s time. Staphylococcus aureus is next in frequency, followed by gram-negative bacilli, fungi, coagulase-negative staphylococci, and a poorly-defined category of “culture negative” cases. Therapy for infection caused by penicillin-susceptible streptococci is straightforward. The preferred agent is intravenous penicillin or ampicillin, with ceftraxione or vancomycin as alternatives. Streptococci less susceptible to penicillin, including nutritionally variant organisms, are treated more vigorously with a penicillin and low-dose aminoglycoside.

The HACEK group of gram-negative bacteria (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella species) often produce large vegetations. Embolic lesions to major organs or extremities are a fairly common presenting feature. Treatment with ceftriaxone or ampicillin plus gentamicin is usually successful.

“Culture negative” endocarditis includes infections due to microorganisms difficult to culture on standard media. These uncommon pathogens include Bartonella, Brucella, Chlamydia, Coxiella, Francisella, Legionella, and Tropheryma whippeli.

Bartonella endocarditis has been reported in the homeless population. Blood cultures are usually negative. Serology is helpful. More recently, polymerase drain reactions (PCR) from resected valve tissue have proven useful. Treatment of choice is ampicillin plus gentamicin, but mortality remains approximately 25%.

Patients with endocarditis due to Coxiella burnetii (Q fever) are likewise difficult to diagnose. They may not have fever. However, there is generally underlying valvular heart disease, and frequently patients are immunosuppressed. Vegetations are rarely detected on echocardiogram. Routine blood cultures are negative. Fortunately, serology is quite specific for the diagnosis. A combination of doxycycline and chloroquine is the current treatment of choice.

PCR and special immunohistochemical techniques may be useful in the diagnosis of these unusual etiologies. Unfortunately, the methodology is not currently available at most hospitals. Broad-range PCR on surgical tissue help to identify more typical organisms (staphylococci and streptococci), whose growth may be suppressed by conventional antibiotic therapy. Although promising, PCR technology may lack specificity in these cases.

Case 3 A 61-year-old executive was admitted with a 4 week history of fevers and fatigue. Three months earlier he had undergone a bovine aortic valve replacement with mitral valve repair. Blood cultures drawn by a local physician grew methicillin-resistant Staphylococcus epidermidis (MRSE). Despite antibiotics, the patient’s fatigue persisted and he returned for further evaluation. On examination, he was afebrile, with a resting pulse of 71 beats/min and a blood pressure of 135/63mm Hg. However, he was very pale. Loud systolic and diastolic murmurs were heard throughout the precordium. His spleen was enlarged and very soft.

The patient underwent urgent reoperation. At surgery, partial aortic valve dehiscence as a result of a large subprosthetic abscess was discovered. Both aortic and mitral valve were replaced. Admission and operative cultures were negative on antibiotic therapy.

Comment: This is a classic presentation of early-onset prosthetic valve endocarditis. Usual organisms are S. epidermidis and S. aureus Streptococci, vancomycin-resistant enterococci (VRE), diphtheroids, gram-negative bacilli, and fungi (yeast and molds) are all seen in this setting, albeit less frequently.

S. epidermidis is of special interest because it produces hemolysins, grows very slowly on cell surfaces, and binds to host and foreign proteins. This biofilm creates a barrier to host defenses and appears to neutralize certain antibiotics. In addition there is clonal variability, with some isolates fully susceptible to oxacillin, while other clones are resistant.

Standard therapy for staphylococcal prosthetic valve endocarditis is oxacillin with gentamicin and rifampin. For oxacillin-resistant species, vancomycin is substituted. Prosthetic valve enterococcal endocarditis resistant to both penicillin and vancomycin is a growing concern. Some medical centers report VRE colonization rates as high as 30%. Therapy is daunting. For strains with a minimum inhibitory concentrations (MIC) less than 128 gr/mL to ampicillin, ampicillin/sulbactam plus an aminoglycoside has been recommended. For strains totally resistant to ampicillin, quinupristin/dalfopristin, linezolid, or daptomycin may be tried, but the overall success rate is probably no better than 50%.

Case 4 A 31-year-old automobile mechanic underwent aortic valve and graft replacement for severe aortic regurgitation with a large aneurysm of the ascending aorta. His post-operative course was complicated by massive bleeding at the distal graft anastomosis, and respiratory failure. After prolonged hospitalization, the patient was discharged improved, but 2 days later he complained of blurred vision and fevers. His wife noted a green hue from his right pupil. The patient was readmitted and started on intravenous acyclovir for presumed acute retinal necrosis. However, several days later, vitrectomy fluid grew Pseudoallescheria boydii.

Therapy was switched to intravenous miconazole but, shortly afterward, the patient suffered a cardiac arrest. Although his pulse and blood pressure were restored, he remained comatose and support was withdrawn. At autopsy, invasive prosthetic aortic valve and graft endocarditis was noted. Blood and tissue cultures also grew P. boydii.

Comment: Fungal prosthetic valve endocarditis is a devastating disease. Predisposing factors are prolonged use of central vascular catheters, often for antibiotic therapy or parenteral nutrition, and immunosuppression. Most success has been reported combining surgery with intravenous antifungal therapy. Patients should be continued on oral suppressive therapy afterward to prevent relapse later in life.

“Pacemaker endocarditis,” seen with increasing frequency, applies to pacemakers, defibrillators, or combinations thereof. Usual causes are skin flora microbes (staphylococci and Propionibacterium species) that gain access through a generator pocket wound. An echocardiogram may not show vegetations unless they extend to the tricuspid valve. Removal of all hardware, combined with intravenous antibiotic therapy, is necessary for cure. Some impacted leads require open heart surgery for removal.

Hospital-associated bacteremia from another source may spread to a heart valve or pacemaker lead, causing endocarditis. S. aureus bacteremia from intravenous catheters, hemodialysis fistula, and surgical wounds is most likely to do this. Patients on hemodialysis may be colonized with methicillin-resistant S. aureus (MRSA), a risk factor for infection. While intra-nasal mupirocin ointment may reduce MRSA colonization transiently, it is probably not effective for long-term prophylaxis.

Case 5 A 54-year-old accountant was admitted with chills and palpitations for several days. A bovine aortic valve prosthesis had been implanted 2 years earlier. The patient had complained of intermittent fevers for 6 months. A single blood culture had grown Propionibacterium acnes. Although a TEE was interpreted as normal, he was treated with intravenous vancomycin. Follow-up blood cultures were negative and a TTE was read as normal.

On examination, the patient was acutely ill with distended neck veins. His pulse was 50 beats/min and blood pressure 110/50mm Hg. Systolic and diastolic murmurs were present. Blood cultures were drawn, and antibiotics started.

An electrocardiogram showed heart block. A temporary pacemaker was placed. A TEE revealed a huge atrial septal abscess with a fistula from the right atrium to the aorta. The patient was taken emergently to surgery, where the prosthesis was found to have nearly completely dehisced. The fistula was resected and the aortic valve replaced with a homograft. Postoperatively the patient remained in cardiogenic shock and died. Admission blood and valve cultures subsequently grew P. acnes.

Comment and Conclusions

Continued fevers despite appropriate antibiotic and medical management are cause for alarm. Ring abscesses may develop. This is a clear indication for surgical intervention. Fevers may also be caused by embolic events (arterial or venous), drug reactions, and intravascular catheter-related infections. Close monitoring is necessary to avoid major events. Vigilance should be maintained for widening pulse pressures and rhythm disturbances as these are ominous signs of progressive infection.

Indications for urgent surgery include progressive valvular dysfunction; aortic root, ring or septal abscesses; large vegetations (greater than l cm in diameter); and organisms such as VRE, MRSA, Pseudomonas species, and fungi refractive to antimicrobial therapy. It is important to note that, even with appropriate therapy and a bacteriologic “cure,” about one half of patients will have enough valve damage to require surgery later in life.

Despite our best efforts, the death rate from infective endocarditis remains in the range of 10–20%. Death is more likely with prosthetic valve endocarditis and when the organism is S. aureus. Patients still succumb from congestive heart failure, embolic phenomenon, and ruptured mycotic aneurysms, just as they did during Osler’s time.

It is clear there is room for improvement in the diagnosis and management of endocarditis. First, we must continue to refine microbiologic techniques, to allow diagnosis more quickly and accurately. Second, we must develop more effective antimicrobial therapy, especially for pathogens resistant to conventional antimicrobials. Third, we must learn how to combat biofilms. Perhaps in the future we can avoid removal of foreign materials. Finally, we must follow our patients closely and pursue timely surgical intervention when indicated. In recent years this has become more difficult, because patients, once stabilized, are often discharged home or to a skilled nursing facility to complete antibiotic therapy.

While we have learned more about infective endocarditis over the past quarter century, the challenges we face today are greater than ever before.

References

1. Osler W. Chronic infectious endocarditis. Q J Med. 1909;2: 219-30.
2. Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med. 2001;345:1318-30.
3. Durack DT, Lukes AS, Bright KD, et al: New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Am J Med. 1994;96:200-9.
4. Salgado AV, Furlan AJ, Keys TF. Neurologic complications of endocarditis: a 12 year experience. Neurology. 1989;39:173-8.
5. Wilson WR, Karchmer AW, Dajani AS, et al: Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, staphylococci and HACEK micro organisms. JAMA. 1995;274:1706-13.
6. Lepidi H, Houpikian P, Liang Z, Raoult D. Cardiac valves in patients with Q-fever endocarditis. J Infect Dis. 2003;187: 1097-106.
7. Bosshard PP, Kronenberg A, Zbinden R, et al. Etiologic diagnosis of infective endocarditis by broad-range PCR. Clin Infect Dis. 2003;37:167-72.
8. Keys TF. Early-onset prosthetic valve endocarditis. Cleve Clin J Med. 1993;60:455-9.
9. Proctor RA. Coagulase-negative staphylococcal infection: a diagnostic and therapeutic challenge. Clin Infect Dis. 2000;31:31-3.
10. Melgar GR, Nasser RM, Gordon SM, et al. Fungal prosthetic-valve endocarditis in 16 patients: an 11-year experience in a tertiary care hospital. Medicine. 1997;76:94-103.
11. Fowler VG, Sanders LL, Kong LK, et al. Infective endocarditis due to Staphylococcus aureus. Clin Infect Dis. 1999;28:106-14.
12. Douglas A, Moore-Gillon J, Eykyn S. Fever during treatment of infective endocarditis. Lancet. 1986;1:1341-3.
13. Tornos MP, Permanyer-Miralda G, Olona J, et al. Long term complications of native valve endocarditis in non-addicts: a 15 year follow up study. Ann Intern Med. 1992;117:567-72.
14. Andrews MM, Von Reyn CF. Patients election criteria and management guidelines for outpatient parenteral antibiotic therapy for native valve infective endocarditis. Clin Infect Dis. 2001;32:203-9.

