In response to Dr. Mark Zimmerman’s article, “Improving the recognition of borderline personality disorder” (Current Psychiatry. October 2017, p. 13-19), I think the topic of improving the diagnosis of borderline personality disorder (BPD) requires us to examine our own biases and stigma toward this diagnosis. Let’s be honest: many psychiatrists don’t make the diagnosis because they don’t want to give their patient that diagnosis and they don’t want to treat a patient with that diagnosis. Evidence suggests that a great proportion of stigma aimed at BPD is initiated by mental health professionals.^1,2

Why all the stigma? Because mental health professionals don’t have complete information. The assumption used to be that BPD was “intractable” with no treatment. Even if this were true, it still would not be a reason to fail to disclose a diagnosis, because in other fields of medicine, the concept of “therapeutic privilege” fell by the wayside long ago. However, we now know that in many individuals with BPD, symptoms improve over time, and there are several effective treatments.

In DSM-II, published in 1968, obsessive-compulsive disorder (OCD) was characterized as an “obsessive compulsive neurosis.” It was not reclassified as the current OCD diagnosis until DSM-III-R was published in 1987, after the FDA approved clomipramine. Why is this important? Because once people realized that there was a treatment, they started acknowledging OCD more often.

The first step in addressing the stigma toward BPD is that mental health professionals must recognize their own bias toward this diagnosis. We must be re-educated that this diagnosis carries hope, symptoms improve, and that there are effective treatments. This is how professionals will increase the recognition of BPD.

Michael Shapiro, MD, FAPA
Assistant Professor and Compliance Officer
Department of Psychiatry
University of Florida
Clinic Director
UF Child and Adolescent Psychiatry Clinic at Springhill Health Center
Gainesville, Florida

References

1. Unruh BT, Gunderson JG. “Good enough” psychiatric residency training in borderline personality disorder: challenges, choice points, and a model generalist curriculum. Harv Rev Psychiatry. 2016;24(5):367-377.
2. Sheehan L, Nieweglowski K, Corrigan P. The stigma of personality disorders. Curr Psychiatry Rep. 2016;18(1):11.

Continue to: The author responds

The author responds

I agree with Dr. Shapiro that stigma by mental health clinicians contributes to the underdiagnosis of BPD. Mental health professions often hold a negative view of patients with personality disorders, particularly those with BPD, and see these patients as being more difficult to treat.^1-3 They are the patients that some clinicians are reluctant to treat.^3,4 Clinicians perceive patients with personality disorders as less mentally ill, more manipulative, and more able to control their behavior than patients with other psychiatric disorders.^3,5 Consistent with this, clinicians have less sympathetic attitudes and behave less empathically toward patients with BPD.^5,6 The term “borderline” also is sometimes used pejoratively to describe patients.¹

As I described in my article, there are several possible reasons BPD is under­diagnosed. Foremost is that mood disorders, anxiety disorders, and substance use disorders are common in patients with BPD, and the symptoms of these other disorders are typically patients’ chief concerns when they present for treatment. Patients with BPD do not usually report the features of BPD—such as abandonment fears, chronic feelings of emptiness, or an identity disturbance—as their chief concerns. If they did, BPD would likely be easier to recognize. On a related note, clinicians do not have the time, or do not take the time, to conduct a thorough enough evaluation to diagnose BPD when it occurs in a patient who presents for treatment of a mood disorder, anxiety disorder, or substance use disorder. Our clinical research group found that when psychiatrists are presented with the results of a semi-structured interview, BPD is much more frequently diagnosed.⁷ Such a finding would not be expected if stigma was the primary or sole reason for underdiagnosis.

Dr. Shapiro highlights the clinical consequence of underrecognition and underdiagnosis: the underutilization of empirically supported psychotherapies for BPD. A corollary of underdiagnosing BPD is overdiagnosis of bipolar disorder and overprescription of medication.⁸

There are other consequences of bias and stigma toward BPD. Despite the high levels of psychosocial morbidity, reduced health-related quality of life, high utilization of services, and excess mortality associated with BPD, this disorder is not included in the Global Burden of Disease Study. Thus, the public health significance of BPD is less fully appreciated. Finally, there is evidence that the level of funding for research from the National Institutes of Health is not commensurate with the level of psychosocial morbidity, mortality, and health expenditures associated with the disorder.⁹ Thus, the stigma toward BPD exists in both clinical and research communities.

Mark Zimmerman, MD
Professor of Psychiatry and Human Behavior
Warren Alpert Medical School of Brown University
Rhode Island Hospital
Providence, Rhode Island

References

1. Cleary M, Siegfried N, Walter G. Experience, knowledge and attitudes of mental health staff regarding clients with a borderline personality disorder. Int J Ment Health Nurs. 2002;11(3):186-191.
2. Gallop R, Lancee WJ, Garfinkel P. How nursing staff respond to the label “borderline personality disorder.” Hosp Community Psychiatry. 1989;40(8):815-819.
3. Lewis G, Appleby L. Personality disorder: the patients psychiatrists dislike. Br J Psychiatry. 1988;153:44-49.
4. Black DW, Pfohl B, Blum N, et al. Attitudes toward borderline personality disorder: a survey of 706 mental health clinicians. CNS Spectr. 2011;16(3):67-74.
5. Markham D, Trower P. The effects of the psychiatric label ‘borderline personality disorder’ on nursing staff’s perceptions and causal attributions for challenging behaviours. Br J Clin Psychol. 2003;42(pt 3):243-256.
6. Fraser K, Gallop R. Nurses’ confirming/disconfirming responses to patients diagnosed with borderline personality disorder. Arch Psychiatr Nurs. 1993;7(6):336-341.
7. Zimmerman M, Mattia JI. Differences between clinical and research practices in diagnosing borderline personality disorder. Am J Psychiatry. 1999;156(10):1570-1574.
8. Zimmerman M, Ruggero CJ, Chelminski I, et al. Is bipolar disorder overdiagnosed? J Clin Psychiatry. 2008;69(6):935-940.
9. Zimmerman M, Gazarian D. Is research on borderline personality disorder underfunded by the National Institute of Health? Psychiatry Res. 2014;220(3):941-944.

In response to Dr. Mark Zimmerman’s article, “Improving the recognition of borderline personality disorder” (Current Psychiatry. October 2017, p. 13-19), I think the topic of improving the diagnosis of borderline personality disorder (BPD) requires us to examine our own biases and stigma toward this diagnosis. Let’s be honest: many psychiatrists don’t make the diagnosis because they don’t want to give their patient that diagnosis and they don’t want to treat a patient with that diagnosis. Evidence suggests that a great proportion of stigma aimed at BPD is initiated by mental health professionals.^1,2

Why all the stigma? Because mental health professionals don’t have complete information. The assumption used to be that BPD was “intractable” with no treatment. Even if this were true, it still would not be a reason to fail to disclose a diagnosis, because in other fields of medicine, the concept of “therapeutic privilege” fell by the wayside long ago. However, we now know that in many individuals with BPD, symptoms improve over time, and there are several effective treatments.

In DSM-II, published in 1968, obsessive-compulsive disorder (OCD) was characterized as an “obsessive compulsive neurosis.” It was not reclassified as the current OCD diagnosis until DSM-III-R was published in 1987, after the FDA approved clomipramine. Why is this important? Because once people realized that there was a treatment, they started acknowledging OCD more often.

The first step in addressing the stigma toward BPD is that mental health professionals must recognize their own bias toward this diagnosis. We must be re-educated that this diagnosis carries hope, symptoms improve, and that there are effective treatments. This is how professionals will increase the recognition of BPD.

Michael Shapiro, MD, FAPA
Assistant Professor and Compliance Officer
Department of Psychiatry
University of Florida
Clinic Director
UF Child and Adolescent Psychiatry Clinic at Springhill Health Center
Gainesville, Florida

References

1. Unruh BT, Gunderson JG. “Good enough” psychiatric residency training in borderline personality disorder: challenges, choice points, and a model generalist curriculum. Harv Rev Psychiatry. 2016;24(5):367-377.
2. Sheehan L, Nieweglowski K, Corrigan P. The stigma of personality disorders. Curr Psychiatry Rep. 2016;18(1):11.

Continue to: The author responds

The author responds

I agree with Dr. Shapiro that stigma by mental health clinicians contributes to the underdiagnosis of BPD. Mental health professions often hold a negative view of patients with personality disorders, particularly those with BPD, and see these patients as being more difficult to treat.^1-3 They are the patients that some clinicians are reluctant to treat.^3,4 Clinicians perceive patients with personality disorders as less mentally ill, more manipulative, and more able to control their behavior than patients with other psychiatric disorders.^3,5 Consistent with this, clinicians have less sympathetic attitudes and behave less empathically toward patients with BPD.^5,6 The term “borderline” also is sometimes used pejoratively to describe patients.¹

As I described in my article, there are several possible reasons BPD is under­diagnosed. Foremost is that mood disorders, anxiety disorders, and substance use disorders are common in patients with BPD, and the symptoms of these other disorders are typically patients’ chief concerns when they present for treatment. Patients with BPD do not usually report the features of BPD—such as abandonment fears, chronic feelings of emptiness, or an identity disturbance—as their chief concerns. If they did, BPD would likely be easier to recognize. On a related note, clinicians do not have the time, or do not take the time, to conduct a thorough enough evaluation to diagnose BPD when it occurs in a patient who presents for treatment of a mood disorder, anxiety disorder, or substance use disorder. Our clinical research group found that when psychiatrists are presented with the results of a semi-structured interview, BPD is much more frequently diagnosed.⁷ Such a finding would not be expected if stigma was the primary or sole reason for underdiagnosis.

Dr. Shapiro highlights the clinical consequence of underrecognition and underdiagnosis: the underutilization of empirically supported psychotherapies for BPD. A corollary of underdiagnosing BPD is overdiagnosis of bipolar disorder and overprescription of medication.⁸

There are other consequences of bias and stigma toward BPD. Despite the high levels of psychosocial morbidity, reduced health-related quality of life, high utilization of services, and excess mortality associated with BPD, this disorder is not included in the Global Burden of Disease Study. Thus, the public health significance of BPD is less fully appreciated. Finally, there is evidence that the level of funding for research from the National Institutes of Health is not commensurate with the level of psychosocial morbidity, mortality, and health expenditures associated with the disorder.⁹ Thus, the stigma toward BPD exists in both clinical and research communities.

Mark Zimmerman, MD
Professor of Psychiatry and Human Behavior
Warren Alpert Medical School of Brown University
Rhode Island Hospital
Providence, Rhode Island

References

1. Cleary M, Siegfried N, Walter G. Experience, knowledge and attitudes of mental health staff regarding clients with a borderline personality disorder. Int J Ment Health Nurs. 2002;11(3):186-191.
2. Gallop R, Lancee WJ, Garfinkel P. How nursing staff respond to the label “borderline personality disorder.” Hosp Community Psychiatry. 1989;40(8):815-819.
3. Lewis G, Appleby L. Personality disorder: the patients psychiatrists dislike. Br J Psychiatry. 1988;153:44-49.
4. Black DW, Pfohl B, Blum N, et al. Attitudes toward borderline personality disorder: a survey of 706 mental health clinicians. CNS Spectr. 2011;16(3):67-74.
5. Markham D, Trower P. The effects of the psychiatric label ‘borderline personality disorder’ on nursing staff’s perceptions and causal attributions for challenging behaviours. Br J Clin Psychol. 2003;42(pt 3):243-256.
6. Fraser K, Gallop R. Nurses’ confirming/disconfirming responses to patients diagnosed with borderline personality disorder. Arch Psychiatr Nurs. 1993;7(6):336-341.
7. Zimmerman M, Mattia JI. Differences between clinical and research practices in diagnosing borderline personality disorder. Am J Psychiatry. 1999;156(10):1570-1574.
8. Zimmerman M, Ruggero CJ, Chelminski I, et al. Is bipolar disorder overdiagnosed? J Clin Psychiatry. 2008;69(6):935-940.
9. Zimmerman M, Gazarian D. Is research on borderline personality disorder underfunded by the National Institute of Health? Psychiatry Res. 2014;220(3):941-944.

In response to Dr. Mark Zimmerman’s article, “Improving the recognition of borderline personality disorder” (Current Psychiatry. October 2017, p. 13-19), I think the topic of improving the diagnosis of borderline personality disorder (BPD) requires us to examine our own biases and stigma toward this diagnosis. Let’s be honest: many psychiatrists don’t make the diagnosis because they don’t want to give their patient that diagnosis and they don’t want to treat a patient with that diagnosis. Evidence suggests that a great proportion of stigma aimed at BPD is initiated by mental health professionals.^1,2

Why all the stigma? Because mental health professionals don’t have complete information. The assumption used to be that BPD was “intractable” with no treatment. Even if this were true, it still would not be a reason to fail to disclose a diagnosis, because in other fields of medicine, the concept of “therapeutic privilege” fell by the wayside long ago. However, we now know that in many individuals with BPD, symptoms improve over time, and there are several effective treatments.

In DSM-II, published in 1968, obsessive-compulsive disorder (OCD) was characterized as an “obsessive compulsive neurosis.” It was not reclassified as the current OCD diagnosis until DSM-III-R was published in 1987, after the FDA approved clomipramine. Why is this important? Because once people realized that there was a treatment, they started acknowledging OCD more often.

The first step in addressing the stigma toward BPD is that mental health professionals must recognize their own bias toward this diagnosis. We must be re-educated that this diagnosis carries hope, symptoms improve, and that there are effective treatments. This is how professionals will increase the recognition of BPD.

Michael Shapiro, MD, FAPA
Assistant Professor and Compliance Officer
Department of Psychiatry
University of Florida
Clinic Director
UF Child and Adolescent Psychiatry Clinic at Springhill Health Center
Gainesville, Florida

References

1. Unruh BT, Gunderson JG. “Good enough” psychiatric residency training in borderline personality disorder: challenges, choice points, and a model generalist curriculum. Harv Rev Psychiatry. 2016;24(5):367-377.
2. Sheehan L, Nieweglowski K, Corrigan P. The stigma of personality disorders. Curr Psychiatry Rep. 2016;18(1):11.

Continue to: The author responds

The author responds

I agree with Dr. Shapiro that stigma by mental health clinicians contributes to the underdiagnosis of BPD. Mental health professions often hold a negative view of patients with personality disorders, particularly those with BPD, and see these patients as being more difficult to treat.^1-3 They are the patients that some clinicians are reluctant to treat.^3,4 Clinicians perceive patients with personality disorders as less mentally ill, more manipulative, and more able to control their behavior than patients with other psychiatric disorders.^3,5 Consistent with this, clinicians have less sympathetic attitudes and behave less empathically toward patients with BPD.^5,6 The term “borderline” also is sometimes used pejoratively to describe patients.¹

As I described in my article, there are several possible reasons BPD is under­diagnosed. Foremost is that mood disorders, anxiety disorders, and substance use disorders are common in patients with BPD, and the symptoms of these other disorders are typically patients’ chief concerns when they present for treatment. Patients with BPD do not usually report the features of BPD—such as abandonment fears, chronic feelings of emptiness, or an identity disturbance—as their chief concerns. If they did, BPD would likely be easier to recognize. On a related note, clinicians do not have the time, or do not take the time, to conduct a thorough enough evaluation to diagnose BPD when it occurs in a patient who presents for treatment of a mood disorder, anxiety disorder, or substance use disorder. Our clinical research group found that when psychiatrists are presented with the results of a semi-structured interview, BPD is much more frequently diagnosed.⁷ Such a finding would not be expected if stigma was the primary or sole reason for underdiagnosis.

Dr. Shapiro highlights the clinical consequence of underrecognition and underdiagnosis: the underutilization of empirically supported psychotherapies for BPD. A corollary of underdiagnosing BPD is overdiagnosis of bipolar disorder and overprescription of medication.⁸

There are other consequences of bias and stigma toward BPD. Despite the high levels of psychosocial morbidity, reduced health-related quality of life, high utilization of services, and excess mortality associated with BPD, this disorder is not included in the Global Burden of Disease Study. Thus, the public health significance of BPD is less fully appreciated. Finally, there is evidence that the level of funding for research from the National Institutes of Health is not commensurate with the level of psychosocial morbidity, mortality, and health expenditures associated with the disorder.⁹ Thus, the stigma toward BPD exists in both clinical and research communities.

Mark Zimmerman, MD
Professor of Psychiatry and Human Behavior
Warren Alpert Medical School of Brown University
Rhode Island Hospital
Providence, Rhode Island

References

1. Cleary M, Siegfried N, Walter G. Experience, knowledge and attitudes of mental health staff regarding clients with a borderline personality disorder. Int J Ment Health Nurs. 2002;11(3):186-191.
2. Gallop R, Lancee WJ, Garfinkel P. How nursing staff respond to the label “borderline personality disorder.” Hosp Community Psychiatry. 1989;40(8):815-819.
3. Lewis G, Appleby L. Personality disorder: the patients psychiatrists dislike. Br J Psychiatry. 1988;153:44-49.
4. Black DW, Pfohl B, Blum N, et al. Attitudes toward borderline personality disorder: a survey of 706 mental health clinicians. CNS Spectr. 2011;16(3):67-74.
5. Markham D, Trower P. The effects of the psychiatric label ‘borderline personality disorder’ on nursing staff’s perceptions and causal attributions for challenging behaviours. Br J Clin Psychol. 2003;42(pt 3):243-256.
6. Fraser K, Gallop R. Nurses’ confirming/disconfirming responses to patients diagnosed with borderline personality disorder. Arch Psychiatr Nurs. 1993;7(6):336-341.
7. Zimmerman M, Mattia JI. Differences between clinical and research practices in diagnosing borderline personality disorder. Am J Psychiatry. 1999;156(10):1570-1574.
8. Zimmerman M, Ruggero CJ, Chelminski I, et al. Is bipolar disorder overdiagnosed? J Clin Psychiatry. 2008;69(6):935-940.
9. Zimmerman M, Gazarian D. Is research on borderline personality disorder underfunded by the National Institute of Health? Psychiatry Res. 2014;220(3):941-944.

Point-of-care ultrasound (POCUS) has been gaining greater traction in recent years as a way to quickly (and cost-effectively) assess for conditions including systolic dysfunction, pleural effusion, abdominal aortic aneurysms (AAAs), and deep vein thrombosis (DVT). It involves limited and specific ultrasound protocols performed at the bedside by the health care provider who is trying to answer a specific question and, thus, help guide treatment of the patient.

POCUS was first widely used by emergency physicians starting in the early 1990s with the widespread adoption of the Focused Assessment with Sonography in Trauma (FAST) scan.^1,2 Since that time, POCUS has expanded beyond trauma applications and into family medicine.

One study assessed physicians’ perceptions of POCUS after its integration into a military family medicine clinic. The study showed that physicians perceived POCUS to be relatively easy to use, not overly time consuming, and of high value to the practice.³ In fact, the literature tells us that POCUS can help decrease the cost of health care and improve outcomes,^4-7 while requiring a relatively brief training period.

If residencies are any indication, POCUS may be headed your way

Ultrasound units are becoming smaller and more affordable, and medical schools are increasingly incorporating ultrasound curricula into medical student training.⁸ As of 2016, only 6% of practicing FPs reported using non-obstetric POCUS in their practices.⁹ Similarly, a survey from 2015 reported that only 2% of family medicine residency programs had established POCUS curricula.¹⁰ However, 50% of respondents in the 2015 survey reported early-stage development or interest in developing a POCUS curriculum.

Since then a validated family medicine residency curriculum has been published,¹¹ and the American Academy of Family Physicians (AAFP) recently released a POCUS Curriculum Guideline for residencies (https://www.aafp.org/dam/AAFP/documents/medical_education_residency/program_directors/Reprint290D_POCUS.pdf).

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The potential applications of POCUS in family medicine are numerous and have been reviewed in several recent publications.^12,13 In this article, we will review the evidence for the use of POCUS in 4 areas: the cardiovascular exam (FIGURES 1 and 2), the lung exam (FIGURES 3-6), the screening exam for AAAs (FIGURE 7), and the evaluation for DVT (FIGURES 8 and 9). (Obstetric and musculoskeletal applications have been sufficiently covered elsewhere.^14-17) For all of these applications, POCUS is safe, accurate, and beneficial and can be performed with a relatively small amount of training by non-radiology specialists, including FPs (TABLEs 1 and 2).

Just 2 hours of cardio POCUS training enhanced Dx accuracy

The American Society of Echocardiography (ASE) issued an expert consensus statement for focused cardiac ultrasound in 2013.¹⁸ The guideline supports non-cardiologists utilizing POCUS to assess for pericardial effusion and right and left ventricular enlargement, as well as to review global cardiac systolic function and intravascular volume status. Cardiovascular POCUS protocols are relatively easy to learn; even small amounts of training and practice can yield competency.

Point-of-care ultrasound is safe, accurate, and beneficial and can be performed with a relatively small amount of training by family physicians.

For example, a 2013 study showed that after 2 hours of training with a pocket ultrasound device, medical students and junior physicians inexperienced with POCUS were able to improve their diagnostic accuracy for heart failure from 50% to 75%.¹⁹ In another study, internal medicine residents with limited cardiac ultrasound training (ie, 20 practice exams) were able to detect decreased left ventricular ejection fraction using a handheld ultrasound device with 94% sensitivity and specificity in patients admitted to the hospital with acute decompensated heart failure.²⁰ Similarly, after only 8 hours of training, a group of Norwegian general practitioners were able to obtain measurements of systolic function with a pocket ultrasound device that were not statistically different from a cardiologist’s measurements.²¹

In another study, rural FPs attended a 4-day course and then performed focused cardiac ultrasounds on primary care patients with a clinical indication for an echocardiogram.²² The scans were uploaded to a Web-based program for remote interpretation by a cardiologist. There was high concordance between the FPs’ interpretations of the focused cardiac ultrasounds and the cardiologist’s interpretations. Only 32% of the patients in the study group required a formal follow-up echocardiogram.

Kimura et al published a POCUS protocol for the rapid assessment of patients with heart failure, called the Cardiopulmonary Limited Ultrasound Exam (CLUE).²³ The CLUE protocol utilizes 4 views to assess left ventricular systolic and diastolic function along with signs of pulmonary edema or systemic volume overload (TABLE 3²³). The presence of pulmonary edema or a plethoric inferior vena cava (IVC) was highly prognostic of in-hospital mortality. The CLUE protocol has been successfully used by novices including internal medicine residents after brief training (ie, up to 60 supervised scans) and can be performed in less than 5 minutes.^24,25

More sensitive, specific than x-rays for pulmonary diagnoses

The chest x-ray has traditionally been the imaging modality of choice to evaluate primary care pulmonary complaints. However, POCUS can be more sensitive and specific than a chest x-ray for evaluating several pulmonary diagnoses including pleural effusion, pneumonia, and pulmonary edema.

Pleural effusion can be difficult to detect with a physical exam alone. A systematic review showed that the physical exam is not sensitive for effusions <300 mL and can have even lower utility in obese patients.²⁸ While an upright lateral chest x-ray can accurately detect effusions as small as 50 mL, portable x-rays have sensitivities of only 53% to 71% for small- or moderate-sized effusions.^29,30 Ultrasound, however, has a sensitivity of 97% for small effusions.³¹

A 2016 meta-analysis showed that POCUS had a pooled sensitivity and specificity of 94% and 98%, respectively, for pleural effusions, while chest x-ray had a pooled sensitivity and specificity of 51% and 91%, respectively, when compared with computed tomography (CT) and expert sonography.³² POCUS evaluation for pleural effusion is technically simple, and at least one study showed that even novice users can achieve high diagnostic accuracy after only 3 hours of training.³³

Pneumonia is the eighth leading cause of death in the United States and the single leading cause of infectious disease death in children worldwide.^34-36 Pneumonia is a difficult diagnosis to make based on a history and physical examination alone, and the Infectious Diseases Society of America recommends diagnostic imaging to make the diagnosis.³⁷

The adult and pediatric literature clearly demonstrate that lung ultrasound is accurate at diagnosing pneumonia. In a 2015 meta-analysis of the pediatric literature, lung ultrasound had a sensitivity of 96% and a specificity of 93% and positive and negative likelihood ratios of 15.3 and 0.06, respectively.³⁸ In adults, a 2016 meta-analysis of lung ultrasound showed a pooled sensitivity and specificity of 90% and 88%, respectively, with positive and negative likelihood ratios of 6.6 and 0.08, respectively.³⁹

In 2015, a prospective study compared the accuracy of lung ultrasound and chest x-ray using CT as the gold standard.⁴⁰ Lung ultrasound had a significantly better sensitivity of 82% compared to a sensitivity of 64% for chest x-ray. Specificities were comparable at 94% for ultrasound and 90% for chest x-ray.⁴⁰

At least one study found novice sonographers to be accurate with lung POCUS for the diagnosis of pneumonia after only two 90-minute training sessions.⁴¹ Moreover, ultrasound has a more favorable safety profile, greater portability, and lower cost compared with chest x-ray and CT.

Pulmonary edema. Lung ultrasound can identify interstitial pulmonary edema via artifacts called B lines, which are produced by the reverberation of sound waves from the pleura due to the widening of the fluid-filled interlobular septa. These are distinctly different from the A-line pattern of repeating horizontal lines that is seen with normal lungs, making lung ultrasound more accurate than chest x-ray for identification of pulmonary edema.^42,43 When final diagnosis via blinded chart review is used as the reference standard, bilateral B lines on a lung ultrasound image have a sensitivity of 86% to 100% and a specificity of 92% to 98% for the diagnosis of pulmonary edema compared to chest x-ray’s sensitivity of 56.9% and specificity of 89.2%.⁴⁴ There is also a linear correlation between the number of B lines present and the extent of pulmonary edema.^42,45,46 The number of B lines decreases in real time as volume is removed in dialysis patients.⁴⁷

POCUS evaluation for B lines can be learned very quickly. Exams of novices who have performed only 5 prior exams correlate highly with those of experts who have performed more than 100 exams.⁴⁸

Simple, efficient screening method for abdominal aortic aneurysm

AAAs are present in up to 7% of men over the age of 50.⁴⁹ The mortality rate of a ruptured AAA is as high as 80% to 95%.⁵⁰ There is, however, a long prodromal period when interventions can make a significant difference, which is why accurate screening is so important.

AAA screening with ultrasound has been shown to decrease mortality.⁵¹ The current recommendation of the US Preventive Services Task Force (USPSTF) is a one-time AAA screening for all men ages 65 to 75 years who have ever smoked (Grade B).⁵² Despite the recommendations of the USPSTF, screening rates are low. One study found that only 9% of eligible patients in primary care practices received appropriate screening.⁵¹

Ultrasound performed by specialists is known to be an excellent screening test for AAA with a sensitivity of 98.9% and a specificity of 99.9%.⁵³ POCUS use by emergency medicine physicians for the evaluation of symptomatic AAA is well established in the literature. A meta-analysis including 7 studies and 655 patients showed a pooled sensitivity of 99% and a specificity of 98%.⁵⁴ Multiple studies also support primary care physicians performing POCUS AAA screening in the clinic setting.

For example, a 2012 prospective, observational study performed in Canada compared office-based ultrasound screening exams performed by a rural FP to scans performed in the hospital on the same patients.⁵⁵ The physician completed 50 training examinations. The average discrepancy in aorta diameters between the 2 was only 2 mm, which is clinically insignificant, and the office-based scans had a sensitivity and specificity of 100%.

Similarly, a second FP study performed in Barcelona, showed that an FP who performed POCUS AAA screening had 100% concordance with a radiologist.⁵⁶ Additionally, POCUS screening for AAA was not time consuming; it was performed in under 4 minutes per patient.^55,57

Ruling out DVT

DVT is a relatively rare occurrence in the ambulatory setting. However, patients who present with a painful, swollen lower extremity are much more common, and DVT must be considered and ruled out in these situations.

