Michael E. Pichichero, MD

It’s summertime, which means that pediatric and family medicine offices are filled with children who have enteroviral infections, and too many of them will receive inappropriate antibiotic prescriptions.

From June through September, children who present with fever and other flulike symptoms nearly always have a nonpolio enterovirus (NPEV) infection, with coxsackievirus groups A and B, echoviruses, and the newer numbered enteroviruses being the most common in the United States. Epidemiologic surveillance suggests that 10 million to 15 million illnesses attributable to NPEV occur in the United States each year. I tell parents that their child has a "summer flu," which helps to communicate that it is usually self-limited and that antibiotics will not work to treat it.

A sudden high fever is usually what brings the child in, and the classic blistering hand-foot-mouth presentation of enterovirus helps us nail down the diagnosis. But sometimes, especially in younger children, symptoms such as myalgia, malaise, irritability, upper respiratory symptoms, or gastrointestinal symptoms may be nonspecific. In addition, the fever can precede hand-foot-mouth blisters by several days. A 9-month-old with a sudden fever of 103° F and a mildly red-looking throat can cause panic for parents, and a physician will often be led to prescribe an antibiotic out of an abundance of caution. In fact, more than 80% of inappropriate antibiotic use in the summertime is for febrile illness related to early enteroviral infection combined with worried parents and physicians.

Obtaining a complete blood count and differential can solve this problem, but it’s often not done because typically it involves sending the patient out for the blood work and waiting 4-6 hours for the results. Depending on when the test is done, results may not be available until the following day. It’s much simpler to "cover" with an antibiotic than to order the diagnostic test.

But I believe we should be using the white blood cell (WBC) count rather than prescribing antibiotics. The WBC count will almost always be low, and if a differential is added it will show a predominance of lymphocytes, indicating a viral infection. With that, parents and physicians can be reassured it’s enterovirus, and that no antibiotic is required.

In recent years, large pediatric practices and urgent care centers have begun purchasing a point-of-care WBC test made by Hemacue. Currently, it is licensed for use only in level 3 Clinical Laboratory Improvement Amendments (CLIA) facilities. A couple of years ago, I testified before a Food and Drug Administration device panel urging broader availability for the machine in clinical practice, but the panel had concerns that physicians would overrely on the WBC – the machine doesn’t give the differential – and possibly miss a more significant illness, such as leukemia.

Of course, the current widespread practice of empirically prescribing an antibiotic with no lab testing won’t pick up leukemia, either. In my view, the point-of-care test is an aid. It’s a piece of information you add to your clinical history and physical exam that assists in your diagnosis. I believe the benefits of avoiding unnecessary antibiotic use in millions of children every summer far outweigh the theoretical possibility that pediatricians would not rely on the broader context, including the time of year, disease rates in the community, and their clinical judgment. I really believe that WBC testing constitutes better care.

My colleagues and I have published two papers regarding the use of the WBC test to aid in judicious antibiotic use. In one, a prospective, 3-year study of 1,956 patients aged 3 months to 21 years with acute upper respiratory illness and fever, 737 did not have a diagnosis established by history and physical. Of those patients, we had WBC counts done for 351 children who appeared ill, had a temperature greater than 101° F, and parents who were demanding an antibiotic or physicians who were inclined to give an antibiotic. Of those, just 14 had a WBC count of 15,000/mcL or greater, and an antibiotic was prescribed for 13 of them. With the selective use of WBC testing, no child had significant bacterial illness that was missed (Clin. Pediatr. [Phila] 2003;42:113-9).

In another study of 120 acutely ill children and potential antibiotic recipients, we found that the point-of-care Hemacue WBC device produced comparable results to the Cell-Dyn countertop machine for total WBC counts (Clin. Pediatr. [Phila] 2009;48:291-4).

I’d just like to add a few more points about enterovirus to keep in mind when you advise patients and families. There is a long-held notion that summer viruses enteroviruses in particular – are of shorter duration than are winter viruses such as influenza, parainfluenza, and respiratory syncytial virus. That’s actually not true. Several years ago, my colleagues and I prospectively studied 380 children aged 4-18 years with systemic NPEV syndromes who presented to private suburban pediatric practices. Overall, NPEV infections were virologically confirmed in 122 of 372 patients (33%). The median duration of illness was 6 days for those with rash, 7 days for those with hand-foot-mouth and viral meningitis, 8 days for those with pleurodynia, and 9 days for those with myalgia/malaise (Pediatrics 1998;102:1126-34). Many children were ill for 10 days to 2 weeks.

Interestingly, in that study we also found that in more than half of the families, there was more than one individual with NPEV illness that was often similar but sometimes had a different clinical presentation. For example, one child might have classic hand-foot-mouth while another just has upper respiratory symptoms or gastrointestinal manifestations. This creates a confusing picture for the family because it is not intuitive to attribute different clinical presentations to the same viral etiology and, as a consequence, medical care may be sought more often.

We also found that 20% of the mothers caught the illness from the child, compared with fewer than 10% of the fathers. Luckily, the mother’s illness was usually less severe.

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Rochester (N.Y.) General Research Institute. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero’s institution received a research grant in 2008 from Hemacue, and he has served as a paid consultant to testify before the FDA in 2009 for Hemacue. He said he has no other conflicts to declare.

It’s summertime, which means that pediatric and family medicine offices are filled with children who have enteroviral infections, and too many of them will receive inappropriate antibiotic prescriptions.

From June through September, children who present with fever and other flulike symptoms nearly always have a nonpolio enterovirus (NPEV) infection, with coxsackievirus groups A and B, echoviruses, and the newer numbered enteroviruses being the most common in the United States. Epidemiologic surveillance suggests that 10 million to 15 million illnesses attributable to NPEV occur in the United States each year. I tell parents that their child has a "summer flu," which helps to communicate that it is usually self-limited and that antibiotics will not work to treat it.

A sudden high fever is usually what brings the child in, and the classic blistering hand-foot-mouth presentation of enterovirus helps us nail down the diagnosis. But sometimes, especially in younger children, symptoms such as myalgia, malaise, irritability, upper respiratory symptoms, or gastrointestinal symptoms may be nonspecific. In addition, the fever can precede hand-foot-mouth blisters by several days. A 9-month-old with a sudden fever of 103° F and a mildly red-looking throat can cause panic for parents, and a physician will often be led to prescribe an antibiotic out of an abundance of caution. In fact, more than 80% of inappropriate antibiotic use in the summertime is for febrile illness related to early enteroviral infection combined with worried parents and physicians.

Obtaining a complete blood count and differential can solve this problem, but it’s often not done because typically it involves sending the patient out for the blood work and waiting 4-6 hours for the results. Depending on when the test is done, results may not be available until the following day. It’s much simpler to "cover" with an antibiotic than to order the diagnostic test.

But I believe we should be using the white blood cell (WBC) count rather than prescribing antibiotics. The WBC count will almost always be low, and if a differential is added it will show a predominance of lymphocytes, indicating a viral infection. With that, parents and physicians can be reassured it’s enterovirus, and that no antibiotic is required.

In recent years, large pediatric practices and urgent care centers have begun purchasing a point-of-care WBC test made by Hemacue. Currently, it is licensed for use only in level 3 Clinical Laboratory Improvement Amendments (CLIA) facilities. A couple of years ago, I testified before a Food and Drug Administration device panel urging broader availability for the machine in clinical practice, but the panel had concerns that physicians would overrely on the WBC – the machine doesn’t give the differential – and possibly miss a more significant illness, such as leukemia.

Of course, the current widespread practice of empirically prescribing an antibiotic with no lab testing won’t pick up leukemia, either. In my view, the point-of-care test is an aid. It’s a piece of information you add to your clinical history and physical exam that assists in your diagnosis. I believe the benefits of avoiding unnecessary antibiotic use in millions of children every summer far outweigh the theoretical possibility that pediatricians would not rely on the broader context, including the time of year, disease rates in the community, and their clinical judgment. I really believe that WBC testing constitutes better care.

My colleagues and I have published two papers regarding the use of the WBC test to aid in judicious antibiotic use. In one, a prospective, 3-year study of 1,956 patients aged 3 months to 21 years with acute upper respiratory illness and fever, 737 did not have a diagnosis established by history and physical. Of those patients, we had WBC counts done for 351 children who appeared ill, had a temperature greater than 101° F, and parents who were demanding an antibiotic or physicians who were inclined to give an antibiotic. Of those, just 14 had a WBC count of 15,000/mcL or greater, and an antibiotic was prescribed for 13 of them. With the selective use of WBC testing, no child had significant bacterial illness that was missed (Clin. Pediatr. [Phila] 2003;42:113-9).

In another study of 120 acutely ill children and potential antibiotic recipients, we found that the point-of-care Hemacue WBC device produced comparable results to the Cell-Dyn countertop machine for total WBC counts (Clin. Pediatr. [Phila] 2009;48:291-4).

I’d just like to add a few more points about enterovirus to keep in mind when you advise patients and families. There is a long-held notion that summer viruses enteroviruses in particular – are of shorter duration than are winter viruses such as influenza, parainfluenza, and respiratory syncytial virus. That’s actually not true. Several years ago, my colleagues and I prospectively studied 380 children aged 4-18 years with systemic NPEV syndromes who presented to private suburban pediatric practices. Overall, NPEV infections were virologically confirmed in 122 of 372 patients (33%). The median duration of illness was 6 days for those with rash, 7 days for those with hand-foot-mouth and viral meningitis, 8 days for those with pleurodynia, and 9 days for those with myalgia/malaise (Pediatrics 1998;102:1126-34). Many children were ill for 10 days to 2 weeks.

Interestingly, in that study we also found that in more than half of the families, there was more than one individual with NPEV illness that was often similar but sometimes had a different clinical presentation. For example, one child might have classic hand-foot-mouth while another just has upper respiratory symptoms or gastrointestinal manifestations. This creates a confusing picture for the family because it is not intuitive to attribute different clinical presentations to the same viral etiology and, as a consequence, medical care may be sought more often.

We also found that 20% of the mothers caught the illness from the child, compared with fewer than 10% of the fathers. Luckily, the mother’s illness was usually less severe.

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Rochester (N.Y.) General Research Institute. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero’s institution received a research grant in 2008 from Hemacue, and he has served as a paid consultant to testify before the FDA in 2009 for Hemacue. He said he has no other conflicts to declare.

It’s summertime, which means that pediatric and family medicine offices are filled with children who have enteroviral infections, and too many of them will receive inappropriate antibiotic prescriptions.

From June through September, children who present with fever and other flulike symptoms nearly always have a nonpolio enterovirus (NPEV) infection, with coxsackievirus groups A and B, echoviruses, and the newer numbered enteroviruses being the most common in the United States. Epidemiologic surveillance suggests that 10 million to 15 million illnesses attributable to NPEV occur in the United States each year. I tell parents that their child has a "summer flu," which helps to communicate that it is usually self-limited and that antibiotics will not work to treat it.

A sudden high fever is usually what brings the child in, and the classic blistering hand-foot-mouth presentation of enterovirus helps us nail down the diagnosis. But sometimes, especially in younger children, symptoms such as myalgia, malaise, irritability, upper respiratory symptoms, or gastrointestinal symptoms may be nonspecific. In addition, the fever can precede hand-foot-mouth blisters by several days. A 9-month-old with a sudden fever of 103° F and a mildly red-looking throat can cause panic for parents, and a physician will often be led to prescribe an antibiotic out of an abundance of caution. In fact, more than 80% of inappropriate antibiotic use in the summertime is for febrile illness related to early enteroviral infection combined with worried parents and physicians.

Obtaining a complete blood count and differential can solve this problem, but it’s often not done because typically it involves sending the patient out for the blood work and waiting 4-6 hours for the results. Depending on when the test is done, results may not be available until the following day. It’s much simpler to "cover" with an antibiotic than to order the diagnostic test.

But I believe we should be using the white blood cell (WBC) count rather than prescribing antibiotics. The WBC count will almost always be low, and if a differential is added it will show a predominance of lymphocytes, indicating a viral infection. With that, parents and physicians can be reassured it’s enterovirus, and that no antibiotic is required.

In recent years, large pediatric practices and urgent care centers have begun purchasing a point-of-care WBC test made by Hemacue. Currently, it is licensed for use only in level 3 Clinical Laboratory Improvement Amendments (CLIA) facilities. A couple of years ago, I testified before a Food and Drug Administration device panel urging broader availability for the machine in clinical practice, but the panel had concerns that physicians would overrely on the WBC – the machine doesn’t give the differential – and possibly miss a more significant illness, such as leukemia.

Of course, the current widespread practice of empirically prescribing an antibiotic with no lab testing won’t pick up leukemia, either. In my view, the point-of-care test is an aid. It’s a piece of information you add to your clinical history and physical exam that assists in your diagnosis. I believe the benefits of avoiding unnecessary antibiotic use in millions of children every summer far outweigh the theoretical possibility that pediatricians would not rely on the broader context, including the time of year, disease rates in the community, and their clinical judgment. I really believe that WBC testing constitutes better care.

My colleagues and I have published two papers regarding the use of the WBC test to aid in judicious antibiotic use. In one, a prospective, 3-year study of 1,956 patients aged 3 months to 21 years with acute upper respiratory illness and fever, 737 did not have a diagnosis established by history and physical. Of those patients, we had WBC counts done for 351 children who appeared ill, had a temperature greater than 101° F, and parents who were demanding an antibiotic or physicians who were inclined to give an antibiotic. Of those, just 14 had a WBC count of 15,000/mcL or greater, and an antibiotic was prescribed for 13 of them. With the selective use of WBC testing, no child had significant bacterial illness that was missed (Clin. Pediatr. [Phila] 2003;42:113-9).

In another study of 120 acutely ill children and potential antibiotic recipients, we found that the point-of-care Hemacue WBC device produced comparable results to the Cell-Dyn countertop machine for total WBC counts (Clin. Pediatr. [Phila] 2009;48:291-4).

I’d just like to add a few more points about enterovirus to keep in mind when you advise patients and families. There is a long-held notion that summer viruses enteroviruses in particular – are of shorter duration than are winter viruses such as influenza, parainfluenza, and respiratory syncytial virus. That’s actually not true. Several years ago, my colleagues and I prospectively studied 380 children aged 4-18 years with systemic NPEV syndromes who presented to private suburban pediatric practices. Overall, NPEV infections were virologically confirmed in 122 of 372 patients (33%). The median duration of illness was 6 days for those with rash, 7 days for those with hand-foot-mouth and viral meningitis, 8 days for those with pleurodynia, and 9 days for those with myalgia/malaise (Pediatrics 1998;102:1126-34). Many children were ill for 10 days to 2 weeks.

Interestingly, in that study we also found that in more than half of the families, there was more than one individual with NPEV illness that was often similar but sometimes had a different clinical presentation. For example, one child might have classic hand-foot-mouth while another just has upper respiratory symptoms or gastrointestinal manifestations. This creates a confusing picture for the family because it is not intuitive to attribute different clinical presentations to the same viral etiology and, as a consequence, medical care may be sought more often.

We also found that 20% of the mothers caught the illness from the child, compared with fewer than 10% of the fathers. Luckily, the mother’s illness was usually less severe.

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Rochester (N.Y.) General Research Institute. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero’s institution received a research grant in 2008 from Hemacue, and he has served as a paid consultant to testify before the FDA in 2009 for Hemacue. He said he has no other conflicts to declare.

Two new, well-designed trials published in the New England Journal of Medicine have demonstrated that when acute otitis media is correctly diagnosed, treatment with effective antibiotics is of clear and substantial benefit. To me, this suggests that the confusion about whether antibiotics help children get better faster is about getting the diagnosis right, a challenging task for pediatricians and family physicians with squirming patients and ear canal wax occluding visualization of the eardrum.

All along, I have believed that the American Academy of Pediatrics’ 2004 "watchful waiting" option for treating acute otitis media (AOM) was well intentioned but not based on good evidence. In an effort to address the growing problem of antimicrobial resistance, the AAP recommended the "observation option" for otherwise healthy children aged 6 months to 2 years with nonsevere illness and an uncertain diagnosis, and for all children above the age of 2 years who were not systemically ill (Pediatrics 2004;113:1451-65).

Problem is, the studies cited by the AAP as evidence for this recommendation were nearly all seriously flawed, because they excluded children with the very criteria that signal a true AOM diagnosis: a full or bulging eardrum ... and in some studies, because it was determined that they were too "unwell" and/or they "needed an antibiotic"! And, many of these trials excluded children younger than 2 years old and included many children who likely did not have AOM at all or had otitis media with effusion.

Dr. Janet R. Casey and I reviewed 25 of the studies in a paper published 3 years ago (Pediatr. Infect. Dis. J. 2008;27:958-62). We found so many serious flaws in the inclusion and exclusion criteria, and diagnostic and outcome criteria, that we were obliged to conclude that no evidence-based conclusion could be drawn.

The flaws we found in individual AOM trials call into question the validity of the conclusions of two major meta-analyses cited by the AAP, one involving 5,400 children from 33 randomized trials (J. Pediatr. 1994;124:355-67), the other of 6 studies of children aged 7 months to 15 years (BMJ 1997;314:1526-9), both of which found only modest benefit for the use of antimicrobials.