Background

An appropriately feared complication of operations, surgical site infections (SSIs) are infections associated with high economic costs and significantly worse clinical outcomes (1). Defined as infections of the superficial incision site, deep incision space, or organ space, SSIs add additional cost ranging from $2,700 to $26,000 per episode according to CDC’s National Nosocomial Infections Surveillance System. Patients who develop an SSI have hospital lengths of stay (LOS) in excess of 7 days longer and are 60% more likely to spend time in the intensive care unit than are patients without an SSI. A patient with an SSI is five times more likely to be readmitted to the hospital and is twice as likely to die (2).

Unfortunately, surgical site infections are common. Among healthcare-acquired infections, SSIs rank second only to urinary tract infections in frequency, making them more common than bloodstream infections and nosocomial pneumonia (3). There are approximately 30 million operations annually in the United States and an SSI complicates 2–5% of clean extra-abdominal sites. The rate is much higher for intra-abdominal operations, approaching 20% (1). Because most SSIs begin within 2 hours of contamination, the perioperative period is the most crucial for development of an SSI (4). By offering clinical expertise in the practice guidelines that reduce the risk of SSIs, hospital medicine programs can help patients and hospital systems lower morbidity, mortality, and costs associated with this complication. Adherence to best practices will likely require coordinated, multidisciplinary process improvement.

Several important interventions fall directly under the control of the anesthesia and surgical teams, such as administering perioperative oxygen, ensuring perioperative normothermia, and avoiding shaving of the surgical site. In coordinated quality improvement efforts, members of the operative team should assume direct responsibility for the performance of these measures. But the performance of two important interventions in this decisive period is likely to be significantly enhanced by the presence of focused hospitalist surgical co-management: antimicrobial prophylaxis and perioperative glycemic control (Table 1).

click for large version

Antimicrobial Prophylaxis

Studies overwhelmingly show a marked reduction in the relative risk of SSIs with the use of antibiotic prophylaxis (1). In June 2004, the National Surgical Infection Prevention Project (NSIPP) published an advisory statement on antimicrobial prophylaxis in which it outlined three performance measures for quality improvement in prevention of SSIs:

1. The proportion of patients who have parenteral antimicrobial prophylaxis initiated within 1 hour before surgical incision
2. The proportion of patients provided with a prophylactic antimicrobial agent that is consistent with currently published guidelines, and
3. The proportion of patients whose prophylactic antimicrobial therapy is discontinued within 24 hours after the end of surgery (5)

Pooled data suggest that attention to timing makes a favorable difference in SSI rates (1). Fully administering the appropriate antibiotic within 60 minutes of incision ensures that serum and tissue drug levels exceed the MICs of the most likely contaminating organisms. Dosing the antibiotic immediately prior to the start of surgery also provides the best opportunity to extend therapeutic levels for the duration of the surgery. The fact that anesthesia and surgical teams are in the most practical time-space positions to apply this measure underscores the multi-disciplinary and process-level efforts necessary to reduce SSI rates.

When it comes to the choice of antimicrobial and the duration of its use, hospitalists may find themselves in superior positions of impact. Familiarity with recommendations of the NSIPP advisory statement (summarized in Table 2) promotes evidence-based selection of antibiotic prophylaxis based on patient-specific factors: type of operation and presence of true drug allergies (5). Compared with other members of the surgical co-management team, hospitalists are more likely to be aware of relevant patient-specific risk factors such as the likelihood of colonization with methicillin-resistant Staphylococcus aureus (MRSA). For example, in patients colonized with MRSA, hospitalists might consider vancomycin as the alternative agent for prophylaxis. Free access to the NSIPP advisory statement is available at www.journals.uchicago.edu/CID/journal/issues/v38n12/33257/33257.html.

click for large version

Antimicrobial prophylaxis after wound closure is unnecessary; published evidence demonstrates the non-inferiority of single dose prophylaxis when compared with multiple dose prophylaxis (5). Further, prolonged use of antimicrobial prophylaxis is associated with the emergence of resistant organisms (6-8). By ensuring that the duration of prophylaxis does not exceed 24 hours past the end of the operation, hospitalists can make valuable contributions to public health and cost containment.

Non-Antimicrobial Measures

Several non-antimicrobial measures also significantly reduce SSI rates. Those that fall outside the domain of the hospitalist and into the direct purview of the operative team include high levels of inspired oxygen, maintenance of perioperative normothermia, and use of clippers rather than a razor when hair removal is necessary. The risk of SSIs is directly related to tissue oxygenation. Bacterial infectivity is enhanced and cellular immunity is compromised in hypoperfused, poorly oxygenated tissue (9). The practice of administering perioperative supplemental oxygen (at least 80% FIO2 in intubated patients) reduces the risk of SSI by nearly one-half (1). For non-intubated patients, oxygen at 12 L/min by non-rebreathing face mask applied intra-operatively and for at least 2 hours following surgery leads to similar reductions of SSI rates. Besides being effective, this intervention is inexpensive, has no recognized adverse effects, and carries the added benefit of significantly reducing post-operative nausea and vomiting (4).

Hypothermia also predisposes the surgical wound to infection. Even mild perioperative hypothermia (i.e., core temperature 35-36.5°C) typically occurs in the absence of specific measures to prevent net heat loss. Perioperative hypothermia is the combined result of exposure and anesthetic-induced thermo-dysregulation, with redistribution of core body heat to the periphery (4). Even mild hypothermia causes vasoconstriction which diminishes perfusion, dropping tissue oxygen tension which impairs phagocytosis and oxidative killing by neutrophils (10). Hypothermia also blunts scar formation which further diminishes wound integrity. Active warming of the patient to maintain a core temperature near 36.5°C constitutes the intra-operative standard of care and is effective at reducing the risk of SSIs by as much as two-thirds (1).

Hyperglycemia, an established independent risk factor for an array of adverse outcomes in hospitalized patients, is also an independent risk factor for SSIs across a range of surgical patients (1). Short-term hyperglycemia depresses immune function through nonenzymatic glycosylation of immunoglobulin and by impairing normal leukocyte performance (11). Among diabetic cardiac surgery patients, reduction of hyperglycemia with an intravenous insulin infusion lowered the incidence of deep sternal wound infection by as much as two-thirds (12). While the value of achieving glycemic targets has already been established for a variety of important endpoints and across a range of inpatient populations, hospitalists should stay tuned. As high quality studies emerge proving that glycemic control lowers SSIs among non-cardiac surgical subpopulations, hospitalists may increasingly be relied upon to achieve strict glycemic targets.

By recognizing and coordinating practices known to reduce SSIs, hospitalists can elevate the level of care provided for surgical patients. At the same time, hospitalists can help lower costs and keep the hospital system mindful of public health goals, such as prevention of antimicrobial resistance. While individual hospitalists have key roles to play, the overall approach to SSI reduction calls for a coordinated, multidisciplinary team approach with process and system-level efforts.

Dr. Stein can be contacted at [email protected].

References

1. Auerbach AD. Prevention of surgical site infections. In: Shojania KG, Duncan BW, McDonald KM, et al., eds. Making health care safer: a critical analysis of patient safety practices. Evidence report/technology assessment no. 43. AHRQ publication no. 01-E058. Rockville, MD: Agency for Healthcare Research and Quality, 20 July 2001:221-44.
2. Kirkland KB, Briggs JP, Trivette SL, Wilkinson WE, Sexton DJ. The impact of surgical site infections in the 1990s: attributable mortality, excess length of hospitalization, and extra costs. Infect Control Hosp Epidemiol. 1999;20:725-30.
3. National Nosocomial Infections Surveillance (NNIS) report, data summary from October 1986-April 1996, issued May 1996: a report from the National Nosocomial Infections Surveillance (NNIS) system. Am J Infect Control. 1996;24:380-8.
4. Sessler DI, Akca O. Nonpharmacologic prevention of surgical wound infections. Clin Infect Dis. 2002;35:1397 404.
5. Bratzler D, Houck PM. Surgical Infection Prevention Guidelines Writers Workgroup. Antimicrobial prophylaxis for surgery: an advisory statement from the National Surgical Infection Prevention Project. Clin Infect Dis. 2004;Jun15;38(12):1706-15. E-pub 2004 May 26.
6. Harbarth S, Samore MH, Lichtenberg D, Carmeli Y. Prolonged antibiotic prophylaxis after cardiovascular surgery and its effect on surgical site infections and antimicrobial resistance. Circulation. 2000;101:2916-21.
7. Eggimann P, Pittet D. Infection control in the ICU. Chest. 2001;120:2059-93.
8. Hecker MT, Aron DC, Patel NP, Lehmann MK, Donskey CJ. Unnecessary use of antimicrobials in hospitalized patients: current patterns of misuse with an emphasis on the antianaerobic spectrum of activity. Arch Intern Med. 2003;163:972-8.
9. Hopf HW, Hunt TK, West JM, et al. Wound tissue oxygen tension predicts the risk of wound infection in surgical patients. Arch Surg. 1997;132:997-1005.
10. Kurz A, Sessler DI, Lenhardt RA. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. N Engl J Med. 1996;334:1209-15.
11. Garber AJ, Moghissi ES, Bransome ED Jr, et al. American College of Endocrinology Task Force on Inpatient Diabetes Metabolic Control. American College of Endocrinology position statement on inpatient diabetes and metabolic control. Endocr Pract. 2004;Mar-Apr;10Suppl2:4-9.
12. Furnary AP, Zerr K, Grunkemeier GL, Starr A. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures [with discussion]. Ann Thorac Surg. 1999;67:352-62.

Background

An appropriately feared complication of operations, surgical site infections (SSIs) are infections associated with high economic costs and significantly worse clinical outcomes (1). Defined as infections of the superficial incision site, deep incision space, or organ space, SSIs add additional cost ranging from $2,700 to $26,000 per episode according to CDC’s National Nosocomial Infections Surveillance System. Patients who develop an SSI have hospital lengths of stay (LOS) in excess of 7 days longer and are 60% more likely to spend time in the intensive care unit than are patients without an SSI. A patient with an SSI is five times more likely to be readmitted to the hospital and is twice as likely to die (2).