Although isolated distal DVTs that occur in the calf veins are usually self-limited and have a very low risk of embolization, they can progress to proximal DVTs of the thigh veins up to 20% of time.^58,59 Similarly, thrombophlebitis of the superficial lower extremity veins rarely embolizes, but can progress to a proximal DVT, especially if large segments are involved or if the segments are within 5 cm of the junction to the deep venous system.⁵⁹ The risk of missing a proximal leg DVT is high because embolization occurs up to 60% of the time if the DVT is left untreated.⁶⁰

The current standard for diagnosis of DVT is the lower extremity Doppler ultrasound examination, but obtaining same-day Doppler evaluations can be difficult in the ambulatory setting. In these instances, the American College of Chest Physicians (ACCP) recommends that even low-risk patients receive anticoagulation pending the evaluation if it cannot be obtained in the first 24 hours.⁵⁹ This approach not only increases the cost of care, but also exposes patients—many of whom will not be diagnosed with thrombosis in the end—to the risks of anticoagulation.

D-dimer blood tests have drawbacks, too. While a negative high-sensitivity D-dimer blood test in a patient with a low pre-test probability of DVT can effectively rule out a DVT, laboratory testing is not always immediately available in the ambulatory setting either.⁶¹ Additionally, false-positive rates are high, and positive D-dimer exams still require evaluation by Doppler ultrasound.

Given these limitations, performing an ultrasound at the bedside or in the exam room can allow for more timely and cost-effective care. In fact, research shows that a limited ultrasound, called the 2-region compression exam, which follows along the course of the common femoral vein and popliteal vein only, ignoring the femoral and calf veins, is highly accurate in assessing for proximal leg DVTs. As such, it has been adopted for POCUS use by emergency medicine physicians.⁶²

Multiple studies show that physicians with minimal training can perform the 2-region compression exam with a high degree of accuracy when full-leg Doppler ultrasound was used as the gold standard.^63,64 In these studies, hands-on training times ranged from only 10 minutes to 5 hours, and the exam could be performed in less than 4 minutes. A systematic review of 6 studies comparing emergency physician-performed ultrasound with radiology-performed ultrasound calculated an overall sensitivity of 0.95 (95% CI, 0.87-0.99) and specificity of 0.96 (95% CI, 0.87-0.99) for those performed by emergency physicians.⁶⁵

The main concern with the 2-region compression exam is that it can miss a distal leg DVT. As stated earlier, distal DVTs are relatively benign and tend to resolve without treatment; however, up to 20% can progress to become a dangerous proximal leg DVT.⁵⁸ Researchers have validated several methods by prospective trials to address this limitation.

Point-of-care ultrasound screening for abdominal aortic aneurysm can be performed in less than 4 minutes.

Specifically, researchers have demonstrated that patients with a low pre-test probability of DVT per the Wells scoring system could have DVT effectively ruled out with a single 2-region compression ultrasound without further evaluation.⁶⁶ In another study, researchers evaluated all patients (regardless of pretest probability) with a 2-point compression exam and found that those with negative exams could be followed with a second exam in 7 to 10 days without initiating anticoagulation. If the second one was negative, no further evaluation was needed.^67,68

And finally, researchers demonstrated that a negative 2-point compression ultrasound in combination with a concurrent negative D-dimer test was effective at ruling out DVT, regardless of pre-test probability.^69,70

A preferred approach

Given this data and the fact that in the ambulatory setting it is often easier and faster to perform a 2-region compression examination than to obtain a D-dimer laboratory test or a formal full-leg Doppler ultrasound, what follows is our preferred approach to a patient with suspected DVT in the outpatient setting (FIGURE 10).

We first assess pre-test probability using the Wells scoring system. We then perform the 2-region compression ultrasound. If the patient has low pre-test risk according to the Wells score, we rule out DVT. If the patient has moderate or high risk with a negative 2-region compression ultrasound, the patient gets a D-dimer test. If the D-dimer test is negative, we rule out DVT. If the D-dimer test is positive, we schedule the patient for a repeat 2-region compression ultrasound in 7 to 10 days. If at any time the 2-region compression evaluation is positive, we treat the patient for DVT.

CORRESPONDENCE
Paul Bornemann, MD, Palmetto Health Family Medicine Residency, Department of Family and Preventive Medicine, University of South Carolina School of Medicine, 3209 Colonial Drive, Columbia, SC 29203; [email protected].

Point-of-care ultrasound (POCUS) has been gaining greater traction in recent years as a way to quickly (and cost-effectively) assess for conditions including systolic dysfunction, pleural effusion, abdominal aortic aneurysms (AAAs), and deep vein thrombosis (DVT). It involves limited and specific ultrasound protocols performed at the bedside by the health care provider who is trying to answer a specific question and, thus, help guide treatment of the patient.

POCUS was first widely used by emergency physicians starting in the early 1990s with the widespread adoption of the Focused Assessment with Sonography in Trauma (FAST) scan.^1,2 Since that time, POCUS has expanded beyond trauma applications and into family medicine.

One study assessed physicians’ perceptions of POCUS after its integration into a military family medicine clinic. The study showed that physicians perceived POCUS to be relatively easy to use, not overly time consuming, and of high value to the practice.³ In fact, the literature tells us that POCUS can help decrease the cost of health care and improve outcomes,^4-7 while requiring a relatively brief training period.

If residencies are any indication, POCUS may be headed your way

Ultrasound units are becoming smaller and more affordable, and medical schools are increasingly incorporating ultrasound curricula into medical student training.⁸ As of 2016, only 6% of practicing FPs reported using non-obstetric POCUS in their practices.⁹ Similarly, a survey from 2015 reported that only 2% of family medicine residency programs had established POCUS curricula.¹⁰ However, 50% of respondents in the 2015 survey reported early-stage development or interest in developing a POCUS curriculum.

Since then a validated family medicine residency curriculum has been published,¹¹ and the American Academy of Family Physicians (AAFP) recently released a POCUS Curriculum Guideline for residencies (https://www.aafp.org/dam/AAFP/documents/medical_education_residency/program_directors/Reprint290D_POCUS.pdf).

[polldaddy:9928416]

The potential applications of POCUS in family medicine are numerous and have been reviewed in several recent publications.^12,13 In this article, we will review the evidence for the use of POCUS in 4 areas: the cardiovascular exam (FIGURES 1 and 2), the lung exam (FIGURES 3-6), the screening exam for AAAs (FIGURE 7), and the evaluation for DVT (FIGURES 8 and 9). (Obstetric and musculoskeletal applications have been sufficiently covered elsewhere.^14-17) For all of these applications, POCUS is safe, accurate, and beneficial and can be performed with a relatively small amount of training by non-radiology specialists, including FPs (TABLEs 1 and 2).

Just 2 hours of cardio POCUS training enhanced Dx accuracy

The American Society of Echocardiography (ASE) issued an expert consensus statement for focused cardiac ultrasound in 2013.¹⁸ The guideline supports non-cardiologists utilizing POCUS to assess for pericardial effusion and right and left ventricular enlargement, as well as to review global cardiac systolic function and intravascular volume status. Cardiovascular POCUS protocols are relatively easy to learn; even small amounts of training and practice can yield competency.

Point-of-care ultrasound is safe, accurate, and beneficial and can be performed with a relatively small amount of training by family physicians.

For example, a 2013 study showed that after 2 hours of training with a pocket ultrasound device, medical students and junior physicians inexperienced with POCUS were able to improve their diagnostic accuracy for heart failure from 50% to 75%.¹⁹ In another study, internal medicine residents with limited cardiac ultrasound training (ie, 20 practice exams) were able to detect decreased left ventricular ejection fraction using a handheld ultrasound device with 94% sensitivity and specificity in patients admitted to the hospital with acute decompensated heart failure.²⁰ Similarly, after only 8 hours of training, a group of Norwegian general practitioners were able to obtain measurements of systolic function with a pocket ultrasound device that were not statistically different from a cardiologist’s measurements.²¹

In another study, rural FPs attended a 4-day course and then performed focused cardiac ultrasounds on primary care patients with a clinical indication for an echocardiogram.²² The scans were uploaded to a Web-based program for remote interpretation by a cardiologist. There was high concordance between the FPs’ interpretations of the focused cardiac ultrasounds and the cardiologist’s interpretations. Only 32% of the patients in the study group required a formal follow-up echocardiogram.

Kimura et al published a POCUS protocol for the rapid assessment of patients with heart failure, called the Cardiopulmonary Limited Ultrasound Exam (CLUE).²³ The CLUE protocol utilizes 4 views to assess left ventricular systolic and diastolic function along with signs of pulmonary edema or systemic volume overload (TABLE 3²³). The presence of pulmonary edema or a plethoric inferior vena cava (IVC) was highly prognostic of in-hospital mortality. The CLUE protocol has been successfully used by novices including internal medicine residents after brief training (ie, up to 60 supervised scans) and can be performed in less than 5 minutes.^24,25

More sensitive, specific than x-rays for pulmonary diagnoses

The chest x-ray has traditionally been the imaging modality of choice to evaluate primary care pulmonary complaints. However, POCUS can be more sensitive and specific than a chest x-ray for evaluating several pulmonary diagnoses including pleural effusion, pneumonia, and pulmonary edema.

Pleural effusion can be difficult to detect with a physical exam alone. A systematic review showed that the physical exam is not sensitive for effusions <300 mL and can have even lower utility in obese patients.²⁸ While an upright lateral chest x-ray can accurately detect effusions as small as 50 mL, portable x-rays have sensitivities of only 53% to 71% for small- or moderate-sized effusions.^29,30 Ultrasound, however, has a sensitivity of 97% for small effusions.³¹

A 2016 meta-analysis showed that POCUS had a pooled sensitivity and specificity of 94% and 98%, respectively, for pleural effusions, while chest x-ray had a pooled sensitivity and specificity of 51% and 91%, respectively, when compared with computed tomography (CT) and expert sonography.³² POCUS evaluation for pleural effusion is technically simple, and at least one study showed that even novice users can achieve high diagnostic accuracy after only 3 hours of training.³³

Pneumonia is the eighth leading cause of death in the United States and the single leading cause of infectious disease death in children worldwide.^34-36 Pneumonia is a difficult diagnosis to make based on a history and physical examination alone, and the Infectious Diseases Society of America recommends diagnostic imaging to make the diagnosis.³⁷

The adult and pediatric literature clearly demonstrate that lung ultrasound is accurate at diagnosing pneumonia. In a 2015 meta-analysis of the pediatric literature, lung ultrasound had a sensitivity of 96% and a specificity of 93% and positive and negative likelihood ratios of 15.3 and 0.06, respectively.³⁸ In adults, a 2016 meta-analysis of lung ultrasound showed a pooled sensitivity and specificity of 90% and 88%, respectively, with positive and negative likelihood ratios of 6.6 and 0.08, respectively.³⁹

In 2015, a prospective study compared the accuracy of lung ultrasound and chest x-ray using CT as the gold standard.⁴⁰ Lung ultrasound had a significantly better sensitivity of 82% compared to a sensitivity of 64% for chest x-ray. Specificities were comparable at 94% for ultrasound and 90% for chest x-ray.⁴⁰

At least one study found novice sonographers to be accurate with lung POCUS for the diagnosis of pneumonia after only two 90-minute training sessions.⁴¹ Moreover, ultrasound has a more favorable safety profile, greater portability, and lower cost compared with chest x-ray and CT.

Pulmonary edema. Lung ultrasound can identify interstitial pulmonary edema via artifacts called B lines, which are produced by the reverberation of sound waves from the pleura due to the widening of the fluid-filled interlobular septa. These are distinctly different from the A-line pattern of repeating horizontal lines that is seen with normal lungs, making lung ultrasound more accurate than chest x-ray for identification of pulmonary edema.^42,43 When final diagnosis via blinded chart review is used as the reference standard, bilateral B lines on a lung ultrasound image have a sensitivity of 86% to 100% and a specificity of 92% to 98% for the diagnosis of pulmonary edema compared to chest x-ray’s sensitivity of 56.9% and specificity of 89.2%.⁴⁴ There is also a linear correlation between the number of B lines present and the extent of pulmonary edema.^42,45,46 The number of B lines decreases in real time as volume is removed in dialysis patients.⁴⁷

POCUS evaluation for B lines can be learned very quickly. Exams of novices who have performed only 5 prior exams correlate highly with those of experts who have performed more than 100 exams.⁴⁸

Simple, efficient screening method for abdominal aortic aneurysm

AAAs are present in up to 7% of men over the age of 50.⁴⁹ The mortality rate of a ruptured AAA is as high as 80% to 95%.⁵⁰ There is, however, a long prodromal period when interventions can make a significant difference, which is why accurate screening is so important.

AAA screening with ultrasound has been shown to decrease mortality.⁵¹ The current recommendation of the US Preventive Services Task Force (USPSTF) is a one-time AAA screening for all men ages 65 to 75 years who have ever smoked (Grade B).⁵² Despite the recommendations of the USPSTF, screening rates are low. One study found that only 9% of eligible patients in primary care practices received appropriate screening.⁵¹

Ultrasound performed by specialists is known to be an excellent screening test for AAA with a sensitivity of 98.9% and a specificity of 99.9%.⁵³ POCUS use by emergency medicine physicians for the evaluation of symptomatic AAA is well established in the literature. A meta-analysis including 7 studies and 655 patients showed a pooled sensitivity of 99% and a specificity of 98%.⁵⁴ Multiple studies also support primary care physicians performing POCUS AAA screening in the clinic setting.

For example, a 2012 prospective, observational study performed in Canada compared office-based ultrasound screening exams performed by a rural FP to scans performed in the hospital on the same patients.⁵⁵ The physician completed 50 training examinations. The average discrepancy in aorta diameters between the 2 was only 2 mm, which is clinically insignificant, and the office-based scans had a sensitivity and specificity of 100%.

Similarly, a second FP study performed in Barcelona, showed that an FP who performed POCUS AAA screening had 100% concordance with a radiologist.⁵⁶ Additionally, POCUS screening for AAA was not time consuming; it was performed in under 4 minutes per patient.^55,57

Ruling out DVT

DVT is a relatively rare occurrence in the ambulatory setting. However, patients who present with a painful, swollen lower extremity are much more common, and DVT must be considered and ruled out in these situations.

Although isolated distal DVTs that occur in the calf veins are usually self-limited and have a very low risk of embolization, they can progress to proximal DVTs of the thigh veins up to 20% of time.^58,59 Similarly, thrombophlebitis of the superficial lower extremity veins rarely embolizes, but can progress to a proximal DVT, especially if large segments are involved or if the segments are within 5 cm of the junction to the deep venous system.⁵⁹ The risk of missing a proximal leg DVT is high because embolization occurs up to 60% of the time if the DVT is left untreated.⁶⁰

The current standard for diagnosis of DVT is the lower extremity Doppler ultrasound examination, but obtaining same-day Doppler evaluations can be difficult in the ambulatory setting. In these instances, the American College of Chest Physicians (ACCP) recommends that even low-risk patients receive anticoagulation pending the evaluation if it cannot be obtained in the first 24 hours.⁵⁹ This approach not only increases the cost of care, but also exposes patients—many of whom will not be diagnosed with thrombosis in the end—to the risks of anticoagulation.

D-dimer blood tests have drawbacks, too. While a negative high-sensitivity D-dimer blood test in a patient with a low pre-test probability of DVT can effectively rule out a DVT, laboratory testing is not always immediately available in the ambulatory setting either.⁶¹ Additionally, false-positive rates are high, and positive D-dimer exams still require evaluation by Doppler ultrasound.

Given these limitations, performing an ultrasound at the bedside or in the exam room can allow for more timely and cost-effective care. In fact, research shows that a limited ultrasound, called the 2-region compression exam, which follows along the course of the common femoral vein and popliteal vein only, ignoring the femoral and calf veins, is highly accurate in assessing for proximal leg DVTs. As such, it has been adopted for POCUS use by emergency medicine physicians.⁶²

Multiple studies show that physicians with minimal training can perform the 2-region compression exam with a high degree of accuracy when full-leg Doppler ultrasound was used as the gold standard.^63,64 In these studies, hands-on training times ranged from only 10 minutes to 5 hours, and the exam could be performed in less than 4 minutes. A systematic review of 6 studies comparing emergency physician-performed ultrasound with radiology-performed ultrasound calculated an overall sensitivity of 0.95 (95% CI, 0.87-0.99) and specificity of 0.96 (95% CI, 0.87-0.99) for those performed by emergency physicians.⁶⁵

The main concern with the 2-region compression exam is that it can miss a distal leg DVT. As stated earlier, distal DVTs are relatively benign and tend to resolve without treatment; however, up to 20% can progress to become a dangerous proximal leg DVT.⁵⁸ Researchers have validated several methods by prospective trials to address this limitation.

Point-of-care ultrasound screening for abdominal aortic aneurysm can be performed in less than 4 minutes.

Specifically, researchers have demonstrated that patients with a low pre-test probability of DVT per the Wells scoring system could have DVT effectively ruled out with a single 2-region compression ultrasound without further evaluation.⁶⁶ In another study, researchers evaluated all patients (regardless of pretest probability) with a 2-point compression exam and found that those with negative exams could be followed with a second exam in 7 to 10 days without initiating anticoagulation. If the second one was negative, no further evaluation was needed.^67,68

And finally, researchers demonstrated that a negative 2-point compression ultrasound in combination with a concurrent negative D-dimer test was effective at ruling out DVT, regardless of pre-test probability.^69,70

A preferred approach

Given this data and the fact that in the ambulatory setting it is often easier and faster to perform a 2-region compression examination than to obtain a D-dimer laboratory test or a formal full-leg Doppler ultrasound, what follows is our preferred approach to a patient with suspected DVT in the outpatient setting (FIGURE 10).

We first assess pre-test probability using the Wells scoring system. We then perform the 2-region compression ultrasound. If the patient has low pre-test risk according to the Wells score, we rule out DVT. If the patient has moderate or high risk with a negative 2-region compression ultrasound, the patient gets a D-dimer test. If the D-dimer test is negative, we rule out DVT. If the D-dimer test is positive, we schedule the patient for a repeat 2-region compression ultrasound in 7 to 10 days. If at any time the 2-region compression evaluation is positive, we treat the patient for DVT.

CORRESPONDENCE
Paul Bornemann, MD, Palmetto Health Family Medicine Residency, Department of Family and Preventive Medicine, University of South Carolina School of Medicine, 3209 Colonial Drive, Columbia, SC 29203; [email protected].

Point-of-care ultrasound (POCUS) has been gaining greater traction in recent years as a way to quickly (and cost-effectively) assess for conditions including systolic dysfunction, pleural effusion, abdominal aortic aneurysms (AAAs), and deep vein thrombosis (DVT). It involves limited and specific ultrasound protocols performed at the bedside by the health care provider who is trying to answer a specific question and, thus, help guide treatment of the patient.

POCUS was first widely used by emergency physicians starting in the early 1990s with the widespread adoption of the Focused Assessment with Sonography in Trauma (FAST) scan.^1,2 Since that time, POCUS has expanded beyond trauma applications and into family medicine.

One study assessed physicians’ perceptions of POCUS after its integration into a military family medicine clinic. The study showed that physicians perceived POCUS to be relatively easy to use, not overly time consuming, and of high value to the practice.³ In fact, the literature tells us that POCUS can help decrease the cost of health care and improve outcomes,^4-7 while requiring a relatively brief training period.

If residencies are any indication, POCUS may be headed your way

Ultrasound units are becoming smaller and more affordable, and medical schools are increasingly incorporating ultrasound curricula into medical student training.⁸ As of 2016, only 6% of practicing FPs reported using non-obstetric POCUS in their practices.⁹ Similarly, a survey from 2015 reported that only 2% of family medicine residency programs had established POCUS curricula.¹⁰ However, 50% of respondents in the 2015 survey reported early-stage development or interest in developing a POCUS curriculum.

Since then a validated family medicine residency curriculum has been published,¹¹ and the American Academy of Family Physicians (AAFP) recently released a POCUS Curriculum Guideline for residencies (https://www.aafp.org/dam/AAFP/documents/medical_education_residency/program_directors/Reprint290D_POCUS.pdf).

[polldaddy:9928416]

The potential applications of POCUS in family medicine are numerous and have been reviewed in several recent publications.^12,13 In this article, we will review the evidence for the use of POCUS in 4 areas: the cardiovascular exam (FIGURES 1 and 2), the lung exam (FIGURES 3-6), the screening exam for AAAs (FIGURE 7), and the evaluation for DVT (FIGURES 8 and 9). (Obstetric and musculoskeletal applications have been sufficiently covered elsewhere.^14-17) For all of these applications, POCUS is safe, accurate, and beneficial and can be performed with a relatively small amount of training by non-radiology specialists, including FPs (TABLEs 1 and 2).

Just 2 hours of cardio POCUS training enhanced Dx accuracy

The American Society of Echocardiography (ASE) issued an expert consensus statement for focused cardiac ultrasound in 2013.¹⁸ The guideline supports non-cardiologists utilizing POCUS to assess for pericardial effusion and right and left ventricular enlargement, as well as to review global cardiac systolic function and intravascular volume status. Cardiovascular POCUS protocols are relatively easy to learn; even small amounts of training and practice can yield competency.

Point-of-care ultrasound is safe, accurate, and beneficial and can be performed with a relatively small amount of training by family physicians.

For example, a 2013 study showed that after 2 hours of training with a pocket ultrasound device, medical students and junior physicians inexperienced with POCUS were able to improve their diagnostic accuracy for heart failure from 50% to 75%.¹⁹ In another study, internal medicine residents with limited cardiac ultrasound training (ie, 20 practice exams) were able to detect decreased left ventricular ejection fraction using a handheld ultrasound device with 94% sensitivity and specificity in patients admitted to the hospital with acute decompensated heart failure.²⁰ Similarly, after only 8 hours of training, a group of Norwegian general practitioners were able to obtain measurements of systolic function with a pocket ultrasound device that were not statistically different from a cardiologist’s measurements.²¹

In another study, rural FPs attended a 4-day course and then performed focused cardiac ultrasounds on primary care patients with a clinical indication for an echocardiogram.²² The scans were uploaded to a Web-based program for remote interpretation by a cardiologist. There was high concordance between the FPs’ interpretations of the focused cardiac ultrasounds and the cardiologist’s interpretations. Only 32% of the patients in the study group required a formal follow-up echocardiogram.

Kimura et al published a POCUS protocol for the rapid assessment of patients with heart failure, called the Cardiopulmonary Limited Ultrasound Exam (CLUE).²³ The CLUE protocol utilizes 4 views to assess left ventricular systolic and diastolic function along with signs of pulmonary edema or systemic volume overload (TABLE 3²³). The presence of pulmonary edema or a plethoric inferior vena cava (IVC) was highly prognostic of in-hospital mortality. The CLUE protocol has been successfully used by novices including internal medicine residents after brief training (ie, up to 60 supervised scans) and can be performed in less than 5 minutes.^24,25

More sensitive, specific than x-rays for pulmonary diagnoses

The chest x-ray has traditionally been the imaging modality of choice to evaluate primary care pulmonary complaints. However, POCUS can be more sensitive and specific than a chest x-ray for evaluating several pulmonary diagnoses including pleural effusion, pneumonia, and pulmonary edema.

Pleural effusion can be difficult to detect with a physical exam alone. A systematic review showed that the physical exam is not sensitive for effusions <300 mL and can have even lower utility in obese patients.²⁸ While an upright lateral chest x-ray can accurately detect effusions as small as 50 mL, portable x-rays have sensitivities of only 53% to 71% for small- or moderate-sized effusions.^29,30 Ultrasound, however, has a sensitivity of 97% for small effusions.³¹

A 2016 meta-analysis showed that POCUS had a pooled sensitivity and specificity of 94% and 98%, respectively, for pleural effusions, while chest x-ray had a pooled sensitivity and specificity of 51% and 91%, respectively, when compared with computed tomography (CT) and expert sonography.³² POCUS evaluation for pleural effusion is technically simple, and at least one study showed that even novice users can achieve high diagnostic accuracy after only 3 hours of training.³³

Pneumonia is the eighth leading cause of death in the United States and the single leading cause of infectious disease death in children worldwide.^34-36 Pneumonia is a difficult diagnosis to make based on a history and physical examination alone, and the Infectious Diseases Society of America recommends diagnostic imaging to make the diagnosis.³⁷

The adult and pediatric literature clearly demonstrate that lung ultrasound is accurate at diagnosing pneumonia. In a 2015 meta-analysis of the pediatric literature, lung ultrasound had a sensitivity of 96% and a specificity of 93% and positive and negative likelihood ratios of 15.3 and 0.06, respectively.³⁸ In adults, a 2016 meta-analysis of lung ultrasound showed a pooled sensitivity and specificity of 90% and 88%, respectively, with positive and negative likelihood ratios of 6.6 and 0.08, respectively.³⁹

In 2015, a prospective study compared the accuracy of lung ultrasound and chest x-ray using CT as the gold standard.⁴⁰ Lung ultrasound had a significantly better sensitivity of 82% compared to a sensitivity of 64% for chest x-ray. Specificities were comparable at 94% for ultrasound and 90% for chest x-ray.⁴⁰

At least one study found novice sonographers to be accurate with lung POCUS for the diagnosis of pneumonia after only two 90-minute training sessions.⁴¹ Moreover, ultrasound has a more favorable safety profile, greater portability, and lower cost compared with chest x-ray and CT.

Pulmonary edema. Lung ultrasound can identify interstitial pulmonary edema via artifacts called B lines, which are produced by the reverberation of sound waves from the pleura due to the widening of the fluid-filled interlobular septa. These are distinctly different from the A-line pattern of repeating horizontal lines that is seen with normal lungs, making lung ultrasound more accurate than chest x-ray for identification of pulmonary edema.^42,43 When final diagnosis via blinded chart review is used as the reference standard, bilateral B lines on a lung ultrasound image have a sensitivity of 86% to 100% and a specificity of 92% to 98% for the diagnosis of pulmonary edema compared to chest x-ray’s sensitivity of 56.9% and specificity of 89.2%.⁴⁴ There is also a linear correlation between the number of B lines present and the extent of pulmonary edema.^42,45,46 The number of B lines decreases in real time as volume is removed in dialysis patients.⁴⁷

POCUS evaluation for B lines can be learned very quickly. Exams of novices who have performed only 5 prior exams correlate highly with those of experts who have performed more than 100 exams.⁴⁸

Simple, efficient screening method for abdominal aortic aneurysm

AAAs are present in up to 7% of men over the age of 50.⁴⁹ The mortality rate of a ruptured AAA is as high as 80% to 95%.⁵⁰ There is, however, a long prodromal period when interventions can make a significant difference, which is why accurate screening is so important.

AAA screening with ultrasound has been shown to decrease mortality.⁵¹ The current recommendation of the US Preventive Services Task Force (USPSTF) is a one-time AAA screening for all men ages 65 to 75 years who have ever smoked (Grade B).⁵² Despite the recommendations of the USPSTF, screening rates are low. One study found that only 9% of eligible patients in primary care practices received appropriate screening.⁵¹

Ultrasound performed by specialists is known to be an excellent screening test for AAA with a sensitivity of 98.9% and a specificity of 99.9%.⁵³ POCUS use by emergency medicine physicians for the evaluation of symptomatic AAA is well established in the literature. A meta-analysis including 7 studies and 655 patients showed a pooled sensitivity of 99% and a specificity of 98%.⁵⁴ Multiple studies also support primary care physicians performing POCUS AAA screening in the clinic setting.

For example, a 2012 prospective, observational study performed in Canada compared office-based ultrasound screening exams performed by a rural FP to scans performed in the hospital on the same patients.⁵⁵ The physician completed 50 training examinations. The average discrepancy in aorta diameters between the 2 was only 2 mm, which is clinically insignificant, and the office-based scans had a sensitivity and specificity of 100%.

Similarly, a second FP study performed in Barcelona, showed that an FP who performed POCUS AAA screening had 100% concordance with a radiologist.⁵⁶ Additionally, POCUS screening for AAA was not time consuming; it was performed in under 4 minutes per patient.^55,57

Ruling out DVT

DVT is a relatively rare occurrence in the ambulatory setting. However, patients who present with a painful, swollen lower extremity are much more common, and DVT must be considered and ruled out in these situations.