Now in the New England Journal of Medicine papers, we have two well-designed studies clearly demonstrating that treatment should not be withheld in children with proven AOM.

One of the studies, from the University of Pittsburgh, randomized 291 children aged 6-23 months to receive amoxicillin-clavulanate or placebo for 10 days. To be eligible, patients had to have AOM that was diagnosed on the basis of three criteria:

• Onset of symptoms within 48 hours that parents rated with a score of at least 3 on the Acute Otitis Media Severity of Symptoms scale,

• Presence of middle-ear effusion, and

• Moderate or marked bulging of the tympanic membrane or slight bulging accompanied by either otalgia or marked erythema of the membrane.

Patients also had to have received at least two doses of pneumococcal conjugate vaccine.

Among the children who received amoxicillin-clavulanate, 35% had initial resolution of symptoms by day 2, 61% by day 4, and 80% by day 7, compared with 28%, 54%, and 74% among those who received placebo, respectively. For sustained resolution of symptoms, the corresponding values were 20%, 41%, and 67% with amoxicillin-clavulanate, vs. 14%, 36%, and 53% with placebo (N. Engl. J. Med. 2011;364:105-15).

The other trial, from Finland, used equally strict criteria for 319 children aged 6-35 months who were randomized to receive amoxicillin-clavulanate or placebo for 7 days. Treatment failure occurred in 18.6% of the children who received amoxicillin-clavulanate, compared with 44.9% of the children who received placebo, a highly statistically significant difference that was already apparent at the first scheduled visit on day 3 (13.7% vs. 25.3%). Overall, amoxicillin-clavulanate reduced the progression to treatment failure by 62% (N. Engl. J. Med. 2011;364:116-26).

As I see it, the problem really lies in our inability to adequately diagnose AOM. For one thing, it’s essential to clean the wax out of the child’s ear in order to visualize the eardrum, given that two-thirds of children diagnosed with AOM have partially or fully occluded ear canals blocking visualization of the eardrum. Yet, physicians often don’t do that because it takes time and it’s difficult to get the child to hold still. It’s far simpler to simply take a quick look and say that the diagnosis is "uncertain," or to say that the eardrum is "red" in order to justify a diagnosis and antibiotic prescription.

Pediatricians and family physicians should all have a good, high-grade otoscope with a fresh battery and bulb, along with the training and ability to use the pneumatic attachment in order to distinguish between a bulging and retracted eardrum, which often look alike with just the otoscope.

Frankly, I find it embarrassing that with a condition as common as AOM, pediatricians and family physicians receive so little training in diagnosing it and, therefore, just don’t do a good job. In otitis media workshops that include testing for competency in diagnosis (Outcomes Management Educational Workshops, West Palm Beach, Fla.), I found that physicians got the diagnosis of AOM wrong at least 50% of the time on video presentation testing. And that was without wax, under ideal classroom conditions.

Diagnosing otitis media needs to become a critical part of medical education, and physicians in practice should be retrained via CME courses. Pharmaceutical companies no longer sponsor those, so now the professional societies such as the American Academy of Pediatrics, the American Academy of Family Physicians, and the nursing organizations need to step up.

With the new evidence from the two well-controlled trials, I don’t see how any clinician can withhold antibiotic treatment in good conscience. AOM is a painful condition that infants and toddlers are too young to explain to us. Can you imagine asking an adult to agree to withholding effective treatment when they are in pain and propose they take acetaminophen instead? Or can you imagine telling an adult who seeks care for an earache that the diagnosis is uncertain after examination, so the recommendation is to "observe"?

As advocates for our pediatric patients, how in the world can we allow a child to remain in severe pain for 24-48 hours longer than is necessary and keep parents up all night and away from work for 2-3 extra days?

Once everyone learns how to better diagnose AOM, we will stop overprescribing antibiotics for those children who don’t have the condition. For the rest, I contend that treatment is a moral imperative.

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Rochester (N.Y.) General Research Institute. Dr. Pichichero disclosed that he is the medical director of Outcome Management Educational Workshops that train providers to improve diagnosis but has no disclosures related to antibiotic use in AOM.

Two new, well-designed trials published in the New England Journal of Medicine have demonstrated that when acute otitis media is correctly diagnosed, treatment with effective antibiotics is of clear and substantial benefit. To me, this suggests that the confusion about whether antibiotics help children get better faster is about getting the diagnosis right, a challenging task for pediatricians and family physicians with squirming patients and ear canal wax occluding visualization of the eardrum.

All along, I have believed that the American Academy of Pediatrics’ 2004 "watchful waiting" option for treating acute otitis media (AOM) was well intentioned but not based on good evidence. In an effort to address the growing problem of antimicrobial resistance, the AAP recommended the "observation option" for otherwise healthy children aged 6 months to 2 years with nonsevere illness and an uncertain diagnosis, and for all children above the age of 2 years who were not systemically ill (Pediatrics 2004;113:1451-65).

Problem is, the studies cited by the AAP as evidence for this recommendation were nearly all seriously flawed, because they excluded children with the very criteria that signal a true AOM diagnosis: a full or bulging eardrum ... and in some studies, because it was determined that they were too "unwell" and/or they "needed an antibiotic"! And, many of these trials excluded children younger than 2 years old and included many children who likely did not have AOM at all or had otitis media with effusion.

Dr. Janet R. Casey and I reviewed 25 of the studies in a paper published 3 years ago (Pediatr. Infect. Dis. J. 2008;27:958-62). We found so many serious flaws in the inclusion and exclusion criteria, and diagnostic and outcome criteria, that we were obliged to conclude that no evidence-based conclusion could be drawn.

The flaws we found in individual AOM trials call into question the validity of the conclusions of two major meta-analyses cited by the AAP, one involving 5,400 children from 33 randomized trials (J. Pediatr. 1994;124:355-67), the other of 6 studies of children aged 7 months to 15 years (BMJ 1997;314:1526-9), both of which found only modest benefit for the use of antimicrobials.

Now in the New England Journal of Medicine papers, we have two well-designed studies clearly demonstrating that treatment should not be withheld in children with proven AOM.

One of the studies, from the University of Pittsburgh, randomized 291 children aged 6-23 months to receive amoxicillin-clavulanate or placebo for 10 days. To be eligible, patients had to have AOM that was diagnosed on the basis of three criteria:

• Onset of symptoms within 48 hours that parents rated with a score of at least 3 on the Acute Otitis Media Severity of Symptoms scale,

• Presence of middle-ear effusion, and

• Moderate or marked bulging of the tympanic membrane or slight bulging accompanied by either otalgia or marked erythema of the membrane.

Patients also had to have received at least two doses of pneumococcal conjugate vaccine.

Among the children who received amoxicillin-clavulanate, 35% had initial resolution of symptoms by day 2, 61% by day 4, and 80% by day 7, compared with 28%, 54%, and 74% among those who received placebo, respectively. For sustained resolution of symptoms, the corresponding values were 20%, 41%, and 67% with amoxicillin-clavulanate, vs. 14%, 36%, and 53% with placebo (N. Engl. J. Med. 2011;364:105-15).

The other trial, from Finland, used equally strict criteria for 319 children aged 6-35 months who were randomized to receive amoxicillin-clavulanate or placebo for 7 days. Treatment failure occurred in 18.6% of the children who received amoxicillin-clavulanate, compared with 44.9% of the children who received placebo, a highly statistically significant difference that was already apparent at the first scheduled visit on day 3 (13.7% vs. 25.3%). Overall, amoxicillin-clavulanate reduced the progression to treatment failure by 62% (N. Engl. J. Med. 2011;364:116-26).

As I see it, the problem really lies in our inability to adequately diagnose AOM. For one thing, it’s essential to clean the wax out of the child’s ear in order to visualize the eardrum, given that two-thirds of children diagnosed with AOM have partially or fully occluded ear canals blocking visualization of the eardrum. Yet, physicians often don’t do that because it takes time and it’s difficult to get the child to hold still. It’s far simpler to simply take a quick look and say that the diagnosis is "uncertain," or to say that the eardrum is "red" in order to justify a diagnosis and antibiotic prescription.

Pediatricians and family physicians should all have a good, high-grade otoscope with a fresh battery and bulb, along with the training and ability to use the pneumatic attachment in order to distinguish between a bulging and retracted eardrum, which often look alike with just the otoscope.

Frankly, I find it embarrassing that with a condition as common as AOM, pediatricians and family physicians receive so little training in diagnosing it and, therefore, just don’t do a good job. In otitis media workshops that include testing for competency in diagnosis (Outcomes Management Educational Workshops, West Palm Beach, Fla.), I found that physicians got the diagnosis of AOM wrong at least 50% of the time on video presentation testing. And that was without wax, under ideal classroom conditions.

Diagnosing otitis media needs to become a critical part of medical education, and physicians in practice should be retrained via CME courses. Pharmaceutical companies no longer sponsor those, so now the professional societies such as the American Academy of Pediatrics, the American Academy of Family Physicians, and the nursing organizations need to step up.

With the new evidence from the two well-controlled trials, I don’t see how any clinician can withhold antibiotic treatment in good conscience. AOM is a painful condition that infants and toddlers are too young to explain to us. Can you imagine asking an adult to agree to withholding effective treatment when they are in pain and propose they take acetaminophen instead? Or can you imagine telling an adult who seeks care for an earache that the diagnosis is uncertain after examination, so the recommendation is to "observe"?

As advocates for our pediatric patients, how in the world can we allow a child to remain in severe pain for 24-48 hours longer than is necessary and keep parents up all night and away from work for 2-3 extra days?

Once everyone learns how to better diagnose AOM, we will stop overprescribing antibiotics for those children who don’t have the condition. For the rest, I contend that treatment is a moral imperative.

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Rochester (N.Y.) General Research Institute. Dr. Pichichero disclosed that he is the medical director of Outcome Management Educational Workshops that train providers to improve diagnosis but has no disclosures related to antibiotic use in AOM.

Two new, well-designed trials published in the New England Journal of Medicine have demonstrated that when acute otitis media is correctly diagnosed, treatment with effective antibiotics is of clear and substantial benefit. To me, this suggests that the confusion about whether antibiotics help children get better faster is about getting the diagnosis right, a challenging task for pediatricians and family physicians with squirming patients and ear canal wax occluding visualization of the eardrum.

All along, I have believed that the American Academy of Pediatrics’ 2004 "watchful waiting" option for treating acute otitis media (AOM) was well intentioned but not based on good evidence. In an effort to address the growing problem of antimicrobial resistance, the AAP recommended the "observation option" for otherwise healthy children aged 6 months to 2 years with nonsevere illness and an uncertain diagnosis, and for all children above the age of 2 years who were not systemically ill (Pediatrics 2004;113:1451-65).

Problem is, the studies cited by the AAP as evidence for this recommendation were nearly all seriously flawed, because they excluded children with the very criteria that signal a true AOM diagnosis: a full or bulging eardrum ... and in some studies, because it was determined that they were too "unwell" and/or they "needed an antibiotic"! And, many of these trials excluded children younger than 2 years old and included many children who likely did not have AOM at all or had otitis media with effusion.

Dr. Janet R. Casey and I reviewed 25 of the studies in a paper published 3 years ago (Pediatr. Infect. Dis. J. 2008;27:958-62). We found so many serious flaws in the inclusion and exclusion criteria, and diagnostic and outcome criteria, that we were obliged to conclude that no evidence-based conclusion could be drawn.

The flaws we found in individual AOM trials call into question the validity of the conclusions of two major meta-analyses cited by the AAP, one involving 5,400 children from 33 randomized trials (J. Pediatr. 1994;124:355-67), the other of 6 studies of children aged 7 months to 15 years (BMJ 1997;314:1526-9), both of which found only modest benefit for the use of antimicrobials.

Now in the New England Journal of Medicine papers, we have two well-designed studies clearly demonstrating that treatment should not be withheld in children with proven AOM.

One of the studies, from the University of Pittsburgh, randomized 291 children aged 6-23 months to receive amoxicillin-clavulanate or placebo for 10 days. To be eligible, patients had to have AOM that was diagnosed on the basis of three criteria:

• Onset of symptoms within 48 hours that parents rated with a score of at least 3 on the Acute Otitis Media Severity of Symptoms scale,

• Presence of middle-ear effusion, and

• Moderate or marked bulging of the tympanic membrane or slight bulging accompanied by either otalgia or marked erythema of the membrane.

Patients also had to have received at least two doses of pneumococcal conjugate vaccine.

Among the children who received amoxicillin-clavulanate, 35% had initial resolution of symptoms by day 2, 61% by day 4, and 80% by day 7, compared with 28%, 54%, and 74% among those who received placebo, respectively. For sustained resolution of symptoms, the corresponding values were 20%, 41%, and 67% with amoxicillin-clavulanate, vs. 14%, 36%, and 53% with placebo (N. Engl. J. Med. 2011;364:105-15).

The other trial, from Finland, used equally strict criteria for 319 children aged 6-35 months who were randomized to receive amoxicillin-clavulanate or placebo for 7 days. Treatment failure occurred in 18.6% of the children who received amoxicillin-clavulanate, compared with 44.9% of the children who received placebo, a highly statistically significant difference that was already apparent at the first scheduled visit on day 3 (13.7% vs. 25.3%). Overall, amoxicillin-clavulanate reduced the progression to treatment failure by 62% (N. Engl. J. Med. 2011;364:116-26).

As I see it, the problem really lies in our inability to adequately diagnose AOM. For one thing, it’s essential to clean the wax out of the child’s ear in order to visualize the eardrum, given that two-thirds of children diagnosed with AOM have partially or fully occluded ear canals blocking visualization of the eardrum. Yet, physicians often don’t do that because it takes time and it’s difficult to get the child to hold still. It’s far simpler to simply take a quick look and say that the diagnosis is "uncertain," or to say that the eardrum is "red" in order to justify a diagnosis and antibiotic prescription.

Pediatricians and family physicians should all have a good, high-grade otoscope with a fresh battery and bulb, along with the training and ability to use the pneumatic attachment in order to distinguish between a bulging and retracted eardrum, which often look alike with just the otoscope.

Frankly, I find it embarrassing that with a condition as common as AOM, pediatricians and family physicians receive so little training in diagnosing it and, therefore, just don’t do a good job. In otitis media workshops that include testing for competency in diagnosis (Outcomes Management Educational Workshops, West Palm Beach, Fla.), I found that physicians got the diagnosis of AOM wrong at least 50% of the time on video presentation testing. And that was without wax, under ideal classroom conditions.

Diagnosing otitis media needs to become a critical part of medical education, and physicians in practice should be retrained via CME courses. Pharmaceutical companies no longer sponsor those, so now the professional societies such as the American Academy of Pediatrics, the American Academy of Family Physicians, and the nursing organizations need to step up.

With the new evidence from the two well-controlled trials, I don’t see how any clinician can withhold antibiotic treatment in good conscience. AOM is a painful condition that infants and toddlers are too young to explain to us. Can you imagine asking an adult to agree to withholding effective treatment when they are in pain and propose they take acetaminophen instead? Or can you imagine telling an adult who seeks care for an earache that the diagnosis is uncertain after examination, so the recommendation is to "observe"?

As advocates for our pediatric patients, how in the world can we allow a child to remain in severe pain for 24-48 hours longer than is necessary and keep parents up all night and away from work for 2-3 extra days?

Once everyone learns how to better diagnose AOM, we will stop overprescribing antibiotics for those children who don’t have the condition. For the rest, I contend that treatment is a moral imperative.

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Rochester (N.Y.) General Research Institute. Dr. Pichichero disclosed that he is the medical director of Outcome Management Educational Workshops that train providers to improve diagnosis but has no disclosures related to antibiotic use in AOM.

Presexual adolescent girls and sexually active women can now lower their lifetime risk of cervical cancer, thanks to a newly available quadrivalent vaccine (Gardasil) directed at human papillomavirus (HPV). This gives us the opportunity to educate parents and adolescents (the primary target group for the vaccine), many of whom remain uninformed about the direct link between HPV infection and cervical cancer.

Ethical, cultural, social, and religious issues that will require attention¹ are beyond the scope of this article.

Who should receive the HPV vaccine?

Pre-adolescent and adolescent girls

Girls ages 11 to 12 years—most of whom have not started sexual activity—are the primary targets of immunization. However, the US Food and Drug Administration also approved the use of Gardasil for girls as young as 9. Girls this age may require other vaccines, such as meningococcal conjugate and tetanus-diphtheria-acellular pertussis, and experience thus far indicates no negative immune effects with co-administration of vaccines.^1,2

According to one study, vaccination of the entire US population of 12-year-old girls would prevent more than 200,000 HPV infections, 100,000 abnormal Pap tests, and 3300 cases of cervical cancer.³ Parental as well as health care provider acceptance of HPV vaccines for adolescents will be critical to the success of the vaccination effort (see “What makes FPs recommend the HPV vaccine” ).⁴

Practical issues. As with any new vaccine added to the childhood/adolescent vaccination schedule, a host of issues will need to be resolved to ensure adequate coverage. Factors likely to influence use of HPV vaccine among adolescents are cost and reimbursement, and adherence to the 3-dose regimen that spans 6 months.