Unfortunately, surgical site infections are common. Among healthcare-acquired infections, SSIs rank second only to urinary tract infections in frequency, making them more common than bloodstream infections and nosocomial pneumonia (3). There are approximately 30 million operations annually in the United States and an SSI complicates 2–5% of clean extra-abdominal sites. The rate is much higher for intra-abdominal operations, approaching 20% (1). Because most SSIs begin within 2 hours of contamination, the perioperative period is the most crucial for development of an SSI (4). By offering clinical expertise in the practice guidelines that reduce the risk of SSIs, hospital medicine programs can help patients and hospital systems lower morbidity, mortality, and costs associated with this complication. Adherence to best practices will likely require coordinated, multidisciplinary process improvement.

Several important interventions fall directly under the control of the anesthesia and surgical teams, such as administering perioperative oxygen, ensuring perioperative normothermia, and avoiding shaving of the surgical site. In coordinated quality improvement efforts, members of the operative team should assume direct responsibility for the performance of these measures. But the performance of two important interventions in this decisive period is likely to be significantly enhanced by the presence of focused hospitalist surgical co-management: antimicrobial prophylaxis and perioperative glycemic control (Table 1).

click for large version

Antimicrobial Prophylaxis

Studies overwhelmingly show a marked reduction in the relative risk of SSIs with the use of antibiotic prophylaxis (1). In June 2004, the National Surgical Infection Prevention Project (NSIPP) published an advisory statement on antimicrobial prophylaxis in which it outlined three performance measures for quality improvement in prevention of SSIs:

1. The proportion of patients who have parenteral antimicrobial prophylaxis initiated within 1 hour before surgical incision
2. The proportion of patients provided with a prophylactic antimicrobial agent that is consistent with currently published guidelines, and
3. The proportion of patients whose prophylactic antimicrobial therapy is discontinued within 24 hours after the end of surgery (5)

Pooled data suggest that attention to timing makes a favorable difference in SSI rates (1). Fully administering the appropriate antibiotic within 60 minutes of incision ensures that serum and tissue drug levels exceed the MICs of the most likely contaminating organisms. Dosing the antibiotic immediately prior to the start of surgery also provides the best opportunity to extend therapeutic levels for the duration of the surgery. The fact that anesthesia and surgical teams are in the most practical time-space positions to apply this measure underscores the multi-disciplinary and process-level efforts necessary to reduce SSI rates.

When it comes to the choice of antimicrobial and the duration of its use, hospitalists may find themselves in superior positions of impact. Familiarity with recommendations of the NSIPP advisory statement (summarized in Table 2) promotes evidence-based selection of antibiotic prophylaxis based on patient-specific factors: type of operation and presence of true drug allergies (5). Compared with other members of the surgical co-management team, hospitalists are more likely to be aware of relevant patient-specific risk factors such as the likelihood of colonization with methicillin-resistant Staphylococcus aureus (MRSA). For example, in patients colonized with MRSA, hospitalists might consider vancomycin as the alternative agent for prophylaxis. Free access to the NSIPP advisory statement is available at www.journals.uchicago.edu/CID/journal/issues/v38n12/33257/33257.html.

click for large version

Antimicrobial prophylaxis after wound closure is unnecessary; published evidence demonstrates the non-inferiority of single dose prophylaxis when compared with multiple dose prophylaxis (5). Further, prolonged use of antimicrobial prophylaxis is associated with the emergence of resistant organisms (6-8). By ensuring that the duration of prophylaxis does not exceed 24 hours past the end of the operation, hospitalists can make valuable contributions to public health and cost containment.

Non-Antimicrobial Measures

Several non-antimicrobial measures also significantly reduce SSI rates. Those that fall outside the domain of the hospitalist and into the direct purview of the operative team include high levels of inspired oxygen, maintenance of perioperative normothermia, and use of clippers rather than a razor when hair removal is necessary. The risk of SSIs is directly related to tissue oxygenation. Bacterial infectivity is enhanced and cellular immunity is compromised in hypoperfused, poorly oxygenated tissue (9). The practice of administering perioperative supplemental oxygen (at least 80% FIO2 in intubated patients) reduces the risk of SSI by nearly one-half (1). For non-intubated patients, oxygen at 12 L/min by non-rebreathing face mask applied intra-operatively and for at least 2 hours following surgery leads to similar reductions of SSI rates. Besides being effective, this intervention is inexpensive, has no recognized adverse effects, and carries the added benefit of significantly reducing post-operative nausea and vomiting (4).

Hypothermia also predisposes the surgical wound to infection. Even mild perioperative hypothermia (i.e., core temperature 35-36.5°C) typically occurs in the absence of specific measures to prevent net heat loss. Perioperative hypothermia is the combined result of exposure and anesthetic-induced thermo-dysregulation, with redistribution of core body heat to the periphery (4). Even mild hypothermia causes vasoconstriction which diminishes perfusion, dropping tissue oxygen tension which impairs phagocytosis and oxidative killing by neutrophils (10). Hypothermia also blunts scar formation which further diminishes wound integrity. Active warming of the patient to maintain a core temperature near 36.5°C constitutes the intra-operative standard of care and is effective at reducing the risk of SSIs by as much as two-thirds (1).

Hyperglycemia, an established independent risk factor for an array of adverse outcomes in hospitalized patients, is also an independent risk factor for SSIs across a range of surgical patients (1). Short-term hyperglycemia depresses immune function through nonenzymatic glycosylation of immunoglobulin and by impairing normal leukocyte performance (11). Among diabetic cardiac surgery patients, reduction of hyperglycemia with an intravenous insulin infusion lowered the incidence of deep sternal wound infection by as much as two-thirds (12). While the value of achieving glycemic targets has already been established for a variety of important endpoints and across a range of inpatient populations, hospitalists should stay tuned. As high quality studies emerge proving that glycemic control lowers SSIs among non-cardiac surgical subpopulations, hospitalists may increasingly be relied upon to achieve strict glycemic targets.

By recognizing and coordinating practices known to reduce SSIs, hospitalists can elevate the level of care provided for surgical patients. At the same time, hospitalists can help lower costs and keep the hospital system mindful of public health goals, such as prevention of antimicrobial resistance. While individual hospitalists have key roles to play, the overall approach to SSI reduction calls for a coordinated, multidisciplinary team approach with process and system-level efforts.

Dr. Stein can be contacted at [email protected].

References

1. Auerbach AD. Prevention of surgical site infections. In: Shojania KG, Duncan BW, McDonald KM, et al., eds. Making health care safer: a critical analysis of patient safety practices. Evidence report/technology assessment no. 43. AHRQ publication no. 01-E058. Rockville, MD: Agency for Healthcare Research and Quality, 20 July 2001:221-44.
2. Kirkland KB, Briggs JP, Trivette SL, Wilkinson WE, Sexton DJ. The impact of surgical site infections in the 1990s: attributable mortality, excess length of hospitalization, and extra costs. Infect Control Hosp Epidemiol. 1999;20:725-30.
3. National Nosocomial Infections Surveillance (NNIS) report, data summary from October 1986-April 1996, issued May 1996: a report from the National Nosocomial Infections Surveillance (NNIS) system. Am J Infect Control. 1996;24:380-8.
4. Sessler DI, Akca O. Nonpharmacologic prevention of surgical wound infections. Clin Infect Dis. 2002;35:1397 404.
5. Bratzler D, Houck PM. Surgical Infection Prevention Guidelines Writers Workgroup. Antimicrobial prophylaxis for surgery: an advisory statement from the National Surgical Infection Prevention Project. Clin Infect Dis. 2004;Jun15;38(12):1706-15. E-pub 2004 May 26.
6. Harbarth S, Samore MH, Lichtenberg D, Carmeli Y. Prolonged antibiotic prophylaxis after cardiovascular surgery and its effect on surgical site infections and antimicrobial resistance. Circulation. 2000;101:2916-21.
7. Eggimann P, Pittet D. Infection control in the ICU. Chest. 2001;120:2059-93.
8. Hecker MT, Aron DC, Patel NP, Lehmann MK, Donskey CJ. Unnecessary use of antimicrobials in hospitalized patients: current patterns of misuse with an emphasis on the antianaerobic spectrum of activity. Arch Intern Med. 2003;163:972-8.
9. Hopf HW, Hunt TK, West JM, et al. Wound tissue oxygen tension predicts the risk of wound infection in surgical patients. Arch Surg. 1997;132:997-1005.
10. Kurz A, Sessler DI, Lenhardt RA. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. N Engl J Med. 1996;334:1209-15.
11. Garber AJ, Moghissi ES, Bransome ED Jr, et al. American College of Endocrinology Task Force on Inpatient Diabetes Metabolic Control. American College of Endocrinology position statement on inpatient diabetes and metabolic control. Endocr Pract. 2004;Mar-Apr;10Suppl2:4-9.
12. Furnary AP, Zerr K, Grunkemeier GL, Starr A. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures [with discussion]. Ann Thorac Surg. 1999;67:352-62.

Background

An appropriately feared complication of operations, surgical site infections (SSIs) are infections associated with high economic costs and significantly worse clinical outcomes (1). Defined as infections of the superficial incision site, deep incision space, or organ space, SSIs add additional cost ranging from $2,700 to $26,000 per episode according to CDC’s National Nosocomial Infections Surveillance System. Patients who develop an SSI have hospital lengths of stay (LOS) in excess of 7 days longer and are 60% more likely to spend time in the intensive care unit than are patients without an SSI. A patient with an SSI is five times more likely to be readmitted to the hospital and is twice as likely to die (2).

Unfortunately, surgical site infections are common. Among healthcare-acquired infections, SSIs rank second only to urinary tract infections in frequency, making them more common than bloodstream infections and nosocomial pneumonia (3). There are approximately 30 million operations annually in the United States and an SSI complicates 2–5% of clean extra-abdominal sites. The rate is much higher for intra-abdominal operations, approaching 20% (1). Because most SSIs begin within 2 hours of contamination, the perioperative period is the most crucial for development of an SSI (4). By offering clinical expertise in the practice guidelines that reduce the risk of SSIs, hospital medicine programs can help patients and hospital systems lower morbidity, mortality, and costs associated with this complication. Adherence to best practices will likely require coordinated, multidisciplinary process improvement.