Although isolated distal DVTs that occur in the calf veins are usually self-limited and have a very low risk of embolization, they can progress to proximal DVTs of the thigh veins up to 20% of time.^58,59 Similarly, thrombophlebitis of the superficial lower extremity veins rarely embolizes, but can progress to a proximal DVT, especially if large segments are involved or if the segments are within 5 cm of the junction to the deep venous system.⁵⁹ The risk of missing a proximal leg DVT is high because embolization occurs up to 60% of the time if the DVT is left untreated.⁶⁰

The current standard for diagnosis of DVT is the lower extremity Doppler ultrasound examination, but obtaining same-day Doppler evaluations can be difficult in the ambulatory setting. In these instances, the American College of Chest Physicians (ACCP) recommends that even low-risk patients receive anticoagulation pending the evaluation if it cannot be obtained in the first 24 hours.⁵⁹ This approach not only increases the cost of care, but also exposes patients—many of whom will not be diagnosed with thrombosis in the end—to the risks of anticoagulation.

D-dimer blood tests have drawbacks, too. While a negative high-sensitivity D-dimer blood test in a patient with a low pre-test probability of DVT can effectively rule out a DVT, laboratory testing is not always immediately available in the ambulatory setting either.⁶¹ Additionally, false-positive rates are high, and positive D-dimer exams still require evaluation by Doppler ultrasound.

Given these limitations, performing an ultrasound at the bedside or in the exam room can allow for more timely and cost-effective care. In fact, research shows that a limited ultrasound, called the 2-region compression exam, which follows along the course of the common femoral vein and popliteal vein only, ignoring the femoral and calf veins, is highly accurate in assessing for proximal leg DVTs. As such, it has been adopted for POCUS use by emergency medicine physicians.⁶²

Multiple studies show that physicians with minimal training can perform the 2-region compression exam with a high degree of accuracy when full-leg Doppler ultrasound was used as the gold standard.^63,64 In these studies, hands-on training times ranged from only 10 minutes to 5 hours, and the exam could be performed in less than 4 minutes. A systematic review of 6 studies comparing emergency physician-performed ultrasound with radiology-performed ultrasound calculated an overall sensitivity of 0.95 (95% CI, 0.87-0.99) and specificity of 0.96 (95% CI, 0.87-0.99) for those performed by emergency physicians.⁶⁵

The main concern with the 2-region compression exam is that it can miss a distal leg DVT. As stated earlier, distal DVTs are relatively benign and tend to resolve without treatment; however, up to 20% can progress to become a dangerous proximal leg DVT.⁵⁸ Researchers have validated several methods by prospective trials to address this limitation.

Point-of-care ultrasound screening for abdominal aortic aneurysm can be performed in less than 4 minutes.

Specifically, researchers have demonstrated that patients with a low pre-test probability of DVT per the Wells scoring system could have DVT effectively ruled out with a single 2-region compression ultrasound without further evaluation.⁶⁶ In another study, researchers evaluated all patients (regardless of pretest probability) with a 2-point compression exam and found that those with negative exams could be followed with a second exam in 7 to 10 days without initiating anticoagulation. If the second one was negative, no further evaluation was needed.^67,68

And finally, researchers demonstrated that a negative 2-point compression ultrasound in combination with a concurrent negative D-dimer test was effective at ruling out DVT, regardless of pre-test probability.^69,70

A preferred approach

Given this data and the fact that in the ambulatory setting it is often easier and faster to perform a 2-region compression examination than to obtain a D-dimer laboratory test or a formal full-leg Doppler ultrasound, what follows is our preferred approach to a patient with suspected DVT in the outpatient setting (FIGURE 10).

We first assess pre-test probability using the Wells scoring system. We then perform the 2-region compression ultrasound. If the patient has low pre-test risk according to the Wells score, we rule out DVT. If the patient has moderate or high risk with a negative 2-region compression ultrasound, the patient gets a D-dimer test. If the D-dimer test is negative, we rule out DVT. If the D-dimer test is positive, we schedule the patient for a repeat 2-region compression ultrasound in 7 to 10 days. If at any time the 2-region compression evaluation is positive, we treat the patient for DVT.

CORRESPONDENCE
Paul Bornemann, MD, Palmetto Health Family Medicine Residency, Department of Family and Preventive Medicine, University of South Carolina School of Medicine, 3209 Colonial Drive, Columbia, SC 29203; [email protected].

Hospital of Philadelphia

Updated results from the phase 2 ELIANA study have shown that tisagenlecleucel can produce durable complete responses (CRs) in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL).

Sixty percent of patients who received the chimeric antigen receptor (CAR) T-cell therapy achieved a CR, and 21% had a CR with incomplete hematologic recovery (CRi).

The median duration of CR/CRi was not reached at a median follow-up of 13.1 months.

The most common treatment-related adverse event (AE) was cytokine release syndrome (CRS), occurring in 77% of patients.

Researchers reported these results in NEJM. The study was sponsored by Novartis.

“This expanded, global study of CAR T-cell therapy gives us further evidence of how remarkable this treatment can be for our young patients in whom all other treatments failed,” said study author Shannon L. Maude, MD, PhD, of Children’s Hospital of Philadelphia in Pennsylvania.

“Our data show not only can we can achieve longer-term durable remissions and longer-term survival for our patients but that these personalized, cancer-fighting cells can remain in the body for months or even years, effectively doing their job.”

The trial included 75 patients who received tisagenlecleucel. At enrollment, the patients’ median age was 11 (range, 3 to 23).

Patients had received a median of 3 prior therapies (range, 1 to 8), and they had a median marrow blast percentage of 74% (range, 5 to 99).

All patients received a single infusion of tisagenlecleucel. Most (n=72) received lymphodepleting chemotherapy prior to the CAR T cells.

Results

The median duration of follow-up was 13.1 months.

The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CRi within 3 months. The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.

All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.

The researchers said tisagenlecleucel persisted in the blood for as long as 20 months.

The relapse-free survival rate among patients with a CR/CRi was 80% at 6 months and 59% at 12 months.

Seventeen patients who had achieved a CR relapsed before receiving subsequent treatment. Three patients went on to subsequent therapy before relapse but ultimately relapsed.

Relapse was also reported in 2 patients who had been classified as non-responders because they did not maintain a response for at least 28 days.

Eight patients underwent allogeneic hematopoietic stem cell transplant while in remission, and all 8 were alive when the manuscript for this study was submitted. Four patients had not relapsed, and the other 4 had unknown disease status.

At 6 months, the event-free survival rate was 73%, and the overall survival rate was 90%. At 12 months, the rates were 50% and 76%, respectively.

All patients experienced at least 1 AE, and 95% had AEs thought to be related to tisagenlecleucel. Grade 3/4 AEs occurred in 88% of patients. In 73% of patients, these AEs were thought to be related to treatment.

AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).

The median duration of CRS was 8 days (range, 1-36). Forty-seven patients were admitted to the intensive care unit to receive treatment for CRS, with a median stay of 7 days (range, 1-34).

“One of our more challenging questions—‘Can we manage the serious side effects of CAR T-cell therapy?’—was asked and answered in this global study,” said author Stephan A. Grupp, MD, PhD, of Children’s Hospital of Philadelphia.

“Some of our patients get very sick, but we showed that most toxic effects can be short-lived and reversible, with the potential for our patients to achieve durable complete remissions. That’s a pretty amazing turnaround for the high-risk child who, up until now, had little chance of surviving.”

Hospital of Philadelphia

Updated results from the phase 2 ELIANA study have shown that tisagenlecleucel can produce durable complete responses (CRs) in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL).

Sixty percent of patients who received the chimeric antigen receptor (CAR) T-cell therapy achieved a CR, and 21% had a CR with incomplete hematologic recovery (CRi).

The median duration of CR/CRi was not reached at a median follow-up of 13.1 months.

The most common treatment-related adverse event (AE) was cytokine release syndrome (CRS), occurring in 77% of patients.

Researchers reported these results in NEJM. The study was sponsored by Novartis.

“This expanded, global study of CAR T-cell therapy gives us further evidence of how remarkable this treatment can be for our young patients in whom all other treatments failed,” said study author Shannon L. Maude, MD, PhD, of Children’s Hospital of Philadelphia in Pennsylvania.

“Our data show not only can we can achieve longer-term durable remissions and longer-term survival for our patients but that these personalized, cancer-fighting cells can remain in the body for months or even years, effectively doing their job.”

The trial included 75 patients who received tisagenlecleucel. At enrollment, the patients’ median age was 11 (range, 3 to 23).

Patients had received a median of 3 prior therapies (range, 1 to 8), and they had a median marrow blast percentage of 74% (range, 5 to 99).

All patients received a single infusion of tisagenlecleucel. Most (n=72) received lymphodepleting chemotherapy prior to the CAR T cells.

Results

The median duration of follow-up was 13.1 months.

The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CRi within 3 months. The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.

All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.

The researchers said tisagenlecleucel persisted in the blood for as long as 20 months.

The relapse-free survival rate among patients with a CR/CRi was 80% at 6 months and 59% at 12 months.

Seventeen patients who had achieved a CR relapsed before receiving subsequent treatment. Three patients went on to subsequent therapy before relapse but ultimately relapsed.

Relapse was also reported in 2 patients who had been classified as non-responders because they did not maintain a response for at least 28 days.

Eight patients underwent allogeneic hematopoietic stem cell transplant while in remission, and all 8 were alive when the manuscript for this study was submitted. Four patients had not relapsed, and the other 4 had unknown disease status.

At 6 months, the event-free survival rate was 73%, and the overall survival rate was 90%. At 12 months, the rates were 50% and 76%, respectively.

All patients experienced at least 1 AE, and 95% had AEs thought to be related to tisagenlecleucel. Grade 3/4 AEs occurred in 88% of patients. In 73% of patients, these AEs were thought to be related to treatment.

AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).

The median duration of CRS was 8 days (range, 1-36). Forty-seven patients were admitted to the intensive care unit to receive treatment for CRS, with a median stay of 7 days (range, 1-34).

“One of our more challenging questions—‘Can we manage the serious side effects of CAR T-cell therapy?’—was asked and answered in this global study,” said author Stephan A. Grupp, MD, PhD, of Children’s Hospital of Philadelphia.

“Some of our patients get very sick, but we showed that most toxic effects can be short-lived and reversible, with the potential for our patients to achieve durable complete remissions. That’s a pretty amazing turnaround for the high-risk child who, up until now, had little chance of surviving.”

Hospital of Philadelphia

Updated results from the phase 2 ELIANA study have shown that tisagenlecleucel can produce durable complete responses (CRs) in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL).

Sixty percent of patients who received the chimeric antigen receptor (CAR) T-cell therapy achieved a CR, and 21% had a CR with incomplete hematologic recovery (CRi).

The median duration of CR/CRi was not reached at a median follow-up of 13.1 months.

The most common treatment-related adverse event (AE) was cytokine release syndrome (CRS), occurring in 77% of patients.

Researchers reported these results in NEJM. The study was sponsored by Novartis.

“This expanded, global study of CAR T-cell therapy gives us further evidence of how remarkable this treatment can be for our young patients in whom all other treatments failed,” said study author Shannon L. Maude, MD, PhD, of Children’s Hospital of Philadelphia in Pennsylvania.

“Our data show not only can we can achieve longer-term durable remissions and longer-term survival for our patients but that these personalized, cancer-fighting cells can remain in the body for months or even years, effectively doing their job.”

The trial included 75 patients who received tisagenlecleucel. At enrollment, the patients’ median age was 11 (range, 3 to 23).

Patients had received a median of 3 prior therapies (range, 1 to 8), and they had a median marrow blast percentage of 74% (range, 5 to 99).

All patients received a single infusion of tisagenlecleucel. Most (n=72) received lymphodepleting chemotherapy prior to the CAR T cells.

Results

The median duration of follow-up was 13.1 months.

The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CRi within 3 months. The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.

All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.

The researchers said tisagenlecleucel persisted in the blood for as long as 20 months.

The relapse-free survival rate among patients with a CR/CRi was 80% at 6 months and 59% at 12 months.

Seventeen patients who had achieved a CR relapsed before receiving subsequent treatment. Three patients went on to subsequent therapy before relapse but ultimately relapsed.

Relapse was also reported in 2 patients who had been classified as non-responders because they did not maintain a response for at least 28 days.

Eight patients underwent allogeneic hematopoietic stem cell transplant while in remission, and all 8 were alive when the manuscript for this study was submitted. Four patients had not relapsed, and the other 4 had unknown disease status.

At 6 months, the event-free survival rate was 73%, and the overall survival rate was 90%. At 12 months, the rates were 50% and 76%, respectively.

All patients experienced at least 1 AE, and 95% had AEs thought to be related to tisagenlecleucel. Grade 3/4 AEs occurred in 88% of patients. In 73% of patients, these AEs were thought to be related to treatment.

AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).

The median duration of CRS was 8 days (range, 1-36). Forty-seven patients were admitted to the intensive care unit to receive treatment for CRS, with a median stay of 7 days (range, 1-34).

“One of our more challenging questions—‘Can we manage the serious side effects of CAR T-cell therapy?’—was asked and answered in this global study,” said author Stephan A. Grupp, MD, PhD, of Children’s Hospital of Philadelphia.

“Some of our patients get very sick, but we showed that most toxic effects can be short-lived and reversible, with the potential for our patients to achieve durable complete remissions. That’s a pretty amazing turnaround for the high-risk child who, up until now, had little chance of surviving.”

Image from NIAID

The US Food and Drug Administration (FDA) has placed BPX-501, a T-cell therapy being evaluated in patients who undergo haploidentical hematopoietic stem cell transplants (HSCTs), on clinical hold.

Three cases of encephalopathy possibly related to BPX-501 prompted the agency to impose the hold.

Bellicum Pharmaceuticals is the developer of BPX-501, and the company was conducting 4 trials in the US in children and adults with hematologic disorders.

The BPX-501 registration trial in Europe is not affected by the clinical hold.

BPX-501 is designed to fight infection, support engraftment, prevent disease relapse, and potentially stop graft-versus-host disease (GVHD) should it occur.

BPX-501 contains a safety switch, CaspaCIDe®, that can be activated with the administration of rimiducid to kill the toxic T cells in the event of GVHD.

The 3 cases of encephalopathy are complex, according to a company press release, and have confounding factors. These include prior failed transplants, prior history of immunodeficiency, concurrent infection, and administration of rimiducid in combination with other medications.

Encephalopathy had not emerged as an adverse event in 240 patients treated with the cell therapy, until now.

BPX-501 had produced encouraging results, according to trial data presented at EHA 2017 and ASH 2017 (abstract 211*).

In this trial, 112 pediatric patients were transfused with BPX-501 cells about 2 weeks after transplant. Patients had acute leukemia (n=53), primary immune deficiencies (n=26), erythroid disorders (n=17), Fanconi anemia (n=7), and other diseases (n=9).

Investigators reported that infused cells expanded and persisted, with peak expansion reached at 9 months after infusion. Investigators continued to detect BPX-501 cells after 2 years.

The European Commission granted BPX-501 orphan drug designation for the agent for treatment in HSCT, and for the activator agent rimiducid for the treatment of GVHD.

And the FDA had granted the agents orphan drug status as a combination replacement T-cell therapy for the treatment of immunodeficiency and GVHD after HSCT.

Bellicum says it is working with the FDA to evaluate the risk of encephalopathy in patients receiving BPX-501.

* Data in the abstract were updated in the oral presentation and reported on the company’s website.

Image from NIAID

The US Food and Drug Administration (FDA) has placed BPX-501, a T-cell therapy being evaluated in patients who undergo haploidentical hematopoietic stem cell transplants (HSCTs), on clinical hold.

Three cases of encephalopathy possibly related to BPX-501 prompted the agency to impose the hold.

Bellicum Pharmaceuticals is the developer of BPX-501, and the company was conducting 4 trials in the US in children and adults with hematologic disorders.

The BPX-501 registration trial in Europe is not affected by the clinical hold.

BPX-501 is designed to fight infection, support engraftment, prevent disease relapse, and potentially stop graft-versus-host disease (GVHD) should it occur.

BPX-501 contains a safety switch, CaspaCIDe®, that can be activated with the administration of rimiducid to kill the toxic T cells in the event of GVHD.

The 3 cases of encephalopathy are complex, according to a company press release, and have confounding factors. These include prior failed transplants, prior history of immunodeficiency, concurrent infection, and administration of rimiducid in combination with other medications.

Encephalopathy had not emerged as an adverse event in 240 patients treated with the cell therapy, until now.

BPX-501 had produced encouraging results, according to trial data presented at EHA 2017 and ASH 2017 (abstract 211*).

In this trial, 112 pediatric patients were transfused with BPX-501 cells about 2 weeks after transplant. Patients had acute leukemia (n=53), primary immune deficiencies (n=26), erythroid disorders (n=17), Fanconi anemia (n=7), and other diseases (n=9).

Investigators reported that infused cells expanded and persisted, with peak expansion reached at 9 months after infusion. Investigators continued to detect BPX-501 cells after 2 years.

The European Commission granted BPX-501 orphan drug designation for the agent for treatment in HSCT, and for the activator agent rimiducid for the treatment of GVHD.

And the FDA had granted the agents orphan drug status as a combination replacement T-cell therapy for the treatment of immunodeficiency and GVHD after HSCT.

Bellicum says it is working with the FDA to evaluate the risk of encephalopathy in patients receiving BPX-501.

* Data in the abstract were updated in the oral presentation and reported on the company’s website.

Image from NIAID

The US Food and Drug Administration (FDA) has placed BPX-501, a T-cell therapy being evaluated in patients who undergo haploidentical hematopoietic stem cell transplants (HSCTs), on clinical hold.

Three cases of encephalopathy possibly related to BPX-501 prompted the agency to impose the hold.

Bellicum Pharmaceuticals is the developer of BPX-501, and the company was conducting 4 trials in the US in children and adults with hematologic disorders.

The BPX-501 registration trial in Europe is not affected by the clinical hold.

BPX-501 is designed to fight infection, support engraftment, prevent disease relapse, and potentially stop graft-versus-host disease (GVHD) should it occur.

BPX-501 contains a safety switch, CaspaCIDe®, that can be activated with the administration of rimiducid to kill the toxic T cells in the event of GVHD.

The 3 cases of encephalopathy are complex, according to a company press release, and have confounding factors. These include prior failed transplants, prior history of immunodeficiency, concurrent infection, and administration of rimiducid in combination with other medications.

Encephalopathy had not emerged as an adverse event in 240 patients treated with the cell therapy, until now.

BPX-501 had produced encouraging results, according to trial data presented at EHA 2017 and ASH 2017 (abstract 211*).

In this trial, 112 pediatric patients were transfused with BPX-501 cells about 2 weeks after transplant. Patients had acute leukemia (n=53), primary immune deficiencies (n=26), erythroid disorders (n=17), Fanconi anemia (n=7), and other diseases (n=9).

Investigators reported that infused cells expanded and persisted, with peak expansion reached at 9 months after infusion. Investigators continued to detect BPX-501 cells after 2 years.

The European Commission granted BPX-501 orphan drug designation for the agent for treatment in HSCT, and for the activator agent rimiducid for the treatment of GVHD.

And the FDA had granted the agents orphan drug status as a combination replacement T-cell therapy for the treatment of immunodeficiency and GVHD after HSCT.

Bellicum says it is working with the FDA to evaluate the risk of encephalopathy in patients receiving BPX-501.

* Data in the abstract were updated in the oral presentation and reported on the company’s website.

A 49-year-old Hispanic woman presented with a 4-month history of scaling and a macerated rash localized between her toes (FIGURE 1). The rash was malodorous, mildly erythematous, and sometimes associated with pruritus. The patient had no relevant medical history. Potassium hydroxide (KOH) testing was performed and found to be negative. So a Wood’s lamp was used to examine the patient’s toes—and it revealed the diagnosis.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Erythrasma

The Wood’s lamp revealed a coral-red fluorescence in the interdigital spaces (FIGURE 2), which led us to a diagnosis of erythrasma.

The coral-red fluorescence seen under the Wood’s lamp is due to porphyrins produced by Corynebacterium minutissimum. The organism invades the stratum corneum where it proliferates and causes erythrasma. Erythrasma typically appears as delineated, dry, red-brown patches in intertriginous areas, such as the axilla, groin, interdigital spaces, intergluteal cleft, perianal skin, and inframammary area.^1,2

Interdigital erythrasma is more common than previously thought; in one study of 151 patients with erythrasma, the most common site was the toe webs (64.9%), followed by the inguinal region (17.9%), the axillary region (14.6%), and the inframammary region (2.6%).² Erythrasma affects 4% of the population; risk factors include poor hygiene, hyperhidrosis, obesity, warm climate, diabetes, and an immunocompromised state.³

Differential includes “athlete’s foot”

The differential diagnosis for a pruritic rash between the toes includes:

Tinea pedis. Erythrasma is often mistaken for tinea pedis, because both conditions cause scaling between the toes. A Wood’s lamp exam can quickly differentiate between the 2,¹ as tinea pedis does not fluoresce under ultraviolet light.

Contact dermatitis mimics many conditions, but a negative Wood’s lamp exam and history of worsening with contact to specific substances helps to make this diagnosis.

Prevention and Tx hinge on good hygiene, topical agents

First-line management of erythrasma includes both nonpharmacologic and pharmacologic modalities. Good hygiene and, depending on the area affected, loose-fitting cotton undergarments can help treat and prevent erythrasma.

Topical 2% miconazole bid for 2 weeks has resulted in clearance rates as high as 88%.⁴ Its affordable price, over-the-counter availability, and lack of adverse effects make miconazole a reasonable choice.^4,5 It is also a smart treatment choice when erythrasma is coexisting with tinea, because it can treat both conditions. This is not uncommon in the interdigital spaces between the toes and in the groin.

Topical 1% clindamycin or 2% erythromycin solution or gel bid for 2 weeks can also be used to treat the condition.^3,6 However, given that topical antibiotics are more expensive than single-dose oral treatment and are no better than the oral formulations of these antibiotics,⁶ clarithromycin 1 g taken once orally may be preferred.^2,6

Our patient was treated with a single dose of clarithromycin 1 g. At follow-up, her erythrasma was clear.

CORRESPONDENCE
Richard P. Usatine, MD, University of Texas Health at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229; [email protected].

A 49-year-old Hispanic woman presented with a 4-month history of scaling and a macerated rash localized between her toes (FIGURE 1). The rash was malodorous, mildly erythematous, and sometimes associated with pruritus. The patient had no relevant medical history. Potassium hydroxide (KOH) testing was performed and found to be negative. So a Wood’s lamp was used to examine the patient’s toes—and it revealed the diagnosis.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Erythrasma

The Wood’s lamp revealed a coral-red fluorescence in the interdigital spaces (FIGURE 2), which led us to a diagnosis of erythrasma.

The coral-red fluorescence seen under the Wood’s lamp is due to porphyrins produced by Corynebacterium minutissimum. The organism invades the stratum corneum where it proliferates and causes erythrasma. Erythrasma typically appears as delineated, dry, red-brown patches in intertriginous areas, such as the axilla, groin, interdigital spaces, intergluteal cleft, perianal skin, and inframammary area.^1,2

Interdigital erythrasma is more common than previously thought; in one study of 151 patients with erythrasma, the most common site was the toe webs (64.9%), followed by the inguinal region (17.9%), the axillary region (14.6%), and the inframammary region (2.6%).² Erythrasma affects 4% of the population; risk factors include poor hygiene, hyperhidrosis, obesity, warm climate, diabetes, and an immunocompromised state.³

Differential includes “athlete’s foot”

The differential diagnosis for a pruritic rash between the toes includes:

Tinea pedis. Erythrasma is often mistaken for tinea pedis, because both conditions cause scaling between the toes. A Wood’s lamp exam can quickly differentiate between the 2,¹ as tinea pedis does not fluoresce under ultraviolet light.

Contact dermatitis mimics many conditions, but a negative Wood’s lamp exam and history of worsening with contact to specific substances helps to make this diagnosis.

Prevention and Tx hinge on good hygiene, topical agents

First-line management of erythrasma includes both nonpharmacologic and pharmacologic modalities. Good hygiene and, depending on the area affected, loose-fitting cotton undergarments can help treat and prevent erythrasma.

Topical 2% miconazole bid for 2 weeks has resulted in clearance rates as high as 88%.⁴ Its affordable price, over-the-counter availability, and lack of adverse effects make miconazole a reasonable choice.^4,5 It is also a smart treatment choice when erythrasma is coexisting with tinea, because it can treat both conditions. This is not uncommon in the interdigital spaces between the toes and in the groin.

Topical 1% clindamycin or 2% erythromycin solution or gel bid for 2 weeks can also be used to treat the condition.^3,6 However, given that topical antibiotics are more expensive than single-dose oral treatment and are no better than the oral formulations of these antibiotics,⁶ clarithromycin 1 g taken once orally may be preferred.^2,6

Our patient was treated with a single dose of clarithromycin 1 g. At follow-up, her erythrasma was clear.

CORRESPONDENCE
Richard P. Usatine, MD, University of Texas Health at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229; [email protected].

A 49-year-old Hispanic woman presented with a 4-month history of scaling and a macerated rash localized between her toes (FIGURE 1). The rash was malodorous, mildly erythematous, and sometimes associated with pruritus. The patient had no relevant medical history. Potassium hydroxide (KOH) testing was performed and found to be negative. So a Wood’s lamp was used to examine the patient’s toes—and it revealed the diagnosis.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Erythrasma

The Wood’s lamp revealed a coral-red fluorescence in the interdigital spaces (FIGURE 2), which led us to a diagnosis of erythrasma.

The coral-red fluorescence seen under the Wood’s lamp is due to porphyrins produced by Corynebacterium minutissimum. The organism invades the stratum corneum where it proliferates and causes erythrasma. Erythrasma typically appears as delineated, dry, red-brown patches in intertriginous areas, such as the axilla, groin, interdigital spaces, intergluteal cleft, perianal skin, and inframammary area.^1,2

Interdigital erythrasma is more common than previously thought; in one study of 151 patients with erythrasma, the most common site was the toe webs (64.9%), followed by the inguinal region (17.9%), the axillary region (14.6%), and the inframammary region (2.6%).² Erythrasma affects 4% of the population; risk factors include poor hygiene, hyperhidrosis, obesity, warm climate, diabetes, and an immunocompromised state.³

Differential includes “athlete’s foot”

The differential diagnosis for a pruritic rash between the toes includes:

Tinea pedis. Erythrasma is often mistaken for tinea pedis, because both conditions cause scaling between the toes. A Wood’s lamp exam can quickly differentiate between the 2,¹ as tinea pedis does not fluoresce under ultraviolet light.

Contact dermatitis mimics many conditions, but a negative Wood’s lamp exam and history of worsening with contact to specific substances helps to make this diagnosis.

Prevention and Tx hinge on good hygiene, topical agents

First-line management of erythrasma includes both nonpharmacologic and pharmacologic modalities. Good hygiene and, depending on the area affected, loose-fitting cotton undergarments can help treat and prevent erythrasma.

Topical 2% miconazole bid for 2 weeks has resulted in clearance rates as high as 88%.⁴ Its affordable price, over-the-counter availability, and lack of adverse effects make miconazole a reasonable choice.^4,5 It is also a smart treatment choice when erythrasma is coexisting with tinea, because it can treat both conditions. This is not uncommon in the interdigital spaces between the toes and in the groin.

Topical 1% clindamycin or 2% erythromycin solution or gel bid for 2 weeks can also be used to treat the condition.^3,6 However, given that topical antibiotics are more expensive than single-dose oral treatment and are no better than the oral formulations of these antibiotics,⁶ clarithromycin 1 g taken once orally may be preferred.^2,6

Our patient was treated with a single dose of clarithromycin 1 g. At follow-up, her erythrasma was clear.

CORRESPONDENCE
Richard P. Usatine, MD, University of Texas Health at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229; [email protected].

THE CASE

A 25-year-old man, who was an active duty US Navy sailor, went to his ship’s medical department complaining of a mild cough that he’d had for 2 days. He denied having any fevers, chills, night sweats, angina, or dyspnea. He said he hadn’t experienced any exertional fatigue or difficulty completing the rigorous physical tasks of his occupation as an engineman on the ship. The patient had no medical or surgical history of significance, and he wasn’t taking any medications or supplements.

On exam, he was not in acute distress and his vital signs were within normal limits. Auscultation revealed mild wheezing throughout the upper lung fields and loud heart sounds throughout his chest that were audible even with gentle contact of the stethoscope diaphragm. He had no discernible murmurs, rubs, or gallops.