The American Academy of Pediatrics’ Committee on Infectious Diseases and the Advisory Committee on Immunization Practices (ACIP) recommends universal use of the HPV vaccine for girls, with a focus on 11- to 12-year-olds. The vaccine is also recommended for 13- to 26-year-old girls and women who have received or completed the 3-dose vaccine series.

Why not vaccinate boys? HPV infection is highly prevalent in sexually active men.⁵ The efficacy of vaccinating boys against HPV infection is currently being explored.⁶ However, one model has suggested that vaccinating adolescent males with a bivalent HPV vaccine would only slightly reduce the incidence of cervical cancer cases beyond that achieved by vaccination of adolescent girls, and with an extremely high cost-effectiveness ratio compared with female-only vaccination.⁵

Women ≤26 years

Indications under FDA approval also include women up to 26 years. Even adults who have been sexually active for years may not have been exposed to all high-risk HPV covered by the vaccine.

Are women older than 26 years eligible?

Though FDA approval of the vaccine is for females aged 9 to 26 years, a recent working group on HPV prevention concluded that any sexually active person may benefit from vaccination and should have the opportunity to receive the vaccine.¹ Importantly, women older than 26 years who request the vaccine should be made fully aware of its off-label application in their case.

The rationale behind the recommendations

HPV transmission occurs easily with skin-to-skin contact.^8-11 HPV can infect the external genitalia during non-intercourse sexual activities, including manual and oral genital contact. Sexual intercourse is the most frequent mode of infection of the cervix. Condoms may help protect against transmission of HPV but are not fully effective.^8,12

Adolescents are particularly vulnerable to HPV, but respond best to vaccine. The cervix is especially susceptible to HPV infection in adolescence because the squamous columnar cell junction transformation zone is more exposed. The adult cervix is less susceptible to HPV than the adolescent cervix because of the smaller area of cervical ectopy comprised of columnar epithelial cells.¹³ However, in adolescents, the immune response to HPV exposure is greater than in than adults.

Risk for acquiring HPV infection. Risk factors for acquiring HPV infection are listed in the TABLE .^8,14,15 According to the Centers for Disease Control and Prevention, sexually active men and women have a 50% lifetime risk of acquiring HPV infection.¹⁶ An estimated 6.2 million people in the US become infected with HPV each year,¹⁶ and approximately 20 million currently harbor HPV infections.¹⁷ This estimate includes more than 9 million sexually active adolescents and young adults 15 to 24 years of age, the group in which nearly 75% of new HPV infections occur.¹⁸ Among women <25 years of age, between 28% and 46% are infected with HPV.^19,20

Infection cannot always be cleared. Most HPV infections (whether high-risk or low-risk type) are asymptomatic and are efficiently cleared (ie, no detection of DNA for a specific HPV type) by the immune system.^21,22 However, if the infection cannot be cleared or controlled by the immune system, it may become a persistent infection.

Persistent infection with HPV increases the probability of progression to high-grade cervical intraepithelial neoplasia (CIN) and invasive carcinoma ( FIGURE ).^18-19 Evidence also increasingly shows that high-risk HPV types likely cause anal, penile, scrotal, vulvar, vaginal, and some head and neck cancers.²⁵

How vaccination prevents cervical cancer

After HPV vaccination, neutralizing antibodies are secreted from memory B cells, and bind to their target HPV type, preventing infection before it occurs, thereby blocking the initial step toward development of cervical cancer.

15 high-risk oncogenic types. Papillomaviruses such as HPV are nonenveloped, double-stranded, DNA viruses. They infect cutaneous and mucosal epithelial tissues. More than 100 HPV types have been identified,³ about 30 to 40 of which are spread by sexual contact.⁴ Of the many known HPVs, only 15 are high-risk oncogenic types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, and 73) that can cause cervical cancer.^5.6 Of these high-risk oncogenic types, HPV 16 and 18 account for about 70% of all cervical cancers.⁷

The new HPV vaccines, Gardasil and Cervarix, (see Web table) both contain virosomal antigens to vaccinate against HPV types 16 and 18. Persistent infection with these high-risk HPV types is necessary for the development of cervical cancer. Chronic infection with low-risk HPV types (eg, HPV 6 or 11) may lead to the development of anogenital warts and other low-grade genital abnormalities, as well as laryngeal cancer or recurrent respiratory papillomatosis. Gardasil also contains virosome antigens for these 2 HPV types. Warts on the hands are usually attributable to HPV 7.⁸

Viral integration is a necessary step in the malignant transformation of HPV infection; infection may progress from residential to episomal, and, finally, to an integrated form. Residential infection typically occurs a minimum of 6 weeks from exposure, can persist without detection for decades, and can be low risk or high risk. In the episomal state, virally active HPV is located in the cell nucleus, separate from the human DNA. In the integrated form of infection, the HPV DNA circle has opened and joined the human DNA. Integrated HPV—always high risk—produces an abnormal Papanicolaou (Pap) test. If recognized on colposcopy, it must be treated to prevent progression to cervical cancer. 

FIGURE
How HPV infection progresses to cervical cancer

TABLE
Factors that put women at risk for HPV infection

Why screening alone isn’t enough

New technologies for Pap testing, HPV DNA testing, and revisions in the Bethesda system for reporting cervical cytology have led to better treatment recommendations for patients with abnormal cytology results.²⁶ But despite these advances, cervical screening is underused or not used at all for many women at risk.

For example, some women with abnormal cervical cytology—especially those of lower socioeconomic status, who often are medically underserved or lack insurance—may not receive adequate follow-up care.²⁷ Though widespread cervical screening in the future may significantly decrease morbidity and mortality associated with cervical cancer, HPV vaccination can also help achieve this goal.

The case for vaccination plus screening

It will likely take at least a decade to assess the impact of HPV vaccination on invasive cervical cancer, and perhaps 20 to 30 years to achieve the maximum benefit from such a program. A computer-based model of the natural history of HPV and cervical cancer developed by the Harvard School of Public Health considered different cancer prevention policies, including vaccination against HPV types 16 and 18 (initiated at the age of 12 years), cytologic screening (initiated at 18, 21, 25, 30, or 35 years,) and combined vaccination and screening strategies. The model showed the combination strategy to be most effective.²⁸

Dramatic reductions expected. The model predicts that with current screening and vaccination against HPV, low-grade cervical abnormalities associated with HPV-16 and HPV-18 infections would be reduced by 15% and high-grade lesions by 49%. Vaccination would decrease the number of cases of cervical cancer by about 66% in conjunction with screening. The vaccine, however, would not prevent cancers caused by other high-risk HPV types.

According to the model, HPV vaccination would produce health gains that are well worth the cost. Specifically, the cost per additional quality-adjusted life-year gained with vaccinating only females was estimated to be $21,000. This ratio compares favorably with many adult and pediatric vaccines currently used in the US.

Looking forward

The long-term efficacy of HPV vaccines remains to be determined. Sustained efficacy up to 4.5 years has been documented²⁹ but it could be that boosters will be needed.

Research has shown that adolescents and parents, and even some providers of adolescent health care, may have a significant misunderstanding about HPV infection and its possible sequelae,³⁰ suggesting the need for educational programs about the disease and its prevention. Education and vaccine advocacy from professional organizations such as the AAFP, the American Academy of Pediatrics, and the American College of Obstetricians and Gynecologists will be essential to foster acceptance of HPV vaccination.

CORRESPONDENCE
Michael E. Pichichero, MD, Elmwood Pediatric Group, 601 Elmwood Avenue, Box 672, Rochester, NY 14642. [email protected]

Presexual adolescent girls and sexually active women can now lower their lifetime risk of cervical cancer, thanks to a newly available quadrivalent vaccine (Gardasil) directed at human papillomavirus (HPV). This gives us the opportunity to educate parents and adolescents (the primary target group for the vaccine), many of whom remain uninformed about the direct link between HPV infection and cervical cancer.

Ethical, cultural, social, and religious issues that will require attention¹ are beyond the scope of this article.

Who should receive the HPV vaccine?

Pre-adolescent and adolescent girls

Girls ages 11 to 12 years—most of whom have not started sexual activity—are the primary targets of immunization. However, the US Food and Drug Administration also approved the use of Gardasil for girls as young as 9. Girls this age may require other vaccines, such as meningococcal conjugate and tetanus-diphtheria-acellular pertussis, and experience thus far indicates no negative immune effects with co-administration of vaccines.^1,2

According to one study, vaccination of the entire US population of 12-year-old girls would prevent more than 200,000 HPV infections, 100,000 abnormal Pap tests, and 3300 cases of cervical cancer.³ Parental as well as health care provider acceptance of HPV vaccines for adolescents will be critical to the success of the vaccination effort (see “What makes FPs recommend the HPV vaccine” ).⁴

Practical issues. As with any new vaccine added to the childhood/adolescent vaccination schedule, a host of issues will need to be resolved to ensure adequate coverage. Factors likely to influence use of HPV vaccine among adolescents are cost and reimbursement, and adherence to the 3-dose regimen that spans 6 months.

The American Academy of Pediatrics’ Committee on Infectious Diseases and the Advisory Committee on Immunization Practices (ACIP) recommends universal use of the HPV vaccine for girls, with a focus on 11- to 12-year-olds. The vaccine is also recommended for 13- to 26-year-old girls and women who have received or completed the 3-dose vaccine series.

Why not vaccinate boys? HPV infection is highly prevalent in sexually active men.⁵ The efficacy of vaccinating boys against HPV infection is currently being explored.⁶ However, one model has suggested that vaccinating adolescent males with a bivalent HPV vaccine would only slightly reduce the incidence of cervical cancer cases beyond that achieved by vaccination of adolescent girls, and with an extremely high cost-effectiveness ratio compared with female-only vaccination.⁵

Women ≤26 years

Indications under FDA approval also include women up to 26 years. Even adults who have been sexually active for years may not have been exposed to all high-risk HPV covered by the vaccine.

Are women older than 26 years eligible?

Though FDA approval of the vaccine is for females aged 9 to 26 years, a recent working group on HPV prevention concluded that any sexually active person may benefit from vaccination and should have the opportunity to receive the vaccine.¹ Importantly, women older than 26 years who request the vaccine should be made fully aware of its off-label application in their case.

The rationale behind the recommendations

HPV transmission occurs easily with skin-to-skin contact.^8-11 HPV can infect the external genitalia during non-intercourse sexual activities, including manual and oral genital contact. Sexual intercourse is the most frequent mode of infection of the cervix. Condoms may help protect against transmission of HPV but are not fully effective.^8,12

Adolescents are particularly vulnerable to HPV, but respond best to vaccine. The cervix is especially susceptible to HPV infection in adolescence because the squamous columnar cell junction transformation zone is more exposed. The adult cervix is less susceptible to HPV than the adolescent cervix because of the smaller area of cervical ectopy comprised of columnar epithelial cells.¹³ However, in adolescents, the immune response to HPV exposure is greater than in than adults.

Risk for acquiring HPV infection. Risk factors for acquiring HPV infection are listed in the TABLE .^8,14,15 According to the Centers for Disease Control and Prevention, sexually active men and women have a 50% lifetime risk of acquiring HPV infection.¹⁶ An estimated 6.2 million people in the US become infected with HPV each year,¹⁶ and approximately 20 million currently harbor HPV infections.¹⁷ This estimate includes more than 9 million sexually active adolescents and young adults 15 to 24 years of age, the group in which nearly 75% of new HPV infections occur.¹⁸ Among women <25 years of age, between 28% and 46% are infected with HPV.^19,20

Infection cannot always be cleared. Most HPV infections (whether high-risk or low-risk type) are asymptomatic and are efficiently cleared (ie, no detection of DNA for a specific HPV type) by the immune system.^21,22 However, if the infection cannot be cleared or controlled by the immune system, it may become a persistent infection.

Persistent infection with HPV increases the probability of progression to high-grade cervical intraepithelial neoplasia (CIN) and invasive carcinoma ( FIGURE ).^18-19 Evidence also increasingly shows that high-risk HPV types likely cause anal, penile, scrotal, vulvar, vaginal, and some head and neck cancers.²⁵

How vaccination prevents cervical cancer

After HPV vaccination, neutralizing antibodies are secreted from memory B cells, and bind to their target HPV type, preventing infection before it occurs, thereby blocking the initial step toward development of cervical cancer.

15 high-risk oncogenic types. Papillomaviruses such as HPV are nonenveloped, double-stranded, DNA viruses. They infect cutaneous and mucosal epithelial tissues. More than 100 HPV types have been identified,³ about 30 to 40 of which are spread by sexual contact.⁴ Of the many known HPVs, only 15 are high-risk oncogenic types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, and 73) that can cause cervical cancer.^5.6 Of these high-risk oncogenic types, HPV 16 and 18 account for about 70% of all cervical cancers.⁷

The new HPV vaccines, Gardasil and Cervarix, (see Web table) both contain virosomal antigens to vaccinate against HPV types 16 and 18. Persistent infection with these high-risk HPV types is necessary for the development of cervical cancer. Chronic infection with low-risk HPV types (eg, HPV 6 or 11) may lead to the development of anogenital warts and other low-grade genital abnormalities, as well as laryngeal cancer or recurrent respiratory papillomatosis. Gardasil also contains virosome antigens for these 2 HPV types. Warts on the hands are usually attributable to HPV 7.⁸

Viral integration is a necessary step in the malignant transformation of HPV infection; infection may progress from residential to episomal, and, finally, to an integrated form. Residential infection typically occurs a minimum of 6 weeks from exposure, can persist without detection for decades, and can be low risk or high risk. In the episomal state, virally active HPV is located in the cell nucleus, separate from the human DNA. In the integrated form of infection, the HPV DNA circle has opened and joined the human DNA. Integrated HPV—always high risk—produces an abnormal Papanicolaou (Pap) test. If recognized on colposcopy, it must be treated to prevent progression to cervical cancer. 

FIGURE
How HPV infection progresses to cervical cancer

TABLE
Factors that put women at risk for HPV infection

Why screening alone isn’t enough

New technologies for Pap testing, HPV DNA testing, and revisions in the Bethesda system for reporting cervical cytology have led to better treatment recommendations for patients with abnormal cytology results.²⁶ But despite these advances, cervical screening is underused or not used at all for many women at risk.

For example, some women with abnormal cervical cytology—especially those of lower socioeconomic status, who often are medically underserved or lack insurance—may not receive adequate follow-up care.²⁷ Though widespread cervical screening in the future may significantly decrease morbidity and mortality associated with cervical cancer, HPV vaccination can also help achieve this goal.

The case for vaccination plus screening

It will likely take at least a decade to assess the impact of HPV vaccination on invasive cervical cancer, and perhaps 20 to 30 years to achieve the maximum benefit from such a program. A computer-based model of the natural history of HPV and cervical cancer developed by the Harvard School of Public Health considered different cancer prevention policies, including vaccination against HPV types 16 and 18 (initiated at the age of 12 years), cytologic screening (initiated at 18, 21, 25, 30, or 35 years,) and combined vaccination and screening strategies. The model showed the combination strategy to be most effective.²⁸

Dramatic reductions expected. The model predicts that with current screening and vaccination against HPV, low-grade cervical abnormalities associated with HPV-16 and HPV-18 infections would be reduced by 15% and high-grade lesions by 49%. Vaccination would decrease the number of cases of cervical cancer by about 66% in conjunction with screening. The vaccine, however, would not prevent cancers caused by other high-risk HPV types.

According to the model, HPV vaccination would produce health gains that are well worth the cost. Specifically, the cost per additional quality-adjusted life-year gained with vaccinating only females was estimated to be $21,000. This ratio compares favorably with many adult and pediatric vaccines currently used in the US.

Looking forward

The long-term efficacy of HPV vaccines remains to be determined. Sustained efficacy up to 4.5 years has been documented²⁹ but it could be that boosters will be needed.

Research has shown that adolescents and parents, and even some providers of adolescent health care, may have a significant misunderstanding about HPV infection and its possible sequelae,³⁰ suggesting the need for educational programs about the disease and its prevention. Education and vaccine advocacy from professional organizations such as the AAFP, the American Academy of Pediatrics, and the American College of Obstetricians and Gynecologists will be essential to foster acceptance of HPV vaccination.

CORRESPONDENCE
Michael E. Pichichero, MD, Elmwood Pediatric Group, 601 Elmwood Avenue, Box 672, Rochester, NY 14642. [email protected]

Presexual adolescent girls and sexually active women can now lower their lifetime risk of cervical cancer, thanks to a newly available quadrivalent vaccine (Gardasil) directed at human papillomavirus (HPV). This gives us the opportunity to educate parents and adolescents (the primary target group for the vaccine), many of whom remain uninformed about the direct link between HPV infection and cervical cancer.

Ethical, cultural, social, and religious issues that will require attention¹ are beyond the scope of this article.

Who should receive the HPV vaccine?