Several important interventions fall directly under the control of the anesthesia and surgical teams, such as administering perioperative oxygen, ensuring perioperative normothermia, and avoiding shaving of the surgical site. In coordinated quality improvement efforts, members of the operative team should assume direct responsibility for the performance of these measures. But the performance of two important interventions in this decisive period is likely to be significantly enhanced by the presence of focused hospitalist surgical co-management: antimicrobial prophylaxis and perioperative glycemic control (Table 1).

click for large version

Antimicrobial Prophylaxis

Studies overwhelmingly show a marked reduction in the relative risk of SSIs with the use of antibiotic prophylaxis (1). In June 2004, the National Surgical Infection Prevention Project (NSIPP) published an advisory statement on antimicrobial prophylaxis in which it outlined three performance measures for quality improvement in prevention of SSIs:

1. The proportion of patients who have parenteral antimicrobial prophylaxis initiated within 1 hour before surgical incision
2. The proportion of patients provided with a prophylactic antimicrobial agent that is consistent with currently published guidelines, and
3. The proportion of patients whose prophylactic antimicrobial therapy is discontinued within 24 hours after the end of surgery (5)

Pooled data suggest that attention to timing makes a favorable difference in SSI rates (1). Fully administering the appropriate antibiotic within 60 minutes of incision ensures that serum and tissue drug levels exceed the MICs of the most likely contaminating organisms. Dosing the antibiotic immediately prior to the start of surgery also provides the best opportunity to extend therapeutic levels for the duration of the surgery. The fact that anesthesia and surgical teams are in the most practical time-space positions to apply this measure underscores the multi-disciplinary and process-level efforts necessary to reduce SSI rates.

When it comes to the choice of antimicrobial and the duration of its use, hospitalists may find themselves in superior positions of impact. Familiarity with recommendations of the NSIPP advisory statement (summarized in Table 2) promotes evidence-based selection of antibiotic prophylaxis based on patient-specific factors: type of operation and presence of true drug allergies (5). Compared with other members of the surgical co-management team, hospitalists are more likely to be aware of relevant patient-specific risk factors such as the likelihood of colonization with methicillin-resistant Staphylococcus aureus (MRSA). For example, in patients colonized with MRSA, hospitalists might consider vancomycin as the alternative agent for prophylaxis. Free access to the NSIPP advisory statement is available at www.journals.uchicago.edu/CID/journal/issues/v38n12/33257/33257.html.

click for large version

Antimicrobial prophylaxis after wound closure is unnecessary; published evidence demonstrates the non-inferiority of single dose prophylaxis when compared with multiple dose prophylaxis (5). Further, prolonged use of antimicrobial prophylaxis is associated with the emergence of resistant organisms (6-8). By ensuring that the duration of prophylaxis does not exceed 24 hours past the end of the operation, hospitalists can make valuable contributions to public health and cost containment.

Non-Antimicrobial Measures

Several non-antimicrobial measures also significantly reduce SSI rates. Those that fall outside the domain of the hospitalist and into the direct purview of the operative team include high levels of inspired oxygen, maintenance of perioperative normothermia, and use of clippers rather than a razor when hair removal is necessary. The risk of SSIs is directly related to tissue oxygenation. Bacterial infectivity is enhanced and cellular immunity is compromised in hypoperfused, poorly oxygenated tissue (9). The practice of administering perioperative supplemental oxygen (at least 80% FIO2 in intubated patients) reduces the risk of SSI by nearly one-half (1). For non-intubated patients, oxygen at 12 L/min by non-rebreathing face mask applied intra-operatively and for at least 2 hours following surgery leads to similar reductions of SSI rates. Besides being effective, this intervention is inexpensive, has no recognized adverse effects, and carries the added benefit of significantly reducing post-operative nausea and vomiting (4).

Hypothermia also predisposes the surgical wound to infection. Even mild perioperative hypothermia (i.e., core temperature 35-36.5°C) typically occurs in the absence of specific measures to prevent net heat loss. Perioperative hypothermia is the combined result of exposure and anesthetic-induced thermo-dysregulation, with redistribution of core body heat to the periphery (4). Even mild hypothermia causes vasoconstriction which diminishes perfusion, dropping tissue oxygen tension which impairs phagocytosis and oxidative killing by neutrophils (10). Hypothermia also blunts scar formation which further diminishes wound integrity. Active warming of the patient to maintain a core temperature near 36.5°C constitutes the intra-operative standard of care and is effective at reducing the risk of SSIs by as much as two-thirds (1).

Hyperglycemia, an established independent risk factor for an array of adverse outcomes in hospitalized patients, is also an independent risk factor for SSIs across a range of surgical patients (1). Short-term hyperglycemia depresses immune function through nonenzymatic glycosylation of immunoglobulin and by impairing normal leukocyte performance (11). Among diabetic cardiac surgery patients, reduction of hyperglycemia with an intravenous insulin infusion lowered the incidence of deep sternal wound infection by as much as two-thirds (12). While the value of achieving glycemic targets has already been established for a variety of important endpoints and across a range of inpatient populations, hospitalists should stay tuned. As high quality studies emerge proving that glycemic control lowers SSIs among non-cardiac surgical subpopulations, hospitalists may increasingly be relied upon to achieve strict glycemic targets.

By recognizing and coordinating practices known to reduce SSIs, hospitalists can elevate the level of care provided for surgical patients. At the same time, hospitalists can help lower costs and keep the hospital system mindful of public health goals, such as prevention of antimicrobial resistance. While individual hospitalists have key roles to play, the overall approach to SSI reduction calls for a coordinated, multidisciplinary team approach with process and system-level efforts.

Dr. Stein can be contacted at [email protected].

References

1. Auerbach AD. Prevention of surgical site infections. In: Shojania KG, Duncan BW, McDonald KM, et al., eds. Making health care safer: a critical analysis of patient safety practices. Evidence report/technology assessment no. 43. AHRQ publication no. 01-E058. Rockville, MD: Agency for Healthcare Research and Quality, 20 July 2001:221-44.
2. Kirkland KB, Briggs JP, Trivette SL, Wilkinson WE, Sexton DJ. The impact of surgical site infections in the 1990s: attributable mortality, excess length of hospitalization, and extra costs. Infect Control Hosp Epidemiol. 1999;20:725-30.
3. National Nosocomial Infections Surveillance (NNIS) report, data summary from October 1986-April 1996, issued May 1996: a report from the National Nosocomial Infections Surveillance (NNIS) system. Am J Infect Control. 1996;24:380-8.
4. Sessler DI, Akca O. Nonpharmacologic prevention of surgical wound infections. Clin Infect Dis. 2002;35:1397 404.
5. Bratzler D, Houck PM. Surgical Infection Prevention Guidelines Writers Workgroup. Antimicrobial prophylaxis for surgery: an advisory statement from the National Surgical Infection Prevention Project. Clin Infect Dis. 2004;Jun15;38(12):1706-15. E-pub 2004 May 26.
6. Harbarth S, Samore MH, Lichtenberg D, Carmeli Y. Prolonged antibiotic prophylaxis after cardiovascular surgery and its effect on surgical site infections and antimicrobial resistance. Circulation. 2000;101:2916-21.
7. Eggimann P, Pittet D. Infection control in the ICU. Chest. 2001;120:2059-93.
8. Hecker MT, Aron DC, Patel NP, Lehmann MK, Donskey CJ. Unnecessary use of antimicrobials in hospitalized patients: current patterns of misuse with an emphasis on the antianaerobic spectrum of activity. Arch Intern Med. 2003;163:972-8.
9. Hopf HW, Hunt TK, West JM, et al. Wound tissue oxygen tension predicts the risk of wound infection in surgical patients. Arch Surg. 1997;132:997-1005.
10. Kurz A, Sessler DI, Lenhardt RA. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. N Engl J Med. 1996;334:1209-15.
11. Garber AJ, Moghissi ES, Bransome ED Jr, et al. American College of Endocrinology Task Force on Inpatient Diabetes Metabolic Control. American College of Endocrinology position statement on inpatient diabetes and metabolic control. Endocr Pract. 2004;Mar-Apr;10Suppl2:4-9.
12. Furnary AP, Zerr K, Grunkemeier GL, Starr A. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures [with discussion]. Ann Thorac Surg. 1999;67:352-62.

Background Acute bacterial meningitis is an inflammation of the meninges, which results from bacterially mediated recruitment and activation of inflammatory cells in the cerebrospinal fluid (CSF). Bacterial meningitis was an almost invariably fatal disease at the start of the 20th century. With the development of and advancements in antimicrobial therapy, however, there has been a significant reduction in the mortality rate, although this has remained stable during the past 20 years (1). One large study of adults with community-acquired bacterial meningitis reported an overall mortality rate of 21%, including a 30% mortality rate associated with Streptococcus pneumoniae meningitis and a 7% mortality rate for Neisseria meningitidis (2). In adults, the most commonly identified organisms are S. pneumoniae (40–50%), Neisseria meningitidis (14–37%), and Listeria monocytogenes (4–10%) (2-4).

Clinical Presentation

Bacterial meningitis is a serious illness that often progresses rapidly. The classic clinical presentation consists of fever, nuchal rigidity, and mental status change (3). One large review of 10 critically appraised studies showed that almost all (99–100%) of the patients with bacterial meningitis presented with at least one of these clinical findings; and 95% of the patients had at least 2 of the clinical findings (5). In contrast, less than half of the patients presented with all 3 findings. Thus, in the absence of all 3 of these classic findings, the diagnosis of meningitis can virtually be dismissed, and further evaluation for meningitis need not be pursued. Individually, fever was the most common presenting finding, with a sensitivity of 85%. Nuchal rigidity had a sensitivity of 70%, and mental status change was 67%. While these physical examination findings may be of value in determining the diagnosis of bacterial meningitis, the accuracy of the clinical history including features such as headache, nausea and vomiting, and neck pain was too low to be of use clinically.

Signs of meningeal irritation may be of benefit in the clinical diagnosis of bacterial meningitis. Kernig’s and Brudzinski’s signs were first described nearly a century ago and have been used by most clinicians in the clinical realm; however, their diagnostic utility has been evaluated only in a limited number of studies. Kernig’s sign is positive when a patient in the supine position with his/her hips flexed at 90 degrees develops pain in the lower back or posterior thigh during an attempt to extend the knee. Brudzinski’s sign is positive when a patient in the supine position whose neck is passively flexed responds with flexion of his/her knees and hips. Recently, a bedside maneuver called jolt accentuation of headache was found to be potentially useful. In this maneuver, the patient is asked to turn his/her head horizontally 2–3 times per second, and a worsening headache is considered a positive sign. A small study showed that this maneuver had 97% sensitivity and 60% specificity for patients with CSF pleocytosis (6).

Other clinical manifestations in patients with bacterial meningitis include photophobia, seizure, rash, focal neurologic deficits, and signs of increased intracranial pressure. While these various findings may be present in many patients with bacterial meningitis, their sensitivities have been found to be low. Thus, their clinical utility in ruling out the diagnosis of bacterial meningitis is limited (5).