In light of the unusually loud heart sounds heard on exam, we performed an electrocardiogram. The EKG revealed a normal sinus rhythm, slight right axis deviation indicated by tall R-waves in V1 (also suggestive of right ventricular hypertrophy), an incomplete right bundle branch block, and a crochetage sign (a notch in the R-waves of the inferior leads).¹ A chest x-ray (FIGURE 1) revealed a normal-sized heart and dilated pulmonary vasculature suggestive of pulmonary hypertension.

THE DIAGNOSIS

To further evaluate the cardiopulmonary findings, ultrasound studies (transthoracic and transesophageal echocardiography) were performed. These demonstrated a very large secundum-type atrial septal defect (ASD), measuring at its largest point about 30 × 48 mm (FIGURE 2 and FIGURE 3C). Doppler flow analysis and a bubble study (VIDEOS 1 and 2) demonstrated significant shunting across the ASD. Gated cardiac computed tomography (CT) was also used to characterize the ASD (FIGURE 3). It revealed that the superior and posterior rims of the ASD were essentially absent and that the right atrium and ventricle were severely enlarged, while the left chambers were normal in size and function with an ejection fraction >55%. The notching of the R-waves of the inferior leads, seen in our patient’s EKG, is typically seen with large ASDs.^1,2

DISCUSSION

ASDs are typically uncovered on exam via auscultation of heart sounds, which might reveal a split of the second heart sound (S2) and diastolic murmurs. ASDs are typically classified by size, and their management depends on this factor, along with the patient’s age and symptoms. In children with small defects (<6 mm), treatment usually consists of conservative observation, as more than half of these ASDs will spontaneously close.³ But, as children age, they are more likely to engage in exertional activity (work, recreational sports) and an unrepaired ASD may yield symptoms (angina, dyspnea, fatigue, other cardiopulmonary strain). With such symptoms and when closure is not spontaneously achieved by adolescence or adulthood, an invasive approach is often necessary to correct the defect.

ASD repair. Traditionally, repair has involved some form of open thoracotomy. More recently, several minimally invasive techniques have been developed. Catheter-based device closure, in which a catheter is percutaneously guided to the defect and a patch is deployed to seal the ASD, is a technique that has been shown to successfully correct large ASDs of up to 40 mm in size.⁴ Robotic procedures have also been developed to correct ASDs through much smaller incisions.⁵ Both of these techniques require a significant rim of residual septal tissue around the defect.

Individualized approach. Since our patient had a rather large ASD that did not have sufficient residual septal rim tissue, percutaneous and robotic approaches were not feasible. Instead, he required more invasive cardiothoracic surgery. In cases such as this, the exact technique and type of incision (sternotomy vs access through the lateral chest wall) depend on age, gender, and the presence of other comorbidities.⁶

Our patient. Because there was concern that any approach other than a median one might not afford enough space to fix an ASD of such considerable size, our patient underwent a median sternotomy by a pediatric cardiothoracic surgeon who specialized in these repairs (in children as well as young adults). During the procedure, the ASD was accessed and confirmed to be as large as predicted by diagnostic imaging. A surgical patch was sutured in place to correct the defect. There were no intra-operative or postop complications.

Four weeks later, the patient had a mild pericardial effusion that was managed medically with daily furosemide and aspirin. At his 8-week postop appointment, the fluid accumulation had resolved, and he was completely asymptomatic. The patient returned to full-time active duty in the US Navy.

THE TAKEAWAY

Adults with rather large ASDs can present in a relatively asymptomatic manner and report none of the classic complaints (angina, dyspnea, fatigue). They may even engage in heavy exertional activity with no difficulty. The underlying defect may be discovered incidentally on exam by noting a split of the S2 on auscultation. If pulmonary hypertension exists, the clinician may also note a loud S2. An exam that raises suspicion for an ASD can then be followed by tests that solidify the diagnosis. Surgery is usually necessary to correct an ASD in an adult who is symptomatic or exhibits significant cardiopulmonary strain.

THE CASE

A 25-year-old man, who was an active duty US Navy sailor, went to his ship’s medical department complaining of a mild cough that he’d had for 2 days. He denied having any fevers, chills, night sweats, angina, or dyspnea. He said he hadn’t experienced any exertional fatigue or difficulty completing the rigorous physical tasks of his occupation as an engineman on the ship. The patient had no medical or surgical history of significance, and he wasn’t taking any medications or supplements.

On exam, he was not in acute distress and his vital signs were within normal limits. Auscultation revealed mild wheezing throughout the upper lung fields and loud heart sounds throughout his chest that were audible even with gentle contact of the stethoscope diaphragm. He had no discernible murmurs, rubs, or gallops.

In light of the unusually loud heart sounds heard on exam, we performed an electrocardiogram. The EKG revealed a normal sinus rhythm, slight right axis deviation indicated by tall R-waves in V1 (also suggestive of right ventricular hypertrophy), an incomplete right bundle branch block, and a crochetage sign (a notch in the R-waves of the inferior leads).¹ A chest x-ray (FIGURE 1) revealed a normal-sized heart and dilated pulmonary vasculature suggestive of pulmonary hypertension.

THE DIAGNOSIS

To further evaluate the cardiopulmonary findings, ultrasound studies (transthoracic and transesophageal echocardiography) were performed. These demonstrated a very large secundum-type atrial septal defect (ASD), measuring at its largest point about 30 × 48 mm (FIGURE 2 and FIGURE 3C). Doppler flow analysis and a bubble study (VIDEOS 1 and 2) demonstrated significant shunting across the ASD. Gated cardiac computed tomography (CT) was also used to characterize the ASD (FIGURE 3). It revealed that the superior and posterior rims of the ASD were essentially absent and that the right atrium and ventricle were severely enlarged, while the left chambers were normal in size and function with an ejection fraction >55%. The notching of the R-waves of the inferior leads, seen in our patient’s EKG, is typically seen with large ASDs.^1,2

DISCUSSION

ASDs are typically uncovered on exam via auscultation of heart sounds, which might reveal a split of the second heart sound (S2) and diastolic murmurs. ASDs are typically classified by size, and their management depends on this factor, along with the patient’s age and symptoms. In children with small defects (<6 mm), treatment usually consists of conservative observation, as more than half of these ASDs will spontaneously close.³ But, as children age, they are more likely to engage in exertional activity (work, recreational sports) and an unrepaired ASD may yield symptoms (angina, dyspnea, fatigue, other cardiopulmonary strain). With such symptoms and when closure is not spontaneously achieved by adolescence or adulthood, an invasive approach is often necessary to correct the defect.

ASD repair. Traditionally, repair has involved some form of open thoracotomy. More recently, several minimally invasive techniques have been developed. Catheter-based device closure, in which a catheter is percutaneously guided to the defect and a patch is deployed to seal the ASD, is a technique that has been shown to successfully correct large ASDs of up to 40 mm in size.⁴ Robotic procedures have also been developed to correct ASDs through much smaller incisions.⁵ Both of these techniques require a significant rim of residual septal tissue around the defect.

Individualized approach. Since our patient had a rather large ASD that did not have sufficient residual septal rim tissue, percutaneous and robotic approaches were not feasible. Instead, he required more invasive cardiothoracic surgery. In cases such as this, the exact technique and type of incision (sternotomy vs access through the lateral chest wall) depend on age, gender, and the presence of other comorbidities.⁶

Our patient. Because there was concern that any approach other than a median one might not afford enough space to fix an ASD of such considerable size, our patient underwent a median sternotomy by a pediatric cardiothoracic surgeon who specialized in these repairs (in children as well as young adults). During the procedure, the ASD was accessed and confirmed to be as large as predicted by diagnostic imaging. A surgical patch was sutured in place to correct the defect. There were no intra-operative or postop complications.

Four weeks later, the patient had a mild pericardial effusion that was managed medically with daily furosemide and aspirin. At his 8-week postop appointment, the fluid accumulation had resolved, and he was completely asymptomatic. The patient returned to full-time active duty in the US Navy.

THE TAKEAWAY

Adults with rather large ASDs can present in a relatively asymptomatic manner and report none of the classic complaints (angina, dyspnea, fatigue). They may even engage in heavy exertional activity with no difficulty. The underlying defect may be discovered incidentally on exam by noting a split of the S2 on auscultation. If pulmonary hypertension exists, the clinician may also note a loud S2. An exam that raises suspicion for an ASD can then be followed by tests that solidify the diagnosis. Surgery is usually necessary to correct an ASD in an adult who is symptomatic or exhibits significant cardiopulmonary strain.

THE CASE

A 25-year-old man, who was an active duty US Navy sailor, went to his ship’s medical department complaining of a mild cough that he’d had for 2 days. He denied having any fevers, chills, night sweats, angina, or dyspnea. He said he hadn’t experienced any exertional fatigue or difficulty completing the rigorous physical tasks of his occupation as an engineman on the ship. The patient had no medical or surgical history of significance, and he wasn’t taking any medications or supplements.

On exam, he was not in acute distress and his vital signs were within normal limits. Auscultation revealed mild wheezing throughout the upper lung fields and loud heart sounds throughout his chest that were audible even with gentle contact of the stethoscope diaphragm. He had no discernible murmurs, rubs, or gallops.

In light of the unusually loud heart sounds heard on exam, we performed an electrocardiogram. The EKG revealed a normal sinus rhythm, slight right axis deviation indicated by tall R-waves in V1 (also suggestive of right ventricular hypertrophy), an incomplete right bundle branch block, and a crochetage sign (a notch in the R-waves of the inferior leads).¹ A chest x-ray (FIGURE 1) revealed a normal-sized heart and dilated pulmonary vasculature suggestive of pulmonary hypertension.

THE DIAGNOSIS

To further evaluate the cardiopulmonary findings, ultrasound studies (transthoracic and transesophageal echocardiography) were performed. These demonstrated a very large secundum-type atrial septal defect (ASD), measuring at its largest point about 30 × 48 mm (FIGURE 2 and FIGURE 3C). Doppler flow analysis and a bubble study (VIDEOS 1 and 2) demonstrated significant shunting across the ASD. Gated cardiac computed tomography (CT) was also used to characterize the ASD (FIGURE 3). It revealed that the superior and posterior rims of the ASD were essentially absent and that the right atrium and ventricle were severely enlarged, while the left chambers were normal in size and function with an ejection fraction >55%. The notching of the R-waves of the inferior leads, seen in our patient’s EKG, is typically seen with large ASDs.^1,2

DISCUSSION

ASDs are typically uncovered on exam via auscultation of heart sounds, which might reveal a split of the second heart sound (S2) and diastolic murmurs. ASDs are typically classified by size, and their management depends on this factor, along with the patient’s age and symptoms. In children with small defects (<6 mm), treatment usually consists of conservative observation, as more than half of these ASDs will spontaneously close.³ But, as children age, they are more likely to engage in exertional activity (work, recreational sports) and an unrepaired ASD may yield symptoms (angina, dyspnea, fatigue, other cardiopulmonary strain). With such symptoms and when closure is not spontaneously achieved by adolescence or adulthood, an invasive approach is often necessary to correct the defect.

ASD repair. Traditionally, repair has involved some form of open thoracotomy. More recently, several minimally invasive techniques have been developed. Catheter-based device closure, in which a catheter is percutaneously guided to the defect and a patch is deployed to seal the ASD, is a technique that has been shown to successfully correct large ASDs of up to 40 mm in size.⁴ Robotic procedures have also been developed to correct ASDs through much smaller incisions.⁵ Both of these techniques require a significant rim of residual septal tissue around the defect.

Individualized approach. Since our patient had a rather large ASD that did not have sufficient residual septal rim tissue, percutaneous and robotic approaches were not feasible. Instead, he required more invasive cardiothoracic surgery. In cases such as this, the exact technique and type of incision (sternotomy vs access through the lateral chest wall) depend on age, gender, and the presence of other comorbidities.⁶

Our patient. Because there was concern that any approach other than a median one might not afford enough space to fix an ASD of such considerable size, our patient underwent a median sternotomy by a pediatric cardiothoracic surgeon who specialized in these repairs (in children as well as young adults). During the procedure, the ASD was accessed and confirmed to be as large as predicted by diagnostic imaging. A surgical patch was sutured in place to correct the defect. There were no intra-operative or postop complications.

Four weeks later, the patient had a mild pericardial effusion that was managed medically with daily furosemide and aspirin. At his 8-week postop appointment, the fluid accumulation had resolved, and he was completely asymptomatic. The patient returned to full-time active duty in the US Navy.

THE TAKEAWAY

Adults with rather large ASDs can present in a relatively asymptomatic manner and report none of the classic complaints (angina, dyspnea, fatigue). They may even engage in heavy exertional activity with no difficulty. The underlying defect may be discovered incidentally on exam by noting a split of the S2 on auscultation. If pulmonary hypertension exists, the clinician may also note a loud S2. An exam that raises suspicion for an ASD can then be followed by tests that solidify the diagnosis. Surgery is usually necessary to correct an ASD in an adult who is symptomatic or exhibits significant cardiopulmonary strain.

THE CASE

A 34-year-old woman was referred to the hepatology clinic for evaluation of an increased serum alkaline phosphatase (ALP) level. She was gravida 5 and in her 38th week of gestation. Her obstetric history was significant for 2 uncomplicated spontaneous term vaginal deliveries resulting in live births and 2 spontaneous abortions. The patient reported generalized pruritus for 2 months prior to the visit. She had no comorbidities and denied any other symptoms. She reported no family history of liver disease or complications during pregnancy in relatives. The patient did not smoke or drink, and had come to our hospital for her prenatal care visits.

The physical exam revealed normal vital signs, no jaundice, a gravid uterus, and acanthosis nigricans on the neck and axilla with scattered excoriations on the arms, legs, and abdomen. Her serum ALP level was 1093 U/L (normal: 50-136 U/L). Immediately before this pregnancy, her serum ALP had been normal at 95 U/L, but it had since been increasing with a peak value of 1134 U/L by 37 weeks’ gestation. Serum transaminase activities and albumin and bilirubin concentrations were normal, as was her prothrombin time. The rest of her lab tests were also normal, including her fasting serum bile acid concentration, which was 9 mcmol/L (normal: 4.5-19.2 mcmol/L).

THE DIAGNOSIS

Although cholestasis of pregnancy was considered, the patient’s markedly elevated serum ALP level suggested the presence of another cholestatic liver disease. Additional tests revealed an antimitochondrial antibody (AMA) titer of 1:320 (normal: <1:20) and immunoglobulin A, G, and M levels within normal limits. Accordingly, we diagnosed primary biliary cholangitis (PBC).

The patient delivered vaginally at another institution uneventfully and returned to the hepatology clinic 7 months postpartum. Repeat laboratory tests (TABLE) revealed increased AMA titer and immunoglobulin M levels from baseline (38 weeks’ gestation). The physical exam was notable for the absence of both jaundice and stigmata of chronic liver disease. A liver ultrasound was normal. The patient still reported pruritus, as well as a new symptom—fatigue. A liver biopsy was performed, and findings were consistent with PBC, stage 1 (FIGURE).

 

 

DISCUSSION

PBC, historically known as primary biliary cirrhosis, is a chronic, likely immune-mediated, cholestatic liver disease characterized by the progressive inflammatory destruction of intrahepatic bile ducts. The disease has a female to male predominance of 10:1, with age of diagnosis most often between 40 and 50 years, although about a quarter of female patients present during their reproductive years.^1,2

PBC in pregnant women

During pregnancy, the profound physiologic changes and adaptations in the endocrine, metabolic, and immune systems that are necessary for normal fetal development can affect the maternal hepatobiliary system. In patients with prior autoimmune liver disease, the liver is known to adapt itself to these physiologic changes by entering a state of immune tolerance. This is induced by relative hypercortisolism, a shift from predominantly cell-mediated immunity to humoral immunity, and inhibition of T-cell activation. These changes can result in remission of autoimmune disease activity during pregnancy and postpartum flaring when these protective mechanisms are lost (although neither remission nor postpartum flaring occurred in this patient’s case).^1-3

While a well-compensated state is associated with better fetal and maternal outcomes than a decompensated condition, cirrhosis is not a contraindication to pregnancy. Vaginal delivery is generally safe for patients with PBC, and studies have reported no childbirth complications or adverse maternal outcomes.^1,3,4

The approved treatment for PBC, ursodeoxycholic acid (UDCA), was classified as a category B agent according to the Food and Drug Administration’s now defunct classification system for drugs used during pregnancy and lactation. It’s considered to be the treatment of choice for intrahepatic cholestasis of pregnancy, but there are no recommendations for its use in pregnant patients with PBC. Several studies have observed no significant teratogenic effect in babies whose mothers were treated with UDCA for PBC during pregnancy.^1-4 Postpartum, 60% to 70% of PBC patients have been reported to exhibit biochemical disease activity,^1,3 and in one case, a liver transplant was required due to liver failure.⁵

Look for AMA, elevated ALP

The diagnosis of the disease in this case was made by the detection of AMA, which has a specificity of 98% for PBC. However, isolated instances of the presence of AMA are not uncommon; they have been documented in up to 64% of healthy individuals.⁶ In addition, while one would expect to see a 2- to 4-fold rise in ALP levels during pregnancy (due to placental isoenzyme production),^2,7 our patient’s serum ALP level was much higher, suggesting probable cholestatic liver disease such as PBC. The diagnosis in this case was confirmed by liver biopsy.

Our patient was started on UDCA 13 to 15 mg/kg/d. She remained clinically stable at subsequent follow-ups.

THE TAKEAWAY

Typically seen in middle-aged women, PBC can be detected by the presence of AMA and elevated ALP levels. Pregnant patients with chronic liver disease, including PBC, should be followed by a hepatologist and a high-risk obstetrician. They should be carefully monitored and frequently reassessed throughout the pregnancy, delivery, and postpartum period, even though studies have documented favorable outcomes for both mother and baby.^1,3,4

THE CASE

A 34-year-old woman was referred to the hepatology clinic for evaluation of an increased serum alkaline phosphatase (ALP) level. She was gravida 5 and in her 38th week of gestation. Her obstetric history was significant for 2 uncomplicated spontaneous term vaginal deliveries resulting in live births and 2 spontaneous abortions. The patient reported generalized pruritus for 2 months prior to the visit. She had no comorbidities and denied any other symptoms. She reported no family history of liver disease or complications during pregnancy in relatives. The patient did not smoke or drink, and had come to our hospital for her prenatal care visits.

The physical exam revealed normal vital signs, no jaundice, a gravid uterus, and acanthosis nigricans on the neck and axilla with scattered excoriations on the arms, legs, and abdomen. Her serum ALP level was 1093 U/L (normal: 50-136 U/L). Immediately before this pregnancy, her serum ALP had been normal at 95 U/L, but it had since been increasing with a peak value of 1134 U/L by 37 weeks’ gestation. Serum transaminase activities and albumin and bilirubin concentrations were normal, as was her prothrombin time. The rest of her lab tests were also normal, including her fasting serum bile acid concentration, which was 9 mcmol/L (normal: 4.5-19.2 mcmol/L).

THE DIAGNOSIS

Although cholestasis of pregnancy was considered, the patient’s markedly elevated serum ALP level suggested the presence of another cholestatic liver disease. Additional tests revealed an antimitochondrial antibody (AMA) titer of 1:320 (normal: <1:20) and immunoglobulin A, G, and M levels within normal limits. Accordingly, we diagnosed primary biliary cholangitis (PBC).

The patient delivered vaginally at another institution uneventfully and returned to the hepatology clinic 7 months postpartum. Repeat laboratory tests (TABLE) revealed increased AMA titer and immunoglobulin M levels from baseline (38 weeks’ gestation). The physical exam was notable for the absence of both jaundice and stigmata of chronic liver disease. A liver ultrasound was normal. The patient still reported pruritus, as well as a new symptom—fatigue. A liver biopsy was performed, and findings were consistent with PBC, stage 1 (FIGURE).

 

 

DISCUSSION

PBC, historically known as primary biliary cirrhosis, is a chronic, likely immune-mediated, cholestatic liver disease characterized by the progressive inflammatory destruction of intrahepatic bile ducts. The disease has a female to male predominance of 10:1, with age of diagnosis most often between 40 and 50 years, although about a quarter of female patients present during their reproductive years.^1,2

PBC in pregnant women

During pregnancy, the profound physiologic changes and adaptations in the endocrine, metabolic, and immune systems that are necessary for normal fetal development can affect the maternal hepatobiliary system. In patients with prior autoimmune liver disease, the liver is known to adapt itself to these physiologic changes by entering a state of immune tolerance. This is induced by relative hypercortisolism, a shift from predominantly cell-mediated immunity to humoral immunity, and inhibition of T-cell activation. These changes can result in remission of autoimmune disease activity during pregnancy and postpartum flaring when these protective mechanisms are lost (although neither remission nor postpartum flaring occurred in this patient’s case).^1-3

While a well-compensated state is associated with better fetal and maternal outcomes than a decompensated condition, cirrhosis is not a contraindication to pregnancy. Vaginal delivery is generally safe for patients with PBC, and studies have reported no childbirth complications or adverse maternal outcomes.^1,3,4

The approved treatment for PBC, ursodeoxycholic acid (UDCA), was classified as a category B agent according to the Food and Drug Administration’s now defunct classification system for drugs used during pregnancy and lactation. It’s considered to be the treatment of choice for intrahepatic cholestasis of pregnancy, but there are no recommendations for its use in pregnant patients with PBC. Several studies have observed no significant teratogenic effect in babies whose mothers were treated with UDCA for PBC during pregnancy.^1-4 Postpartum, 60% to 70% of PBC patients have been reported to exhibit biochemical disease activity,^1,3 and in one case, a liver transplant was required due to liver failure.⁵

Look for AMA, elevated ALP

The diagnosis of the disease in this case was made by the detection of AMA, which has a specificity of 98% for PBC. However, isolated instances of the presence of AMA are not uncommon; they have been documented in up to 64% of healthy individuals.⁶ In addition, while one would expect to see a 2- to 4-fold rise in ALP levels during pregnancy (due to placental isoenzyme production),^2,7 our patient’s serum ALP level was much higher, suggesting probable cholestatic liver disease such as PBC. The diagnosis in this case was confirmed by liver biopsy.

Our patient was started on UDCA 13 to 15 mg/kg/d. She remained clinically stable at subsequent follow-ups.

THE TAKEAWAY

Typically seen in middle-aged women, PBC can be detected by the presence of AMA and elevated ALP levels. Pregnant patients with chronic liver disease, including PBC, should be followed by a hepatologist and a high-risk obstetrician. They should be carefully monitored and frequently reassessed throughout the pregnancy, delivery, and postpartum period, even though studies have documented favorable outcomes for both mother and baby.^1,3,4

THE CASE

A 34-year-old woman was referred to the hepatology clinic for evaluation of an increased serum alkaline phosphatase (ALP) level. She was gravida 5 and in her 38th week of gestation. Her obstetric history was significant for 2 uncomplicated spontaneous term vaginal deliveries resulting in live births and 2 spontaneous abortions. The patient reported generalized pruritus for 2 months prior to the visit. She had no comorbidities and denied any other symptoms. She reported no family history of liver disease or complications during pregnancy in relatives. The patient did not smoke or drink, and had come to our hospital for her prenatal care visits.

The physical exam revealed normal vital signs, no jaundice, a gravid uterus, and acanthosis nigricans on the neck and axilla with scattered excoriations on the arms, legs, and abdomen. Her serum ALP level was 1093 U/L (normal: 50-136 U/L). Immediately before this pregnancy, her serum ALP had been normal at 95 U/L, but it had since been increasing with a peak value of 1134 U/L by 37 weeks’ gestation. Serum transaminase activities and albumin and bilirubin concentrations were normal, as was her prothrombin time. The rest of her lab tests were also normal, including her fasting serum bile acid concentration, which was 9 mcmol/L (normal: 4.5-19.2 mcmol/L).

THE DIAGNOSIS

Although cholestasis of pregnancy was considered, the patient’s markedly elevated serum ALP level suggested the presence of another cholestatic liver disease. Additional tests revealed an antimitochondrial antibody (AMA) titer of 1:320 (normal: <1:20) and immunoglobulin A, G, and M levels within normal limits. Accordingly, we diagnosed primary biliary cholangitis (PBC).

The patient delivered vaginally at another institution uneventfully and returned to the hepatology clinic 7 months postpartum. Repeat laboratory tests (TABLE) revealed increased AMA titer and immunoglobulin M levels from baseline (38 weeks’ gestation). The physical exam was notable for the absence of both jaundice and stigmata of chronic liver disease. A liver ultrasound was normal. The patient still reported pruritus, as well as a new symptom—fatigue. A liver biopsy was performed, and findings were consistent with PBC, stage 1 (FIGURE).

 

 

DISCUSSION

PBC, historically known as primary biliary cirrhosis, is a chronic, likely immune-mediated, cholestatic liver disease characterized by the progressive inflammatory destruction of intrahepatic bile ducts. The disease has a female to male predominance of 10:1, with age of diagnosis most often between 40 and 50 years, although about a quarter of female patients present during their reproductive years.^1,2

PBC in pregnant women

During pregnancy, the profound physiologic changes and adaptations in the endocrine, metabolic, and immune systems that are necessary for normal fetal development can affect the maternal hepatobiliary system. In patients with prior autoimmune liver disease, the liver is known to adapt itself to these physiologic changes by entering a state of immune tolerance. This is induced by relative hypercortisolism, a shift from predominantly cell-mediated immunity to humoral immunity, and inhibition of T-cell activation. These changes can result in remission of autoimmune disease activity during pregnancy and postpartum flaring when these protective mechanisms are lost (although neither remission nor postpartum flaring occurred in this patient’s case).^1-3

While a well-compensated state is associated with better fetal and maternal outcomes than a decompensated condition, cirrhosis is not a contraindication to pregnancy. Vaginal delivery is generally safe for patients with PBC, and studies have reported no childbirth complications or adverse maternal outcomes.^1,3,4

The approved treatment for PBC, ursodeoxycholic acid (UDCA), was classified as a category B agent according to the Food and Drug Administration’s now defunct classification system for drugs used during pregnancy and lactation. It’s considered to be the treatment of choice for intrahepatic cholestasis of pregnancy, but there are no recommendations for its use in pregnant patients with PBC. Several studies have observed no significant teratogenic effect in babies whose mothers were treated with UDCA for PBC during pregnancy.^1-4 Postpartum, 60% to 70% of PBC patients have been reported to exhibit biochemical disease activity,^1,3 and in one case, a liver transplant was required due to liver failure.⁵

Look for AMA, elevated ALP

The diagnosis of the disease in this case was made by the detection of AMA, which has a specificity of 98% for PBC. However, isolated instances of the presence of AMA are not uncommon; they have been documented in up to 64% of healthy individuals.⁶ In addition, while one would expect to see a 2- to 4-fold rise in ALP levels during pregnancy (due to placental isoenzyme production),^2,7 our patient’s serum ALP level was much higher, suggesting probable cholestatic liver disease such as PBC. The diagnosis in this case was confirmed by liver biopsy.

Our patient was started on UDCA 13 to 15 mg/kg/d. She remained clinically stable at subsequent follow-ups.

THE TAKEAWAY

Typically seen in middle-aged women, PBC can be detected by the presence of AMA and elevated ALP levels. Pregnant patients with chronic liver disease, including PBC, should be followed by a hepatologist and a high-risk obstetrician. They should be carefully monitored and frequently reassessed throughout the pregnancy, delivery, and postpartum period, even though studies have documented favorable outcomes for both mother and baby.^1,3,4

CASE 

A 68-year-old woman is admitted to the hospital from home with acute onset, unrelenting, upper abdominal pain radiating to the back and nausea/vomiting. Her medical history includes bile duct obstruction secondary to gall stones, which was managed in another facility 6 days earlier with endoscopic retrograde cholangiopancreatography and stenting. The patient has type 2 diabetes (managed with metformin and glargine insulin), hypertension (managed with lisinopril and hydrochlorothiazide), and cholesterolemia (managed with atorvastatin).

On admission, the patient's white blood cell count is 14.7 x 10³ cells/mm³, heart rate is 100 bpm, blood pressure is 90/68 mm Hg, and temperature is 101.5° F. Serum amylase and lipase are 3 and 2 times the upper limit of normal, respectively. A working diagnosis of acute pancreatitis with sepsis is made. Blood cultures are drawn. A computed tomography scan confirms acute pancreatitis. She receives one dose of meropenem, is started on intravenous fluids and morphine, and is transferred to the intensive care unit (ICU) for further management.