Pre-adolescent and adolescent girls

Girls ages 11 to 12 years—most of whom have not started sexual activity—are the primary targets of immunization. However, the US Food and Drug Administration also approved the use of Gardasil for girls as young as 9. Girls this age may require other vaccines, such as meningococcal conjugate and tetanus-diphtheria-acellular pertussis, and experience thus far indicates no negative immune effects with co-administration of vaccines.^1,2

According to one study, vaccination of the entire US population of 12-year-old girls would prevent more than 200,000 HPV infections, 100,000 abnormal Pap tests, and 3300 cases of cervical cancer.³ Parental as well as health care provider acceptance of HPV vaccines for adolescents will be critical to the success of the vaccination effort (see “What makes FPs recommend the HPV vaccine” ).⁴

Practical issues. As with any new vaccine added to the childhood/adolescent vaccination schedule, a host of issues will need to be resolved to ensure adequate coverage. Factors likely to influence use of HPV vaccine among adolescents are cost and reimbursement, and adherence to the 3-dose regimen that spans 6 months.

The American Academy of Pediatrics’ Committee on Infectious Diseases and the Advisory Committee on Immunization Practices (ACIP) recommends universal use of the HPV vaccine for girls, with a focus on 11- to 12-year-olds. The vaccine is also recommended for 13- to 26-year-old girls and women who have received or completed the 3-dose vaccine series.

Why not vaccinate boys? HPV infection is highly prevalent in sexually active men.⁵ The efficacy of vaccinating boys against HPV infection is currently being explored.⁶ However, one model has suggested that vaccinating adolescent males with a bivalent HPV vaccine would only slightly reduce the incidence of cervical cancer cases beyond that achieved by vaccination of adolescent girls, and with an extremely high cost-effectiveness ratio compared with female-only vaccination.⁵

Women ≤26 years

Indications under FDA approval also include women up to 26 years. Even adults who have been sexually active for years may not have been exposed to all high-risk HPV covered by the vaccine.

Are women older than 26 years eligible?

Though FDA approval of the vaccine is for females aged 9 to 26 years, a recent working group on HPV prevention concluded that any sexually active person may benefit from vaccination and should have the opportunity to receive the vaccine.¹ Importantly, women older than 26 years who request the vaccine should be made fully aware of its off-label application in their case.

The rationale behind the recommendations

HPV transmission occurs easily with skin-to-skin contact.^8-11 HPV can infect the external genitalia during non-intercourse sexual activities, including manual and oral genital contact. Sexual intercourse is the most frequent mode of infection of the cervix. Condoms may help protect against transmission of HPV but are not fully effective.^8,12

Adolescents are particularly vulnerable to HPV, but respond best to vaccine. The cervix is especially susceptible to HPV infection in adolescence because the squamous columnar cell junction transformation zone is more exposed. The adult cervix is less susceptible to HPV than the adolescent cervix because of the smaller area of cervical ectopy comprised of columnar epithelial cells.¹³ However, in adolescents, the immune response to HPV exposure is greater than in than adults.

Risk for acquiring HPV infection. Risk factors for acquiring HPV infection are listed in the TABLE .^8,14,15 According to the Centers for Disease Control and Prevention, sexually active men and women have a 50% lifetime risk of acquiring HPV infection.¹⁶ An estimated 6.2 million people in the US become infected with HPV each year,¹⁶ and approximately 20 million currently harbor HPV infections.¹⁷ This estimate includes more than 9 million sexually active adolescents and young adults 15 to 24 years of age, the group in which nearly 75% of new HPV infections occur.¹⁸ Among women <25 years of age, between 28% and 46% are infected with HPV.^19,20

Infection cannot always be cleared. Most HPV infections (whether high-risk or low-risk type) are asymptomatic and are efficiently cleared (ie, no detection of DNA for a specific HPV type) by the immune system.^21,22 However, if the infection cannot be cleared or controlled by the immune system, it may become a persistent infection.

Persistent infection with HPV increases the probability of progression to high-grade cervical intraepithelial neoplasia (CIN) and invasive carcinoma ( FIGURE ).^18-19 Evidence also increasingly shows that high-risk HPV types likely cause anal, penile, scrotal, vulvar, vaginal, and some head and neck cancers.²⁵

How vaccination prevents cervical cancer

After HPV vaccination, neutralizing antibodies are secreted from memory B cells, and bind to their target HPV type, preventing infection before it occurs, thereby blocking the initial step toward development of cervical cancer.

15 high-risk oncogenic types. Papillomaviruses such as HPV are nonenveloped, double-stranded, DNA viruses. They infect cutaneous and mucosal epithelial tissues. More than 100 HPV types have been identified,³ about 30 to 40 of which are spread by sexual contact.⁴ Of the many known HPVs, only 15 are high-risk oncogenic types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, and 73) that can cause cervical cancer.^5.6 Of these high-risk oncogenic types, HPV 16 and 18 account for about 70% of all cervical cancers.⁷

The new HPV vaccines, Gardasil and Cervarix, (see Web table) both contain virosomal antigens to vaccinate against HPV types 16 and 18. Persistent infection with these high-risk HPV types is necessary for the development of cervical cancer. Chronic infection with low-risk HPV types (eg, HPV 6 or 11) may lead to the development of anogenital warts and other low-grade genital abnormalities, as well as laryngeal cancer or recurrent respiratory papillomatosis. Gardasil also contains virosome antigens for these 2 HPV types. Warts on the hands are usually attributable to HPV 7.⁸

Viral integration is a necessary step in the malignant transformation of HPV infection; infection may progress from residential to episomal, and, finally, to an integrated form. Residential infection typically occurs a minimum of 6 weeks from exposure, can persist without detection for decades, and can be low risk or high risk. In the episomal state, virally active HPV is located in the cell nucleus, separate from the human DNA. In the integrated form of infection, the HPV DNA circle has opened and joined the human DNA. Integrated HPV—always high risk—produces an abnormal Papanicolaou (Pap) test. If recognized on colposcopy, it must be treated to prevent progression to cervical cancer. 

FIGURE
How HPV infection progresses to cervical cancer

TABLE
Factors that put women at risk for HPV infection

Why screening alone isn’t enough

New technologies for Pap testing, HPV DNA testing, and revisions in the Bethesda system for reporting cervical cytology have led to better treatment recommendations for patients with abnormal cytology results.²⁶ But despite these advances, cervical screening is underused or not used at all for many women at risk.

For example, some women with abnormal cervical cytology—especially those of lower socioeconomic status, who often are medically underserved or lack insurance—may not receive adequate follow-up care.²⁷ Though widespread cervical screening in the future may significantly decrease morbidity and mortality associated with cervical cancer, HPV vaccination can also help achieve this goal.

The case for vaccination plus screening

It will likely take at least a decade to assess the impact of HPV vaccination on invasive cervical cancer, and perhaps 20 to 30 years to achieve the maximum benefit from such a program. A computer-based model of the natural history of HPV and cervical cancer developed by the Harvard School of Public Health considered different cancer prevention policies, including vaccination against HPV types 16 and 18 (initiated at the age of 12 years), cytologic screening (initiated at 18, 21, 25, 30, or 35 years,) and combined vaccination and screening strategies. The model showed the combination strategy to be most effective.²⁸

Dramatic reductions expected. The model predicts that with current screening and vaccination against HPV, low-grade cervical abnormalities associated with HPV-16 and HPV-18 infections would be reduced by 15% and high-grade lesions by 49%. Vaccination would decrease the number of cases of cervical cancer by about 66% in conjunction with screening. The vaccine, however, would not prevent cancers caused by other high-risk HPV types.

According to the model, HPV vaccination would produce health gains that are well worth the cost. Specifically, the cost per additional quality-adjusted life-year gained with vaccinating only females was estimated to be $21,000. This ratio compares favorably with many adult and pediatric vaccines currently used in the US.

Looking forward

The long-term efficacy of HPV vaccines remains to be determined. Sustained efficacy up to 4.5 years has been documented²⁹ but it could be that boosters will be needed.

Research has shown that adolescents and parents, and even some providers of adolescent health care, may have a significant misunderstanding about HPV infection and its possible sequelae,³⁰ suggesting the need for educational programs about the disease and its prevention. Education and vaccine advocacy from professional organizations such as the AAFP, the American Academy of Pediatrics, and the American College of Obstetricians and Gynecologists will be essential to foster acceptance of HPV vaccination.

CORRESPONDENCE
Michael E. Pichichero, MD, Elmwood Pediatric Group, 601 Elmwood Avenue, Box 672, Rochester, NY 14642. [email protected]

Undoubtedly you have patients who say they are allergic to penicillin but have difficulty recalling details of the reactions they experienced. To be safe, we often label these patients as penicillin-allergic without further questioning and withhold not only penicillins but cephalosporins due to concerns about potential cross-reactivity and resultant IgE-mediated, type I reactions. But even for patients truly allergic to penicillin, is the concern over cephalosporins justified? It depends on the specific agent. What is certain is that a blanket dismissal of all cephalosporins is unfounded.

The truth about the myth

Despite myriad studies spanning decades and involving varied patient populations, results have not conclusively established that penicillin allergy increases the risk of an allergic reaction to cephalosporins, compared with the incidence of a primary (and unrelated) cephalosporin allergy. Most people produce IgG and IgM antibodies in response to exposure to penicillin¹ that may cross-react with cephalosporin antigens.² The presence of these antibodies does not predict allergic, IgE cross-sensitivity to a cephalosporin. Even penicillin skin testing is generally not predictive of cephalosporin allergy.³

Reliably predicting cross-reactivity

A comprehensive review of the evidence shows that the attributable risk of a cross-reactive allergic reaction varies and is strongest when the chemical side chain of the specific cephalosporin is similar to that of penicillin or amoxicillin.

Administration of cephalothin, cephalexin, cefadroxil, and cefazolin in penicillin-allergic patients is associated with a significant increase in the rate of allergic reactions; whereas administration of cefprozil, cefuroxime, cefpodoxime, ceftazidime, and ceftriaxone is not.

Penicillin skin testing can accurately predict a penicillin-allergic reaction, but is not predictive for cephalosporin allergy unless the side chain of the penicillin or ampicillin testing reagent is similar to the cephalosporin side chain being evaluated. Patients who have a reaction to a penicillin or a cephalosporin that is not IgE mediated and not serious may receive repeated courses of that antibiotic and related antibiotics.

This article provides a comprehensive review of the frequency of allergic cross-reactivity between penicillin/amoxicillin and cephalosporin antibiotics, supporting the recent American Academy of Family Physicians evidence-based clinical practice guideline on treatment of acute otitis media recommending the use of cefuroxime, cefpodoxime, cefdinir, and ceftriaxone cephalosporins for patients allergic to penicillin.

Methods

We searched Medline and EMBASE databases for English-language articles using the keywords cephalosporin, penicillin, allergy, and cross-sensitivity for the years 1960 to 2005. Among 219 articles identified, 101 were included as source material for this review. Articles we excluded were reviews, republication of results, or ones irrelevant to our purpose.

Five articles described the rate of rashes following use of penicillin and cephalosporins,^4-8 and 4 articles described rates of anaphylaxis.^5,9-11 We included 26 articles for the evidence base evaluating penicillin/amoxicillin cross-allergy.^3,12-36 Eleven articles relied on patient history of penicillin/amoxicillin allergy to categorize results and establish reaction rates and relative risks for the penicillin/amoxicillin allergic vs nonallergic when receiving cephalosporins.^{12-15,17-20,27,28,31} Fourteen articles relied on patient history of penicillin/amoxicillin allergy plus skin testing results to penicillin/amoxicillin to categorize patients.^{16,21-25,29,30,32-37} One article³ provided data on a subset where penicillin/amoxicillin allergy was established based on history, and a separate subset where penicillin/amoxicillin allergy was established by skin testing. Other articles related to antibiotic chemical structures, animal studies, monoclonal antibody studies, cross-reactive antibody studies, and antibiotic skin testing were also reviewed.

Results

True incidence of reactions to cephalosporins

The most frequent reactions to cephalosporins are non-pruritic, non-urticarial rashes, which occur in 1.0% to 2.8% of patients;^4-8 for most, the mechanism is idiopathic and not a contraindication for future use.³⁸ Retrospective studies suggest a 1% to 3% incidence of immune or allergic reactions to cephalosporins independent of any history of penicillin/amoxicillin allergy.³¹ Anaphylactic reactions from cephalosporins are extremely rare, with the risk estimated at 0.0001% to 0.1%.^31,38 A seminal study suggested approximately 0.004% to 0.015% of treatment courses with penicillin results in anaphylaxis.^5,9-11 Several studies suggest that cephalosporin-induced anaphylaxis occurs no more frequently among patients with known penicillin allergy than among those without such allergy.^23,27,38-41

Determining cross-reactivity

Penicillins and cephalosporins both possess a beta-lactam ring for antimicrobial activity. They differ in that the 5-membered thiazolidine ring of penicillin is replaced in the cephalosporins with a 6-membered dihydrothiazine ring. After degradation, penicillin forms a stable ring, whereas cephalosporins undergo rapid fragmentation of their rings.⁴² Immunologic cross-reactivity between the penicillin and cephalosporin beta-lactam rings is, therefore, very unlikely—an observation confirmed by monoclonal antibody analysis.⁴³

How the “10% cross-reactivity” myth took hold. When the first-generation cephalosporins cephaloridine and cephalothin were introduced in the 1960s, allergic and anaphylactic reactions were reported in patients with previous allergic reactions to penicillins. Subsequent reports, which attributed up to 10% cross-reactivity between the 2 drug classes, involved these same first-generation cephalosporins plus cephalexin and cefadroxil and a second-generation drug, cefamandole. However, these studies were flawed because the penicillin test compounds had been contaminated with cephalosporins. Until 1982, penicillin was produced commercially using the cephalosporium mold.³⁸

Many recent studies have established that the rate of cross-reactivity between penicillin and cephalosporins has been grossly overestimated. In fact, the rate of cross-reactivity between penicillin/amoxicillin and second- or third-generation cephalosporins is very low and may actually be lower than that between penicillins and other classes of antibiotics.⁴⁴

The evidence for limited cross-reactivity. A summary of publications evaluating 38,846 children and adults with and without a history of penicillin allergy is presented in TABLE 1. The database included 2435 patients with a history of penicillin allergy and 961 patients with a history of penicillin allergy and positive skin-test results for penicillin or amoxicillin (total penicillin-allergic patients=3396). The allergic reaction rate is compared with 34,047 patients without a history of penicillin allergy and 1403 patients without a history of penicillin allergy and negative skin-test results for penicillin or amoxicillin (total penicillin-nonallergic patients=35,450).

When patients with a positive history of penicillin-allergy received first-generation cephalosporins, which share a chemical side chain similar to penicillin or amoxicillin (cephalothin, cephaloridine, cephalexin, cefadroxil, and cefazolin, plus the early second-generation cephalosporin, cefamandole), they exhibited a significant increased risk of an allergic reaction to the cephalosporin.

Second- and third-generation cephalosporins modified in size and the complexity of their side chains (eg, cefprozil, cefuroxime, ceftazidime, cefpodoxime, and ceftriaxone) were different enough from penicillin and ampicillin that they did not increase risk of allergic cross-reactivity (TABLE 1).

Many other studies have suggested that cross-reactive immune responses to cephalosporins depend on side chain structure;^{22,23,27,32,37,38,44-49} that is, cephalosporins with a 7-position side chain similar to benzylpenicillin are more likely to cross-react with penicillin (TABLE 2). Cephalosporins that share a similar 7-position or 3-position side chain are more likely to cross-react with each other.

Cephalosporin/penicillin cross-reactivity

Few studies have evaluated whether patients with primary hypersensitivity to cephalosporins will experience cross-reactivity with penicillin. Romano et al⁴⁹ conducted skin tests and RASTs in patients with immediate allergic reactions to cephalosporins to examine responses to other cephalosporins and to classic penicillin determinants. About 1 in 5 patients allergic to a cephalosporin reacted to penicillin determinants, while most had positive results to other cephalosporins with the same or similar side-chains.

Limitations of skin testing

Penicillin skin testing in patients with a history of penicillin allergy does not reliably predict allergy to a cephalosporin unless the side chain of the penicillin or ampicillin reagent is similar to the cephalosporin side chain being tested.³ The positive and negative predictive values of skin testing results for cephalosporins are not well established; if the haptens that cause cephalosporin allergy were known, cross-reactivity with penicillins could be assessed directly. Cephalosporin skin testing works only for the specific drug and drugs with the same side chains, and can be done only if the drug is available in an IV or IM formulation.

Even a positive result does not guarantee a clinical reaction. When penicillin and cephalosporin skin tests or radioallergosorbent tests (RASTs) are positive, a clinical reaction is observed in only 10% to 60% of patients, depending on the reagent and study.⁵⁰ For example, among 19 well-characterized patients allergic to penicillin who were studied for their sensitivity to the cephalosporins, cephaloridine and cefamandole (which have identical or very similar side chains to penicillin and were therefore potentially cross-reactive) only 2 (10.5%) reacted to cefamandole, while the other 17 patients tolerated both agents.²⁶ In another study of clinical cross-reactivity between amoxicillin and cefadroxil in patients allergic to amoxicillin with good tolerance of penicillin, only 12% had an immediate allergic reaction to cefadroxil, despite the 2 drugs sharing an identical side chain.³³ In a third study, allergenic cross-reactivity with cefadroxil and cefamandole was studied among 21 patients selectively allergic to amoxicillin; 8 (38%) had a positive response to cefadroxil (same side chain) and none to cefamandole (different side chain).³²

Discussion

Sensible approach to penicillin-allergic patients

Question patients who report penicillin allergy. In many cases, penicillin may not actually have been taken, or patients may have had non-immunologic adverse events such as vomiting, diarrhea, or nonspecific rash; toxic effects; or contemporaneous side effects inappropriately attributed to the drug. These patients can receive penicillin, amoxicillin, or the cephalosporins.