Laboratory Findings

Any patient who presents with a reasonable likelihood of having bacterial meningitis should undergo a lumbar puncture (LP) to evaluate the CSF as soon as possible. The initial CSF study should measure the opening pressure. One study demonstrated that 39% of patients with bacterial meningitis had opening pressures greater than 300 mg H₂0 (3). Other CSF laboratory studies should be sent for analysis in 4 sterile tubes filled with approximately 1 mL of CSF each. The first tube is typically reserved for gram stain and culture. The gram stain is positive in about 70% of patients with bacterial meningitis, and the culture will be positive in about 80% of cases. The second tube is sent for protein and glucose levels. Patients who have markedly elevated CSF protein counts (>500 mg/dL) and low glucose levels (<45 mg/dL, or ratio of serum: CSF glucose levels <0.4) are likely to have bacterial meningitis. The third tube is sent for cell count and differential. Patients with bacterial meningitis are likely to have >10 WBC/μL that are predominantly polymorphonucleocytes and have few or no red blood cells in the absence of a traumatic LP. We recommend the fourth tube be used for any viral, fungal, or other miscellaneous studies. In addition to the CSF studies, other diagnostic evaluations should include blood cultures, complete blood count with platelets and differential (CBCPD), and basic chemistry labs.

The CSF studies described above are the primary tools in diagnosing bacterial meningitis; however, there are other studies that may be helpful in certain clinical settings. Latex agglutination tests for bacterial antigens may be used in cases in which bacterial meningitis remains a possible diagnosis despite negative CSF studies. This test is available for S. pneumoniae, N. meningitidis, H. influenzae type B, group B Streptococcus, and E. coli. The polymerase chain reaction (PCR) test of the CSF has been developed for some bacterial pathogens including S. pneumoniae, N. meningitidis, H. influenzae type B, and Mycobacterium tuberculosis. The limulus amebocyte lysate assay is a very sensitive test for gram-negative endotoxins, which may aid in identifying gram-negative organisms as potential pathogens in the CSF. While these alternative CSF diagnostic tests are available, many laboratories do not perform the tests on site and require send-out to a specialty laboratory. The time required for this may negate the clinical utility of these tests.

Role of Brain Imaging

The decision to obtain a brain imaging study prior to performing an LP has been a controversial issue for both patient safety and medical-legal reasons. Two large studies have been published in an attempt to derive a clinically useful decision analysis tool (7,8). In summary, the studies found that 5 clinical features were associated with an abnormal head cranial tomography (CT) scan. These were:

1. Age >60 years
2. Immunocompromised state
3. Any history of central nervous system (CNS) disease
4. A history of seizure within 1 week prior to presentation
5. Presence of a focal neurologic abnormality, including altered level of consciousness, inability to answer or follow 2 consecutive requests, gaze palsy, abnormal visual fields, facial palsy, arm or leg drift, and abnormal language.

In patients with none of these findings, there was a 97% negative predictive value of having an abnormal CT scan, with the few patients with positive scans nonetheless tolerating LP without adverse effects. Thus, in patients with none of these findings, it appears that an LP can safely be performed without obtaining a CT scan. One study also demonstrated that patients who underwent a CT scan prior to their LP waited, on average, 2 hours longer to get an LP; with antibiotic administration delayed by an average of 1 hour (8). Antibiotic administration should not be delayed in any patient suspected of having bacterial meningitis, whether brain imaging is performed or not.

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Differential Diagnosis

Given the severe nature of this disease, the diagnosis of bacterial meningitis must be differentiated from other conditions that may present in similar ways. Infectious causes that may present similarly to bacterial meningitis include other types of meningitis (viral, tuberculous, Lyme disease, syphilitic), viral encephalitis, Rocky Mountain spotted fever, fungal meningitis, parasitic causes, brain abscess, and epidural and subdural empyema. Other infectious etiologies not originating from the CNS may be mistaken for bacterial meningitis when these patients present with concomitant mental-status changes. This is especially common in elderly patients with pneumonia and urinary tract infections. Other noninfectious considerations include a CNS bleed such as a subarachnoid hemorrhage, drug-induced aseptic meningitis, and CNS vasculitis.

Treatment

When the patient’s presentation is suggestive of bacterial meningitis, empiric antibiotics should be administered without delay, while awaiting diagnostic evaluation. The initial dose of antibiotics should not alter the results of the diagnostic studies significantly. The choice of antibiotics is based upon the most likely offending organism from epidemiologic data and underlying predisposing conditions. S. pneumoniae and N. meningitidis are the 2 most common causes of bacterial meningitis in adults.

The development of antibiotic resistance by S. pneumoniae to penicillin and cephalosporins has been one of the major developments in the past 20 years. Due to this resistance, the recommended empiric therapy is a combination of a third-generation cephalosporin (ceftriaxone or cefotaxime) and vancomycin. For special cases, additional or alternative therapy should be given. Ampicillin should be added for patients at risk for Listeria monocytogenes; and postsurgical or post-trauma patients should have expanded coverage to include staphylococcal and gram-negative infections. Table 1 lists the recommended antibiotic therapy for patients with possible bacterial meningitis, along with the most commonly associated organisms.

Once the offending organism has been identified, antibiotic therapy should be narrowed to target the bacteria based on laboratory minimal inhibitory concentrations (MIC). The antibiotic should also have excellent CSF penetration and bactericidal activity. For S. pneumoniae that are susceptible to penicillin, penicillin G and ampicillin remain the therapy of choice (9). The increasing trend toward antibiotic resistance by S. pneumoniae has increased the use of vancomycin as therapy. In patients with resistant strains of S. pneumoniae, however, vancomycin should not be used alone. Vancomycin should be used in combination with a third-generation cephalosporin while keeping the serum vancomycin levels in the range of 15–20 μg/mL (10). It is imperative that the treatment course outlined be completed through its full duration. Table 2 lists specific antibiotic therapy with dosages and recommended duration of therapy based on isolated organisms.

click for large version

Adjunctive Therapy

The release and production of inflammatory cytokines in bacterial meningitis is thought to be a major cause of adverse outcomes. To counteract this inflammatory process, use of adjunctive steroids in patients with bacterial meningitis has been evaluated. Initial data from children with bacterial meningitis, mostly due to H. influenzae and S. pneumoniae, demonstrated improved neurologic outcomes, with significant reductions in deafness, in patients treated with dexamethasone as an adjunctive therapy to antibiotics (11). In adults with bacterial meningitis, a recent major trial demonstrated that treatment with adjunctive steroids, along with antibiotics, led to significant improvement in mortality and morbidity in patients with meningitis due to S. pneumoniae (12). Among patients with meningococcal meningitis, there was a trend toward improved outcomes. Patients with suspected pneumococcal meningitis should receive their first dose of dexamethasone 20–30 minutes prior to or at the same time as the initial antibiotic administration. The recommended dose and duration is 0.15 mg/kg every 6 hours for 2 to 4 days. The use of dexamethasone appears to have no benefit if administered after antibiotics have already been given, and data are lacking for patients with meningitis due to organisms other than S. pneumoniae. Most experts recommend against the use of adjunctive corticosteroids in these cases (10-13). Several questions, however, remain unanswered with regard to adjunctive corticosteroid use. These include the optimal duration of treatment, whether the penetration of vancomycin into the CSF is significantly decreased by dexamethasone, and whether they should be administered to immunocompromised patients (14).

Prevention

Currently, prevention of some types of bacterial meningitis can be accomplished by appropriate use of vaccines, or through antibiotic chemoprophylaxis in certain situations. For adults, vaccines are available against the 2 most common causes of bacterial meningitis. The 23 polyvalent pneumococcal vaccine is recommended for all adults >65 years of age and for anyone age >2 with a compromised immune status. The meningococcal vaccine is available as a quadravalent vaccine (serotypes A, C, Y, and W-135) and should be administered to anyone with functional asplenia, terminal complement deficiencies, those traveling to endemic areas of meningococcal meningitis, and any college freshman requesting the vaccine who will be living in college dormitories (15).

Antibiotic chemoprophylaxis can be administered to individuals who have had close contact with an index patient with meningococcal meningitis. Antibiotics should be administered as soon as exposure has been determined. There are several options available for meningococcal meningitis exposure. Ciprofloxacin is probably the simplest regimen due to its 1-time 500-mg oral dose. Other options include rifampin 600 mg every 12 hours ×4 doses and ceftriaxone 250 mg IM as a 1-time dose. Pregnant women should avoid ciprofloxacin and rifampin due to their potential teratogenic effects.

Prognosis and Follow-up

Prognosis of bacterial meningitis is closely linked to the causative organism, the severity of disease at the time of presentation, and the speed at which the disease progresses. One large retrospective study demonstrated in-hospital mortality rates of 25% for S. pneumoniae, 10% for N. meningitidis, and 21% for L. monocytogenes. Conditions associated with an increased risk of mortality included age >60, state of obtundation on admission, and development of seizure within 24 hours of admission. This study also showed that 21% of patients developed some type of neurologic deficits, and, overall, 9% had persistence of these deficits at time of discharge (3). Another study showed that baseline features of hypotension, mental status changes, and seizures were associated with increased mortality and neurologic morbidity (16). A more recent large study evaluating the efficacy of adjunctive corticosteroids reported a mortality rate of 15% in the control arm, with mortality of 34% in patients infected with S. pneumoniae (12). Another study suggested that if patients had a rapid progression of their disease, this seemed to correlate with worse outcomes. These investigators found an uncertain correlation between antibiotic timing and unfavorable outcomes (16).

Patients discharged from the hospital should have close follow-up with their primary care physician or infectious disease specialist. Evaluation in the short-term should focus on any complications that may have developed as a result of the bacterial meningitis; such as mental status change, seizure, focal neurologic deficits, and hearing loss. Long-term evaluations should also address cognitive functioning and the neuropsychiatric well-being of the patient, in addition to those issues addressed during short-term follow-up (11, 12).

Dr. Kim may be reached at [email protected].