Her ICU course is complicated by worsening sepsis despite aggressive fluid resuscitation, nutrition, and broad-spectrum antibiotics. On post-admission Day 2, blood culture results reveal Escherichia coli that is resistant to gentamicin, amoxicillin/clavulanate, ceftriaxone, piperacillin/tazobactam, imipenem, trimethoprim/sulfamethoxazole, ciprofloxacin, and tetracycline. Additional susceptibility testing is ordered.

The Centers for Disease Control and Prevention (CDC) conservatively estimates that antibiotic-resistant bacteria are responsible for 2 billion infections annually, resulting in approximately 23,000 deaths and $20 billion in excess health care expenditures annually.¹ Infections caused by antibiotic-resistant bacteria typically require longer hospitalizations, more expensive drug therapies, and additional follow-up visits.¹ They also result in greater morbidity and mortality compared with similar infections involving non-resistant bacteria.¹ To compound the problem, antibiotic development has steadily declined over the last 3 decades, with few novel antimicrobials developed in recent years.² The most recently approved antibiotics with new mechanisms of action were linezolid in 2000 and daptomycin in 2003, preceded by the carbapenems 15 years earlier. (See “New antimicrobials in the pipeline.”)

Greater efforts aimed at using antimicrobials sparingly and appropriately, as well as developing new antimicrobials with activity against multidrug-resistant pathogens, are ultimately needed to address the threat of antimicrobial resistance. This article describes the evidence-based management of inpatient infections caused by resistant bacteria and the role family physicians (FPs) can play in reducing further development of resistance through antimicrobial stewardship practices.

 

 

Health care-associated methicillin-resistant Staphylococcus aureus

S. aureus is a common culprit of hospital-acquired infections, including central line-associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonia, and nosocomial skin and soft tissue infections. In fact, nearly half of all isolates from these infections are reported to be methicillin-resistant S. aureus (MRSA).³

Nearly half of all Staphylococcus aureus isolates from hospital-acquired infections are reported to be methicillin-resistant.

Patients at greatest risk for MRSA infections include those who have been recently hospitalized, those receiving recent antibiotic therapy or surgery, long-term care residents, intravenous drug abusers, immunocompromised patients, hemodialysis patients, military personnel, and athletes who play contact sports.^4,5 Patients with these infections often require the use of an anti-MRSA agent (eg, vancomycin, linezolid) in empiric antibiotic regimens.^6,7 The focus of this discussion is on MRSA in hospital and long-term care settings; a discussion of community-acquired MRSA is addressed elsewhere. (See “Antibiotic stewardship: The FP’s role,” J Fam Pract. 2016;65:876-885.⁸)

Efforts are working, but problems remain. MRSA accounts for almost 60% of S. aureus isolates in ICUs.⁹ Thankfully, rates of health care-associated MRSA are now either static or declining nationwide, as a result of major initiatives targeted toward preventing health care-associated infection in recent years.¹⁰

Methicillin resistance in S. aureus results from expression of PBP2a, an altered penicillin-binding protein with reduced binding affinity for beta-lactam antibiotics. As a result, MRSA isolates are resistant to most beta-lactams.⁹ Resistance to macrolides, azithromycin, aminoglycosides, fluoroquinolones, and clindamycin is also common in health care-associated MRSA.⁹

The first case of true vancomycin-resistant S. aureus (VRSA) in the United States was reported in 2002.¹¹ Fortunately, both VRSA and vancomycin-intermediate S. aureus (VISA) have remained rare throughout the United States and abroad.^9,11 Heterogeneous VISA (hVISA), which is characterized by a few resistant subpopulations within a fully susceptible population of S. aureus, is more common than VRSA or VISA. Unfortunately, hVISA is difficult to detect using commercially available susceptibility tests. This can result in treatment failure with vancomycin, even though the MRSA isolate may appear fully susceptible and the patient has received clinically appropriate doses of the drug.¹²

Treatment. Vancomycin is the mainstay of therapy for many systemic health care-associated MRSA infections. Alternative therapies (daptomycin or linezolid) should be considered for isolates with a vancomycin minimum inhibitory concentration (MIC) >2 mcg/mL or in the setting of a poor clinical response.⁴ Combination therapy may be warranted in the setting of treatment failure. Because comparative efficacy data for alternative therapies is lacking, agent selection should be tailored to the site of infection and patient-specific factors such as allergies, drug interactions, and the risk for adverse events (TABLE 1^13-17).

Oritavancin and dalbavancin both have dosing regimens that may allow for earlier hospital discharge or treatment in an outpatient setting.^13,14 Telavancin, quinupristin/dalfopristin, and tigecycline are typically reserved for salvage therapy due to adverse event profiles and/or limited efficacy data.¹⁵

Vancomycin-resistant enterococci (VRE)

Enterococci are typically considered normal gastrointestinal tract flora. However, antibiotic exposure can alter gut flora allowing for VRE colonization, which in some instances, can progress to the development of a health care-associated infection.¹⁵ Therefore, it is important to distinguish whether a patient is colonized or infected with VRE because treatment of colonization is unnecessary and may lead to resistance and other adverse effects.¹⁵

It's important to distinguish whether a patient is colonized or infected with vancomycin-resistant enterococci to avoid unnecessary treatment.

Enterococci may be the culprit in nosocomially-acquired intra-abdominal infections, bacteremia, endocarditis, urinary tract infections (UTIs), and skin and skin structure infections, and can exhibit resistance to ampicillin, aminoglycosides, and vancomycin.¹⁵ VRE is predominantly a health care-associated pathogen and may account for up to 77% of all health care-associated Enterococcus faecium infections and 9% of Enterococcus faecalis infections.¹

Treatment. Antibiotic selection for VRE infections depends upon the site of infection, patient comorbidities, the potential for drug interactions, and treatment duration. Current treatment options include linezolid, daptomycin, quinupristin/dalfopristin (for E. faecium only), tigecycline, and ampicillin if the organism is susceptible (TABLE 1^13-17).¹⁵ For cystitis caused by VRE (not urinary colonization), fosfomycin and nitrofurantoin are additional options.¹⁶

Resistant Enterobacteriaceae

Resistant Enterobacteriaceae such as Escherichia coli and Klebsiella pneumoniae have emerged as a result of increased broad-spectrum antibiotic utilization and have been implicated in health care-associated UTIs, intra-abdominal infections, bacteremia, and even pneumonia.¹ Patients with prolonged hospital stays and invasive medical devices, such as urinary and vascular catheters, endotracheal tubes, and endoscopy scopes, have the highest risk for infection with these organisms.²⁰

The genotypic profiles of resistance among the Enterobacteriaceae are diverse and complex, resulting in different levels of activity for the various beta-lactam agents (TABLE 2^21-24).²⁵ Furthermore, extended-spectrum beta-lactamase (ESBL)-producers and carbapenem-resistant Enterobacteriaceae (CRE) are often resistant to other classes of antibiotics, too, including aminoglycosides and fluoroquinolones.^20,25 The increasing diversity among beta-lactamase enzymes has made the selection of appropriate antibiotic therapy challenging, since the ability to identify specific beta-lactamase genes is not yet available in the clinical setting.

Cefepime may retain activity against some ESBL-producing isolates, but it is also susceptible to the inoculum effect and should only be used for non–life-threatening infections and at higher doses.²³ Fosfomycin has activity against ESBL-producing bacteria, but is only approved for oral use in UTIs in the United States.^20,27 Ceftolozane/tazobactam (Zerbaxa) and ceftazidime/avibactam (Avycaz) were approved in 2014 and 2015, respectively, by the FDA for the management of complicated urinary tract and intra-abdominal infections caused by susceptible ESBL-producing Enterobacteriaceae. In order to preserve the antimicrobial efficacy of these 2 newer agents, however, they are typically reserved for definitive therapy when in vitro susceptibility is demonstrated and there are no other viable options.

AmpC beta-lactamases are resistant to similar agents as the ESBLs, in addition to cefoxitin and the beta-lactam/beta-lactamase inhibitor combinations containing clavulanic acid, sulbactam, and in some cases, tazobactam. Resistance can be induced and emerges in certain pathogens while patients are on therapy.²⁸ Fluoroquinolones and aminoglycosides have a low risk of developing resistance while patients are on therapy, but are more likely to cause adverse effects and toxicity compared with the beta-lactams.²⁸ Carbapenems have the lowest risk of emerging resistance and are the empiric treatment of choice for known AmpC-producing Enterobacteriaceae in serious infections.^20,28 Cefepime may also be an option in less severe infections, such as UTIs or those in which adequate source control has been achieved.^28,29

Carbapenem-resistant Enterobacteriaceae (CRE) have become a serious threat as a result of increased carbapenem use. While carbapenem resistance is less common in the United States than worldwide, rates have increased nearly 4-fold (1.2% to 4.2%) in the last decade, with some regions of the country experiencing substantially higher rates.²⁴ The most commonly reported CRE genotypes identified in the United States include the serine carbapenemase (K. pneumoniae carbapenemase, or KPC), and the metallo-beta-lactamases (Verona integrin-encoded metallo-beta-lactamase, or VIM, and the New Dehli metallo-beta-lactamase, or NDM), with each class conferring slightly different resistance patterns (TABLE 2^21-24).^20,30

Few treatment options exist for Enterobacteriaceae producing a serine carbapenemase, and, unfortunately, evidence to support these therapies is extremely limited. Some CRE isolates retain susceptibility to the polymyxins, the aminoglycosides, and tigecycline.³⁰ Even fewer options exist for treating Enterobacteriaceae producing metallo-beta-lactamases, which are typically only susceptible to the polymyxins and tigecycline.^43-45

The increasing diversity among beta-lactamase enzymes has made the selection of appropriate antibiotics more challenging in recent years.

Several studies have demonstrated lower mortality rates when combination therapy is utilized for CRE bloodstream infections.^31,32 Furthermore, the combination of colistin, tigecycline, and meropenem was found to have a significant mortality advantage.³² Double carbapenem therapy has been effective in several cases of invasive KPC-producing K. pneumoniae infections.^33,34 However, it is important to note that current clinical evidence comes from small, single-center, retrospective studies, and additional research is needed to determine optimal combinations and dosing strategies for these infections.

Lastly, ceftazidime/avibactam (Avycaz) was recently approved for the treatment of complicated urinary tract and intra-abdominal infections, and has activity against KPC-producing Enterobacteriaceae, but not those producing metallo-beta-lactamases, like VIM or NDM. In the absence of strong evidence to support one therapy over another, it may be reasonable to select at least 2 active agents when treating serious CRE infections. Agent selection should be based on the site of the infection, susceptibility data, and patient-specific factors (TABLE 3^{20,22,,23,25,27-42}). The CDC also recommends contact precautions for patients who are colonized or infected with CRE.³⁵

Multi-drug resistant Pseudomonas aeruginosa

Pseudomonas aeruginosa is a gram-negative rod that can be isolated from nosocomial infections such as UTIs, bacteremias, pneumonias, skin and skin structure infections, and burn infections.²⁰ Pseudomonal infections are associated with high morbidity and mortality and can cause recurrent infections in patients with cystic fibrosis.²⁰ Multidrug-resistant P. aeruginosa (MDR-P) infections account for approximately 13% of all health care-associated pseudomonal infections nationally.¹ Both fluoroquinolone and aminoglycoside resistance has emerged, and multiple types of beta-lactamases (ESBL, AmpC, carbapenemases) have resulted in organisms that are resistant to nearly all anti-pseudomonal beta-lactams.²⁰

Treatment. For patients at risk for MDR-P, some clinical practice guidelines have recommended using an empiric therapy regimen that contains antimicrobial agents from 2 different classes with activity against P. aeruginosa to increase the likelihood of susceptibility to at least one agent.⁶ De-escalation can occur once culture and susceptibility results are available.⁶ Dose optimization based on pharmacodynamic principles is critical for ensuring clinical efficacy and minimizing resistance.³⁶ The use of high-dose, prolonged-infusion beta-lactams (piperacillin/tazobactam, cefepime, ceftazidime, and carbapenems) is becoming common practice at institutions with higher rates of resistance.^36-38

A resurgence of polymyxin (colistin) use for MDR-P isolates has occurred, and may be warranted empirically in select patients, based on local resistance patterns and patient history. Newer pharmacokinetic data are available, resulting in improved dosing strategies that may enhance efficacy while alleviating some of the nephrotoxicity concerns associated with colistin therapy.³⁹

Ceftolozane/tazobactam (Zerbaxa) and ceftazidime/avibactam (Avycaz) are options for complicated urinary tract and intra-abdominal infections caused by susceptible P. aeruginosa isolates. Given the lack of comparative efficacy data available for the management of MDR-P infections, agent selection should be based on site of infection, susceptibility data, and patient-specific factors.

Multi-drug resistant Acinetobacter baumannii

A. baumannii is a lactose-fermenting, gram-negative rod sometimes implicated in nosocomial pneumonias, line-related bloodstream infections, UTIs, and surgical site infections.²⁰ Resistance has been documented for nearly all classes of antibiotics, including carbapenems.^1,20 Over half of all health care-associated A. baumannii isolates in the United States are multidrug resistant.¹

Treatment. Therapy options for A. baumannii infections are often limited to polymyxins, tigecycline, carbapenems (except ertapenem), aminoglycosides, and high-dose ampicillin/sulbactam, depending on in vitro susceptibilities.^40,41 When using ampicillin/sulbactam for A. baumannii infections, sulbactam is the active ingredient. Doses of 2 to 4 g/d of sulbactam have demonstrated efficacy in non-critically ill patients, while critically ill patients may require higher doses (up to 12 g/d).⁴⁰ Colistin is considered the mainstay of therapy for carbapenem-resistant A. baumannii. It should be used in combination with either a carbapenem, rifampin, an aminoglycoside, or tigecycline.⁴²

Drug therapies for nosocomial-resistant gram-negative infections, along with clinical pearls for use, are summarized in TABLE 3.^{20,22,23,25,27-42} Because efficacy data are limited for treating infections caused by these pathogens, appropriate antimicrobial selection is frequently guided by location of infection, susceptibility patterns, and patient-specific factors such as allergies and the risk for adverse effects.

Antimicrobial stewardship

Antibiotic misuse has been a significant driver of antibiotic resistance.⁴⁶ Efforts to improve and measure the appropriate use of antibiotics have historically focused on acute care settings. Broad interventions to reduce antibiotic use include prospective audit with intervention and feedback, formulary restriction and preauthorization, and antibiotic time-outs.^47,48

Multidrug-resistant Pseudomonas aeruginosa infections account for approximately 13% of all health care-associated pseudomonal infections nationally.

Pharmacy-driven interventions include intravenous-to-oral conversions, dose adjustments for organ dysfunction, pharmacokinetic or pharmacodynamic interventions to optimize treatment for organisms with reduced susceptibility, therapeutic duplication alerts, and automatic-stop orders.^47,48

Diagnosis-specific interventions include order sets for common infections and the use of rapid diagnostic assays (TABLE 4^49,50). Rapid diagnostic testing is increasingly being considered an essential component of stewardship programs because it permits significantly shortened time to organism identification and susceptibility testing and allows for improved antibiotic utilization and patient outcomes when coupled with other effective stewardship strategies.⁴⁹

The core elements. The CDC has defined the core elements of successful inpatient ASPs.⁴⁶ These include:

• commitment from hospital leadership
• a physician leader who is responsible for overall program outcomes
• a pharmacist leader who co-leads the program and is accountable for enterprise-wide improvements in antibiotic use
• implementation of at least one systemic intervention (broad, pharmacy-driven, or infection/syndrome-specific)
• monitoring of prescribing and resistance patterns
• reporting antibiotic use and resistance patterns to all involved in the medication use process
• Education directed at the health care team about optimal antibiotic use.

Above all, success with antibiotic stewardship is dependent on identified leadership and an enterprise-wide multidisciplinary approach.

The FP’s role in hospital ASPs can take a number of forms. FPs who practice inpatient medicine should work with all members of their department and be supportive of efforts to improve antibiotic use. Prescribers should help develop and implement hospital-specific treatment recommendations, as well as be responsive to measurements and audits aimed at determining the quantity and quality of antibiotic use. Hospital-specific updates on antibiotic prescribing and antibiotic resistance should be shared widely through formal and informal settings. FPs should know if patients with resistant organisms are hospitalized at institutions where they practice, and should remain abreast of infection rates and resistance patterns.

Over half of all health care-associated Acinetobacter baumannii isolates in the United States are multidrug resistant.

When admitting a patient, the FP should ask if the patient has received medical care elsewhere, including in another country. When caring for patients known to be currently or previously colonized or infected with resistant organisms, the FP should follow the appropriate precautions and insist that all members of the health care team follow suit.

CASE

A diagnosis of carbapenem-resistant E.coli sepsis is eventually made. Additional susceptibility test results reported later the same day revealed sensitivity to tigecycline and colistin, with intermediate sensitivity to doripenem. An infectious disease expert recommended contact precautions and combination treatment with tigecycline and doripenem for at least 7 days. The addition of a polymyxin was also considered; however, the patient’s renal function was not favorable enough to support a course of that agent. Longer duration of therapy may be required if adequate source control is not achieved.

After a complicated ICU stay, including the need for surgical wound drainage, the patient responded satisfactorily and was transferred to a medical step-down unit for continued recovery and eventual discharge.

CORRESPONDENCE
Dora E. Wiskirchen, PharmD, BCPS, Department of Pharmacy, St. Francis Hospital and Medical Center, 114 Woodland St., Hartford, CT 06105; Email: [email protected].

CASE 

A 68-year-old woman is admitted to the hospital from home with acute onset, unrelenting, upper abdominal pain radiating to the back and nausea/vomiting. Her medical history includes bile duct obstruction secondary to gall stones, which was managed in another facility 6 days earlier with endoscopic retrograde cholangiopancreatography and stenting. The patient has type 2 diabetes (managed with metformin and glargine insulin), hypertension (managed with lisinopril and hydrochlorothiazide), and cholesterolemia (managed with atorvastatin).

On admission, the patient's white blood cell count is 14.7 x 10³ cells/mm³, heart rate is 100 bpm, blood pressure is 90/68 mm Hg, and temperature is 101.5° F. Serum amylase and lipase are 3 and 2 times the upper limit of normal, respectively. A working diagnosis of acute pancreatitis with sepsis is made. Blood cultures are drawn. A computed tomography scan confirms acute pancreatitis. She receives one dose of meropenem, is started on intravenous fluids and morphine, and is transferred to the intensive care unit (ICU) for further management.

Her ICU course is complicated by worsening sepsis despite aggressive fluid resuscitation, nutrition, and broad-spectrum antibiotics. On post-admission Day 2, blood culture results reveal Escherichia coli that is resistant to gentamicin, amoxicillin/clavulanate, ceftriaxone, piperacillin/tazobactam, imipenem, trimethoprim/sulfamethoxazole, ciprofloxacin, and tetracycline. Additional susceptibility testing is ordered.

The Centers for Disease Control and Prevention (CDC) conservatively estimates that antibiotic-resistant bacteria are responsible for 2 billion infections annually, resulting in approximately 23,000 deaths and $20 billion in excess health care expenditures annually.¹ Infections caused by antibiotic-resistant bacteria typically require longer hospitalizations, more expensive drug therapies, and additional follow-up visits.¹ They also result in greater morbidity and mortality compared with similar infections involving non-resistant bacteria.¹ To compound the problem, antibiotic development has steadily declined over the last 3 decades, with few novel antimicrobials developed in recent years.² The most recently approved antibiotics with new mechanisms of action were linezolid in 2000 and daptomycin in 2003, preceded by the carbapenems 15 years earlier. (See “New antimicrobials in the pipeline.”)

Greater efforts aimed at using antimicrobials sparingly and appropriately, as well as developing new antimicrobials with activity against multidrug-resistant pathogens, are ultimately needed to address the threat of antimicrobial resistance. This article describes the evidence-based management of inpatient infections caused by resistant bacteria and the role family physicians (FPs) can play in reducing further development of resistance through antimicrobial stewardship practices.

 

 

Health care-associated methicillin-resistant Staphylococcus aureus

S. aureus is a common culprit of hospital-acquired infections, including central line-associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonia, and nosocomial skin and soft tissue infections. In fact, nearly half of all isolates from these infections are reported to be methicillin-resistant S. aureus (MRSA).³

Nearly half of all Staphylococcus aureus isolates from hospital-acquired infections are reported to be methicillin-resistant.

Patients at greatest risk for MRSA infections include those who have been recently hospitalized, those receiving recent antibiotic therapy or surgery, long-term care residents, intravenous drug abusers, immunocompromised patients, hemodialysis patients, military personnel, and athletes who play contact sports.^4,5 Patients with these infections often require the use of an anti-MRSA agent (eg, vancomycin, linezolid) in empiric antibiotic regimens.^6,7 The focus of this discussion is on MRSA in hospital and long-term care settings; a discussion of community-acquired MRSA is addressed elsewhere. (See “Antibiotic stewardship: The FP’s role,” J Fam Pract. 2016;65:876-885.⁸)

Efforts are working, but problems remain. MRSA accounts for almost 60% of S. aureus isolates in ICUs.⁹ Thankfully, rates of health care-associated MRSA are now either static or declining nationwide, as a result of major initiatives targeted toward preventing health care-associated infection in recent years.¹⁰

Methicillin resistance in S. aureus results from expression of PBP2a, an altered penicillin-binding protein with reduced binding affinity for beta-lactam antibiotics. As a result, MRSA isolates are resistant to most beta-lactams.⁹ Resistance to macrolides, azithromycin, aminoglycosides, fluoroquinolones, and clindamycin is also common in health care-associated MRSA.⁹

The first case of true vancomycin-resistant S. aureus (VRSA) in the United States was reported in 2002.¹¹ Fortunately, both VRSA and vancomycin-intermediate S. aureus (VISA) have remained rare throughout the United States and abroad.^9,11 Heterogeneous VISA (hVISA), which is characterized by a few resistant subpopulations within a fully susceptible population of S. aureus, is more common than VRSA or VISA. Unfortunately, hVISA is difficult to detect using commercially available susceptibility tests. This can result in treatment failure with vancomycin, even though the MRSA isolate may appear fully susceptible and the patient has received clinically appropriate doses of the drug.¹²

Treatment. Vancomycin is the mainstay of therapy for many systemic health care-associated MRSA infections. Alternative therapies (daptomycin or linezolid) should be considered for isolates with a vancomycin minimum inhibitory concentration (MIC) >2 mcg/mL or in the setting of a poor clinical response.⁴ Combination therapy may be warranted in the setting of treatment failure. Because comparative efficacy data for alternative therapies is lacking, agent selection should be tailored to the site of infection and patient-specific factors such as allergies, drug interactions, and the risk for adverse events (TABLE 1^13-17).

Oritavancin and dalbavancin both have dosing regimens that may allow for earlier hospital discharge or treatment in an outpatient setting.^13,14 Telavancin, quinupristin/dalfopristin, and tigecycline are typically reserved for salvage therapy due to adverse event profiles and/or limited efficacy data.¹⁵

Vancomycin-resistant enterococci (VRE)

Enterococci are typically considered normal gastrointestinal tract flora. However, antibiotic exposure can alter gut flora allowing for VRE colonization, which in some instances, can progress to the development of a health care-associated infection.¹⁵ Therefore, it is important to distinguish whether a patient is colonized or infected with VRE because treatment of colonization is unnecessary and may lead to resistance and other adverse effects.¹⁵

It's important to distinguish whether a patient is colonized or infected with vancomycin-resistant enterococci to avoid unnecessary treatment.

Enterococci may be the culprit in nosocomially-acquired intra-abdominal infections, bacteremia, endocarditis, urinary tract infections (UTIs), and skin and skin structure infections, and can exhibit resistance to ampicillin, aminoglycosides, and vancomycin.¹⁵ VRE is predominantly a health care-associated pathogen and may account for up to 77% of all health care-associated Enterococcus faecium infections and 9% of Enterococcus faecalis infections.¹

Treatment. Antibiotic selection for VRE infections depends upon the site of infection, patient comorbidities, the potential for drug interactions, and treatment duration. Current treatment options include linezolid, daptomycin, quinupristin/dalfopristin (for E. faecium only), tigecycline, and ampicillin if the organism is susceptible (TABLE 1^13-17).¹⁵ For cystitis caused by VRE (not urinary colonization), fosfomycin and nitrofurantoin are additional options.¹⁶

Resistant Enterobacteriaceae

Resistant Enterobacteriaceae such as Escherichia coli and Klebsiella pneumoniae have emerged as a result of increased broad-spectrum antibiotic utilization and have been implicated in health care-associated UTIs, intra-abdominal infections, bacteremia, and even pneumonia.¹ Patients with prolonged hospital stays and invasive medical devices, such as urinary and vascular catheters, endotracheal tubes, and endoscopy scopes, have the highest risk for infection with these organisms.²⁰

The genotypic profiles of resistance among the Enterobacteriaceae are diverse and complex, resulting in different levels of activity for the various beta-lactam agents (TABLE 2^21-24).²⁵ Furthermore, extended-spectrum beta-lactamase (ESBL)-producers and carbapenem-resistant Enterobacteriaceae (CRE) are often resistant to other classes of antibiotics, too, including aminoglycosides and fluoroquinolones.^20,25 The increasing diversity among beta-lactamase enzymes has made the selection of appropriate antibiotic therapy challenging, since the ability to identify specific beta-lactamase genes is not yet available in the clinical setting.

Cefepime may retain activity against some ESBL-producing isolates, but it is also susceptible to the inoculum effect and should only be used for non–life-threatening infections and at higher doses.²³ Fosfomycin has activity against ESBL-producing bacteria, but is only approved for oral use in UTIs in the United States.^20,27 Ceftolozane/tazobactam (Zerbaxa) and ceftazidime/avibactam (Avycaz) were approved in 2014 and 2015, respectively, by the FDA for the management of complicated urinary tract and intra-abdominal infections caused by susceptible ESBL-producing Enterobacteriaceae. In order to preserve the antimicrobial efficacy of these 2 newer agents, however, they are typically reserved for definitive therapy when in vitro susceptibility is demonstrated and there are no other viable options.

AmpC beta-lactamases are resistant to similar agents as the ESBLs, in addition to cefoxitin and the beta-lactam/beta-lactamase inhibitor combinations containing clavulanic acid, sulbactam, and in some cases, tazobactam. Resistance can be induced and emerges in certain pathogens while patients are on therapy.²⁸ Fluoroquinolones and aminoglycosides have a low risk of developing resistance while patients are on therapy, but are more likely to cause adverse effects and toxicity compared with the beta-lactams.²⁸ Carbapenems have the lowest risk of emerging resistance and are the empiric treatment of choice for known AmpC-producing Enterobacteriaceae in serious infections.^20,28 Cefepime may also be an option in less severe infections, such as UTIs or those in which adequate source control has been achieved.^28,29

Carbapenem-resistant Enterobacteriaceae (CRE) have become a serious threat as a result of increased carbapenem use. While carbapenem resistance is less common in the United States than worldwide, rates have increased nearly 4-fold (1.2% to 4.2%) in the last decade, with some regions of the country experiencing substantially higher rates.²⁴ The most commonly reported CRE genotypes identified in the United States include the serine carbapenemase (K. pneumoniae carbapenemase, or KPC), and the metallo-beta-lactamases (Verona integrin-encoded metallo-beta-lactamase, or VIM, and the New Dehli metallo-beta-lactamase, or NDM), with each class conferring slightly different resistance patterns (TABLE 2^21-24).^20,30

Few treatment options exist for Enterobacteriaceae producing a serine carbapenemase, and, unfortunately, evidence to support these therapies is extremely limited. Some CRE isolates retain susceptibility to the polymyxins, the aminoglycosides, and tigecycline.³⁰ Even fewer options exist for treating Enterobacteriaceae producing metallo-beta-lactamases, which are typically only susceptible to the polymyxins and tigecycline.^43-45

The increasing diversity among beta-lactamase enzymes has made the selection of appropriate antibiotics more challenging in recent years.