Without the ability to detect patients with IgE antibody to penicillin prospectively or to distinguish true IgE immunologic reactions from idiopathic reactions in patients receiving cephalosporins, it is impossible to definitely claim that increased immune or IgE-mediated reactions to cephalosporins occur in true penicillinallergic (IgE) patients.

When a cephalosporin is/is not safe for a penicillin-allergic patient. Only IgE-mediated reactions—such as anaphylaxis or hypotension, laryngeal edema, wheezing, angioedema, or urticaria—are likely to become more severe with time. Therefore, with a patient who has had a true IgE-mediated reaction to a penicillin, avoid using cephalosporins with a similar side chain. You may, however, give cephalosporins that have different side chains. Cephalosporins may also be used for patients who have had non-IgE-mediated adverse reactions (“non-type I allergy”)²¹ to a penicillin, such as a non-pruritic, non-urticarial morbilliform or maculopapular rash.

How prevalent is primary cephalosporin allergy? Even if the patient is not allergic to penicillin, cephalosporins can cause allergic or immune-mediated reactions in approximately 1% to 3% of patients. A patient who had an allergic reaction to a specific cephalosporin probably should not receive that cephalosporin again. The risk of a reaction with a different cephalosporin is very low to nonexistent if the side chains of the 2 drugs are dissimilar.

Bottom line. Penicillin-allergic patients have indeed shown an increased incidence of allergic reactions to cephalothin, cephaloridine, cephalexin, cefadroxil, cefazolin, and cefamandole. However, the risk has been overestimated because most studies reporting this cross-reactivity were flawed (because penicillins were contaminated with cephalosporins) and then failed to account for the fact that penicillin-allergic patients have a 3-fold increased risk of allergic reactions even to nonrelated drugs.⁵¹

For patients truly allergic to penicillin, the risk of a reaction from a cephalosporin with side chains that differ from penicillin/amoxicillin (cefuroxime, cefpodoxime, cefdinir, and ceftriaxone, as endorsed by the AAFP) is so low that use is justified and medico-legally defensible by the currently available evidence.

CORRESPONDENCE
Michael E. Pichichero, MD, University of Rochester Medical Center, 601 Elmwood Avenue, Box 672, Rochester, New York 14642. E-mail: [email protected]

Undoubtedly you have patients who say they are allergic to penicillin but have difficulty recalling details of the reactions they experienced. To be safe, we often label these patients as penicillin-allergic without further questioning and withhold not only penicillins but cephalosporins due to concerns about potential cross-reactivity and resultant IgE-mediated, type I reactions. But even for patients truly allergic to penicillin, is the concern over cephalosporins justified? It depends on the specific agent. What is certain is that a blanket dismissal of all cephalosporins is unfounded.

The truth about the myth

Despite myriad studies spanning decades and involving varied patient populations, results have not conclusively established that penicillin allergy increases the risk of an allergic reaction to cephalosporins, compared with the incidence of a primary (and unrelated) cephalosporin allergy. Most people produce IgG and IgM antibodies in response to exposure to penicillin¹ that may cross-react with cephalosporin antigens.² The presence of these antibodies does not predict allergic, IgE cross-sensitivity to a cephalosporin. Even penicillin skin testing is generally not predictive of cephalosporin allergy.³

Reliably predicting cross-reactivity

A comprehensive review of the evidence shows that the attributable risk of a cross-reactive allergic reaction varies and is strongest when the chemical side chain of the specific cephalosporin is similar to that of penicillin or amoxicillin.

Administration of cephalothin, cephalexin, cefadroxil, and cefazolin in penicillin-allergic patients is associated with a significant increase in the rate of allergic reactions; whereas administration of cefprozil, cefuroxime, cefpodoxime, ceftazidime, and ceftriaxone is not.

Penicillin skin testing can accurately predict a penicillin-allergic reaction, but is not predictive for cephalosporin allergy unless the side chain of the penicillin or ampicillin testing reagent is similar to the cephalosporin side chain being evaluated. Patients who have a reaction to a penicillin or a cephalosporin that is not IgE mediated and not serious may receive repeated courses of that antibiotic and related antibiotics.

This article provides a comprehensive review of the frequency of allergic cross-reactivity between penicillin/amoxicillin and cephalosporin antibiotics, supporting the recent American Academy of Family Physicians evidence-based clinical practice guideline on treatment of acute otitis media recommending the use of cefuroxime, cefpodoxime, cefdinir, and ceftriaxone cephalosporins for patients allergic to penicillin.

Methods

We searched Medline and EMBASE databases for English-language articles using the keywords cephalosporin, penicillin, allergy, and cross-sensitivity for the years 1960 to 2005. Among 219 articles identified, 101 were included as source material for this review. Articles we excluded were reviews, republication of results, or ones irrelevant to our purpose.

Five articles described the rate of rashes following use of penicillin and cephalosporins,^4-8 and 4 articles described rates of anaphylaxis.^5,9-11 We included 26 articles for the evidence base evaluating penicillin/amoxicillin cross-allergy.^3,12-36 Eleven articles relied on patient history of penicillin/amoxicillin allergy to categorize results and establish reaction rates and relative risks for the penicillin/amoxicillin allergic vs nonallergic when receiving cephalosporins.^{12-15,17-20,27,28,31} Fourteen articles relied on patient history of penicillin/amoxicillin allergy plus skin testing results to penicillin/amoxicillin to categorize patients.^{16,21-25,29,30,32-37} One article³ provided data on a subset where penicillin/amoxicillin allergy was established based on history, and a separate subset where penicillin/amoxicillin allergy was established by skin testing. Other articles related to antibiotic chemical structures, animal studies, monoclonal antibody studies, cross-reactive antibody studies, and antibiotic skin testing were also reviewed.

Results

True incidence of reactions to cephalosporins

The most frequent reactions to cephalosporins are non-pruritic, non-urticarial rashes, which occur in 1.0% to 2.8% of patients;^4-8 for most, the mechanism is idiopathic and not a contraindication for future use.³⁸ Retrospective studies suggest a 1% to 3% incidence of immune or allergic reactions to cephalosporins independent of any history of penicillin/amoxicillin allergy.³¹ Anaphylactic reactions from cephalosporins are extremely rare, with the risk estimated at 0.0001% to 0.1%.^31,38 A seminal study suggested approximately 0.004% to 0.015% of treatment courses with penicillin results in anaphylaxis.^5,9-11 Several studies suggest that cephalosporin-induced anaphylaxis occurs no more frequently among patients with known penicillin allergy than among those without such allergy.^23,27,38-41

Determining cross-reactivity

Penicillins and cephalosporins both possess a beta-lactam ring for antimicrobial activity. They differ in that the 5-membered thiazolidine ring of penicillin is replaced in the cephalosporins with a 6-membered dihydrothiazine ring. After degradation, penicillin forms a stable ring, whereas cephalosporins undergo rapid fragmentation of their rings.⁴² Immunologic cross-reactivity between the penicillin and cephalosporin beta-lactam rings is, therefore, very unlikely—an observation confirmed by monoclonal antibody analysis.⁴³

How the “10% cross-reactivity” myth took hold. When the first-generation cephalosporins cephaloridine and cephalothin were introduced in the 1960s, allergic and anaphylactic reactions were reported in patients with previous allergic reactions to penicillins. Subsequent reports, which attributed up to 10% cross-reactivity between the 2 drug classes, involved these same first-generation cephalosporins plus cephalexin and cefadroxil and a second-generation drug, cefamandole. However, these studies were flawed because the penicillin test compounds had been contaminated with cephalosporins. Until 1982, penicillin was produced commercially using the cephalosporium mold.³⁸

Many recent studies have established that the rate of cross-reactivity between penicillin and cephalosporins has been grossly overestimated. In fact, the rate of cross-reactivity between penicillin/amoxicillin and second- or third-generation cephalosporins is very low and may actually be lower than that between penicillins and other classes of antibiotics.⁴⁴

The evidence for limited cross-reactivity. A summary of publications evaluating 38,846 children and adults with and without a history of penicillin allergy is presented in TABLE 1. The database included 2435 patients with a history of penicillin allergy and 961 patients with a history of penicillin allergy and positive skin-test results for penicillin or amoxicillin (total penicillin-allergic patients=3396). The allergic reaction rate is compared with 34,047 patients without a history of penicillin allergy and 1403 patients without a history of penicillin allergy and negative skin-test results for penicillin or amoxicillin (total penicillin-nonallergic patients=35,450).

When patients with a positive history of penicillin-allergy received first-generation cephalosporins, which share a chemical side chain similar to penicillin or amoxicillin (cephalothin, cephaloridine, cephalexin, cefadroxil, and cefazolin, plus the early second-generation cephalosporin, cefamandole), they exhibited a significant increased risk of an allergic reaction to the cephalosporin.

Second- and third-generation cephalosporins modified in size and the complexity of their side chains (eg, cefprozil, cefuroxime, ceftazidime, cefpodoxime, and ceftriaxone) were different enough from penicillin and ampicillin that they did not increase risk of allergic cross-reactivity (TABLE 1).

Many other studies have suggested that cross-reactive immune responses to cephalosporins depend on side chain structure;^{22,23,27,32,37,38,44-49} that is, cephalosporins with a 7-position side chain similar to benzylpenicillin are more likely to cross-react with penicillin (TABLE 2). Cephalosporins that share a similar 7-position or 3-position side chain are more likely to cross-react with each other.

Cephalosporin/penicillin cross-reactivity

Few studies have evaluated whether patients with primary hypersensitivity to cephalosporins will experience cross-reactivity with penicillin. Romano et al⁴⁹ conducted skin tests and RASTs in patients with immediate allergic reactions to cephalosporins to examine responses to other cephalosporins and to classic penicillin determinants. About 1 in 5 patients allergic to a cephalosporin reacted to penicillin determinants, while most had positive results to other cephalosporins with the same or similar side-chains.

Limitations of skin testing

Penicillin skin testing in patients with a history of penicillin allergy does not reliably predict allergy to a cephalosporin unless the side chain of the penicillin or ampicillin reagent is similar to the cephalosporin side chain being tested.³ The positive and negative predictive values of skin testing results for cephalosporins are not well established; if the haptens that cause cephalosporin allergy were known, cross-reactivity with penicillins could be assessed directly. Cephalosporin skin testing works only for the specific drug and drugs with the same side chains, and can be done only if the drug is available in an IV or IM formulation.

Even a positive result does not guarantee a clinical reaction. When penicillin and cephalosporin skin tests or radioallergosorbent tests (RASTs) are positive, a clinical reaction is observed in only 10% to 60% of patients, depending on the reagent and study.⁵⁰ For example, among 19 well-characterized patients allergic to penicillin who were studied for their sensitivity to the cephalosporins, cephaloridine and cefamandole (which have identical or very similar side chains to penicillin and were therefore potentially cross-reactive) only 2 (10.5%) reacted to cefamandole, while the other 17 patients tolerated both agents.²⁶ In another study of clinical cross-reactivity between amoxicillin and cefadroxil in patients allergic to amoxicillin with good tolerance of penicillin, only 12% had an immediate allergic reaction to cefadroxil, despite the 2 drugs sharing an identical side chain.³³ In a third study, allergenic cross-reactivity with cefadroxil and cefamandole was studied among 21 patients selectively allergic to amoxicillin; 8 (38%) had a positive response to cefadroxil (same side chain) and none to cefamandole (different side chain).³²

Discussion

Sensible approach to penicillin-allergic patients

Question patients who report penicillin allergy. In many cases, penicillin may not actually have been taken, or patients may have had non-immunologic adverse events such as vomiting, diarrhea, or nonspecific rash; toxic effects; or contemporaneous side effects inappropriately attributed to the drug. These patients can receive penicillin, amoxicillin, or the cephalosporins.

Without the ability to detect patients with IgE antibody to penicillin prospectively or to distinguish true IgE immunologic reactions from idiopathic reactions in patients receiving cephalosporins, it is impossible to definitely claim that increased immune or IgE-mediated reactions to cephalosporins occur in true penicillinallergic (IgE) patients.

When a cephalosporin is/is not safe for a penicillin-allergic patient. Only IgE-mediated reactions—such as anaphylaxis or hypotension, laryngeal edema, wheezing, angioedema, or urticaria—are likely to become more severe with time. Therefore, with a patient who has had a true IgE-mediated reaction to a penicillin, avoid using cephalosporins with a similar side chain. You may, however, give cephalosporins that have different side chains. Cephalosporins may also be used for patients who have had non-IgE-mediated adverse reactions (“non-type I allergy”)²¹ to a penicillin, such as a non-pruritic, non-urticarial morbilliform or maculopapular rash.

How prevalent is primary cephalosporin allergy? Even if the patient is not allergic to penicillin, cephalosporins can cause allergic or immune-mediated reactions in approximately 1% to 3% of patients. A patient who had an allergic reaction to a specific cephalosporin probably should not receive that cephalosporin again. The risk of a reaction with a different cephalosporin is very low to nonexistent if the side chains of the 2 drugs are dissimilar.

Bottom line. Penicillin-allergic patients have indeed shown an increased incidence of allergic reactions to cephalothin, cephaloridine, cephalexin, cefadroxil, cefazolin, and cefamandole. However, the risk has been overestimated because most studies reporting this cross-reactivity were flawed (because penicillins were contaminated with cephalosporins) and then failed to account for the fact that penicillin-allergic patients have a 3-fold increased risk of allergic reactions even to nonrelated drugs.⁵¹

For patients truly allergic to penicillin, the risk of a reaction from a cephalosporin with side chains that differ from penicillin/amoxicillin (cefuroxime, cefpodoxime, cefdinir, and ceftriaxone, as endorsed by the AAFP) is so low that use is justified and medico-legally defensible by the currently available evidence.

CORRESPONDENCE
Michael E. Pichichero, MD, University of Rochester Medical Center, 601 Elmwood Avenue, Box 672, Rochester, New York 14642. E-mail: [email protected]

Undoubtedly you have patients who say they are allergic to penicillin but have difficulty recalling details of the reactions they experienced. To be safe, we often label these patients as penicillin-allergic without further questioning and withhold not only penicillins but cephalosporins due to concerns about potential cross-reactivity and resultant IgE-mediated, type I reactions. But even for patients truly allergic to penicillin, is the concern over cephalosporins justified? It depends on the specific agent. What is certain is that a blanket dismissal of all cephalosporins is unfounded.

The truth about the myth

Despite myriad studies spanning decades and involving varied patient populations, results have not conclusively established that penicillin allergy increases the risk of an allergic reaction to cephalosporins, compared with the incidence of a primary (and unrelated) cephalosporin allergy. Most people produce IgG and IgM antibodies in response to exposure to penicillin¹ that may cross-react with cephalosporin antigens.² The presence of these antibodies does not predict allergic, IgE cross-sensitivity to a cephalosporin. Even penicillin skin testing is generally not predictive of cephalosporin allergy.³

Reliably predicting cross-reactivity

A comprehensive review of the evidence shows that the attributable risk of a cross-reactive allergic reaction varies and is strongest when the chemical side chain of the specific cephalosporin is similar to that of penicillin or amoxicillin.

Administration of cephalothin, cephalexin, cefadroxil, and cefazolin in penicillin-allergic patients is associated with a significant increase in the rate of allergic reactions; whereas administration of cefprozil, cefuroxime, cefpodoxime, ceftazidime, and ceftriaxone is not.

Penicillin skin testing can accurately predict a penicillin-allergic reaction, but is not predictive for cephalosporin allergy unless the side chain of the penicillin or ampicillin testing reagent is similar to the cephalosporin side chain being evaluated. Patients who have a reaction to a penicillin or a cephalosporin that is not IgE mediated and not serious may receive repeated courses of that antibiotic and related antibiotics.

This article provides a comprehensive review of the frequency of allergic cross-reactivity between penicillin/amoxicillin and cephalosporin antibiotics, supporting the recent American Academy of Family Physicians evidence-based clinical practice guideline on treatment of acute otitis media recommending the use of cefuroxime, cefpodoxime, cefdinir, and ceftriaxone cephalosporins for patients allergic to penicillin.

Methods

We searched Medline and EMBASE databases for English-language articles using the keywords cephalosporin, penicillin, allergy, and cross-sensitivity for the years 1960 to 2005. Among 219 articles identified, 101 were included as source material for this review. Articles we excluded were reviews, republication of results, or ones irrelevant to our purpose.