References

1. Swartz, Morton N. Bacterial Meningitis—A View of the Past 90 Years. N Engl J Med. 2004;351:1826-8.
2. van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med. 2004;351:1849-59.
3. Durand ML, Calderwood SB, Weber DJ, et al. Acute Bacterial Meningitis in Adults. A review of 493 episodes. N Engl J Med. 1993;328:21-8.
4. Schuchat A, Robinson K, Wenger J, et al. Bacterial meningitis in the United States in 1995. Active Surveillance Team. N Engl J Med. 1997;337:970-6.
5. Attia J, Hatala R, Cook DJ, Wong JG. The rational clinical examination. Does this adult patient have acute meningitis? JAMA. 1999;282:175-181.
6. Uchihara T, Tsukagoshi H. Jolt accentuation of headache: the most sensitive sign of CSF pleocytosis. Headache. 1991;31:167-71.
7. Gopal AK, Whitehouse JD, Simel DL, Corey RG. Cranial computed tomography before lumbar puncture: a prospective clinical evaluation. Arch Intern Med. 1999;159:2681-5.
8. Hasbun R, Abrahams J, Jekel J, Quagliarello VJ. Computed tomography of the head before LP in adults with suspected meningitis. N Engl J Med. 2001;345:1727-33.
9. Quagliarello VJ, Scheld WM. Treatment of bacterial meningitis. N Engl J Med. 1997;336:708-16.
10. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice Guidelines for the Management of Bacterial Meningitis. Clin Infect Dis. 2004;39:1267-84.
11. McIntyre PB, Berkey CS, King SM, et al. Dexamethasone as adjunctive therapy in bacterial meningitis. A meta-analysis of randomized clinical trials since 1988. JAMA. 1997;278:928-31.
12. de Gans J, van de Beek D Dexamethasone in adults with bacterial meningitis. N Engl J Med. 2002;347:1549-56.
13. van de Beek D, de Gans J, McIntyre P, Prasad K. Steroids in adults with acute bacterial meningitis: a systematic review. Lancet Infect Dis 2004;4: 139-43.
14. Pile JC, Longworth DL. Should adults with suspected acute bacterial meningitis get adjunctive corticosteroids? Cleve Clin J Med. 2005;72:67-70.
15. Control and prevention of meningococcal disease and control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1997;4613-21.
16. Aronin SI, Peduzzi P, Quagliarello VJ. Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med. 1998;129:862-9.

Background Acute bacterial meningitis is an inflammation of the meninges, which results from bacterially mediated recruitment and activation of inflammatory cells in the cerebrospinal fluid (CSF). Bacterial meningitis was an almost invariably fatal disease at the start of the 20th century. With the development of and advancements in antimicrobial therapy, however, there has been a significant reduction in the mortality rate, although this has remained stable during the past 20 years (1). One large study of adults with community-acquired bacterial meningitis reported an overall mortality rate of 21%, including a 30% mortality rate associated with Streptococcus pneumoniae meningitis and a 7% mortality rate for Neisseria meningitidis (2). In adults, the most commonly identified organisms are S. pneumoniae (40–50%), Neisseria meningitidis (14–37%), and Listeria monocytogenes (4–10%) (2-4).

Clinical Presentation

Bacterial meningitis is a serious illness that often progresses rapidly. The classic clinical presentation consists of fever, nuchal rigidity, and mental status change (3). One large review of 10 critically appraised studies showed that almost all (99–100%) of the patients with bacterial meningitis presented with at least one of these clinical findings; and 95% of the patients had at least 2 of the clinical findings (5). In contrast, less than half of the patients presented with all 3 findings. Thus, in the absence of all 3 of these classic findings, the diagnosis of meningitis can virtually be dismissed, and further evaluation for meningitis need not be pursued. Individually, fever was the most common presenting finding, with a sensitivity of 85%. Nuchal rigidity had a sensitivity of 70%, and mental status change was 67%. While these physical examination findings may be of value in determining the diagnosis of bacterial meningitis, the accuracy of the clinical history including features such as headache, nausea and vomiting, and neck pain was too low to be of use clinically.

Signs of meningeal irritation may be of benefit in the clinical diagnosis of bacterial meningitis. Kernig’s and Brudzinski’s signs were first described nearly a century ago and have been used by most clinicians in the clinical realm; however, their diagnostic utility has been evaluated only in a limited number of studies. Kernig’s sign is positive when a patient in the supine position with his/her hips flexed at 90 degrees develops pain in the lower back or posterior thigh during an attempt to extend the knee. Brudzinski’s sign is positive when a patient in the supine position whose neck is passively flexed responds with flexion of his/her knees and hips. Recently, a bedside maneuver called jolt accentuation of headache was found to be potentially useful. In this maneuver, the patient is asked to turn his/her head horizontally 2–3 times per second, and a worsening headache is considered a positive sign. A small study showed that this maneuver had 97% sensitivity and 60% specificity for patients with CSF pleocytosis (6).

Other clinical manifestations in patients with bacterial meningitis include photophobia, seizure, rash, focal neurologic deficits, and signs of increased intracranial pressure. While these various findings may be present in many patients with bacterial meningitis, their sensitivities have been found to be low. Thus, their clinical utility in ruling out the diagnosis of bacterial meningitis is limited (5).

Laboratory Findings

Any patient who presents with a reasonable likelihood of having bacterial meningitis should undergo a lumbar puncture (LP) to evaluate the CSF as soon as possible. The initial CSF study should measure the opening pressure. One study demonstrated that 39% of patients with bacterial meningitis had opening pressures greater than 300 mg H₂0 (3). Other CSF laboratory studies should be sent for analysis in 4 sterile tubes filled with approximately 1 mL of CSF each. The first tube is typically reserved for gram stain and culture. The gram stain is positive in about 70% of patients with bacterial meningitis, and the culture will be positive in about 80% of cases. The second tube is sent for protein and glucose levels. Patients who have markedly elevated CSF protein counts (>500 mg/dL) and low glucose levels (<45 mg/dL, or ratio of serum: CSF glucose levels <0.4) are likely to have bacterial meningitis. The third tube is sent for cell count and differential. Patients with bacterial meningitis are likely to have >10 WBC/μL that are predominantly polymorphonucleocytes and have few or no red blood cells in the absence of a traumatic LP. We recommend the fourth tube be used for any viral, fungal, or other miscellaneous studies. In addition to the CSF studies, other diagnostic evaluations should include blood cultures, complete blood count with platelets and differential (CBCPD), and basic chemistry labs.

The CSF studies described above are the primary tools in diagnosing bacterial meningitis; however, there are other studies that may be helpful in certain clinical settings. Latex agglutination tests for bacterial antigens may be used in cases in which bacterial meningitis remains a possible diagnosis despite negative CSF studies. This test is available for S. pneumoniae, N. meningitidis, H. influenzae type B, group B Streptococcus, and E. coli. The polymerase chain reaction (PCR) test of the CSF has been developed for some bacterial pathogens including S. pneumoniae, N. meningitidis, H. influenzae type B, and Mycobacterium tuberculosis. The limulus amebocyte lysate assay is a very sensitive test for gram-negative endotoxins, which may aid in identifying gram-negative organisms as potential pathogens in the CSF. While these alternative CSF diagnostic tests are available, many laboratories do not perform the tests on site and require send-out to a specialty laboratory. The time required for this may negate the clinical utility of these tests.

Role of Brain Imaging

The decision to obtain a brain imaging study prior to performing an LP has been a controversial issue for both patient safety and medical-legal reasons. Two large studies have been published in an attempt to derive a clinically useful decision analysis tool (7,8). In summary, the studies found that 5 clinical features were associated with an abnormal head cranial tomography (CT) scan. These were:

1. Age >60 years
2. Immunocompromised state
3. Any history of central nervous system (CNS) disease
4. A history of seizure within 1 week prior to presentation
5. Presence of a focal neurologic abnormality, including altered level of consciousness, inability to answer or follow 2 consecutive requests, gaze palsy, abnormal visual fields, facial palsy, arm or leg drift, and abnormal language.

In patients with none of these findings, there was a 97% negative predictive value of having an abnormal CT scan, with the few patients with positive scans nonetheless tolerating LP without adverse effects. Thus, in patients with none of these findings, it appears that an LP can safely be performed without obtaining a CT scan. One study also demonstrated that patients who underwent a CT scan prior to their LP waited, on average, 2 hours longer to get an LP; with antibiotic administration delayed by an average of 1 hour (8). Antibiotic administration should not be delayed in any patient suspected of having bacterial meningitis, whether brain imaging is performed or not.

click for large version

Differential Diagnosis

Given the severe nature of this disease, the diagnosis of bacterial meningitis must be differentiated from other conditions that may present in similar ways. Infectious causes that may present similarly to bacterial meningitis include other types of meningitis (viral, tuberculous, Lyme disease, syphilitic), viral encephalitis, Rocky Mountain spotted fever, fungal meningitis, parasitic causes, brain abscess, and epidural and subdural empyema. Other infectious etiologies not originating from the CNS may be mistaken for bacterial meningitis when these patients present with concomitant mental-status changes. This is especially common in elderly patients with pneumonia and urinary tract infections. Other noninfectious considerations include a CNS bleed such as a subarachnoid hemorrhage, drug-induced aseptic meningitis, and CNS vasculitis.

Treatment

When the patient’s presentation is suggestive of bacterial meningitis, empiric antibiotics should be administered without delay, while awaiting diagnostic evaluation. The initial dose of antibiotics should not alter the results of the diagnostic studies significantly. The choice of antibiotics is based upon the most likely offending organism from epidemiologic data and underlying predisposing conditions. S. pneumoniae and N. meningitidis are the 2 most common causes of bacterial meningitis in adults.

The development of antibiotic resistance by S. pneumoniae to penicillin and cephalosporins has been one of the major developments in the past 20 years. Due to this resistance, the recommended empiric therapy is a combination of a third-generation cephalosporin (ceftriaxone or cefotaxime) and vancomycin. For special cases, additional or alternative therapy should be given. Ampicillin should be added for patients at risk for Listeria monocytogenes; and postsurgical or post-trauma patients should have expanded coverage to include staphylococcal and gram-negative infections. Table 1 lists the recommended antibiotic therapy for patients with possible bacterial meningitis, along with the most commonly associated organisms.

Once the offending organism has been identified, antibiotic therapy should be narrowed to target the bacteria based on laboratory minimal inhibitory concentrations (MIC). The antibiotic should also have excellent CSF penetration and bactericidal activity. For S. pneumoniae that are susceptible to penicillin, penicillin G and ampicillin remain the therapy of choice (9). The increasing trend toward antibiotic resistance by S. pneumoniae has increased the use of vancomycin as therapy. In patients with resistant strains of S. pneumoniae, however, vancomycin should not be used alone. Vancomycin should be used in combination with a third-generation cephalosporin while keeping the serum vancomycin levels in the range of 15–20 μg/mL (10). It is imperative that the treatment course outlined be completed through its full duration. Table 2 lists specific antibiotic therapy with dosages and recommended duration of therapy based on isolated organisms.

click for large version

Adjunctive Therapy

The release and production of inflammatory cytokines in bacterial meningitis is thought to be a major cause of adverse outcomes. To counteract this inflammatory process, use of adjunctive steroids in patients with bacterial meningitis has been evaluated. Initial data from children with bacterial meningitis, mostly due to H. influenzae and S. pneumoniae, demonstrated improved neurologic outcomes, with significant reductions in deafness, in patients treated with dexamethasone as an adjunctive therapy to antibiotics (11). In adults with bacterial meningitis, a recent major trial demonstrated that treatment with adjunctive steroids, along with antibiotics, led to significant improvement in mortality and morbidity in patients with meningitis due to S. pneumoniae (12). Among patients with meningococcal meningitis, there was a trend toward improved outcomes. Patients with suspected pneumococcal meningitis should receive their first dose of dexamethasone 20–30 minutes prior to or at the same time as the initial antibiotic administration. The recommended dose and duration is 0.15 mg/kg every 6 hours for 2 to 4 days. The use of dexamethasone appears to have no benefit if administered after antibiotics have already been given, and data are lacking for patients with meningitis due to organisms other than S. pneumoniae. Most experts recommend against the use of adjunctive corticosteroids in these cases (10-13). Several questions, however, remain unanswered with regard to adjunctive corticosteroid use. These include the optimal duration of treatment, whether the penetration of vancomycin into the CSF is significantly decreased by dexamethasone, and whether they should be administered to immunocompromised patients (14).