Several studies have demonstrated lower mortality rates when combination therapy is utilized for CRE bloodstream infections.^31,32 Furthermore, the combination of colistin, tigecycline, and meropenem was found to have a significant mortality advantage.³² Double carbapenem therapy has been effective in several cases of invasive KPC-producing K. pneumoniae infections.^33,34 However, it is important to note that current clinical evidence comes from small, single-center, retrospective studies, and additional research is needed to determine optimal combinations and dosing strategies for these infections.

Lastly, ceftazidime/avibactam (Avycaz) was recently approved for the treatment of complicated urinary tract and intra-abdominal infections, and has activity against KPC-producing Enterobacteriaceae, but not those producing metallo-beta-lactamases, like VIM or NDM. In the absence of strong evidence to support one therapy over another, it may be reasonable to select at least 2 active agents when treating serious CRE infections. Agent selection should be based on the site of the infection, susceptibility data, and patient-specific factors (TABLE 3^{20,22,,23,25,27-42}). The CDC also recommends contact precautions for patients who are colonized or infected with CRE.³⁵

Multi-drug resistant Pseudomonas aeruginosa

Pseudomonas aeruginosa is a gram-negative rod that can be isolated from nosocomial infections such as UTIs, bacteremias, pneumonias, skin and skin structure infections, and burn infections.²⁰ Pseudomonal infections are associated with high morbidity and mortality and can cause recurrent infections in patients with cystic fibrosis.²⁰ Multidrug-resistant P. aeruginosa (MDR-P) infections account for approximately 13% of all health care-associated pseudomonal infections nationally.¹ Both fluoroquinolone and aminoglycoside resistance has emerged, and multiple types of beta-lactamases (ESBL, AmpC, carbapenemases) have resulted in organisms that are resistant to nearly all anti-pseudomonal beta-lactams.²⁰

Treatment. For patients at risk for MDR-P, some clinical practice guidelines have recommended using an empiric therapy regimen that contains antimicrobial agents from 2 different classes with activity against P. aeruginosa to increase the likelihood of susceptibility to at least one agent.⁶ De-escalation can occur once culture and susceptibility results are available.⁶ Dose optimization based on pharmacodynamic principles is critical for ensuring clinical efficacy and minimizing resistance.³⁶ The use of high-dose, prolonged-infusion beta-lactams (piperacillin/tazobactam, cefepime, ceftazidime, and carbapenems) is becoming common practice at institutions with higher rates of resistance.^36-38

A resurgence of polymyxin (colistin) use for MDR-P isolates has occurred, and may be warranted empirically in select patients, based on local resistance patterns and patient history. Newer pharmacokinetic data are available, resulting in improved dosing strategies that may enhance efficacy while alleviating some of the nephrotoxicity concerns associated with colistin therapy.³⁹

Ceftolozane/tazobactam (Zerbaxa) and ceftazidime/avibactam (Avycaz) are options for complicated urinary tract and intra-abdominal infections caused by susceptible P. aeruginosa isolates. Given the lack of comparative efficacy data available for the management of MDR-P infections, agent selection should be based on site of infection, susceptibility data, and patient-specific factors.

Multi-drug resistant Acinetobacter baumannii

A. baumannii is a lactose-fermenting, gram-negative rod sometimes implicated in nosocomial pneumonias, line-related bloodstream infections, UTIs, and surgical site infections.²⁰ Resistance has been documented for nearly all classes of antibiotics, including carbapenems.^1,20 Over half of all health care-associated A. baumannii isolates in the United States are multidrug resistant.¹

Treatment. Therapy options for A. baumannii infections are often limited to polymyxins, tigecycline, carbapenems (except ertapenem), aminoglycosides, and high-dose ampicillin/sulbactam, depending on in vitro susceptibilities.^40,41 When using ampicillin/sulbactam for A. baumannii infections, sulbactam is the active ingredient. Doses of 2 to 4 g/d of sulbactam have demonstrated efficacy in non-critically ill patients, while critically ill patients may require higher doses (up to 12 g/d).⁴⁰ Colistin is considered the mainstay of therapy for carbapenem-resistant A. baumannii. It should be used in combination with either a carbapenem, rifampin, an aminoglycoside, or tigecycline.⁴²

Drug therapies for nosocomial-resistant gram-negative infections, along with clinical pearls for use, are summarized in TABLE 3.^{20,22,23,25,27-42} Because efficacy data are limited for treating infections caused by these pathogens, appropriate antimicrobial selection is frequently guided by location of infection, susceptibility patterns, and patient-specific factors such as allergies and the risk for adverse effects.

Antimicrobial stewardship

Antibiotic misuse has been a significant driver of antibiotic resistance.⁴⁶ Efforts to improve and measure the appropriate use of antibiotics have historically focused on acute care settings. Broad interventions to reduce antibiotic use include prospective audit with intervention and feedback, formulary restriction and preauthorization, and antibiotic time-outs.^47,48

Multidrug-resistant Pseudomonas aeruginosa infections account for approximately 13% of all health care-associated pseudomonal infections nationally.

Pharmacy-driven interventions include intravenous-to-oral conversions, dose adjustments for organ dysfunction, pharmacokinetic or pharmacodynamic interventions to optimize treatment for organisms with reduced susceptibility, therapeutic duplication alerts, and automatic-stop orders.^47,48

Diagnosis-specific interventions include order sets for common infections and the use of rapid diagnostic assays (TABLE 4^49,50). Rapid diagnostic testing is increasingly being considered an essential component of stewardship programs because it permits significantly shortened time to organism identification and susceptibility testing and allows for improved antibiotic utilization and patient outcomes when coupled with other effective stewardship strategies.⁴⁹

The core elements. The CDC has defined the core elements of successful inpatient ASPs.⁴⁶ These include:

• commitment from hospital leadership
• a physician leader who is responsible for overall program outcomes
• a pharmacist leader who co-leads the program and is accountable for enterprise-wide improvements in antibiotic use
• implementation of at least one systemic intervention (broad, pharmacy-driven, or infection/syndrome-specific)
• monitoring of prescribing and resistance patterns
• reporting antibiotic use and resistance patterns to all involved in the medication use process
• Education directed at the health care team about optimal antibiotic use.

Above all, success with antibiotic stewardship is dependent on identified leadership and an enterprise-wide multidisciplinary approach.

The FP’s role in hospital ASPs can take a number of forms. FPs who practice inpatient medicine should work with all members of their department and be supportive of efforts to improve antibiotic use. Prescribers should help develop and implement hospital-specific treatment recommendations, as well as be responsive to measurements and audits aimed at determining the quantity and quality of antibiotic use. Hospital-specific updates on antibiotic prescribing and antibiotic resistance should be shared widely through formal and informal settings. FPs should know if patients with resistant organisms are hospitalized at institutions where they practice, and should remain abreast of infection rates and resistance patterns.

Over half of all health care-associated Acinetobacter baumannii isolates in the United States are multidrug resistant.

When admitting a patient, the FP should ask if the patient has received medical care elsewhere, including in another country. When caring for patients known to be currently or previously colonized or infected with resistant organisms, the FP should follow the appropriate precautions and insist that all members of the health care team follow suit.

CASE

A diagnosis of carbapenem-resistant E.coli sepsis is eventually made. Additional susceptibility test results reported later the same day revealed sensitivity to tigecycline and colistin, with intermediate sensitivity to doripenem. An infectious disease expert recommended contact precautions and combination treatment with tigecycline and doripenem for at least 7 days. The addition of a polymyxin was also considered; however, the patient’s renal function was not favorable enough to support a course of that agent. Longer duration of therapy may be required if adequate source control is not achieved.

After a complicated ICU stay, including the need for surgical wound drainage, the patient responded satisfactorily and was transferred to a medical step-down unit for continued recovery and eventual discharge.

CORRESPONDENCE
Dora E. Wiskirchen, PharmD, BCPS, Department of Pharmacy, St. Francis Hospital and Medical Center, 114 Woodland St., Hartford, CT 06105; Email: [email protected].

CASE 

A 68-year-old woman is admitted to the hospital from home with acute onset, unrelenting, upper abdominal pain radiating to the back and nausea/vomiting. Her medical history includes bile duct obstruction secondary to gall stones, which was managed in another facility 6 days earlier with endoscopic retrograde cholangiopancreatography and stenting. The patient has type 2 diabetes (managed with metformin and glargine insulin), hypertension (managed with lisinopril and hydrochlorothiazide), and cholesterolemia (managed with atorvastatin).

On admission, the patient's white blood cell count is 14.7 x 10³ cells/mm³, heart rate is 100 bpm, blood pressure is 90/68 mm Hg, and temperature is 101.5° F. Serum amylase and lipase are 3 and 2 times the upper limit of normal, respectively. A working diagnosis of acute pancreatitis with sepsis is made. Blood cultures are drawn. A computed tomography scan confirms acute pancreatitis. She receives one dose of meropenem, is started on intravenous fluids and morphine, and is transferred to the intensive care unit (ICU) for further management.

Her ICU course is complicated by worsening sepsis despite aggressive fluid resuscitation, nutrition, and broad-spectrum antibiotics. On post-admission Day 2, blood culture results reveal Escherichia coli that is resistant to gentamicin, amoxicillin/clavulanate, ceftriaxone, piperacillin/tazobactam, imipenem, trimethoprim/sulfamethoxazole, ciprofloxacin, and tetracycline. Additional susceptibility testing is ordered.

The Centers for Disease Control and Prevention (CDC) conservatively estimates that antibiotic-resistant bacteria are responsible for 2 billion infections annually, resulting in approximately 23,000 deaths and $20 billion in excess health care expenditures annually.¹ Infections caused by antibiotic-resistant bacteria typically require longer hospitalizations, more expensive drug therapies, and additional follow-up visits.¹ They also result in greater morbidity and mortality compared with similar infections involving non-resistant bacteria.¹ To compound the problem, antibiotic development has steadily declined over the last 3 decades, with few novel antimicrobials developed in recent years.² The most recently approved antibiotics with new mechanisms of action were linezolid in 2000 and daptomycin in 2003, preceded by the carbapenems 15 years earlier. (See “New antimicrobials in the pipeline.”)

Greater efforts aimed at using antimicrobials sparingly and appropriately, as well as developing new antimicrobials with activity against multidrug-resistant pathogens, are ultimately needed to address the threat of antimicrobial resistance. This article describes the evidence-based management of inpatient infections caused by resistant bacteria and the role family physicians (FPs) can play in reducing further development of resistance through antimicrobial stewardship practices.

 

 

Health care-associated methicillin-resistant Staphylococcus aureus

S. aureus is a common culprit of hospital-acquired infections, including central line-associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonia, and nosocomial skin and soft tissue infections. In fact, nearly half of all isolates from these infections are reported to be methicillin-resistant S. aureus (MRSA).³

Nearly half of all Staphylococcus aureus isolates from hospital-acquired infections are reported to be methicillin-resistant.

Patients at greatest risk for MRSA infections include those who have been recently hospitalized, those receiving recent antibiotic therapy or surgery, long-term care residents, intravenous drug abusers, immunocompromised patients, hemodialysis patients, military personnel, and athletes who play contact sports.^4,5 Patients with these infections often require the use of an anti-MRSA agent (eg, vancomycin, linezolid) in empiric antibiotic regimens.^6,7 The focus of this discussion is on MRSA in hospital and long-term care settings; a discussion of community-acquired MRSA is addressed elsewhere. (See “Antibiotic stewardship: The FP’s role,” J Fam Pract. 2016;65:876-885.⁸)

Efforts are working, but problems remain. MRSA accounts for almost 60% of S. aureus isolates in ICUs.⁹ Thankfully, rates of health care-associated MRSA are now either static or declining nationwide, as a result of major initiatives targeted toward preventing health care-associated infection in recent years.¹⁰

Methicillin resistance in S. aureus results from expression of PBP2a, an altered penicillin-binding protein with reduced binding affinity for beta-lactam antibiotics. As a result, MRSA isolates are resistant to most beta-lactams.⁹ Resistance to macrolides, azithromycin, aminoglycosides, fluoroquinolones, and clindamycin is also common in health care-associated MRSA.⁹

The first case of true vancomycin-resistant S. aureus (VRSA) in the United States was reported in 2002.¹¹ Fortunately, both VRSA and vancomycin-intermediate S. aureus (VISA) have remained rare throughout the United States and abroad.^9,11 Heterogeneous VISA (hVISA), which is characterized by a few resistant subpopulations within a fully susceptible population of S. aureus, is more common than VRSA or VISA. Unfortunately, hVISA is difficult to detect using commercially available susceptibility tests. This can result in treatment failure with vancomycin, even though the MRSA isolate may appear fully susceptible and the patient has received clinically appropriate doses of the drug.¹²

Treatment. Vancomycin is the mainstay of therapy for many systemic health care-associated MRSA infections. Alternative therapies (daptomycin or linezolid) should be considered for isolates with a vancomycin minimum inhibitory concentration (MIC) >2 mcg/mL or in the setting of a poor clinical response.⁴ Combination therapy may be warranted in the setting of treatment failure. Because comparative efficacy data for alternative therapies is lacking, agent selection should be tailored to the site of infection and patient-specific factors such as allergies, drug interactions, and the risk for adverse events (TABLE 1^13-17).

Oritavancin and dalbavancin both have dosing regimens that may allow for earlier hospital discharge or treatment in an outpatient setting.^13,14 Telavancin, quinupristin/dalfopristin, and tigecycline are typically reserved for salvage therapy due to adverse event profiles and/or limited efficacy data.¹⁵

Vancomycin-resistant enterococci (VRE)

Enterococci are typically considered normal gastrointestinal tract flora. However, antibiotic exposure can alter gut flora allowing for VRE colonization, which in some instances, can progress to the development of a health care-associated infection.¹⁵ Therefore, it is important to distinguish whether a patient is colonized or infected with VRE because treatment of colonization is unnecessary and may lead to resistance and other adverse effects.¹⁵

It's important to distinguish whether a patient is colonized or infected with vancomycin-resistant enterococci to avoid unnecessary treatment.

Enterococci may be the culprit in nosocomially-acquired intra-abdominal infections, bacteremia, endocarditis, urinary tract infections (UTIs), and skin and skin structure infections, and can exhibit resistance to ampicillin, aminoglycosides, and vancomycin.¹⁵ VRE is predominantly a health care-associated pathogen and may account for up to 77% of all health care-associated Enterococcus faecium infections and 9% of Enterococcus faecalis infections.¹

Treatment. Antibiotic selection for VRE infections depends upon the site of infection, patient comorbidities, the potential for drug interactions, and treatment duration. Current treatment options include linezolid, daptomycin, quinupristin/dalfopristin (for E. faecium only), tigecycline, and ampicillin if the organism is susceptible (TABLE 1^13-17).¹⁵ For cystitis caused by VRE (not urinary colonization), fosfomycin and nitrofurantoin are additional options.¹⁶

Resistant Enterobacteriaceae

Resistant Enterobacteriaceae such as Escherichia coli and Klebsiella pneumoniae have emerged as a result of increased broad-spectrum antibiotic utilization and have been implicated in health care-associated UTIs, intra-abdominal infections, bacteremia, and even pneumonia.¹ Patients with prolonged hospital stays and invasive medical devices, such as urinary and vascular catheters, endotracheal tubes, and endoscopy scopes, have the highest risk for infection with these organisms.²⁰

The genotypic profiles of resistance among the Enterobacteriaceae are diverse and complex, resulting in different levels of activity for the various beta-lactam agents (TABLE 2^21-24).²⁵ Furthermore, extended-spectrum beta-lactamase (ESBL)-producers and carbapenem-resistant Enterobacteriaceae (CRE) are often resistant to other classes of antibiotics, too, including aminoglycosides and fluoroquinolones.^20,25 The increasing diversity among beta-lactamase enzymes has made the selection of appropriate antibiotic therapy challenging, since the ability to identify specific beta-lactamase genes is not yet available in the clinical setting.

Cefepime may retain activity against some ESBL-producing isolates, but it is also susceptible to the inoculum effect and should only be used for non–life-threatening infections and at higher doses.²³ Fosfomycin has activity against ESBL-producing bacteria, but is only approved for oral use in UTIs in the United States.^20,27 Ceftolozane/tazobactam (Zerbaxa) and ceftazidime/avibactam (Avycaz) were approved in 2014 and 2015, respectively, by the FDA for the management of complicated urinary tract and intra-abdominal infections caused by susceptible ESBL-producing Enterobacteriaceae. In order to preserve the antimicrobial efficacy of these 2 newer agents, however, they are typically reserved for definitive therapy when in vitro susceptibility is demonstrated and there are no other viable options.

AmpC beta-lactamases are resistant to similar agents as the ESBLs, in addition to cefoxitin and the beta-lactam/beta-lactamase inhibitor combinations containing clavulanic acid, sulbactam, and in some cases, tazobactam. Resistance can be induced and emerges in certain pathogens while patients are on therapy.²⁸ Fluoroquinolones and aminoglycosides have a low risk of developing resistance while patients are on therapy, but are more likely to cause adverse effects and toxicity compared with the beta-lactams.²⁸ Carbapenems have the lowest risk of emerging resistance and are the empiric treatment of choice for known AmpC-producing Enterobacteriaceae in serious infections.^20,28 Cefepime may also be an option in less severe infections, such as UTIs or those in which adequate source control has been achieved.^28,29

Carbapenem-resistant Enterobacteriaceae (CRE) have become a serious threat as a result of increased carbapenem use. While carbapenem resistance is less common in the United States than worldwide, rates have increased nearly 4-fold (1.2% to 4.2%) in the last decade, with some regions of the country experiencing substantially higher rates.²⁴ The most commonly reported CRE genotypes identified in the United States include the serine carbapenemase (K. pneumoniae carbapenemase, or KPC), and the metallo-beta-lactamases (Verona integrin-encoded metallo-beta-lactamase, or VIM, and the New Dehli metallo-beta-lactamase, or NDM), with each class conferring slightly different resistance patterns (TABLE 2^21-24).^20,30

Few treatment options exist for Enterobacteriaceae producing a serine carbapenemase, and, unfortunately, evidence to support these therapies is extremely limited. Some CRE isolates retain susceptibility to the polymyxins, the aminoglycosides, and tigecycline.³⁰ Even fewer options exist for treating Enterobacteriaceae producing metallo-beta-lactamases, which are typically only susceptible to the polymyxins and tigecycline.^43-45

The increasing diversity among beta-lactamase enzymes has made the selection of appropriate antibiotics more challenging in recent years.

Several studies have demonstrated lower mortality rates when combination therapy is utilized for CRE bloodstream infections.^31,32 Furthermore, the combination of colistin, tigecycline, and meropenem was found to have a significant mortality advantage.³² Double carbapenem therapy has been effective in several cases of invasive KPC-producing K. pneumoniae infections.^33,34 However, it is important to note that current clinical evidence comes from small, single-center, retrospective studies, and additional research is needed to determine optimal combinations and dosing strategies for these infections.

Lastly, ceftazidime/avibactam (Avycaz) was recently approved for the treatment of complicated urinary tract and intra-abdominal infections, and has activity against KPC-producing Enterobacteriaceae, but not those producing metallo-beta-lactamases, like VIM or NDM. In the absence of strong evidence to support one therapy over another, it may be reasonable to select at least 2 active agents when treating serious CRE infections. Agent selection should be based on the site of the infection, susceptibility data, and patient-specific factors (TABLE 3^{20,22,,23,25,27-42}). The CDC also recommends contact precautions for patients who are colonized or infected with CRE.³⁵

Multi-drug resistant Pseudomonas aeruginosa

Pseudomonas aeruginosa is a gram-negative rod that can be isolated from nosocomial infections such as UTIs, bacteremias, pneumonias, skin and skin structure infections, and burn infections.²⁰ Pseudomonal infections are associated with high morbidity and mortality and can cause recurrent infections in patients with cystic fibrosis.²⁰ Multidrug-resistant P. aeruginosa (MDR-P) infections account for approximately 13% of all health care-associated pseudomonal infections nationally.¹ Both fluoroquinolone and aminoglycoside resistance has emerged, and multiple types of beta-lactamases (ESBL, AmpC, carbapenemases) have resulted in organisms that are resistant to nearly all anti-pseudomonal beta-lactams.²⁰

Treatment. For patients at risk for MDR-P, some clinical practice guidelines have recommended using an empiric therapy regimen that contains antimicrobial agents from 2 different classes with activity against P. aeruginosa to increase the likelihood of susceptibility to at least one agent.⁶ De-escalation can occur once culture and susceptibility results are available.⁶ Dose optimization based on pharmacodynamic principles is critical for ensuring clinical efficacy and minimizing resistance.³⁶ The use of high-dose, prolonged-infusion beta-lactams (piperacillin/tazobactam, cefepime, ceftazidime, and carbapenems) is becoming common practice at institutions with higher rates of resistance.^36-38

A resurgence of polymyxin (colistin) use for MDR-P isolates has occurred, and may be warranted empirically in select patients, based on local resistance patterns and patient history. Newer pharmacokinetic data are available, resulting in improved dosing strategies that may enhance efficacy while alleviating some of the nephrotoxicity concerns associated with colistin therapy.³⁹

Ceftolozane/tazobactam (Zerbaxa) and ceftazidime/avibactam (Avycaz) are options for complicated urinary tract and intra-abdominal infections caused by susceptible P. aeruginosa isolates. Given the lack of comparative efficacy data available for the management of MDR-P infections, agent selection should be based on site of infection, susceptibility data, and patient-specific factors.

Multi-drug resistant Acinetobacter baumannii

A. baumannii is a lactose-fermenting, gram-negative rod sometimes implicated in nosocomial pneumonias, line-related bloodstream infections, UTIs, and surgical site infections.²⁰ Resistance has been documented for nearly all classes of antibiotics, including carbapenems.^1,20 Over half of all health care-associated A. baumannii isolates in the United States are multidrug resistant.¹

Treatment. Therapy options for A. baumannii infections are often limited to polymyxins, tigecycline, carbapenems (except ertapenem), aminoglycosides, and high-dose ampicillin/sulbactam, depending on in vitro susceptibilities.^40,41 When using ampicillin/sulbactam for A. baumannii infections, sulbactam is the active ingredient. Doses of 2 to 4 g/d of sulbactam have demonstrated efficacy in non-critically ill patients, while critically ill patients may require higher doses (up to 12 g/d).⁴⁰ Colistin is considered the mainstay of therapy for carbapenem-resistant A. baumannii. It should be used in combination with either a carbapenem, rifampin, an aminoglycoside, or tigecycline.⁴²

Drug therapies for nosocomial-resistant gram-negative infections, along with clinical pearls for use, are summarized in TABLE 3.^{20,22,23,25,27-42} Because efficacy data are limited for treating infections caused by these pathogens, appropriate antimicrobial selection is frequently guided by location of infection, susceptibility patterns, and patient-specific factors such as allergies and the risk for adverse effects.

Antimicrobial stewardship

Antibiotic misuse has been a significant driver of antibiotic resistance.⁴⁶ Efforts to improve and measure the appropriate use of antibiotics have historically focused on acute care settings. Broad interventions to reduce antibiotic use include prospective audit with intervention and feedback, formulary restriction and preauthorization, and antibiotic time-outs.^47,48

Multidrug-resistant Pseudomonas aeruginosa infections account for approximately 13% of all health care-associated pseudomonal infections nationally.

Pharmacy-driven interventions include intravenous-to-oral conversions, dose adjustments for organ dysfunction, pharmacokinetic or pharmacodynamic interventions to optimize treatment for organisms with reduced susceptibility, therapeutic duplication alerts, and automatic-stop orders.^47,48

Diagnosis-specific interventions include order sets for common infections and the use of rapid diagnostic assays (TABLE 4^49,50). Rapid diagnostic testing is increasingly being considered an essential component of stewardship programs because it permits significantly shortened time to organism identification and susceptibility testing and allows for improved antibiotic utilization and patient outcomes when coupled with other effective stewardship strategies.⁴⁹

The core elements. The CDC has defined the core elements of successful inpatient ASPs.⁴⁶ These include:

• commitment from hospital leadership
• a physician leader who is responsible for overall program outcomes
• a pharmacist leader who co-leads the program and is accountable for enterprise-wide improvements in antibiotic use
• implementation of at least one systemic intervention (broad, pharmacy-driven, or infection/syndrome-specific)
• monitoring of prescribing and resistance patterns
• reporting antibiotic use and resistance patterns to all involved in the medication use process
• Education directed at the health care team about optimal antibiotic use.

Above all, success with antibiotic stewardship is dependent on identified leadership and an enterprise-wide multidisciplinary approach.

The FP’s role in hospital ASPs can take a number of forms. FPs who practice inpatient medicine should work with all members of their department and be supportive of efforts to improve antibiotic use. Prescribers should help develop and implement hospital-specific treatment recommendations, as well as be responsive to measurements and audits aimed at determining the quantity and quality of antibiotic use. Hospital-specific updates on antibiotic prescribing and antibiotic resistance should be shared widely through formal and informal settings. FPs should know if patients with resistant organisms are hospitalized at institutions where they practice, and should remain abreast of infection rates and resistance patterns.

Over half of all health care-associated Acinetobacter baumannii isolates in the United States are multidrug resistant.

When admitting a patient, the FP should ask if the patient has received medical care elsewhere, including in another country. When caring for patients known to be currently or previously colonized or infected with resistant organisms, the FP should follow the appropriate precautions and insist that all members of the health care team follow suit.

CASE

A diagnosis of carbapenem-resistant E.coli sepsis is eventually made. Additional susceptibility test results reported later the same day revealed sensitivity to tigecycline and colistin, with intermediate sensitivity to doripenem. An infectious disease expert recommended contact precautions and combination treatment with tigecycline and doripenem for at least 7 days. The addition of a polymyxin was also considered; however, the patient’s renal function was not favorable enough to support a course of that agent. Longer duration of therapy may be required if adequate source control is not achieved.

After a complicated ICU stay, including the need for surgical wound drainage, the patient responded satisfactorily and was transferred to a medical step-down unit for continued recovery and eventual discharge.

CORRESPONDENCE
Dora E. Wiskirchen, PharmD, BCPS, Department of Pharmacy, St. Francis Hospital and Medical Center, 114 Woodland St., Hartford, CT 06105; Email: [email protected].

THE CASE

Steven R,* a 21-year-old man, visited the clinic accompanied by his mother. He did not speak much, and his mother provided his history. Over the previous 2 months, she had overheard him whispering in an agitated voice, even though no one else was nearby. And, lately, he refused to answer or make calls on his cell phone, claiming that if he did it would activate a deadly chip that had been implanted in his brain by evil aliens. He also stopped attending classes at the community college. He occasionally had a few beers with his friends, but he had never been known to abuse alcohol or use other recreational drugs.

How would you proceed with this patient?

* The patient’s name has been changed to protect his identity.

 

 

CHARACTERISTICS AND SCOPE OF SCHIZOPHRENIA

Schizophrenia is a psychotic illness in which the individual loses contact with reality and often experiences hallucinations, delusions, or thought disorders. Criteria for schizophrenia described in the Diagnostic and Statistical Manual of Mental Disorders 5^th edition (DSM-5) include signs and symptoms of at least 6 months’ duration, as well as at least one month of active-phase positive and negative symptoms.¹

Delusions, hallucinations, disorganized speech, and disorganized behavior are examples of positive symptoms. Negative symptoms include a decrease in the range and intensity of expressed emotions (ie, affective flattening) and a diminished initiation of goal-directed activities (ie, avolition).

Approximately 7 in 1000 people will develop the disorder in their lifetime.² Schizophrenia is considered a “serious mental illness” because of its chronic course and often poor long-term social and vocational outcomes.^3,4 Symptom onset is generally between late adolescence and the mid-30s.⁵

Getting closer to understanding its origin

Both genetic susceptibility and environmental factors influence the incidence of schizophrenia.⁴ Newer models of the disease have identified genes (ZDHHC8 and DTNBP1) whose mutations may increase the risk of schizophrenia.⁶ Physiologic insults during fetal life—hypoxia, maternal infection, maternal stress, and maternal malnutrition—account for a small portion of schizophrenia cases.⁶

Abnormalities in neurotransmission are the basis for theories on the pathophysiology of schizophrenia. Most of these theories center on either an excess or a deficiency of neurotransmitters, including dopamine, serotonin, and glutamate. Other theories implicate aspartate, glycine, and gamma-aminobutyric acid as part of the neurochemical imbalance of schizophrenia.⁷

ESTABLISHING A DIAGNOSIS

Although psychotic symptoms may be a prominent part of schizophrenia, not all psychoses indicate a primary psychiatric disorder such as schizophrenia. Broadly, psychoses can be categorized as primary or secondary.