Five articles described the rate of rashes following use of penicillin and cephalosporins,^4-8 and 4 articles described rates of anaphylaxis.^5,9-11 We included 26 articles for the evidence base evaluating penicillin/amoxicillin cross-allergy.^3,12-36 Eleven articles relied on patient history of penicillin/amoxicillin allergy to categorize results and establish reaction rates and relative risks for the penicillin/amoxicillin allergic vs nonallergic when receiving cephalosporins.^{12-15,17-20,27,28,31} Fourteen articles relied on patient history of penicillin/amoxicillin allergy plus skin testing results to penicillin/amoxicillin to categorize patients.^{16,21-25,29,30,32-37} One article³ provided data on a subset where penicillin/amoxicillin allergy was established based on history, and a separate subset where penicillin/amoxicillin allergy was established by skin testing. Other articles related to antibiotic chemical structures, animal studies, monoclonal antibody studies, cross-reactive antibody studies, and antibiotic skin testing were also reviewed.

Results

True incidence of reactions to cephalosporins

The most frequent reactions to cephalosporins are non-pruritic, non-urticarial rashes, which occur in 1.0% to 2.8% of patients;^4-8 for most, the mechanism is idiopathic and not a contraindication for future use.³⁸ Retrospective studies suggest a 1% to 3% incidence of immune or allergic reactions to cephalosporins independent of any history of penicillin/amoxicillin allergy.³¹ Anaphylactic reactions from cephalosporins are extremely rare, with the risk estimated at 0.0001% to 0.1%.^31,38 A seminal study suggested approximately 0.004% to 0.015% of treatment courses with penicillin results in anaphylaxis.^5,9-11 Several studies suggest that cephalosporin-induced anaphylaxis occurs no more frequently among patients with known penicillin allergy than among those without such allergy.^23,27,38-41

Determining cross-reactivity

Penicillins and cephalosporins both possess a beta-lactam ring for antimicrobial activity. They differ in that the 5-membered thiazolidine ring of penicillin is replaced in the cephalosporins with a 6-membered dihydrothiazine ring. After degradation, penicillin forms a stable ring, whereas cephalosporins undergo rapid fragmentation of their rings.⁴² Immunologic cross-reactivity between the penicillin and cephalosporin beta-lactam rings is, therefore, very unlikely—an observation confirmed by monoclonal antibody analysis.⁴³

How the “10% cross-reactivity” myth took hold. When the first-generation cephalosporins cephaloridine and cephalothin were introduced in the 1960s, allergic and anaphylactic reactions were reported in patients with previous allergic reactions to penicillins. Subsequent reports, which attributed up to 10% cross-reactivity between the 2 drug classes, involved these same first-generation cephalosporins plus cephalexin and cefadroxil and a second-generation drug, cefamandole. However, these studies were flawed because the penicillin test compounds had been contaminated with cephalosporins. Until 1982, penicillin was produced commercially using the cephalosporium mold.³⁸

Many recent studies have established that the rate of cross-reactivity between penicillin and cephalosporins has been grossly overestimated. In fact, the rate of cross-reactivity between penicillin/amoxicillin and second- or third-generation cephalosporins is very low and may actually be lower than that between penicillins and other classes of antibiotics.⁴⁴

The evidence for limited cross-reactivity. A summary of publications evaluating 38,846 children and adults with and without a history of penicillin allergy is presented in TABLE 1. The database included 2435 patients with a history of penicillin allergy and 961 patients with a history of penicillin allergy and positive skin-test results for penicillin or amoxicillin (total penicillin-allergic patients=3396). The allergic reaction rate is compared with 34,047 patients without a history of penicillin allergy and 1403 patients without a history of penicillin allergy and negative skin-test results for penicillin or amoxicillin (total penicillin-nonallergic patients=35,450).

When patients with a positive history of penicillin-allergy received first-generation cephalosporins, which share a chemical side chain similar to penicillin or amoxicillin (cephalothin, cephaloridine, cephalexin, cefadroxil, and cefazolin, plus the early second-generation cephalosporin, cefamandole), they exhibited a significant increased risk of an allergic reaction to the cephalosporin.

Second- and third-generation cephalosporins modified in size and the complexity of their side chains (eg, cefprozil, cefuroxime, ceftazidime, cefpodoxime, and ceftriaxone) were different enough from penicillin and ampicillin that they did not increase risk of allergic cross-reactivity (TABLE 1).

Many other studies have suggested that cross-reactive immune responses to cephalosporins depend on side chain structure;^{22,23,27,32,37,38,44-49} that is, cephalosporins with a 7-position side chain similar to benzylpenicillin are more likely to cross-react with penicillin (TABLE 2). Cephalosporins that share a similar 7-position or 3-position side chain are more likely to cross-react with each other.

Cephalosporin/penicillin cross-reactivity

Few studies have evaluated whether patients with primary hypersensitivity to cephalosporins will experience cross-reactivity with penicillin. Romano et al⁴⁹ conducted skin tests and RASTs in patients with immediate allergic reactions to cephalosporins to examine responses to other cephalosporins and to classic penicillin determinants. About 1 in 5 patients allergic to a cephalosporin reacted to penicillin determinants, while most had positive results to other cephalosporins with the same or similar side-chains.

Limitations of skin testing

Penicillin skin testing in patients with a history of penicillin allergy does not reliably predict allergy to a cephalosporin unless the side chain of the penicillin or ampicillin reagent is similar to the cephalosporin side chain being tested.³ The positive and negative predictive values of skin testing results for cephalosporins are not well established; if the haptens that cause cephalosporin allergy were known, cross-reactivity with penicillins could be assessed directly. Cephalosporin skin testing works only for the specific drug and drugs with the same side chains, and can be done only if the drug is available in an IV or IM formulation.

Even a positive result does not guarantee a clinical reaction. When penicillin and cephalosporin skin tests or radioallergosorbent tests (RASTs) are positive, a clinical reaction is observed in only 10% to 60% of patients, depending on the reagent and study.⁵⁰ For example, among 19 well-characterized patients allergic to penicillin who were studied for their sensitivity to the cephalosporins, cephaloridine and cefamandole (which have identical or very similar side chains to penicillin and were therefore potentially cross-reactive) only 2 (10.5%) reacted to cefamandole, while the other 17 patients tolerated both agents.²⁶ In another study of clinical cross-reactivity between amoxicillin and cefadroxil in patients allergic to amoxicillin with good tolerance of penicillin, only 12% had an immediate allergic reaction to cefadroxil, despite the 2 drugs sharing an identical side chain.³³ In a third study, allergenic cross-reactivity with cefadroxil and cefamandole was studied among 21 patients selectively allergic to amoxicillin; 8 (38%) had a positive response to cefadroxil (same side chain) and none to cefamandole (different side chain).³²

Discussion

Sensible approach to penicillin-allergic patients

Question patients who report penicillin allergy. In many cases, penicillin may not actually have been taken, or patients may have had non-immunologic adverse events such as vomiting, diarrhea, or nonspecific rash; toxic effects; or contemporaneous side effects inappropriately attributed to the drug. These patients can receive penicillin, amoxicillin, or the cephalosporins.

Without the ability to detect patients with IgE antibody to penicillin prospectively or to distinguish true IgE immunologic reactions from idiopathic reactions in patients receiving cephalosporins, it is impossible to definitely claim that increased immune or IgE-mediated reactions to cephalosporins occur in true penicillinallergic (IgE) patients.

When a cephalosporin is/is not safe for a penicillin-allergic patient. Only IgE-mediated reactions—such as anaphylaxis or hypotension, laryngeal edema, wheezing, angioedema, or urticaria—are likely to become more severe with time. Therefore, with a patient who has had a true IgE-mediated reaction to a penicillin, avoid using cephalosporins with a similar side chain. You may, however, give cephalosporins that have different side chains. Cephalosporins may also be used for patients who have had non-IgE-mediated adverse reactions (“non-type I allergy”)²¹ to a penicillin, such as a non-pruritic, non-urticarial morbilliform or maculopapular rash.

How prevalent is primary cephalosporin allergy? Even if the patient is not allergic to penicillin, cephalosporins can cause allergic or immune-mediated reactions in approximately 1% to 3% of patients. A patient who had an allergic reaction to a specific cephalosporin probably should not receive that cephalosporin again. The risk of a reaction with a different cephalosporin is very low to nonexistent if the side chains of the 2 drugs are dissimilar.

Bottom line. Penicillin-allergic patients have indeed shown an increased incidence of allergic reactions to cephalothin, cephaloridine, cephalexin, cefadroxil, cefazolin, and cefamandole. However, the risk has been overestimated because most studies reporting this cross-reactivity were flawed (because penicillins were contaminated with cephalosporins) and then failed to account for the fact that penicillin-allergic patients have a 3-fold increased risk of allergic reactions even to nonrelated drugs.⁵¹

For patients truly allergic to penicillin, the risk of a reaction from a cephalosporin with side chains that differ from penicillin/amoxicillin (cefuroxime, cefpodoxime, cefdinir, and ceftriaxone, as endorsed by the AAFP) is so low that use is justified and medico-legally defensible by the currently available evidence.

CORRESPONDENCE
Michael E. Pichichero, MD, University of Rochester Medical Center, 601 Elmwood Avenue, Box 672, Rochester, New York 14642. E-mail: [email protected]

Since the approval of the 7-valent pneumococcal conjugate vaccine (PCV-7) for use in children younger than 24 months in February 2000, occurrences of acute otitis media (AOM) and the frequency of recurrent AOM have declined. Based on results from early clinical trials, PCV-7 may reduce total AOM by 6% to 8%, recurrent AOM by 10% to 26%, and tympanostomy tube placements by 24%.^1,2

Acute otitis media occurs most frequently in children between the ages of 6 months and 18 months. By the end of their first year, approximately 86% of children will experience at least 1 episode of AOM.³

The condition remains a leading reason for visits to pediatricians and family physicians in the United States.⁴ It accounted for 16 million visits in 2000.⁴ This is a decrease from almost 25 million visits in 1995, prior to use of PCV-7. Additionally, AOM is associated with significant costs: In 1995, the direct and indirect costs of AOM were estimated to be about $3 billion.⁵

Changes in pathogen frequency for AOM in the ERA of PCV-7

The true impact of PCV-7 on management practice is not characterized by the modest reduction in incidence of uncomplicated AOM but in the PCV-7–associated shift in causative pathogens. Pre-PCV-7, 40% to 50% of cases of AOM in young children were caused by Streptococcus pneumoniae, 20% to 30% by Haemophilus influenzae, and 10% to 15% by Moraxella catarrhalis.⁶ In studies conducted prior to 2000, diagnostic tympanocentesis isolated S pneumoniae from 25% to 55% of all middle ear aspirates from children with AOM.^6-8

Conversely, 1 study published in 2001 and 2 studies published in 2004 appear to document a reverse trend with the advent of the conjugate pneumococcal vaccine.^9,10 Compared with children studied in an earlier era, those vaccinated with PCV-7 may be more likely to have H influenzae isolates. These studies will be described in detail below.

Bacterial AOM: initial antibiotic therapy and specific pathogens

Current guidelines recommend amoxicillin (45 mg/kg/day) or high-dose amoxicillin (80-90 mg/kg/day) as initial therapy in presumed or documented bacterial AOM.⁵ Although amoxicillin is effective against pneumococcus and β-lactamase–negative strains of H influenzae, it is ineffective against β-lactamase–positive strains of H influenzae.⁹ Significant initial failures may point to a changing pathogen per population frequency. A 2004 review assessed children with continued (persistence of infection detected within 30 days after treatment completion) or refractory (clinical failure while receiving antimicrobial therapy) AOM who have received high-dose amoxicillin as initial empiric therapy. The authors noted that the rate of infection due to H influenzae has increased from 43% among those treated prior to the licensure of PCV-7 to 57% among those who received 2 or more doses of PCV-7.¹⁰

Evidence from the medical literature

Three studies provide the major evidence concerning the pathogen shift associated with the adoption of the PCV-7 conjugate vaccine:

• The Finnish Otitis Media Vaccine Trial²
• A published collection of clinical trial results from a rural practice in Kentucky in which 94% of children were immunized with PCV-7⁹
• A prospective study conducted in a suburban community-based private practice in Rochester, NY that evaluated children with persistent or nonresponsive AOM.¹⁰

The Finnish Otitis Media Vaccine Trial

In this trial, 1662 infants received either the PCV-7 vaccine or a control vaccine at ages 2, 4, 6, and 12 months and were monitored from ages 6.5 months to 24 months.² An overall 6.9% reduction in episodes of clinical AOM were diagnosed (n=1251) in PCV-7–vaccinated children compared with the control group (n=1345). This suggested that fewer AOM cases were caused by the S pneumoniae vaccine serotypes than nonvaccine serotypes. The bacteriologic findings in the samples of middle ear fluid taken during 93% of the visits for AOM (TABLE 1) show a 34% reduction in culture-confirmed episodes in the PCV-7–vaccinated group, a decrease of more than 50% in pneumococcal AOM episodes caused by vaccine or vaccine cross-reactive serotypes, a 33% increase in infections caused by other pneumococcal serotypes, and an 11% increase in the proportion of AOM cases due to H influenzae.²

TABLE 1

Finnish Otitis Media Vaccine Trial: Causes of AOM Episodes and Impact of PCV-7 Immunization on Incidence

Study Results From a Rural Kentucky Practice

In this practice, data on isolates from middle ear fluid were collected in children with severe or refractory AOM aged 7 to 24 months.⁹ Data were obtained from 1992 to 1998, before the introduction of PCV-7, and from 2000 to 2003, following immunization with 3 or 4 doses of PCV-7 during the first 18 months of life.

As shown in TABLE 2, the pre-PCV-7 group of children (N=336; 1992-1998) had a proportion of 48% culture-confirmed pneumococcus vs a proportion of 31% in the PCV-7-vaccinated group (N=83; 2000-2003), a 17% decrease. The decrease in proportion of AOM episodes resulting from vaccine serotypes was 34%.

In this investigation, 28% of the pre-PCV-7 group and 34% of the post-PCV-7 group had received antibiotic therapy within the previous 3 days. Additionally, 59% and 76%, respectively, had received antibiotic therapy within the preceding 30 days. There were increases of 30% in vaccine cross-reactive serotypes and 45% in nonvaccine serotypes. Vaccine cross-reactive serotypes 6A and 19A accounted for most of the penicillin-nonsusceptible S pneumoniae strains in the vaccinated population.

Most impressive, however, in the post-PCV-7 group, was that gram-negative bacteria, mainly H influenzae, accounted for two thirds of AOM isolates, an increase from 41% in the pre-PCV-7 group to 56% in the vaccinated group. A 56% increase was noted in β-lactamase–positive organisms from the pre-PCV-7 group to the post-PCV-7 group. The combined H influenzae and M catarrhalis β-lactamase–producing organisms accounted for nearly half of all isolates.⁹

TABLE 2

Results From a Rural Kentucky Practice: Change in AOM Microbiology From Pre-PCV-7 (1992–1998) to Post-PCV-7 (2000–2003)

The Prospective Rochester, New York Study

Changes in pre- and post-PVC-7 patterns also were seen in a prospective study of 551 children with persistent or nonresponsive AOM (defined as nonresponders after 1 or 2 empiric antibiotic courses or failures after 48 hours of treatment). These children underwent tympanocentesis to identify bacterial isolates during the 9-year period from 1995 to 2003.¹⁰

From 1995 to 1997, enrollees received a standard dose of amoxicillin (40-50 mg/kg, divided into 3 doses daily) as initial empiric treatment. From 1998 to 2000 and 2001 to 2003, all children received high-dose amoxicillin (80-100 mg/kg, divided into twice-daily doses).

During the latter period, the children also were vaccinated with PCV-7, with 63% receiving the primary series of 3 doses and 10% receiving the booster dose. In this investigation, shortages in vaccine supply, discussed below, caused vaccination schedules to be compromised.

Study results (TABLE 3) show that in the post-PCV-7 group, there was a 13% decrease in the proportion of S pneumoniae isolates and a 14% increase in the proportion of H influenzae isolates compared with the pre-PCV-7 group (1998-2000 enrollees). An increase of 22% for β-lactamase–positive bacteria was also observed, along with a trend toward an increased proportion of penicillin-susceptible S pneumoniae isolates (58% vs 72%; P=.017) post-PCV-7.¹⁰ A 24% reduction (P=.009) in the frequency of the diagnosis of persistent or AOM treatment failure occurred in the period after PCV-7 vaccination. These changes were considered to be the result of the use of the conjugate pneumococcal vaccine rather than of the change in amoxicillin dosing.¹⁰

TABLE 3

The Prospective Rochester, New York Study: Pathogens Isolated in Persistent AOM and AOM Treatment Failure Pre- and Post-PCV-7

Pneumococcal serotype shifts

In addition to the change in causative pathogens, use of the conjugate pneumococcal vaccine appears to have led to a significant shift in the pneumococcal strains causing AOM. Studies at urban medical centers and in the Kentucky practice documented an increase in the proportion of nonvaccine serotypes, accounting for 32% to 38% of pneumococcal AOM.^10-12 A 33% increase was seen in the Finnish Trial.² These nonvaccine pneumococcal serotypes do not carry the same level of resistance seen with those serotypes included in PCV-7.