Prevention

Currently, prevention of some types of bacterial meningitis can be accomplished by appropriate use of vaccines, or through antibiotic chemoprophylaxis in certain situations. For adults, vaccines are available against the 2 most common causes of bacterial meningitis. The 23 polyvalent pneumococcal vaccine is recommended for all adults >65 years of age and for anyone age >2 with a compromised immune status. The meningococcal vaccine is available as a quadravalent vaccine (serotypes A, C, Y, and W-135) and should be administered to anyone with functional asplenia, terminal complement deficiencies, those traveling to endemic areas of meningococcal meningitis, and any college freshman requesting the vaccine who will be living in college dormitories (15).

Antibiotic chemoprophylaxis can be administered to individuals who have had close contact with an index patient with meningococcal meningitis. Antibiotics should be administered as soon as exposure has been determined. There are several options available for meningococcal meningitis exposure. Ciprofloxacin is probably the simplest regimen due to its 1-time 500-mg oral dose. Other options include rifampin 600 mg every 12 hours ×4 doses and ceftriaxone 250 mg IM as a 1-time dose. Pregnant women should avoid ciprofloxacin and rifampin due to their potential teratogenic effects.

Prognosis and Follow-up

Prognosis of bacterial meningitis is closely linked to the causative organism, the severity of disease at the time of presentation, and the speed at which the disease progresses. One large retrospective study demonstrated in-hospital mortality rates of 25% for S. pneumoniae, 10% for N. meningitidis, and 21% for L. monocytogenes. Conditions associated with an increased risk of mortality included age >60, state of obtundation on admission, and development of seizure within 24 hours of admission. This study also showed that 21% of patients developed some type of neurologic deficits, and, overall, 9% had persistence of these deficits at time of discharge (3). Another study showed that baseline features of hypotension, mental status changes, and seizures were associated with increased mortality and neurologic morbidity (16). A more recent large study evaluating the efficacy of adjunctive corticosteroids reported a mortality rate of 15% in the control arm, with mortality of 34% in patients infected with S. pneumoniae (12). Another study suggested that if patients had a rapid progression of their disease, this seemed to correlate with worse outcomes. These investigators found an uncertain correlation between antibiotic timing and unfavorable outcomes (16).

Patients discharged from the hospital should have close follow-up with their primary care physician or infectious disease specialist. Evaluation in the short-term should focus on any complications that may have developed as a result of the bacterial meningitis; such as mental status change, seizure, focal neurologic deficits, and hearing loss. Long-term evaluations should also address cognitive functioning and the neuropsychiatric well-being of the patient, in addition to those issues addressed during short-term follow-up (11, 12).

Dr. Kim may be reached at [email protected].

References

1. Swartz, Morton N. Bacterial Meningitis—A View of the Past 90 Years. N Engl J Med. 2004;351:1826-8.
2. van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med. 2004;351:1849-59.
3. Durand ML, Calderwood SB, Weber DJ, et al. Acute Bacterial Meningitis in Adults. A review of 493 episodes. N Engl J Med. 1993;328:21-8.
4. Schuchat A, Robinson K, Wenger J, et al. Bacterial meningitis in the United States in 1995. Active Surveillance Team. N Engl J Med. 1997;337:970-6.
5. Attia J, Hatala R, Cook DJ, Wong JG. The rational clinical examination. Does this adult patient have acute meningitis? JAMA. 1999;282:175-181.
6. Uchihara T, Tsukagoshi H. Jolt accentuation of headache: the most sensitive sign of CSF pleocytosis. Headache. 1991;31:167-71.
7. Gopal AK, Whitehouse JD, Simel DL, Corey RG. Cranial computed tomography before lumbar puncture: a prospective clinical evaluation. Arch Intern Med. 1999;159:2681-5.
8. Hasbun R, Abrahams J, Jekel J, Quagliarello VJ. Computed tomography of the head before LP in adults with suspected meningitis. N Engl J Med. 2001;345:1727-33.
9. Quagliarello VJ, Scheld WM. Treatment of bacterial meningitis. N Engl J Med. 1997;336:708-16.
10. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice Guidelines for the Management of Bacterial Meningitis. Clin Infect Dis. 2004;39:1267-84.
11. McIntyre PB, Berkey CS, King SM, et al. Dexamethasone as adjunctive therapy in bacterial meningitis. A meta-analysis of randomized clinical trials since 1988. JAMA. 1997;278:928-31.
12. de Gans J, van de Beek D Dexamethasone in adults with bacterial meningitis. N Engl J Med. 2002;347:1549-56.
13. van de Beek D, de Gans J, McIntyre P, Prasad K. Steroids in adults with acute bacterial meningitis: a systematic review. Lancet Infect Dis 2004;4: 139-43.
14. Pile JC, Longworth DL. Should adults with suspected acute bacterial meningitis get adjunctive corticosteroids? Cleve Clin J Med. 2005;72:67-70.
15. Control and prevention of meningococcal disease and control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1997;4613-21.
16. Aronin SI, Peduzzi P, Quagliarello VJ. Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med. 1998;129:862-9.

Background Acute bacterial meningitis is an inflammation of the meninges, which results from bacterially mediated recruitment and activation of inflammatory cells in the cerebrospinal fluid (CSF). Bacterial meningitis was an almost invariably fatal disease at the start of the 20th century. With the development of and advancements in antimicrobial therapy, however, there has been a significant reduction in the mortality rate, although this has remained stable during the past 20 years (1). One large study of adults with community-acquired bacterial meningitis reported an overall mortality rate of 21%, including a 30% mortality rate associated with Streptococcus pneumoniae meningitis and a 7% mortality rate for Neisseria meningitidis (2). In adults, the most commonly identified organisms are S. pneumoniae (40–50%), Neisseria meningitidis (14–37%), and Listeria monocytogenes (4–10%) (2-4).

Clinical Presentation

Bacterial meningitis is a serious illness that often progresses rapidly. The classic clinical presentation consists of fever, nuchal rigidity, and mental status change (3). One large review of 10 critically appraised studies showed that almost all (99–100%) of the patients with bacterial meningitis presented with at least one of these clinical findings; and 95% of the patients had at least 2 of the clinical findings (5). In contrast, less than half of the patients presented with all 3 findings. Thus, in the absence of all 3 of these classic findings, the diagnosis of meningitis can virtually be dismissed, and further evaluation for meningitis need not be pursued. Individually, fever was the most common presenting finding, with a sensitivity of 85%. Nuchal rigidity had a sensitivity of 70%, and mental status change was 67%. While these physical examination findings may be of value in determining the diagnosis of bacterial meningitis, the accuracy of the clinical history including features such as headache, nausea and vomiting, and neck pain was too low to be of use clinically.

Signs of meningeal irritation may be of benefit in the clinical diagnosis of bacterial meningitis. Kernig’s and Brudzinski’s signs were first described nearly a century ago and have been used by most clinicians in the clinical realm; however, their diagnostic utility has been evaluated only in a limited number of studies. Kernig’s sign is positive when a patient in the supine position with his/her hips flexed at 90 degrees develops pain in the lower back or posterior thigh during an attempt to extend the knee. Brudzinski’s sign is positive when a patient in the supine position whose neck is passively flexed responds with flexion of his/her knees and hips. Recently, a bedside maneuver called jolt accentuation of headache was found to be potentially useful. In this maneuver, the patient is asked to turn his/her head horizontally 2–3 times per second, and a worsening headache is considered a positive sign. A small study showed that this maneuver had 97% sensitivity and 60% specificity for patients with CSF pleocytosis (6).

Other clinical manifestations in patients with bacterial meningitis include photophobia, seizure, rash, focal neurologic deficits, and signs of increased intracranial pressure. While these various findings may be present in many patients with bacterial meningitis, their sensitivities have been found to be low. Thus, their clinical utility in ruling out the diagnosis of bacterial meningitis is limited (5).

Laboratory Findings

Any patient who presents with a reasonable likelihood of having bacterial meningitis should undergo a lumbar puncture (LP) to evaluate the CSF as soon as possible. The initial CSF study should measure the opening pressure. One study demonstrated that 39% of patients with bacterial meningitis had opening pressures greater than 300 mg H₂0 (3). Other CSF laboratory studies should be sent for analysis in 4 sterile tubes filled with approximately 1 mL of CSF each. The first tube is typically reserved for gram stain and culture. The gram stain is positive in about 70% of patients with bacterial meningitis, and the culture will be positive in about 80% of cases. The second tube is sent for protein and glucose levels. Patients who have markedly elevated CSF protein counts (>500 mg/dL) and low glucose levels (<45 mg/dL, or ratio of serum: CSF glucose levels <0.4) are likely to have bacterial meningitis. The third tube is sent for cell count and differential. Patients with bacterial meningitis are likely to have >10 WBC/μL that are predominantly polymorphonucleocytes and have few or no red blood cells in the absence of a traumatic LP. We recommend the fourth tube be used for any viral, fungal, or other miscellaneous studies. In addition to the CSF studies, other diagnostic evaluations should include blood cultures, complete blood count with platelets and differential (CBCPD), and basic chemistry labs.

The CSF studies described above are the primary tools in diagnosing bacterial meningitis; however, there are other studies that may be helpful in certain clinical settings. Latex agglutination tests for bacterial antigens may be used in cases in which bacterial meningitis remains a possible diagnosis despite negative CSF studies. This test is available for S. pneumoniae, N. meningitidis, H. influenzae type B, group B Streptococcus, and E. coli. The polymerase chain reaction (PCR) test of the CSF has been developed for some bacterial pathogens including S. pneumoniae, N. meningitidis, H. influenzae type B, and Mycobacterium tuberculosis. The limulus amebocyte lysate assay is a very sensitive test for gram-negative endotoxins, which may aid in identifying gram-negative organisms as potential pathogens in the CSF. While these alternative CSF diagnostic tests are available, many laboratories do not perform the tests on site and require send-out to a specialty laboratory. The time required for this may negate the clinical utility of these tests.