Primary psychoses include schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, delusional disorder, and mood disorders (major depressive disorder and borderline personality disorder) with psychotic features.¹ Difficulty in distinguishing between these entities can necessitate referral to a psychiatrist.

Secondary psychoses arise from a precursor such as delirium, dementia, medical illness, or adverse effects of medications or illicit substances. Medical illnesses that cause psychotic symptoms include: ^5,8

• seizures (especially temporal lobe epilepsy),
• cerebrovascular accidents,
• intracranial space-occupying lesions,
• neuropsychiatric disorders (eg, Wilson’s or Parkinson’s disease),
• endocrine disorders (eg, thyroid or adrenal disease),
• autoimmune disease (eg, systemic lupus erythematosus, Hashimoto encephalopathy),
• deficiencies of vitamins A, B₁, B₁₂, or niacin,
• infections (eg, human immunodeficiency virus [HIV], encephalitis, parasites, and prion disease),
• narcolepsy, and
• metabolic disease (eg, acute intermittent porphyria, Tay-Sach’s disease, Niemann-Pick disease).

Several recreational drugs can cause psychotic symptoms: cocaine, amphetamines, cannabis, synthetic cannabinoids, inhalants, opioids, and hallucinogens. Psychotic symptoms can also appear during withdrawal from alcohol (delirium tremens) and from sedative hypnotics such as benzodiazepines. Prescribed medications such as anticholinergics, corticosteroids, dopaminergic agents (L-dopa), stimulants (amphetamines), and interferons can also induce psychotic symptoms.

First rule out causes of secondary psychosis

Rule out causes of secondary psychosis by conducting a detailed history and physical examination and ordering appropriate lab tests and imaging studies. If the patient’s psychosis is of recent onset, make sure the laboratory work-up includes a complete blood count (CBC), renal function testing, urine culture and sensitivity and urine toxicology, and measures of electrolytes, blood glucose, thyroid-stimulating hormone (TSH), vitamin B₁₂, folic acid, erythrocyte sedimentation rate (ESR), antinuclear antibodies (ANA), HIV antibody, and serum fluorescent treponemal antibody absorption (FTA-ABS).⁹

All antipsychotic agents are comparably effective, but adverse effects differ.

Consider cranial computed tomography or magnetic resonance imaging if there are focal neurologic deficits or if the patient’s presentation is atypical (eg, new onset psychosis in old age).⁹ Clinical presentation may also indicate a need for electroencephalography, ceruloplasmin measurement, a dexamethasone suppression test, a corticotropin stimulation test, 24-hour urine porphyrin and copper assays, chest radiography, or cerebrospinal fluid analysis.⁹

FACTORS TO CONSIDER IN TREATMENT DECISIONS

Although primary care physicians may encounter individuals experiencing their first episode of psychosis, it’s more likely that patients presenting with signs and symptoms of the disorder have been experiencing them for some time and have received no psychiatric care. In both instances, schizophrenia is best managed in conjunction with a psychiatrist until symptoms are stabilized.⁵ Psychosis does not always require hospitalization. But urgent psychiatry referral is recommended, if possible. Consider admission to a psychiatric inpatient unit for anyone who poses a danger to self or others.^8,10

Patients with schizophrenia have a higher incidence of medical illness—particularly cardiovascular disease—than the general population.

Treatment for schizophrenia is most effective with an interprofessional and collaborative approach that includes medication, psychological treatment, social supports, and primary care clinical management.^11,12 The last aspect takes on particular importance given that people with schizophrenia, compared with the general population, have a higher incidence of medical illness, particularly cardiovascular disease.¹³

Medications (TABLE 1^5,8) are grouped into first-generation antipsychotics (FGAs) and second-generation, or atypical, antipsychotics (SGAs), with the 2 classes being equally effective.^14-16 Quality of life is also similar at one year for patients treated with either drug class.¹⁴

Adverse effects can differ. The main difference between these medications is their adverse effect profiles. FGAs cause extrapyramidal symptoms (dystonia, akathisia, and tardive dyskinesia) more often than SGAs. Among the SGAs, olanzapine, asenapine, paliperidone, clozapine, and quetiapine cause significant weight gain, glucose dysregulation, and lipid abnormalities.^5,8,12,17 Clozapine is associated with agranulocytosis, as well. Risperidone causes mild to moderate weight gain.^5,8,12,17 Aripiprazole, lurasidone, and ziprasidone are considered weight neutral and cause no significant glucose dysregulation or lipid abnormalities.^5,8,12,17 All antipsychotics can cause QT prolongation and neuroleptic malignant syndrome.^5,8,12,17

Keys to successful treatment. Antipsychotics are most effective in treating positive symptoms of schizophrenia and show limited, if any, effect on negative or cognitive symptoms.^18,19 Give patients an adequate trial of therapy (at least 4 weeks at a therapeutic dose) before discontinuing the drug or offering a different medication.²⁰ All patients who report symptom relief while receiving antipsychotics should receive maintenance therapy.¹²

As with all chronic illnesses, success in managing schizophrenia requires patient adherence to the medication regimen. Discontinuation of antipsychotics is a common problem in schizophrenia, resulting in relapse. Long-acting injectable agents (LAIs) were developed to address this problem (TABLE 2).²¹ Although LAIs are typically used to ensure adherence during maintenance treatment, recent research has suggested they may also be effective for patients with early-phase or first-episode disease.²²

What to watch for. Patients on SGAs may develop metabolic abnormalities, and ongoing monitoring of relevant parameters is key (TABLE 3^23-27). More frequent monitoring may be necessary in patients with cardiovascular risk factors. Continue antipsychotics for at least 6 months to prevent relapse.¹² Also keep in mind the “Choosing Wisely” recommendation from the American Psychiatric Association of not prescribing 2 or more antipsychotics concurrently.²⁸

Adjunctive treatment should also be offered

In addition to receiving medication, patients with schizophrenia should be offered adjunctive therapies such as cognitive behavioral therapy, family intervention, and social skills training.^10-12 Among patients with schizophrenia, the incidences of anxiety disorder, panic symptoms, posttraumatic stress disorder, and obsessive compulsive disorder are higher than in the general population.²⁹ To address these conditions, medications such as selective serotonin reuptake inhibitors and anxiolytics can be used simultaneously with antipsychotic agents.

CLINICAL COURSE AND PROGNOSIS CAN VARY

Schizophrenia can have a variable clinical course that includes remissions and exacerbations, or it can follow a more persistently chronic course.

Mortality for patients with schizophrenia is 2 to 3 times higher than that of the general population.³⁰ Most deaths are due to an increased incidence of cardiovascular disease, respiratory illness, cancer, stroke, and other thromboembolic events.³⁰

The lifetime prevalence of suicide attempts among individuals with schizophrenia is 20% to 40%,³¹ and approximately 5% complete suicide.³² Risk factors include command hallucinations, a history of suicide attempts, intoxication with substances, anxiety, and physical pain.³² Clozapine has been shown to reduce suicide risk and may be considered for patients who are at high risk for suicide.³²

Therapeutic response varies among patients with schizophrenia, with one-third remaining symptomatic despite adequate treatment regimens.⁴

CARE MANAGERS CAN HELP ADDRESS BARRIERS TO CARE

Certain patient, provider, and health care system factors can hamper the provision of primary care to people with schizophrenia. Symptoms of the illness may disrupt the patient’s ability to engage with a provider or clinic. Access to mental health services may be limited based on geography. Even when primary care and mental health services are available, a patient with schizophrenia can find it challenging to schedule appointments. Reducing such barriers by using care managers may be an effective way to improve the overall quality and effectiveness of primary care for patients with schizophrenia.³³

A review of the literature suggests that up to one-third of individuals with serious mental illnesses who have had some contact with the mental health system disengage from care.¹² Poor engagement may lead to worse clinical outcomes, with symptom relapse and re-hospitalizations. Disengagement from treatment may indicate a patient’s belief that treatment is not necessary, is not meeting his or her needs, or is not being provided in a collaborative manner.

Consider a long-acting agent if patient adherence to treatment is uncertain.

Although shared decision-making is difficult with patients who have schizophrenia, emerging evidence suggests that this approach coupled with patient-centered care will improve engagement with mental health treatment.¹² Models of integrated care are being developed and have shown promise in ensuring access to behavioral health for these patients.³⁴

CASE

The primary care physician talked with Mr. R and his mother about the diagnosis of schizophrenia. He screened for suicide risk, and the patient denied having suicidal thoughts. Both the patient and his mother agreed to his starting medication.

Blood and urine samples were collected for a CBC and ESR, as well as to evaluate renal function, electrolytes, glucose, TSH, vitamin B₁₂, folic acid, ANAs, and HIV antibodies. A serum FTA-ABS test was done, as was a urine culture and sensitivity test and a toxicology screen. Because of the patient’s obesity, the physician decided to prescribe a weight-neutral SGA, aripiprazole 10 mg/d. The physician spoke with the clinic’s care coordinator to schedule an appointment with the psychiatry intake department and to follow up on the phone with the patient and his mother. He also scheduled a follow-up appointment for 2 weeks later.

At the follow-up visit, the patient showed no improvement. His blood and urine test results revealed no metabolic abnormalities or infectious or inflammatory illnesses. His urine toxicology result showed no illicit substances. The physician increased the dosage of aripiprazole to 15 mg/d and asked the patient to return in 2 weeks.

At the next follow-up visit, the patient was more verbal and said he was not hearing voices. His mother also acknowledged an improvement. He had already been scheduled for a psychiatry intake appointment, and he and his mother were reminded about this. Mr. R was also asked to make a follow-up primary care appointment for one month from the current visit.

CORRESPONDENCE
Rajesh (Fnu) Rajesh, MD, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109; [email protected].

THE CASE

Steven R,* a 21-year-old man, visited the clinic accompanied by his mother. He did not speak much, and his mother provided his history. Over the previous 2 months, she had overheard him whispering in an agitated voice, even though no one else was nearby. And, lately, he refused to answer or make calls on his cell phone, claiming that if he did it would activate a deadly chip that had been implanted in his brain by evil aliens. He also stopped attending classes at the community college. He occasionally had a few beers with his friends, but he had never been known to abuse alcohol or use other recreational drugs.

How would you proceed with this patient?

* The patient’s name has been changed to protect his identity.

 

 

CHARACTERISTICS AND SCOPE OF SCHIZOPHRENIA

Schizophrenia is a psychotic illness in which the individual loses contact with reality and often experiences hallucinations, delusions, or thought disorders. Criteria for schizophrenia described in the Diagnostic and Statistical Manual of Mental Disorders 5^th edition (DSM-5) include signs and symptoms of at least 6 months’ duration, as well as at least one month of active-phase positive and negative symptoms.¹

Delusions, hallucinations, disorganized speech, and disorganized behavior are examples of positive symptoms. Negative symptoms include a decrease in the range and intensity of expressed emotions (ie, affective flattening) and a diminished initiation of goal-directed activities (ie, avolition).

Approximately 7 in 1000 people will develop the disorder in their lifetime.² Schizophrenia is considered a “serious mental illness” because of its chronic course and often poor long-term social and vocational outcomes.^3,4 Symptom onset is generally between late adolescence and the mid-30s.⁵

Getting closer to understanding its origin

Both genetic susceptibility and environmental factors influence the incidence of schizophrenia.⁴ Newer models of the disease have identified genes (ZDHHC8 and DTNBP1) whose mutations may increase the risk of schizophrenia.⁶ Physiologic insults during fetal life—hypoxia, maternal infection, maternal stress, and maternal malnutrition—account for a small portion of schizophrenia cases.⁶

Abnormalities in neurotransmission are the basis for theories on the pathophysiology of schizophrenia. Most of these theories center on either an excess or a deficiency of neurotransmitters, including dopamine, serotonin, and glutamate. Other theories implicate aspartate, glycine, and gamma-aminobutyric acid as part of the neurochemical imbalance of schizophrenia.⁷

ESTABLISHING A DIAGNOSIS

Although psychotic symptoms may be a prominent part of schizophrenia, not all psychoses indicate a primary psychiatric disorder such as schizophrenia. Broadly, psychoses can be categorized as primary or secondary.

Primary psychoses include schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, delusional disorder, and mood disorders (major depressive disorder and borderline personality disorder) with psychotic features.¹ Difficulty in distinguishing between these entities can necessitate referral to a psychiatrist.

Secondary psychoses arise from a precursor such as delirium, dementia, medical illness, or adverse effects of medications or illicit substances. Medical illnesses that cause psychotic symptoms include: ^5,8

• seizures (especially temporal lobe epilepsy),
• cerebrovascular accidents,
• intracranial space-occupying lesions,
• neuropsychiatric disorders (eg, Wilson’s or Parkinson’s disease),
• endocrine disorders (eg, thyroid or adrenal disease),
• autoimmune disease (eg, systemic lupus erythematosus, Hashimoto encephalopathy),
• deficiencies of vitamins A, B₁, B₁₂, or niacin,
• infections (eg, human immunodeficiency virus [HIV], encephalitis, parasites, and prion disease),
• narcolepsy, and
• metabolic disease (eg, acute intermittent porphyria, Tay-Sach’s disease, Niemann-Pick disease).

Several recreational drugs can cause psychotic symptoms: cocaine, amphetamines, cannabis, synthetic cannabinoids, inhalants, opioids, and hallucinogens. Psychotic symptoms can also appear during withdrawal from alcohol (delirium tremens) and from sedative hypnotics such as benzodiazepines. Prescribed medications such as anticholinergics, corticosteroids, dopaminergic agents (L-dopa), stimulants (amphetamines), and interferons can also induce psychotic symptoms.

First rule out causes of secondary psychosis

Rule out causes of secondary psychosis by conducting a detailed history and physical examination and ordering appropriate lab tests and imaging studies. If the patient’s psychosis is of recent onset, make sure the laboratory work-up includes a complete blood count (CBC), renal function testing, urine culture and sensitivity and urine toxicology, and measures of electrolytes, blood glucose, thyroid-stimulating hormone (TSH), vitamin B₁₂, folic acid, erythrocyte sedimentation rate (ESR), antinuclear antibodies (ANA), HIV antibody, and serum fluorescent treponemal antibody absorption (FTA-ABS).⁹

All antipsychotic agents are comparably effective, but adverse effects differ.

Consider cranial computed tomography or magnetic resonance imaging if there are focal neurologic deficits or if the patient’s presentation is atypical (eg, new onset psychosis in old age).⁹ Clinical presentation may also indicate a need for electroencephalography, ceruloplasmin measurement, a dexamethasone suppression test, a corticotropin stimulation test, 24-hour urine porphyrin and copper assays, chest radiography, or cerebrospinal fluid analysis.⁹

FACTORS TO CONSIDER IN TREATMENT DECISIONS

Although primary care physicians may encounter individuals experiencing their first episode of psychosis, it’s more likely that patients presenting with signs and symptoms of the disorder have been experiencing them for some time and have received no psychiatric care. In both instances, schizophrenia is best managed in conjunction with a psychiatrist until symptoms are stabilized.⁵ Psychosis does not always require hospitalization. But urgent psychiatry referral is recommended, if possible. Consider admission to a psychiatric inpatient unit for anyone who poses a danger to self or others.^8,10

Patients with schizophrenia have a higher incidence of medical illness—particularly cardiovascular disease—than the general population.

Treatment for schizophrenia is most effective with an interprofessional and collaborative approach that includes medication, psychological treatment, social supports, and primary care clinical management.^11,12 The last aspect takes on particular importance given that people with schizophrenia, compared with the general population, have a higher incidence of medical illness, particularly cardiovascular disease.¹³

Medications (TABLE 1^5,8) are grouped into first-generation antipsychotics (FGAs) and second-generation, or atypical, antipsychotics (SGAs), with the 2 classes being equally effective.^14-16 Quality of life is also similar at one year for patients treated with either drug class.¹⁴

Adverse effects can differ. The main difference between these medications is their adverse effect profiles. FGAs cause extrapyramidal symptoms (dystonia, akathisia, and tardive dyskinesia) more often than SGAs. Among the SGAs, olanzapine, asenapine, paliperidone, clozapine, and quetiapine cause significant weight gain, glucose dysregulation, and lipid abnormalities.^5,8,12,17 Clozapine is associated with agranulocytosis, as well. Risperidone causes mild to moderate weight gain.^5,8,12,17 Aripiprazole, lurasidone, and ziprasidone are considered weight neutral and cause no significant glucose dysregulation or lipid abnormalities.^5,8,12,17 All antipsychotics can cause QT prolongation and neuroleptic malignant syndrome.^5,8,12,17

Keys to successful treatment. Antipsychotics are most effective in treating positive symptoms of schizophrenia and show limited, if any, effect on negative or cognitive symptoms.^18,19 Give patients an adequate trial of therapy (at least 4 weeks at a therapeutic dose) before discontinuing the drug or offering a different medication.²⁰ All patients who report symptom relief while receiving antipsychotics should receive maintenance therapy.¹²

As with all chronic illnesses, success in managing schizophrenia requires patient adherence to the medication regimen. Discontinuation of antipsychotics is a common problem in schizophrenia, resulting in relapse. Long-acting injectable agents (LAIs) were developed to address this problem (TABLE 2).²¹ Although LAIs are typically used to ensure adherence during maintenance treatment, recent research has suggested they may also be effective for patients with early-phase or first-episode disease.²²

What to watch for. Patients on SGAs may develop metabolic abnormalities, and ongoing monitoring of relevant parameters is key (TABLE 3^23-27). More frequent monitoring may be necessary in patients with cardiovascular risk factors. Continue antipsychotics for at least 6 months to prevent relapse.¹² Also keep in mind the “Choosing Wisely” recommendation from the American Psychiatric Association of not prescribing 2 or more antipsychotics concurrently.²⁸

Adjunctive treatment should also be offered

In addition to receiving medication, patients with schizophrenia should be offered adjunctive therapies such as cognitive behavioral therapy, family intervention, and social skills training.^10-12 Among patients with schizophrenia, the incidences of anxiety disorder, panic symptoms, posttraumatic stress disorder, and obsessive compulsive disorder are higher than in the general population.²⁹ To address these conditions, medications such as selective serotonin reuptake inhibitors and anxiolytics can be used simultaneously with antipsychotic agents.

CLINICAL COURSE AND PROGNOSIS CAN VARY

Schizophrenia can have a variable clinical course that includes remissions and exacerbations, or it can follow a more persistently chronic course.

Mortality for patients with schizophrenia is 2 to 3 times higher than that of the general population.³⁰ Most deaths are due to an increased incidence of cardiovascular disease, respiratory illness, cancer, stroke, and other thromboembolic events.³⁰

The lifetime prevalence of suicide attempts among individuals with schizophrenia is 20% to 40%,³¹ and approximately 5% complete suicide.³² Risk factors include command hallucinations, a history of suicide attempts, intoxication with substances, anxiety, and physical pain.³² Clozapine has been shown to reduce suicide risk and may be considered for patients who are at high risk for suicide.³²

Therapeutic response varies among patients with schizophrenia, with one-third remaining symptomatic despite adequate treatment regimens.⁴

CARE MANAGERS CAN HELP ADDRESS BARRIERS TO CARE

Certain patient, provider, and health care system factors can hamper the provision of primary care to people with schizophrenia. Symptoms of the illness may disrupt the patient’s ability to engage with a provider or clinic. Access to mental health services may be limited based on geography. Even when primary care and mental health services are available, a patient with schizophrenia can find it challenging to schedule appointments. Reducing such barriers by using care managers may be an effective way to improve the overall quality and effectiveness of primary care for patients with schizophrenia.³³

A review of the literature suggests that up to one-third of individuals with serious mental illnesses who have had some contact with the mental health system disengage from care.¹² Poor engagement may lead to worse clinical outcomes, with symptom relapse and re-hospitalizations. Disengagement from treatment may indicate a patient’s belief that treatment is not necessary, is not meeting his or her needs, or is not being provided in a collaborative manner.

Consider a long-acting agent if patient adherence to treatment is uncertain.

Although shared decision-making is difficult with patients who have schizophrenia, emerging evidence suggests that this approach coupled with patient-centered care will improve engagement with mental health treatment.¹² Models of integrated care are being developed and have shown promise in ensuring access to behavioral health for these patients.³⁴

CASE

The primary care physician talked with Mr. R and his mother about the diagnosis of schizophrenia. He screened for suicide risk, and the patient denied having suicidal thoughts. Both the patient and his mother agreed to his starting medication.

Blood and urine samples were collected for a CBC and ESR, as well as to evaluate renal function, electrolytes, glucose, TSH, vitamin B₁₂, folic acid, ANAs, and HIV antibodies. A serum FTA-ABS test was done, as was a urine culture and sensitivity test and a toxicology screen. Because of the patient’s obesity, the physician decided to prescribe a weight-neutral SGA, aripiprazole 10 mg/d. The physician spoke with the clinic’s care coordinator to schedule an appointment with the psychiatry intake department and to follow up on the phone with the patient and his mother. He also scheduled a follow-up appointment for 2 weeks later.

At the follow-up visit, the patient showed no improvement. His blood and urine test results revealed no metabolic abnormalities or infectious or inflammatory illnesses. His urine toxicology result showed no illicit substances. The physician increased the dosage of aripiprazole to 15 mg/d and asked the patient to return in 2 weeks.

At the next follow-up visit, the patient was more verbal and said he was not hearing voices. His mother also acknowledged an improvement. He had already been scheduled for a psychiatry intake appointment, and he and his mother were reminded about this. Mr. R was also asked to make a follow-up primary care appointment for one month from the current visit.

CORRESPONDENCE
Rajesh (Fnu) Rajesh, MD, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109; [email protected].

THE CASE

Steven R,* a 21-year-old man, visited the clinic accompanied by his mother. He did not speak much, and his mother provided his history. Over the previous 2 months, she had overheard him whispering in an agitated voice, even though no one else was nearby. And, lately, he refused to answer or make calls on his cell phone, claiming that if he did it would activate a deadly chip that had been implanted in his brain by evil aliens. He also stopped attending classes at the community college. He occasionally had a few beers with his friends, but he had never been known to abuse alcohol or use other recreational drugs.

How would you proceed with this patient?

* The patient’s name has been changed to protect his identity.

 

 

CHARACTERISTICS AND SCOPE OF SCHIZOPHRENIA

Schizophrenia is a psychotic illness in which the individual loses contact with reality and often experiences hallucinations, delusions, or thought disorders. Criteria for schizophrenia described in the Diagnostic and Statistical Manual of Mental Disorders 5^th edition (DSM-5) include signs and symptoms of at least 6 months’ duration, as well as at least one month of active-phase positive and negative symptoms.¹

Delusions, hallucinations, disorganized speech, and disorganized behavior are examples of positive symptoms. Negative symptoms include a decrease in the range and intensity of expressed emotions (ie, affective flattening) and a diminished initiation of goal-directed activities (ie, avolition).

Approximately 7 in 1000 people will develop the disorder in their lifetime.² Schizophrenia is considered a “serious mental illness” because of its chronic course and often poor long-term social and vocational outcomes.^3,4 Symptom onset is generally between late adolescence and the mid-30s.⁵

Getting closer to understanding its origin

Both genetic susceptibility and environmental factors influence the incidence of schizophrenia.⁴ Newer models of the disease have identified genes (ZDHHC8 and DTNBP1) whose mutations may increase the risk of schizophrenia.⁶ Physiologic insults during fetal life—hypoxia, maternal infection, maternal stress, and maternal malnutrition—account for a small portion of schizophrenia cases.⁶

Abnormalities in neurotransmission are the basis for theories on the pathophysiology of schizophrenia. Most of these theories center on either an excess or a deficiency of neurotransmitters, including dopamine, serotonin, and glutamate. Other theories implicate aspartate, glycine, and gamma-aminobutyric acid as part of the neurochemical imbalance of schizophrenia.⁷

ESTABLISHING A DIAGNOSIS

Although psychotic symptoms may be a prominent part of schizophrenia, not all psychoses indicate a primary psychiatric disorder such as schizophrenia. Broadly, psychoses can be categorized as primary or secondary.

Primary psychoses include schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, delusional disorder, and mood disorders (major depressive disorder and borderline personality disorder) with psychotic features.¹ Difficulty in distinguishing between these entities can necessitate referral to a psychiatrist.

Secondary psychoses arise from a precursor such as delirium, dementia, medical illness, or adverse effects of medications or illicit substances. Medical illnesses that cause psychotic symptoms include: ^5,8

• seizures (especially temporal lobe epilepsy),
• cerebrovascular accidents,
• intracranial space-occupying lesions,
• neuropsychiatric disorders (eg, Wilson’s or Parkinson’s disease),
• endocrine disorders (eg, thyroid or adrenal disease),
• autoimmune disease (eg, systemic lupus erythematosus, Hashimoto encephalopathy),
• deficiencies of vitamins A, B₁, B₁₂, or niacin,
• infections (eg, human immunodeficiency virus [HIV], encephalitis, parasites, and prion disease),
• narcolepsy, and
• metabolic disease (eg, acute intermittent porphyria, Tay-Sach’s disease, Niemann-Pick disease).

Several recreational drugs can cause psychotic symptoms: cocaine, amphetamines, cannabis, synthetic cannabinoids, inhalants, opioids, and hallucinogens. Psychotic symptoms can also appear during withdrawal from alcohol (delirium tremens) and from sedative hypnotics such as benzodiazepines. Prescribed medications such as anticholinergics, corticosteroids, dopaminergic agents (L-dopa), stimulants (amphetamines), and interferons can also induce psychotic symptoms.

First rule out causes of secondary psychosis

Rule out causes of secondary psychosis by conducting a detailed history and physical examination and ordering appropriate lab tests and imaging studies. If the patient’s psychosis is of recent onset, make sure the laboratory work-up includes a complete blood count (CBC), renal function testing, urine culture and sensitivity and urine toxicology, and measures of electrolytes, blood glucose, thyroid-stimulating hormone (TSH), vitamin B₁₂, folic acid, erythrocyte sedimentation rate (ESR), antinuclear antibodies (ANA), HIV antibody, and serum fluorescent treponemal antibody absorption (FTA-ABS).⁹

All antipsychotic agents are comparably effective, but adverse effects differ.

Consider cranial computed tomography or magnetic resonance imaging if there are focal neurologic deficits or if the patient’s presentation is atypical (eg, new onset psychosis in old age).⁹ Clinical presentation may also indicate a need for electroencephalography, ceruloplasmin measurement, a dexamethasone suppression test, a corticotropin stimulation test, 24-hour urine porphyrin and copper assays, chest radiography, or cerebrospinal fluid analysis.⁹

FACTORS TO CONSIDER IN TREATMENT DECISIONS

Although primary care physicians may encounter individuals experiencing their first episode of psychosis, it’s more likely that patients presenting with signs and symptoms of the disorder have been experiencing them for some time and have received no psychiatric care. In both instances, schizophrenia is best managed in conjunction with a psychiatrist until symptoms are stabilized.⁵ Psychosis does not always require hospitalization. But urgent psychiatry referral is recommended, if possible. Consider admission to a psychiatric inpatient unit for anyone who poses a danger to self or others.^8,10

Patients with schizophrenia have a higher incidence of medical illness—particularly cardiovascular disease—than the general population.