PCV-7 conjugate vaccine

The PCV-7 conjugate vaccine was approved for use in February 2000. It is a 7-valent pneumococcal conjugate of the capsular antigens of the S pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F, individually conjugated to diphtheria CRM197 protein.¹³ These serotypes have been responsible for approximately 80% of invasive pneumococcal disease in children younger than 6 years in the United States.^13,14 They also accounted for 74% of penicillin-susceptible S pneumoniae and 100% of pneumococci with high-level penicillin resistance isolated from children younger than age 6 years with invasive disease during a 1993-1994 surveillance by the Centers for Disease Control and Prevention (CDC).¹³

Mechanism of Action and Recommended Immunization Schedule

The conjugate vaccine is converted to a T-cell–dependent antigen, antibody formation is enhanced, and memory B cells are primed.¹⁴

The recommended immunization schedule was established as 3 primary doses at ages 2, 4, and 6 months and a booster dose at 12 to 15 months.¹ It is the first multivalent pneumococcal vaccine approved for use in children younger than 24 months.

An 89% reduction in invasive pneumococcal disease was observed in children receiving 1 or more doses, and the vaccine appears to reduce nasopharyngeal carriage of vaccine serotypes.^15,16

The older 23-valent polysaccharide vaccine does not stimulate good response in children younger than 2 years of age¹⁴ and does not reduce mucosal carriage or limit the spread of resistant strains.¹⁵

PCV-7 Supply Since 2000

In August 2001, a serious shortage of the vaccine developed in 34 state immunization programs.¹⁷ The following month, the CDC advised physicians to administer it only to children younger than 12 months and to those aged 1 to 5 years at increased risk of pneumococcal disease.¹⁸ As demand continued despite the change in recommendations, the CDC further changed recommendations to conserve vaccine supply, first suspending the fourth dose temporarily in healthy children¹⁹ and then discontinuing both the third and fourth doses.¹¹ In July 2004, production problems seemed to have resolved; the CDC recommended that every child receive 3 doses. In September, supplies were adequate for return to the 4-dose schedule.¹² As of June 2004, 67.7% of children aged 24 months had received 3 or more doses of PCV-7.²⁰ Thus, the effects of PCV-7 on the changing microbiology of AOM may only now, at the end of 2005, be fully realized.

Herd Immunity and Reduction in Carriage

Despite the shortages of vaccine during the first years of use, evidence of herd immunity and a decrease in antibiotic resistance in pneumococcal pathogens has been reported throughout the United States.^21,22 A 29% decrease in the rate of pneumococcal disease in both young children and adults has also been observed, along with a 35% reduction in the rate of disease caused by nonpenicillin-susceptible pneumococcal strains.²¹ The reduction in carriage among vaccinated children may be the reason.^21,22 Because of the impact of PCV-7, it will be important to record immunization history when collecting AOM data.

AOM treatment choices

The basis of recommendations for treating AOM depends on the presumed responsible pathogens, their susceptibility to antibiotics, and concerns for developing resistance, all influenced by clinical trial data. In practice, however, empiric choices are often made based on knowledge of local resistance patterns and of other patient characteristics; that is cost concerns, adverse event profiles, need to avoid initial treatment failure, adherence issues (eg, taste or palatability), convenience, and duration of dosing regimen.

All current guidelines recommend oral amoxicillin as first-line therapy in documented or presumed bacterial AOM. The 2004 American Academy of Pediatrics/American Academy of Family Physicians’ (AAP/AAFP) guidelines⁴ recommended increasing the dosage used for empiric treatment from 40 to 45 mg/kg/day to 80 to 90 mg/kg/day for all children. This was a result of concerns about the prevalence of penicillin-resistant S pneumoniae for which standard-dose amoxicillin is inadequate.²³

The guidelines were written and published before the data from the Kentucky and New York studies were available; therefore, although the guidelines recommended that empiric treatment of bacterial AOM should target S pneumoniae, H influenzae, and M catarrhalis, the pathogen shift discussed previously might today produce a modified antibiotic selection paradigm. The pathogen mix in persistent or recurrent AOM has already led to a guideline recommendation for high-dose amoxicillin/clavulanate, 90/6.4 mg/kg/day, cefdinir, cefprozil, cefpodoxime, cefuroxime, or ceftriaxone in these patients.²³

If an increase in the proportion of β-lactamase–producing pathogens due to PCV-7 occurs, amoxicillin may no longer be the best first choice.

Selecting Among Recommended Antibiotic Choices

As antibiotic preparations for treating bacterial AOM are oral suspensions, taste is a major factor for pediatric patients. TABLE 4 summarizes comparative taste ratings for antibiotic suspensions based on several studies and shows the range, from those that can enhance compliance to those that discourage compliance.²³

Adverse events, especially diarrhea, nausea/vomiting, and gastritis, are also of concern. These are shortcomings of amoxicillin/clavulanate, which has a higher incidence of diarrhea and nausea than cephalosporins.²⁴

Dosing frequency is also a factor among recommended agents. Amoxicillin, amoxicillin/clavulanate, cefprozil, and cefpodoxime require twice-daily dosing. Cefdinir can be effective at once-daily dosing.²⁴

Duration of approved therapy is perhaps the most critical selection factor given the reality of patient behaviors. Cefpodoxime and cefdinir are the only 2 FDA-approved agents for 5-day treatment of bacterial AOM that are also guideline-recommended.

TABLE 4

Compliance-Enhancing Ranking of Antibiotic Suspensions

Choices for Effective Initial Therapy

Considering the changing microbial population in bacterial AOM and the increasing concern of effectiveness of amoxicillin and other antibiotics against β-lactamase–producing H influenzae, the choice of therapy may need modification. Specifically, that may mean changing the choice of effective antibiotic, taking into consideration the compliance-enhancing advantages of available options.

Based on efficacy, the overall prevalence of antibiotic-resistant AOM pathogens for PCV-7-vaccinated children, the potential for adverse effects, and patient compliance issues, Block and Harrison developed an algorithm (FIGURE) for the management of AOM diagnosed by strict criteria in an otherwise healthy child between 4 months and 36 months old.²⁴ As the environment of AOM evolves, the choices for treatment must be not only effective but also the best and most appropriate.

FIGURE Antibiotic Choices for Acute Otitis Media in the 2000s

Since the approval of the 7-valent pneumococcal conjugate vaccine (PCV-7) for use in children younger than 24 months in February 2000, occurrences of acute otitis media (AOM) and the frequency of recurrent AOM have declined. Based on results from early clinical trials, PCV-7 may reduce total AOM by 6% to 8%, recurrent AOM by 10% to 26%, and tympanostomy tube placements by 24%.^1,2

Acute otitis media occurs most frequently in children between the ages of 6 months and 18 months. By the end of their first year, approximately 86% of children will experience at least 1 episode of AOM.³

The condition remains a leading reason for visits to pediatricians and family physicians in the United States.⁴ It accounted for 16 million visits in 2000.⁴ This is a decrease from almost 25 million visits in 1995, prior to use of PCV-7. Additionally, AOM is associated with significant costs: In 1995, the direct and indirect costs of AOM were estimated to be about $3 billion.⁵

Changes in pathogen frequency for AOM in the ERA of PCV-7

The true impact of PCV-7 on management practice is not characterized by the modest reduction in incidence of uncomplicated AOM but in the PCV-7–associated shift in causative pathogens. Pre-PCV-7, 40% to 50% of cases of AOM in young children were caused by Streptococcus pneumoniae, 20% to 30% by Haemophilus influenzae, and 10% to 15% by Moraxella catarrhalis.⁶ In studies conducted prior to 2000, diagnostic tympanocentesis isolated S pneumoniae from 25% to 55% of all middle ear aspirates from children with AOM.^6-8

Conversely, 1 study published in 2001 and 2 studies published in 2004 appear to document a reverse trend with the advent of the conjugate pneumococcal vaccine.^9,10 Compared with children studied in an earlier era, those vaccinated with PCV-7 may be more likely to have H influenzae isolates. These studies will be described in detail below.

Bacterial AOM: initial antibiotic therapy and specific pathogens

Current guidelines recommend amoxicillin (45 mg/kg/day) or high-dose amoxicillin (80-90 mg/kg/day) as initial therapy in presumed or documented bacterial AOM.⁵ Although amoxicillin is effective against pneumococcus and β-lactamase–negative strains of H influenzae, it is ineffective against β-lactamase–positive strains of H influenzae.⁹ Significant initial failures may point to a changing pathogen per population frequency. A 2004 review assessed children with continued (persistence of infection detected within 30 days after treatment completion) or refractory (clinical failure while receiving antimicrobial therapy) AOM who have received high-dose amoxicillin as initial empiric therapy. The authors noted that the rate of infection due to H influenzae has increased from 43% among those treated prior to the licensure of PCV-7 to 57% among those who received 2 or more doses of PCV-7.¹⁰

Evidence from the medical literature

Three studies provide the major evidence concerning the pathogen shift associated with the adoption of the PCV-7 conjugate vaccine:

• The Finnish Otitis Media Vaccine Trial²
• A published collection of clinical trial results from a rural practice in Kentucky in which 94% of children were immunized with PCV-7⁹
• A prospective study conducted in a suburban community-based private practice in Rochester, NY that evaluated children with persistent or nonresponsive AOM.¹⁰

The Finnish Otitis Media Vaccine Trial

In this trial, 1662 infants received either the PCV-7 vaccine or a control vaccine at ages 2, 4, 6, and 12 months and were monitored from ages 6.5 months to 24 months.² An overall 6.9% reduction in episodes of clinical AOM were diagnosed (n=1251) in PCV-7–vaccinated children compared with the control group (n=1345). This suggested that fewer AOM cases were caused by the S pneumoniae vaccine serotypes than nonvaccine serotypes. The bacteriologic findings in the samples of middle ear fluid taken during 93% of the visits for AOM (TABLE 1) show a 34% reduction in culture-confirmed episodes in the PCV-7–vaccinated group, a decrease of more than 50% in pneumococcal AOM episodes caused by vaccine or vaccine cross-reactive serotypes, a 33% increase in infections caused by other pneumococcal serotypes, and an 11% increase in the proportion of AOM cases due to H influenzae.²

TABLE 1

Finnish Otitis Media Vaccine Trial: Causes of AOM Episodes and Impact of PCV-7 Immunization on Incidence

Study Results From a Rural Kentucky Practice

In this practice, data on isolates from middle ear fluid were collected in children with severe or refractory AOM aged 7 to 24 months.⁹ Data were obtained from 1992 to 1998, before the introduction of PCV-7, and from 2000 to 2003, following immunization with 3 or 4 doses of PCV-7 during the first 18 months of life.

As shown in TABLE 2, the pre-PCV-7 group of children (N=336; 1992-1998) had a proportion of 48% culture-confirmed pneumococcus vs a proportion of 31% in the PCV-7-vaccinated group (N=83; 2000-2003), a 17% decrease. The decrease in proportion of AOM episodes resulting from vaccine serotypes was 34%.

In this investigation, 28% of the pre-PCV-7 group and 34% of the post-PCV-7 group had received antibiotic therapy within the previous 3 days. Additionally, 59% and 76%, respectively, had received antibiotic therapy within the preceding 30 days. There were increases of 30% in vaccine cross-reactive serotypes and 45% in nonvaccine serotypes. Vaccine cross-reactive serotypes 6A and 19A accounted for most of the penicillin-nonsusceptible S pneumoniae strains in the vaccinated population.

Most impressive, however, in the post-PCV-7 group, was that gram-negative bacteria, mainly H influenzae, accounted for two thirds of AOM isolates, an increase from 41% in the pre-PCV-7 group to 56% in the vaccinated group. A 56% increase was noted in β-lactamase–positive organisms from the pre-PCV-7 group to the post-PCV-7 group. The combined H influenzae and M catarrhalis β-lactamase–producing organisms accounted for nearly half of all isolates.⁹

TABLE 2

Results From a Rural Kentucky Practice: Change in AOM Microbiology From Pre-PCV-7 (1992–1998) to Post-PCV-7 (2000–2003)

The Prospective Rochester, New York Study

Changes in pre- and post-PVC-7 patterns also were seen in a prospective study of 551 children with persistent or nonresponsive AOM (defined as nonresponders after 1 or 2 empiric antibiotic courses or failures after 48 hours of treatment). These children underwent tympanocentesis to identify bacterial isolates during the 9-year period from 1995 to 2003.¹⁰

From 1995 to 1997, enrollees received a standard dose of amoxicillin (40-50 mg/kg, divided into 3 doses daily) as initial empiric treatment. From 1998 to 2000 and 2001 to 2003, all children received high-dose amoxicillin (80-100 mg/kg, divided into twice-daily doses).

During the latter period, the children also were vaccinated with PCV-7, with 63% receiving the primary series of 3 doses and 10% receiving the booster dose. In this investigation, shortages in vaccine supply, discussed below, caused vaccination schedules to be compromised.

Study results (TABLE 3) show that in the post-PCV-7 group, there was a 13% decrease in the proportion of S pneumoniae isolates and a 14% increase in the proportion of H influenzae isolates compared with the pre-PCV-7 group (1998-2000 enrollees). An increase of 22% for β-lactamase–positive bacteria was also observed, along with a trend toward an increased proportion of penicillin-susceptible S pneumoniae isolates (58% vs 72%; P=.017) post-PCV-7.¹⁰ A 24% reduction (P=.009) in the frequency of the diagnosis of persistent or AOM treatment failure occurred in the period after PCV-7 vaccination. These changes were considered to be the result of the use of the conjugate pneumococcal vaccine rather than of the change in amoxicillin dosing.¹⁰

TABLE 3

The Prospective Rochester, New York Study: Pathogens Isolated in Persistent AOM and AOM Treatment Failure Pre- and Post-PCV-7

Pneumococcal serotype shifts

In addition to the change in causative pathogens, use of the conjugate pneumococcal vaccine appears to have led to a significant shift in the pneumococcal strains causing AOM. Studies at urban medical centers and in the Kentucky practice documented an increase in the proportion of nonvaccine serotypes, accounting for 32% to 38% of pneumococcal AOM.^10-12 A 33% increase was seen in the Finnish Trial.² These nonvaccine pneumococcal serotypes do not carry the same level of resistance seen with those serotypes included in PCV-7.

PCV-7 conjugate vaccine

The PCV-7 conjugate vaccine was approved for use in February 2000. It is a 7-valent pneumococcal conjugate of the capsular antigens of the S pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F, individually conjugated to diphtheria CRM197 protein.¹³ These serotypes have been responsible for approximately 80% of invasive pneumococcal disease in children younger than 6 years in the United States.^13,14 They also accounted for 74% of penicillin-susceptible S pneumoniae and 100% of pneumococci with high-level penicillin resistance isolated from children younger than age 6 years with invasive disease during a 1993-1994 surveillance by the Centers for Disease Control and Prevention (CDC).¹³

Mechanism of Action and Recommended Immunization Schedule

The conjugate vaccine is converted to a T-cell–dependent antigen, antibody formation is enhanced, and memory B cells are primed.¹⁴

The recommended immunization schedule was established as 3 primary doses at ages 2, 4, and 6 months and a booster dose at 12 to 15 months.¹ It is the first multivalent pneumococcal vaccine approved for use in children younger than 24 months.

An 89% reduction in invasive pneumococcal disease was observed in children receiving 1 or more doses, and the vaccine appears to reduce nasopharyngeal carriage of vaccine serotypes.^15,16

The older 23-valent polysaccharide vaccine does not stimulate good response in children younger than 2 years of age¹⁴ and does not reduce mucosal carriage or limit the spread of resistant strains.¹⁵

PCV-7 Supply Since 2000

In August 2001, a serious shortage of the vaccine developed in 34 state immunization programs.¹⁷ The following month, the CDC advised physicians to administer it only to children younger than 12 months and to those aged 1 to 5 years at increased risk of pneumococcal disease.¹⁸ As demand continued despite the change in recommendations, the CDC further changed recommendations to conserve vaccine supply, first suspending the fourth dose temporarily in healthy children¹⁹ and then discontinuing both the third and fourth doses.¹¹ In July 2004, production problems seemed to have resolved; the CDC recommended that every child receive 3 doses. In September, supplies were adequate for return to the 4-dose schedule.¹² As of June 2004, 67.7% of children aged 24 months had received 3 or more doses of PCV-7.²⁰ Thus, the effects of PCV-7 on the changing microbiology of AOM may only now, at the end of 2005, be fully realized.

Herd Immunity and Reduction in Carriage

Despite the shortages of vaccine during the first years of use, evidence of herd immunity and a decrease in antibiotic resistance in pneumococcal pathogens has been reported throughout the United States.^21,22 A 29% decrease in the rate of pneumococcal disease in both young children and adults has also been observed, along with a 35% reduction in the rate of disease caused by nonpenicillin-susceptible pneumococcal strains.²¹ The reduction in carriage among vaccinated children may be the reason.^21,22 Because of the impact of PCV-7, it will be important to record immunization history when collecting AOM data.

AOM treatment choices

The basis of recommendations for treating AOM depends on the presumed responsible pathogens, their susceptibility to antibiotics, and concerns for developing resistance, all influenced by clinical trial data. In practice, however, empiric choices are often made based on knowledge of local resistance patterns and of other patient characteristics; that is cost concerns, adverse event profiles, need to avoid initial treatment failure, adherence issues (eg, taste or palatability), convenience, and duration of dosing regimen.