Role of Brain Imaging

The decision to obtain a brain imaging study prior to performing an LP has been a controversial issue for both patient safety and medical-legal reasons. Two large studies have been published in an attempt to derive a clinically useful decision analysis tool (7,8). In summary, the studies found that 5 clinical features were associated with an abnormal head cranial tomography (CT) scan. These were:

1. Age >60 years
2. Immunocompromised state
3. Any history of central nervous system (CNS) disease
4. A history of seizure within 1 week prior to presentation
5. Presence of a focal neurologic abnormality, including altered level of consciousness, inability to answer or follow 2 consecutive requests, gaze palsy, abnormal visual fields, facial palsy, arm or leg drift, and abnormal language.

In patients with none of these findings, there was a 97% negative predictive value of having an abnormal CT scan, with the few patients with positive scans nonetheless tolerating LP without adverse effects. Thus, in patients with none of these findings, it appears that an LP can safely be performed without obtaining a CT scan. One study also demonstrated that patients who underwent a CT scan prior to their LP waited, on average, 2 hours longer to get an LP; with antibiotic administration delayed by an average of 1 hour (8). Antibiotic administration should not be delayed in any patient suspected of having bacterial meningitis, whether brain imaging is performed or not.

click for large version

Differential Diagnosis

Given the severe nature of this disease, the diagnosis of bacterial meningitis must be differentiated from other conditions that may present in similar ways. Infectious causes that may present similarly to bacterial meningitis include other types of meningitis (viral, tuberculous, Lyme disease, syphilitic), viral encephalitis, Rocky Mountain spotted fever, fungal meningitis, parasitic causes, brain abscess, and epidural and subdural empyema. Other infectious etiologies not originating from the CNS may be mistaken for bacterial meningitis when these patients present with concomitant mental-status changes. This is especially common in elderly patients with pneumonia and urinary tract infections. Other noninfectious considerations include a CNS bleed such as a subarachnoid hemorrhage, drug-induced aseptic meningitis, and CNS vasculitis.

Treatment

When the patient’s presentation is suggestive of bacterial meningitis, empiric antibiotics should be administered without delay, while awaiting diagnostic evaluation. The initial dose of antibiotics should not alter the results of the diagnostic studies significantly. The choice of antibiotics is based upon the most likely offending organism from epidemiologic data and underlying predisposing conditions. S. pneumoniae and N. meningitidis are the 2 most common causes of bacterial meningitis in adults.

The development of antibiotic resistance by S. pneumoniae to penicillin and cephalosporins has been one of the major developments in the past 20 years. Due to this resistance, the recommended empiric therapy is a combination of a third-generation cephalosporin (ceftriaxone or cefotaxime) and vancomycin. For special cases, additional or alternative therapy should be given. Ampicillin should be added for patients at risk for Listeria monocytogenes; and postsurgical or post-trauma patients should have expanded coverage to include staphylococcal and gram-negative infections. Table 1 lists the recommended antibiotic therapy for patients with possible bacterial meningitis, along with the most commonly associated organisms.

Once the offending organism has been identified, antibiotic therapy should be narrowed to target the bacteria based on laboratory minimal inhibitory concentrations (MIC). The antibiotic should also have excellent CSF penetration and bactericidal activity. For S. pneumoniae that are susceptible to penicillin, penicillin G and ampicillin remain the therapy of choice (9). The increasing trend toward antibiotic resistance by S. pneumoniae has increased the use of vancomycin as therapy. In patients with resistant strains of S. pneumoniae, however, vancomycin should not be used alone. Vancomycin should be used in combination with a third-generation cephalosporin while keeping the serum vancomycin levels in the range of 15–20 μg/mL (10). It is imperative that the treatment course outlined be completed through its full duration. Table 2 lists specific antibiotic therapy with dosages and recommended duration of therapy based on isolated organisms.

click for large version

Adjunctive Therapy

The release and production of inflammatory cytokines in bacterial meningitis is thought to be a major cause of adverse outcomes. To counteract this inflammatory process, use of adjunctive steroids in patients with bacterial meningitis has been evaluated. Initial data from children with bacterial meningitis, mostly due to H. influenzae and S. pneumoniae, demonstrated improved neurologic outcomes, with significant reductions in deafness, in patients treated with dexamethasone as an adjunctive therapy to antibiotics (11). In adults with bacterial meningitis, a recent major trial demonstrated that treatment with adjunctive steroids, along with antibiotics, led to significant improvement in mortality and morbidity in patients with meningitis due to S. pneumoniae (12). Among patients with meningococcal meningitis, there was a trend toward improved outcomes. Patients with suspected pneumococcal meningitis should receive their first dose of dexamethasone 20–30 minutes prior to or at the same time as the initial antibiotic administration. The recommended dose and duration is 0.15 mg/kg every 6 hours for 2 to 4 days. The use of dexamethasone appears to have no benefit if administered after antibiotics have already been given, and data are lacking for patients with meningitis due to organisms other than S. pneumoniae. Most experts recommend against the use of adjunctive corticosteroids in these cases (10-13). Several questions, however, remain unanswered with regard to adjunctive corticosteroid use. These include the optimal duration of treatment, whether the penetration of vancomycin into the CSF is significantly decreased by dexamethasone, and whether they should be administered to immunocompromised patients (14).

Prevention

Currently, prevention of some types of bacterial meningitis can be accomplished by appropriate use of vaccines, or through antibiotic chemoprophylaxis in certain situations. For adults, vaccines are available against the 2 most common causes of bacterial meningitis. The 23 polyvalent pneumococcal vaccine is recommended for all adults >65 years of age and for anyone age >2 with a compromised immune status. The meningococcal vaccine is available as a quadravalent vaccine (serotypes A, C, Y, and W-135) and should be administered to anyone with functional asplenia, terminal complement deficiencies, those traveling to endemic areas of meningococcal meningitis, and any college freshman requesting the vaccine who will be living in college dormitories (15).

Antibiotic chemoprophylaxis can be administered to individuals who have had close contact with an index patient with meningococcal meningitis. Antibiotics should be administered as soon as exposure has been determined. There are several options available for meningococcal meningitis exposure. Ciprofloxacin is probably the simplest regimen due to its 1-time 500-mg oral dose. Other options include rifampin 600 mg every 12 hours ×4 doses and ceftriaxone 250 mg IM as a 1-time dose. Pregnant women should avoid ciprofloxacin and rifampin due to their potential teratogenic effects.

Prognosis and Follow-up

Prognosis of bacterial meningitis is closely linked to the causative organism, the severity of disease at the time of presentation, and the speed at which the disease progresses. One large retrospective study demonstrated in-hospital mortality rates of 25% for S. pneumoniae, 10% for N. meningitidis, and 21% for L. monocytogenes. Conditions associated with an increased risk of mortality included age >60, state of obtundation on admission, and development of seizure within 24 hours of admission. This study also showed that 21% of patients developed some type of neurologic deficits, and, overall, 9% had persistence of these deficits at time of discharge (3). Another study showed that baseline features of hypotension, mental status changes, and seizures were associated with increased mortality and neurologic morbidity (16). A more recent large study evaluating the efficacy of adjunctive corticosteroids reported a mortality rate of 15% in the control arm, with mortality of 34% in patients infected with S. pneumoniae (12). Another study suggested that if patients had a rapid progression of their disease, this seemed to correlate with worse outcomes. These investigators found an uncertain correlation between antibiotic timing and unfavorable outcomes (16).

Patients discharged from the hospital should have close follow-up with their primary care physician or infectious disease specialist. Evaluation in the short-term should focus on any complications that may have developed as a result of the bacterial meningitis; such as mental status change, seizure, focal neurologic deficits, and hearing loss. Long-term evaluations should also address cognitive functioning and the neuropsychiatric well-being of the patient, in addition to those issues addressed during short-term follow-up (11, 12).

Dr. Kim may be reached at [email protected].

References

1. Swartz, Morton N. Bacterial Meningitis—A View of the Past 90 Years. N Engl J Med. 2004;351:1826-8.
2. van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med. 2004;351:1849-59.
3. Durand ML, Calderwood SB, Weber DJ, et al. Acute Bacterial Meningitis in Adults. A review of 493 episodes. N Engl J Med. 1993;328:21-8.
4. Schuchat A, Robinson K, Wenger J, et al. Bacterial meningitis in the United States in 1995. Active Surveillance Team. N Engl J Med. 1997;337:970-6.
5. Attia J, Hatala R, Cook DJ, Wong JG. The rational clinical examination. Does this adult patient have acute meningitis? JAMA. 1999;282:175-181.
6. Uchihara T, Tsukagoshi H. Jolt accentuation of headache: the most sensitive sign of CSF pleocytosis. Headache. 1991;31:167-71.
7. Gopal AK, Whitehouse JD, Simel DL, Corey RG. Cranial computed tomography before lumbar puncture: a prospective clinical evaluation. Arch Intern Med. 1999;159:2681-5.
8. Hasbun R, Abrahams J, Jekel J, Quagliarello VJ. Computed tomography of the head before LP in adults with suspected meningitis. N Engl J Med. 2001;345:1727-33.
9. Quagliarello VJ, Scheld WM. Treatment of bacterial meningitis. N Engl J Med. 1997;336:708-16.
10. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice Guidelines for the Management of Bacterial Meningitis. Clin Infect Dis. 2004;39:1267-84.
11. McIntyre PB, Berkey CS, King SM, et al. Dexamethasone as adjunctive therapy in bacterial meningitis. A meta-analysis of randomized clinical trials since 1988. JAMA. 1997;278:928-31.
12. de Gans J, van de Beek D Dexamethasone in adults with bacterial meningitis. N Engl J Med. 2002;347:1549-56.
13. van de Beek D, de Gans J, McIntyre P, Prasad K. Steroids in adults with acute bacterial meningitis: a systematic review. Lancet Infect Dis 2004;4: 139-43.
14. Pile JC, Longworth DL. Should adults with suspected acute bacterial meningitis get adjunctive corticosteroids? Cleve Clin J Med. 2005;72:67-70.
15. Control and prevention of meningococcal disease and control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1997;4613-21.
16. Aronin SI, Peduzzi P, Quagliarello VJ. Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med. 1998;129:862-9.