Treatment for schizophrenia is most effective with an interprofessional and collaborative approach that includes medication, psychological treatment, social supports, and primary care clinical management.^11,12 The last aspect takes on particular importance given that people with schizophrenia, compared with the general population, have a higher incidence of medical illness, particularly cardiovascular disease.¹³

Medications (TABLE 1^5,8) are grouped into first-generation antipsychotics (FGAs) and second-generation, or atypical, antipsychotics (SGAs), with the 2 classes being equally effective.^14-16 Quality of life is also similar at one year for patients treated with either drug class.¹⁴

Adverse effects can differ. The main difference between these medications is their adverse effect profiles. FGAs cause extrapyramidal symptoms (dystonia, akathisia, and tardive dyskinesia) more often than SGAs. Among the SGAs, olanzapine, asenapine, paliperidone, clozapine, and quetiapine cause significant weight gain, glucose dysregulation, and lipid abnormalities.^5,8,12,17 Clozapine is associated with agranulocytosis, as well. Risperidone causes mild to moderate weight gain.^5,8,12,17 Aripiprazole, lurasidone, and ziprasidone are considered weight neutral and cause no significant glucose dysregulation or lipid abnormalities.^5,8,12,17 All antipsychotics can cause QT prolongation and neuroleptic malignant syndrome.^5,8,12,17

Keys to successful treatment. Antipsychotics are most effective in treating positive symptoms of schizophrenia and show limited, if any, effect on negative or cognitive symptoms.^18,19 Give patients an adequate trial of therapy (at least 4 weeks at a therapeutic dose) before discontinuing the drug or offering a different medication.²⁰ All patients who report symptom relief while receiving antipsychotics should receive maintenance therapy.¹²

As with all chronic illnesses, success in managing schizophrenia requires patient adherence to the medication regimen. Discontinuation of antipsychotics is a common problem in schizophrenia, resulting in relapse. Long-acting injectable agents (LAIs) were developed to address this problem (TABLE 2).²¹ Although LAIs are typically used to ensure adherence during maintenance treatment, recent research has suggested they may also be effective for patients with early-phase or first-episode disease.²²

What to watch for. Patients on SGAs may develop metabolic abnormalities, and ongoing monitoring of relevant parameters is key (TABLE 3^23-27). More frequent monitoring may be necessary in patients with cardiovascular risk factors. Continue antipsychotics for at least 6 months to prevent relapse.¹² Also keep in mind the “Choosing Wisely” recommendation from the American Psychiatric Association of not prescribing 2 or more antipsychotics concurrently.²⁸

Adjunctive treatment should also be offered

In addition to receiving medication, patients with schizophrenia should be offered adjunctive therapies such as cognitive behavioral therapy, family intervention, and social skills training.^10-12 Among patients with schizophrenia, the incidences of anxiety disorder, panic symptoms, posttraumatic stress disorder, and obsessive compulsive disorder are higher than in the general population.²⁹ To address these conditions, medications such as selective serotonin reuptake inhibitors and anxiolytics can be used simultaneously with antipsychotic agents.

CLINICAL COURSE AND PROGNOSIS CAN VARY

Schizophrenia can have a variable clinical course that includes remissions and exacerbations, or it can follow a more persistently chronic course.

Mortality for patients with schizophrenia is 2 to 3 times higher than that of the general population.³⁰ Most deaths are due to an increased incidence of cardiovascular disease, respiratory illness, cancer, stroke, and other thromboembolic events.³⁰

The lifetime prevalence of suicide attempts among individuals with schizophrenia is 20% to 40%,³¹ and approximately 5% complete suicide.³² Risk factors include command hallucinations, a history of suicide attempts, intoxication with substances, anxiety, and physical pain.³² Clozapine has been shown to reduce suicide risk and may be considered for patients who are at high risk for suicide.³²

Therapeutic response varies among patients with schizophrenia, with one-third remaining symptomatic despite adequate treatment regimens.⁴

CARE MANAGERS CAN HELP ADDRESS BARRIERS TO CARE

Certain patient, provider, and health care system factors can hamper the provision of primary care to people with schizophrenia. Symptoms of the illness may disrupt the patient’s ability to engage with a provider or clinic. Access to mental health services may be limited based on geography. Even when primary care and mental health services are available, a patient with schizophrenia can find it challenging to schedule appointments. Reducing such barriers by using care managers may be an effective way to improve the overall quality and effectiveness of primary care for patients with schizophrenia.³³

A review of the literature suggests that up to one-third of individuals with serious mental illnesses who have had some contact with the mental health system disengage from care.¹² Poor engagement may lead to worse clinical outcomes, with symptom relapse and re-hospitalizations. Disengagement from treatment may indicate a patient’s belief that treatment is not necessary, is not meeting his or her needs, or is not being provided in a collaborative manner.

Consider a long-acting agent if patient adherence to treatment is uncertain.

Although shared decision-making is difficult with patients who have schizophrenia, emerging evidence suggests that this approach coupled with patient-centered care will improve engagement with mental health treatment.¹² Models of integrated care are being developed and have shown promise in ensuring access to behavioral health for these patients.³⁴

CASE

The primary care physician talked with Mr. R and his mother about the diagnosis of schizophrenia. He screened for suicide risk, and the patient denied having suicidal thoughts. Both the patient and his mother agreed to his starting medication.

Blood and urine samples were collected for a CBC and ESR, as well as to evaluate renal function, electrolytes, glucose, TSH, vitamin B₁₂, folic acid, ANAs, and HIV antibodies. A serum FTA-ABS test was done, as was a urine culture and sensitivity test and a toxicology screen. Because of the patient’s obesity, the physician decided to prescribe a weight-neutral SGA, aripiprazole 10 mg/d. The physician spoke with the clinic’s care coordinator to schedule an appointment with the psychiatry intake department and to follow up on the phone with the patient and his mother. He also scheduled a follow-up appointment for 2 weeks later.

At the follow-up visit, the patient showed no improvement. His blood and urine test results revealed no metabolic abnormalities or infectious or inflammatory illnesses. His urine toxicology result showed no illicit substances. The physician increased the dosage of aripiprazole to 15 mg/d and asked the patient to return in 2 weeks.

At the next follow-up visit, the patient was more verbal and said he was not hearing voices. His mother also acknowledged an improvement. He had already been scheduled for a psychiatry intake appointment, and he and his mother were reminded about this. Mr. R was also asked to make a follow-up primary care appointment for one month from the current visit.

CORRESPONDENCE
Rajesh (Fnu) Rajesh, MD, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109; [email protected].

Researchers estimate that approximately 10.2 million Americans have osteoporosis, and an additional 43 million have low bone density.¹ Equally stark are the ramifications of these numbers. About one out of every 2 Caucasian women will experience an osteoporosis-related fracture at some point in their lifetime, as will approximately one in 5 men.² Although African American women tend to have a higher bone mineral density (BMD) than white women throughout their lives, those who have osteoporosis have the same elevated risk for fractures as Caucasians.

Osteoporotic fractures are associated with increased risk of disability, mortality, and nursing home placement. Given the aging population, researchers expect annual direct costs from osteoporosis to reach $25.3 billion by 2025.³

Family physicians (FPs) can have a meaningful impact on the extent to which this condition affects the population. To that end, we’ve put together a brief summary of the screening recommendations to keep in mind and a comparison of the different agents used to treat and prevent osteoporosis. The reference tables throughout will put these details at your fingertips.

Screening recommendations vary, Dx doesn’t require BMD testing

Guidelines for screening for osteoporosis vary considerably by professional organization. For example, the US Preventive Services Task Force (USPSTF) recommends screening all women ≥65 years, and younger women whose fracture risk is the same, or greater than, that of a 65-year-old white woman who has no additional risk factors (TABLE 1⁴).⁵ In addition, the USPSTF concludes that the current evidence is insufficient to recommend routine screening for osteoporosis in men.⁵ 

The National Osteoporosis Foundation (NOF) recommends that BMD testing be performed in all women ≥65 years and in men ≥70 years.⁶ In terms of frequency, NOF recommends BMD testing one to 2 years after initiating therapy to reduce fracture risk and every 2 years thereafter. The American College of Obstetricians and Gynecologists recommends BMD screening for women no more than every 2 years starting at age 65 years.⁷ It also recommends selective screening in women younger than 65 years of age if they are postmenopausal and have other risk factors for osteoporosis.⁷

Bone mineral density testing is not always necessary to establish a diagnosis of osteoporosis.

The most recent guideline regarding osteoporosis was published in May 2017 by the American College of Physicians (ACP) and endorsed by the American Academy of Family Physicians.⁸ But the guideline focuses on treatment rather than screening.

Although guidelines vary by society, most experts agree with BMD assessment in all women ≥65 years and postmenopausal women <65 years if one or more of the risk factors identified in TABLE 1⁴ are present.

Diagnosis. Osteoporosis can be diagnosed using dual energy x-ray absorptiometry (DXA) and T-score (TABLE 2⁶),⁹ but BMD testing is not always necessary to establish the diagnosis. For example, osteoporosis can be diagnosed clinically in both men and women who have sustained a hip fracture (with or without BMD testing). Osteoporosis may also be diagnosed in patients with osteopenia (determined by DXA and T-score) who have had a vertebral, proximal humeral, or pelvic fracture. Generally speaking, a detailed history and physical together with BMD assessment, vertebral imaging to diagnose vertebral fractures, and, when appropriate, the World Health Organization’s 10-year estimated fracture probability, are all utilized to establish patients’ fracture risk.^6,10

Treatment: Which agents and for how long?

Once a patient is diagnosed with osteoporosis, answering the following questions will help with selection of the best therapy for the patient:

1. Where on the body is BMD the lowest (vertebral, nonvertebral, or hip) and, consequently, at highest risk for a fracture?
2. Does the patient have any conditions that would interfere with therapy (difficulty swallowing, esophageal/gastrointestinal irritation)? This is important, as certain agents are associated with severe esophagitis.
3. Does the patient have any issues that would prevent adherence? Adherence may improve with therapy that is administered less frequently (weekly, monthly, once every 3 months, or annually).

TABLE 3^6,11-14 lists the prescription medications used to treat and prevent osteoporosis, their effect on the risk of vertebral, hip, and nonvertebral fractures, and contraindications/major adverse effects. First-line therapies are recommended based on clinical trials comparing the medication to placebo and evaluating their effectiveness in lowering the risk of vertebral, hip, and nonvertebral fractures.¹⁵ Given the absence of studies comparing these drugs to one another, TABLE 3^6,11-14 should not be used to make direct comparisons.

A new monoclonal antibody, romosozumab, has shown statistically significant decreases in the risk of new vertebral and nonvertebral fractures compared to alendronate after 12 months of use.¹⁶ However, there was a statistically significant higher number of patients who had a cardiac ischemic event or revascularization while taking romosozumab compared with those taking alendronate in the one-year double-blind period of the study.¹⁶ As of press time, the US Food and Drug Administration has not approved romosozumab.

Duration of treatment should be individualized based on specific patient factors, the pharmacologic agent, and, of course, adverse effects. However, no pharmacologic agent should be used indefinitely.⁶ In its clinical practice guidelines, the ACP recommends that patients be treated for 5 years with an appropriate pharmacologic therapy.⁸ The American Society for Bone and Mineral Research (ASBMR) Task Force recommends a review of therapy after 3 years with an intravenous bisphosphonate (BP; strength of recommendation [SOR]=C).¹⁷

Individualize duration of therapy based on patient factors and the pharmacologic agent being used, but no agent should be used indefinitely.

A review of 2 recent long-term trials analyzing the effects of BPs offers some additional guidance regarding duration of therapy in Caucasian postmenopausal women.¹⁸ In one study, women who received 10 years of therapy with alendronate reported fewer vertebral fractures than those who were switched to placebo after 5 years of treatment.¹⁹

In the second trial, which studied zoledronic acid, there were fewer morphometric vertebral fractures for those participants given annual injections for 6 years vs 3 years.²⁰ This trial found a significant transient increase in serum creatinine >0.5 mg/dL in the zoledronic acid treatment group.

These findings have prompted some experts in the field of osteoporosis to call for physicians to consider longer therapy with a BP (10 years with oral therapy or 6 years with intravenous therapy) in high-risk postmenopausal women (older women, those with a low hip T-score or high fracture risk score, those with a previous major osteoporotic fracture, and those who experienced fracture while on therapy) (SOR=B).¹⁸

Two rare adverse effects to keep in mind

The incidence of atypical femoral fracture, although rare (2-100 per 100,000 women), increases with duration of BP use. As a result, a drug holiday of 2 to 3 years should be considered for women with a low risk for fracture after 3 to 5 years of BP therapy (SOR=C).¹⁸

Osteonecrosis of the jaw (ONJ), also known as antiresorptive-associated osteonecrosis of the jaw, is a rare adverse effect of BPs that is associated with higher drug potency, higher cumulative dose, and parenteral route of administration, as well as other risk factors.^17,21 The American Association of Maxillofacial Surgeons (AAOMS) states that the risk of developing ONJ increases with use of oral BPs for more than 4 years;²² however, the Task Force of the ASBMR states that the evidence to support this is of poor quality.¹⁸ No recommendations on duration of therapy based on risk for ONJ have been made; however, AAOMS recommends discontinuation of oral BPs for a period of 2 months prior to, and 3 months following (or until osseous healing has occurred), elective invasive dental surgery for patients who have been taking an oral BP ≥4 years (SOR=C).²²

Review therapy after 5 years with an oral bisphosphonate and after 3 years with an intravenous one.

If a long-term drug holiday is selected, patients should be reassessed in 2 years. Shorter duration of follow-up is warranted for patients taking denosumab, teriparatide, or raloxifene, since bone loss will resume once therapy is discontinued.¹⁸

Because the benefits of BPs (in terms of reducing the risk of vertebral fracture) are significantly greater than the risks of an atypical fracture or ONJ, therapy should be started in appropriate patients, but duration of therapy should be monitored closely.

CORRESPONDENCE
Lovedhi Aggarwal, MD, 95-390 Kuahelani Avenue, Mililani, HI 96789; [email protected].

Researchers estimate that approximately 10.2 million Americans have osteoporosis, and an additional 43 million have low bone density.¹ Equally stark are the ramifications of these numbers. About one out of every 2 Caucasian women will experience an osteoporosis-related fracture at some point in their lifetime, as will approximately one in 5 men.² Although African American women tend to have a higher bone mineral density (BMD) than white women throughout their lives, those who have osteoporosis have the same elevated risk for fractures as Caucasians.

Osteoporotic fractures are associated with increased risk of disability, mortality, and nursing home placement. Given the aging population, researchers expect annual direct costs from osteoporosis to reach $25.3 billion by 2025.³

Family physicians (FPs) can have a meaningful impact on the extent to which this condition affects the population. To that end, we’ve put together a brief summary of the screening recommendations to keep in mind and a comparison of the different agents used to treat and prevent osteoporosis. The reference tables throughout will put these details at your fingertips.

Screening recommendations vary, Dx doesn’t require BMD testing

Guidelines for screening for osteoporosis vary considerably by professional organization. For example, the US Preventive Services Task Force (USPSTF) recommends screening all women ≥65 years, and younger women whose fracture risk is the same, or greater than, that of a 65-year-old white woman who has no additional risk factors (TABLE 1⁴).⁵ In addition, the USPSTF concludes that the current evidence is insufficient to recommend routine screening for osteoporosis in men.⁵ 

The National Osteoporosis Foundation (NOF) recommends that BMD testing be performed in all women ≥65 years and in men ≥70 years.⁶ In terms of frequency, NOF recommends BMD testing one to 2 years after initiating therapy to reduce fracture risk and every 2 years thereafter. The American College of Obstetricians and Gynecologists recommends BMD screening for women no more than every 2 years starting at age 65 years.⁷ It also recommends selective screening in women younger than 65 years of age if they are postmenopausal and have other risk factors for osteoporosis.⁷

Bone mineral density testing is not always necessary to establish a diagnosis of osteoporosis.

The most recent guideline regarding osteoporosis was published in May 2017 by the American College of Physicians (ACP) and endorsed by the American Academy of Family Physicians.⁸ But the guideline focuses on treatment rather than screening.

Although guidelines vary by society, most experts agree with BMD assessment in all women ≥65 years and postmenopausal women <65 years if one or more of the risk factors identified in TABLE 1⁴ are present.

Diagnosis. Osteoporosis can be diagnosed using dual energy x-ray absorptiometry (DXA) and T-score (TABLE 2⁶),⁹ but BMD testing is not always necessary to establish the diagnosis. For example, osteoporosis can be diagnosed clinically in both men and women who have sustained a hip fracture (with or without BMD testing). Osteoporosis may also be diagnosed in patients with osteopenia (determined by DXA and T-score) who have had a vertebral, proximal humeral, or pelvic fracture. Generally speaking, a detailed history and physical together with BMD assessment, vertebral imaging to diagnose vertebral fractures, and, when appropriate, the World Health Organization’s 10-year estimated fracture probability, are all utilized to establish patients’ fracture risk.^6,10

Treatment: Which agents and for how long?

Once a patient is diagnosed with osteoporosis, answering the following questions will help with selection of the best therapy for the patient:

1. Where on the body is BMD the lowest (vertebral, nonvertebral, or hip) and, consequently, at highest risk for a fracture?
2. Does the patient have any conditions that would interfere with therapy (difficulty swallowing, esophageal/gastrointestinal irritation)? This is important, as certain agents are associated with severe esophagitis.
3. Does the patient have any issues that would prevent adherence? Adherence may improve with therapy that is administered less frequently (weekly, monthly, once every 3 months, or annually).

TABLE 3^6,11-14 lists the prescription medications used to treat and prevent osteoporosis, their effect on the risk of vertebral, hip, and nonvertebral fractures, and contraindications/major adverse effects. First-line therapies are recommended based on clinical trials comparing the medication to placebo and evaluating their effectiveness in lowering the risk of vertebral, hip, and nonvertebral fractures.¹⁵ Given the absence of studies comparing these drugs to one another, TABLE 3^6,11-14 should not be used to make direct comparisons.

A new monoclonal antibody, romosozumab, has shown statistically significant decreases in the risk of new vertebral and nonvertebral fractures compared to alendronate after 12 months of use.¹⁶ However, there was a statistically significant higher number of patients who had a cardiac ischemic event or revascularization while taking romosozumab compared with those taking alendronate in the one-year double-blind period of the study.¹⁶ As of press time, the US Food and Drug Administration has not approved romosozumab.

Duration of treatment should be individualized based on specific patient factors, the pharmacologic agent, and, of course, adverse effects. However, no pharmacologic agent should be used indefinitely.⁶ In its clinical practice guidelines, the ACP recommends that patients be treated for 5 years with an appropriate pharmacologic therapy.⁸ The American Society for Bone and Mineral Research (ASBMR) Task Force recommends a review of therapy after 3 years with an intravenous bisphosphonate (BP; strength of recommendation [SOR]=C).¹⁷

Individualize duration of therapy based on patient factors and the pharmacologic agent being used, but no agent should be used indefinitely.

A review of 2 recent long-term trials analyzing the effects of BPs offers some additional guidance regarding duration of therapy in Caucasian postmenopausal women.¹⁸ In one study, women who received 10 years of therapy with alendronate reported fewer vertebral fractures than those who were switched to placebo after 5 years of treatment.¹⁹

In the second trial, which studied zoledronic acid, there were fewer morphometric vertebral fractures for those participants given annual injections for 6 years vs 3 years.²⁰ This trial found a significant transient increase in serum creatinine >0.5 mg/dL in the zoledronic acid treatment group.

These findings have prompted some experts in the field of osteoporosis to call for physicians to consider longer therapy with a BP (10 years with oral therapy or 6 years with intravenous therapy) in high-risk postmenopausal women (older women, those with a low hip T-score or high fracture risk score, those with a previous major osteoporotic fracture, and those who experienced fracture while on therapy) (SOR=B).¹⁸

Two rare adverse effects to keep in mind

The incidence of atypical femoral fracture, although rare (2-100 per 100,000 women), increases with duration of BP use. As a result, a drug holiday of 2 to 3 years should be considered for women with a low risk for fracture after 3 to 5 years of BP therapy (SOR=C).¹⁸

Osteonecrosis of the jaw (ONJ), also known as antiresorptive-associated osteonecrosis of the jaw, is a rare adverse effect of BPs that is associated with higher drug potency, higher cumulative dose, and parenteral route of administration, as well as other risk factors.^17,21 The American Association of Maxillofacial Surgeons (AAOMS) states that the risk of developing ONJ increases with use of oral BPs for more than 4 years;²² however, the Task Force of the ASBMR states that the evidence to support this is of poor quality.¹⁸ No recommendations on duration of therapy based on risk for ONJ have been made; however, AAOMS recommends discontinuation of oral BPs for a period of 2 months prior to, and 3 months following (or until osseous healing has occurred), elective invasive dental surgery for patients who have been taking an oral BP ≥4 years (SOR=C).²²

Review therapy after 5 years with an oral bisphosphonate and after 3 years with an intravenous one.

If a long-term drug holiday is selected, patients should be reassessed in 2 years. Shorter duration of follow-up is warranted for patients taking denosumab, teriparatide, or raloxifene, since bone loss will resume once therapy is discontinued.¹⁸

Because the benefits of BPs (in terms of reducing the risk of vertebral fracture) are significantly greater than the risks of an atypical fracture or ONJ, therapy should be started in appropriate patients, but duration of therapy should be monitored closely.

CORRESPONDENCE
Lovedhi Aggarwal, MD, 95-390 Kuahelani Avenue, Mililani, HI 96789; [email protected].

Researchers estimate that approximately 10.2 million Americans have osteoporosis, and an additional 43 million have low bone density.¹ Equally stark are the ramifications of these numbers. About one out of every 2 Caucasian women will experience an osteoporosis-related fracture at some point in their lifetime, as will approximately one in 5 men.² Although African American women tend to have a higher bone mineral density (BMD) than white women throughout their lives, those who have osteoporosis have the same elevated risk for fractures as Caucasians.

Osteoporotic fractures are associated with increased risk of disability, mortality, and nursing home placement. Given the aging population, researchers expect annual direct costs from osteoporosis to reach $25.3 billion by 2025.³

Family physicians (FPs) can have a meaningful impact on the extent to which this condition affects the population. To that end, we’ve put together a brief summary of the screening recommendations to keep in mind and a comparison of the different agents used to treat and prevent osteoporosis. The reference tables throughout will put these details at your fingertips.

Screening recommendations vary, Dx doesn’t require BMD testing

Guidelines for screening for osteoporosis vary considerably by professional organization. For example, the US Preventive Services Task Force (USPSTF) recommends screening all women ≥65 years, and younger women whose fracture risk is the same, or greater than, that of a 65-year-old white woman who has no additional risk factors (TABLE 1⁴).⁵ In addition, the USPSTF concludes that the current evidence is insufficient to recommend routine screening for osteoporosis in men.⁵ 

The National Osteoporosis Foundation (NOF) recommends that BMD testing be performed in all women ≥65 years and in men ≥70 years.⁶ In terms of frequency, NOF recommends BMD testing one to 2 years after initiating therapy to reduce fracture risk and every 2 years thereafter. The American College of Obstetricians and Gynecologists recommends BMD screening for women no more than every 2 years starting at age 65 years.⁷ It also recommends selective screening in women younger than 65 years of age if they are postmenopausal and have other risk factors for osteoporosis.⁷

Bone mineral density testing is not always necessary to establish a diagnosis of osteoporosis.

The most recent guideline regarding osteoporosis was published in May 2017 by the American College of Physicians (ACP) and endorsed by the American Academy of Family Physicians.⁸ But the guideline focuses on treatment rather than screening.

Although guidelines vary by society, most experts agree with BMD assessment in all women ≥65 years and postmenopausal women <65 years if one or more of the risk factors identified in TABLE 1⁴ are present.

Diagnosis. Osteoporosis can be diagnosed using dual energy x-ray absorptiometry (DXA) and T-score (TABLE 2⁶),⁹ but BMD testing is not always necessary to establish the diagnosis. For example, osteoporosis can be diagnosed clinically in both men and women who have sustained a hip fracture (with or without BMD testing). Osteoporosis may also be diagnosed in patients with osteopenia (determined by DXA and T-score) who have had a vertebral, proximal humeral, or pelvic fracture. Generally speaking, a detailed history and physical together with BMD assessment, vertebral imaging to diagnose vertebral fractures, and, when appropriate, the World Health Organization’s 10-year estimated fracture probability, are all utilized to establish patients’ fracture risk.^6,10

Treatment: Which agents and for how long?

Once a patient is diagnosed with osteoporosis, answering the following questions will help with selection of the best therapy for the patient:

1. Where on the body is BMD the lowest (vertebral, nonvertebral, or hip) and, consequently, at highest risk for a fracture?
2. Does the patient have any conditions that would interfere with therapy (difficulty swallowing, esophageal/gastrointestinal irritation)? This is important, as certain agents are associated with severe esophagitis.
3. Does the patient have any issues that would prevent adherence? Adherence may improve with therapy that is administered less frequently (weekly, monthly, once every 3 months, or annually).

TABLE 3^6,11-14 lists the prescription medications used to treat and prevent osteoporosis, their effect on the risk of vertebral, hip, and nonvertebral fractures, and contraindications/major adverse effects. First-line therapies are recommended based on clinical trials comparing the medication to placebo and evaluating their effectiveness in lowering the risk of vertebral, hip, and nonvertebral fractures.¹⁵ Given the absence of studies comparing these drugs to one another, TABLE 3^6,11-14 should not be used to make direct comparisons.

A new monoclonal antibody, romosozumab, has shown statistically significant decreases in the risk of new vertebral and nonvertebral fractures compared to alendronate after 12 months of use.¹⁶ However, there was a statistically significant higher number of patients who had a cardiac ischemic event or revascularization while taking romosozumab compared with those taking alendronate in the one-year double-blind period of the study.¹⁶ As of press time, the US Food and Drug Administration has not approved romosozumab.

Duration of treatment should be individualized based on specific patient factors, the pharmacologic agent, and, of course, adverse effects. However, no pharmacologic agent should be used indefinitely.⁶ In its clinical practice guidelines, the ACP recommends that patients be treated for 5 years with an appropriate pharmacologic therapy.⁸ The American Society for Bone and Mineral Research (ASBMR) Task Force recommends a review of therapy after 3 years with an intravenous bisphosphonate (BP; strength of recommendation [SOR]=C).¹⁷

Individualize duration of therapy based on patient factors and the pharmacologic agent being used, but no agent should be used indefinitely.

A review of 2 recent long-term trials analyzing the effects of BPs offers some additional guidance regarding duration of therapy in Caucasian postmenopausal women.¹⁸ In one study, women who received 10 years of therapy with alendronate reported fewer vertebral fractures than those who were switched to placebo after 5 years of treatment.¹⁹

In the second trial, which studied zoledronic acid, there were fewer morphometric vertebral fractures for those participants given annual injections for 6 years vs 3 years.²⁰ This trial found a significant transient increase in serum creatinine >0.5 mg/dL in the zoledronic acid treatment group.

These findings have prompted some experts in the field of osteoporosis to call for physicians to consider longer therapy with a BP (10 years with oral therapy or 6 years with intravenous therapy) in high-risk postmenopausal women (older women, those with a low hip T-score or high fracture risk score, those with a previous major osteoporotic fracture, and those who experienced fracture while on therapy) (SOR=B).¹⁸

Two rare adverse effects to keep in mind

The incidence of atypical femoral fracture, although rare (2-100 per 100,000 women), increases with duration of BP use. As a result, a drug holiday of 2 to 3 years should be considered for women with a low risk for fracture after 3 to 5 years of BP therapy (SOR=C).¹⁸

Osteonecrosis of the jaw (ONJ), also known as antiresorptive-associated osteonecrosis of the jaw, is a rare adverse effect of BPs that is associated with higher drug potency, higher cumulative dose, and parenteral route of administration, as well as other risk factors.^17,21 The American Association of Maxillofacial Surgeons (AAOMS) states that the risk of developing ONJ increases with use of oral BPs for more than 4 years;²² however, the Task Force of the ASBMR states that the evidence to support this is of poor quality.¹⁸ No recommendations on duration of therapy based on risk for ONJ have been made; however, AAOMS recommends discontinuation of oral BPs for a period of 2 months prior to, and 3 months following (or until osseous healing has occurred), elective invasive dental surgery for patients who have been taking an oral BP ≥4 years (SOR=C).²²

Review therapy after 5 years with an oral bisphosphonate and after 3 years with an intravenous one.

If a long-term drug holiday is selected, patients should be reassessed in 2 years. Shorter duration of follow-up is warranted for patients taking denosumab, teriparatide, or raloxifene, since bone loss will resume once therapy is discontinued.¹⁸

Because the benefits of BPs (in terms of reducing the risk of vertebral fracture) are significantly greater than the risks of an atypical fracture or ONJ, therapy should be started in appropriate patients, but duration of therapy should be monitored closely.

CORRESPONDENCE
Lovedhi Aggarwal, MD, 95-390 Kuahelani Avenue, Mililani, HI 96789; [email protected].