All current guidelines recommend oral amoxicillin as first-line therapy in documented or presumed bacterial AOM. The 2004 American Academy of Pediatrics/American Academy of Family Physicians’ (AAP/AAFP) guidelines⁴ recommended increasing the dosage used for empiric treatment from 40 to 45 mg/kg/day to 80 to 90 mg/kg/day for all children. This was a result of concerns about the prevalence of penicillin-resistant S pneumoniae for which standard-dose amoxicillin is inadequate.²³

The guidelines were written and published before the data from the Kentucky and New York studies were available; therefore, although the guidelines recommended that empiric treatment of bacterial AOM should target S pneumoniae, H influenzae, and M catarrhalis, the pathogen shift discussed previously might today produce a modified antibiotic selection paradigm. The pathogen mix in persistent or recurrent AOM has already led to a guideline recommendation for high-dose amoxicillin/clavulanate, 90/6.4 mg/kg/day, cefdinir, cefprozil, cefpodoxime, cefuroxime, or ceftriaxone in these patients.²³

If an increase in the proportion of β-lactamase–producing pathogens due to PCV-7 occurs, amoxicillin may no longer be the best first choice.

Selecting Among Recommended Antibiotic Choices

As antibiotic preparations for treating bacterial AOM are oral suspensions, taste is a major factor for pediatric patients. TABLE 4 summarizes comparative taste ratings for antibiotic suspensions based on several studies and shows the range, from those that can enhance compliance to those that discourage compliance.²³

Adverse events, especially diarrhea, nausea/vomiting, and gastritis, are also of concern. These are shortcomings of amoxicillin/clavulanate, which has a higher incidence of diarrhea and nausea than cephalosporins.²⁴

Dosing frequency is also a factor among recommended agents. Amoxicillin, amoxicillin/clavulanate, cefprozil, and cefpodoxime require twice-daily dosing. Cefdinir can be effective at once-daily dosing.²⁴

Duration of approved therapy is perhaps the most critical selection factor given the reality of patient behaviors. Cefpodoxime and cefdinir are the only 2 FDA-approved agents for 5-day treatment of bacterial AOM that are also guideline-recommended.

TABLE 4

Compliance-Enhancing Ranking of Antibiotic Suspensions

Choices for Effective Initial Therapy

Considering the changing microbial population in bacterial AOM and the increasing concern of effectiveness of amoxicillin and other antibiotics against β-lactamase–producing H influenzae, the choice of therapy may need modification. Specifically, that may mean changing the choice of effective antibiotic, taking into consideration the compliance-enhancing advantages of available options.

Based on efficacy, the overall prevalence of antibiotic-resistant AOM pathogens for PCV-7-vaccinated children, the potential for adverse effects, and patient compliance issues, Block and Harrison developed an algorithm (FIGURE) for the management of AOM diagnosed by strict criteria in an otherwise healthy child between 4 months and 36 months old.²⁴ As the environment of AOM evolves, the choices for treatment must be not only effective but also the best and most appropriate.

FIGURE Antibiotic Choices for Acute Otitis Media in the 2000s

Since the approval of the 7-valent pneumococcal conjugate vaccine (PCV-7) for use in children younger than 24 months in February 2000, occurrences of acute otitis media (AOM) and the frequency of recurrent AOM have declined. Based on results from early clinical trials, PCV-7 may reduce total AOM by 6% to 8%, recurrent AOM by 10% to 26%, and tympanostomy tube placements by 24%.^1,2

Acute otitis media occurs most frequently in children between the ages of 6 months and 18 months. By the end of their first year, approximately 86% of children will experience at least 1 episode of AOM.³

The condition remains a leading reason for visits to pediatricians and family physicians in the United States.⁴ It accounted for 16 million visits in 2000.⁴ This is a decrease from almost 25 million visits in 1995, prior to use of PCV-7. Additionally, AOM is associated with significant costs: In 1995, the direct and indirect costs of AOM were estimated to be about $3 billion.⁵

Changes in pathogen frequency for AOM in the ERA of PCV-7

The true impact of PCV-7 on management practice is not characterized by the modest reduction in incidence of uncomplicated AOM but in the PCV-7–associated shift in causative pathogens. Pre-PCV-7, 40% to 50% of cases of AOM in young children were caused by Streptococcus pneumoniae, 20% to 30% by Haemophilus influenzae, and 10% to 15% by Moraxella catarrhalis.⁶ In studies conducted prior to 2000, diagnostic tympanocentesis isolated S pneumoniae from 25% to 55% of all middle ear aspirates from children with AOM.^6-8

Conversely, 1 study published in 2001 and 2 studies published in 2004 appear to document a reverse trend with the advent of the conjugate pneumococcal vaccine.^9,10 Compared with children studied in an earlier era, those vaccinated with PCV-7 may be more likely to have H influenzae isolates. These studies will be described in detail below.

Bacterial AOM: initial antibiotic therapy and specific pathogens

Current guidelines recommend amoxicillin (45 mg/kg/day) or high-dose amoxicillin (80-90 mg/kg/day) as initial therapy in presumed or documented bacterial AOM.⁵ Although amoxicillin is effective against pneumococcus and β-lactamase–negative strains of H influenzae, it is ineffective against β-lactamase–positive strains of H influenzae.⁹ Significant initial failures may point to a changing pathogen per population frequency. A 2004 review assessed children with continued (persistence of infection detected within 30 days after treatment completion) or refractory (clinical failure while receiving antimicrobial therapy) AOM who have received high-dose amoxicillin as initial empiric therapy. The authors noted that the rate of infection due to H influenzae has increased from 43% among those treated prior to the licensure of PCV-7 to 57% among those who received 2 or more doses of PCV-7.¹⁰

Evidence from the medical literature

Three studies provide the major evidence concerning the pathogen shift associated with the adoption of the PCV-7 conjugate vaccine:

• The Finnish Otitis Media Vaccine Trial²
• A published collection of clinical trial results from a rural practice in Kentucky in which 94% of children were immunized with PCV-7⁹
• A prospective study conducted in a suburban community-based private practice in Rochester, NY that evaluated children with persistent or nonresponsive AOM.¹⁰

The Finnish Otitis Media Vaccine Trial

In this trial, 1662 infants received either the PCV-7 vaccine or a control vaccine at ages 2, 4, 6, and 12 months and were monitored from ages 6.5 months to 24 months.² An overall 6.9% reduction in episodes of clinical AOM were diagnosed (n=1251) in PCV-7–vaccinated children compared with the control group (n=1345). This suggested that fewer AOM cases were caused by the S pneumoniae vaccine serotypes than nonvaccine serotypes. The bacteriologic findings in the samples of middle ear fluid taken during 93% of the visits for AOM (TABLE 1) show a 34% reduction in culture-confirmed episodes in the PCV-7–vaccinated group, a decrease of more than 50% in pneumococcal AOM episodes caused by vaccine or vaccine cross-reactive serotypes, a 33% increase in infections caused by other pneumococcal serotypes, and an 11% increase in the proportion of AOM cases due to H influenzae.²

TABLE 1

Finnish Otitis Media Vaccine Trial: Causes of AOM Episodes and Impact of PCV-7 Immunization on Incidence

Study Results From a Rural Kentucky Practice

In this practice, data on isolates from middle ear fluid were collected in children with severe or refractory AOM aged 7 to 24 months.⁹ Data were obtained from 1992 to 1998, before the introduction of PCV-7, and from 2000 to 2003, following immunization with 3 or 4 doses of PCV-7 during the first 18 months of life.

As shown in TABLE 2, the pre-PCV-7 group of children (N=336; 1992-1998) had a proportion of 48% culture-confirmed pneumococcus vs a proportion of 31% in the PCV-7-vaccinated group (N=83; 2000-2003), a 17% decrease. The decrease in proportion of AOM episodes resulting from vaccine serotypes was 34%.

In this investigation, 28% of the pre-PCV-7 group and 34% of the post-PCV-7 group had received antibiotic therapy within the previous 3 days. Additionally, 59% and 76%, respectively, had received antibiotic therapy within the preceding 30 days. There were increases of 30% in vaccine cross-reactive serotypes and 45% in nonvaccine serotypes. Vaccine cross-reactive serotypes 6A and 19A accounted for most of the penicillin-nonsusceptible S pneumoniae strains in the vaccinated population.

Most impressive, however, in the post-PCV-7 group, was that gram-negative bacteria, mainly H influenzae, accounted for two thirds of AOM isolates, an increase from 41% in the pre-PCV-7 group to 56% in the vaccinated group. A 56% increase was noted in β-lactamase–positive organisms from the pre-PCV-7 group to the post-PCV-7 group. The combined H influenzae and M catarrhalis β-lactamase–producing organisms accounted for nearly half of all isolates.⁹

TABLE 2

Results From a Rural Kentucky Practice: Change in AOM Microbiology From Pre-PCV-7 (1992–1998) to Post-PCV-7 (2000–2003)

The Prospective Rochester, New York Study

Changes in pre- and post-PVC-7 patterns also were seen in a prospective study of 551 children with persistent or nonresponsive AOM (defined as nonresponders after 1 or 2 empiric antibiotic courses or failures after 48 hours of treatment). These children underwent tympanocentesis to identify bacterial isolates during the 9-year period from 1995 to 2003.¹⁰

From 1995 to 1997, enrollees received a standard dose of amoxicillin (40-50 mg/kg, divided into 3 doses daily) as initial empiric treatment. From 1998 to 2000 and 2001 to 2003, all children received high-dose amoxicillin (80-100 mg/kg, divided into twice-daily doses).

During the latter period, the children also were vaccinated with PCV-7, with 63% receiving the primary series of 3 doses and 10% receiving the booster dose. In this investigation, shortages in vaccine supply, discussed below, caused vaccination schedules to be compromised.

Study results (TABLE 3) show that in the post-PCV-7 group, there was a 13% decrease in the proportion of S pneumoniae isolates and a 14% increase in the proportion of H influenzae isolates compared with the pre-PCV-7 group (1998-2000 enrollees). An increase of 22% for β-lactamase–positive bacteria was also observed, along with a trend toward an increased proportion of penicillin-susceptible S pneumoniae isolates (58% vs 72%; P=.017) post-PCV-7.¹⁰ A 24% reduction (P=.009) in the frequency of the diagnosis of persistent or AOM treatment failure occurred in the period after PCV-7 vaccination. These changes were considered to be the result of the use of the conjugate pneumococcal vaccine rather than of the change in amoxicillin dosing.¹⁰

TABLE 3

The Prospective Rochester, New York Study: Pathogens Isolated in Persistent AOM and AOM Treatment Failure Pre- and Post-PCV-7

Pneumococcal serotype shifts

In addition to the change in causative pathogens, use of the conjugate pneumococcal vaccine appears to have led to a significant shift in the pneumococcal strains causing AOM. Studies at urban medical centers and in the Kentucky practice documented an increase in the proportion of nonvaccine serotypes, accounting for 32% to 38% of pneumococcal AOM.^10-12 A 33% increase was seen in the Finnish Trial.² These nonvaccine pneumococcal serotypes do not carry the same level of resistance seen with those serotypes included in PCV-7.

PCV-7 conjugate vaccine

The PCV-7 conjugate vaccine was approved for use in February 2000. It is a 7-valent pneumococcal conjugate of the capsular antigens of the S pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F, individually conjugated to diphtheria CRM197 protein.¹³ These serotypes have been responsible for approximately 80% of invasive pneumococcal disease in children younger than 6 years in the United States.^13,14 They also accounted for 74% of penicillin-susceptible S pneumoniae and 100% of pneumococci with high-level penicillin resistance isolated from children younger than age 6 years with invasive disease during a 1993-1994 surveillance by the Centers for Disease Control and Prevention (CDC).¹³

Mechanism of Action and Recommended Immunization Schedule

The conjugate vaccine is converted to a T-cell–dependent antigen, antibody formation is enhanced, and memory B cells are primed.¹⁴

The recommended immunization schedule was established as 3 primary doses at ages 2, 4, and 6 months and a booster dose at 12 to 15 months.¹ It is the first multivalent pneumococcal vaccine approved for use in children younger than 24 months.

An 89% reduction in invasive pneumococcal disease was observed in children receiving 1 or more doses, and the vaccine appears to reduce nasopharyngeal carriage of vaccine serotypes.^15,16

The older 23-valent polysaccharide vaccine does not stimulate good response in children younger than 2 years of age¹⁴ and does not reduce mucosal carriage or limit the spread of resistant strains.¹⁵

PCV-7 Supply Since 2000

In August 2001, a serious shortage of the vaccine developed in 34 state immunization programs.¹⁷ The following month, the CDC advised physicians to administer it only to children younger than 12 months and to those aged 1 to 5 years at increased risk of pneumococcal disease.¹⁸ As demand continued despite the change in recommendations, the CDC further changed recommendations to conserve vaccine supply, first suspending the fourth dose temporarily in healthy children¹⁹ and then discontinuing both the third and fourth doses.¹¹ In July 2004, production problems seemed to have resolved; the CDC recommended that every child receive 3 doses. In September, supplies were adequate for return to the 4-dose schedule.¹² As of June 2004, 67.7% of children aged 24 months had received 3 or more doses of PCV-7.²⁰ Thus, the effects of PCV-7 on the changing microbiology of AOM may only now, at the end of 2005, be fully realized.

Herd Immunity and Reduction in Carriage

Despite the shortages of vaccine during the first years of use, evidence of herd immunity and a decrease in antibiotic resistance in pneumococcal pathogens has been reported throughout the United States.^21,22 A 29% decrease in the rate of pneumococcal disease in both young children and adults has also been observed, along with a 35% reduction in the rate of disease caused by nonpenicillin-susceptible pneumococcal strains.²¹ The reduction in carriage among vaccinated children may be the reason.^21,22 Because of the impact of PCV-7, it will be important to record immunization history when collecting AOM data.

AOM treatment choices

The basis of recommendations for treating AOM depends on the presumed responsible pathogens, their susceptibility to antibiotics, and concerns for developing resistance, all influenced by clinical trial data. In practice, however, empiric choices are often made based on knowledge of local resistance patterns and of other patient characteristics; that is cost concerns, adverse event profiles, need to avoid initial treatment failure, adherence issues (eg, taste or palatability), convenience, and duration of dosing regimen.

All current guidelines recommend oral amoxicillin as first-line therapy in documented or presumed bacterial AOM. The 2004 American Academy of Pediatrics/American Academy of Family Physicians’ (AAP/AAFP) guidelines⁴ recommended increasing the dosage used for empiric treatment from 40 to 45 mg/kg/day to 80 to 90 mg/kg/day for all children. This was a result of concerns about the prevalence of penicillin-resistant S pneumoniae for which standard-dose amoxicillin is inadequate.²³

The guidelines were written and published before the data from the Kentucky and New York studies were available; therefore, although the guidelines recommended that empiric treatment of bacterial AOM should target S pneumoniae, H influenzae, and M catarrhalis, the pathogen shift discussed previously might today produce a modified antibiotic selection paradigm. The pathogen mix in persistent or recurrent AOM has already led to a guideline recommendation for high-dose amoxicillin/clavulanate, 90/6.4 mg/kg/day, cefdinir, cefprozil, cefpodoxime, cefuroxime, or ceftriaxone in these patients.²³

If an increase in the proportion of β-lactamase–producing pathogens due to PCV-7 occurs, amoxicillin may no longer be the best first choice.

Selecting Among Recommended Antibiotic Choices

As antibiotic preparations for treating bacterial AOM are oral suspensions, taste is a major factor for pediatric patients. TABLE 4 summarizes comparative taste ratings for antibiotic suspensions based on several studies and shows the range, from those that can enhance compliance to those that discourage compliance.²³

Adverse events, especially diarrhea, nausea/vomiting, and gastritis, are also of concern. These are shortcomings of amoxicillin/clavulanate, which has a higher incidence of diarrhea and nausea than cephalosporins.²⁴

Dosing frequency is also a factor among recommended agents. Amoxicillin, amoxicillin/clavulanate, cefprozil, and cefpodoxime require twice-daily dosing. Cefdinir can be effective at once-daily dosing.²⁴

Duration of approved therapy is perhaps the most critical selection factor given the reality of patient behaviors. Cefpodoxime and cefdinir are the only 2 FDA-approved agents for 5-day treatment of bacterial AOM that are also guideline-recommended.

TABLE 4

Compliance-Enhancing Ranking of Antibiotic Suspensions

Choices for Effective Initial Therapy

Considering the changing microbial population in bacterial AOM and the increasing concern of effectiveness of amoxicillin and other antibiotics against β-lactamase–producing H influenzae, the choice of therapy may need modification. Specifically, that may mean changing the choice of effective antibiotic, taking into consideration the compliance-enhancing advantages of available options.

Based on efficacy, the overall prevalence of antibiotic-resistant AOM pathogens for PCV-7-vaccinated children, the potential for adverse effects, and patient compliance issues, Block and Harrison developed an algorithm (FIGURE) for the management of AOM diagnosed by strict criteria in an otherwise healthy child between 4 months and 36 months old.²⁴ As the environment of AOM evolves, the choices for treatment must be not only effective but also the best and most appropriate.

FIGURE Antibiotic Choices for Acute Otitis Media in the 2000s