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?

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?

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?

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).

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).

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).

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.

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.

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.

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.

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.

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.

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].

CE/CME No: CR-1802

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Identify patients who are at the greatest risk for the effects of polypharmacy.
• Recognize which medications are most likely to cause adverse drug events (ADEs) in the elderly population.
• Understand the effects of aging on the pharmacokinetics and pharmacodynamics of medications.
• Learn strategies to reduce the risk for polypharmacy and ADEs, including use of the Beers Criteria and the STOPP/START Criteria.

FACULTY
Kelsey Barclay practices in orthopedic surgery at Stanford Medical Center in Palo Alto, California. Amy Frassetto practices in Ob-Gyn at NewYork-Presbyterian in New York City. Julie Robb practices in emergency medicine at South Nassau Communities Hospital in Oceanside, New York. Ellen D. Mandel is a Clinical Professor in the Department of PA Studies at Pace University-Lenox Hill Hospital in New York City.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid through January 31, 2019.

Article begins on next page >>

Managing medications in the elderly can be complicated by the physiologic effects of aging and the prevalence of comorbidities. Consistent use of tools such as the Beers criteria and the STOPP/START criteria, as well as medication reconciliation, can reduce polypharmacy and its adverse drug effects, improving health outcomes in this population.

Older adults (those 65 and older) often have a number of comorbidities requiring pharmacologic intervention, making medication management a complicated but essential part of caring for the elderly. A recent analysis of trends in prescription drug use by community-dwelling adults found that 39% of older adults used five or more prescribed medications.¹ Furthermore, about 72% of older adults also take a nonprescription medication (OTC or supplement); while OTC medication use has declined in this population in recent years, dietary supplement use has increased.²

These patients are also more susceptible to adverse drug events (ADEs)—including adverse drug reactions (ADRs)—resulting from the physiologic changes of aging. By one estimate, ADRs are about seven times more common in those older than 70 than in younger persons.³ One out of every 30 urgent hospital admissions in patients ages 65 and older is related to an ADR.⁴

Providers must therefore be cognizant of drug indications, dosing, and drug interactions when prescribing medications to elderly patients. Fortunately, tools and methods to avoid polypharmacy and the adverse effects of commonly prescribed medications—such as anticholinergics and psychotropic drugs—are available.

POLYPHARMACY AND PRESCRIPTION CASCADING

While there is no specific number of medications required to define polypharmacy, the term is generally used when a nonhospitalized individual is taking five or more medications.⁵ The more medications a patient is taking, the more at risk he or she will be for ADRs, drug interactions, and prescription cascading.

Prescription cascading begins when an ADR is thought to be a new symptom and a new drug is prescribed to control it. Ultimately, a cascade of prescriptions occurs to control avoidable ADRs, resulting in polypharmacy. As many as 57% of women older than 65 in the United States are currently prescribed five or more medications, with 12% prescribed nine or more drugs.⁶ Not only do these medications cause independent ADRs, but there is also increased risk for drug interactions—and potentially, additional avoidable ADRs.

The elderly population is at greater risk for ADEs because these patients are more likely to have multiple comorbidities and chronic diseases, requiring multiple therapies.⁷ Polypharmacy is also more dangerous in the elderly because the physiologic changes that occur during natural aging can affect both the pharmacokinetics and pharmacodynamics of medications. The absorption, distribution, metabolism, and excretion of drugs within the human body changes as a person ages, while certain drug classes can alter the way the body functions. For example, muscle mass naturally declines and the proportion of body fat to muscle increases; this change affects the distribution of drugs such as benzodiazepines or lithium.⁷ If the medication dosage is not corrected, the toxicity of the drug will be increased.⁷

Medication excretion is largely controlled by the kidneys. Renal perfusion and function decline with age, leading to a decrease in glomerular filtration rate—which requires closer monitoring of medication selection and dosing. The risk is heightened when the elderly patient becomes acutely ill. An acute decrease in kidney function results in decreased excretion of medications, leading to an increase in ADRs.⁷

Ultimately, the safety of many medications in the elderly patient is unknown.⁸ But there is a growing body of knowledge on the adverse effects of some classes of medication in this population.

COMMONLY PRESCRIBED MEDICATIONS—AND RISKS

ADEs result from medication errors, ADRs, allergic reactions, and overdoses. The incidence of ADEs—specifically ADRs and medication errors—is elevated in elderly patients who are prescribed certain classes of medications or multiple drugs simultaneously.⁸ Anticholinergic drugs and psychotropic drugs (specifically antipsychotics and benzodiazepines) are among the medications most commonly prescribed to elderly patients—and among the most likely to contribute to ADEs.⁹ Diabetes is a chronic condition whose treatment may also put elderly patients at risk for ADEs.¹⁰

Anticholinergic medications

Anticholinergic drugs—commonly prescribed for Parkinson disease, depression, urinary incontinence, pulmonary disorders, intestinal motility, and muscle spasms—competitively inhibit the binding of acetylcholine to muscarinic acetylcholine receptors.⁹ Because this mechanism tends to be nonselective, the adverse effects may be widespread. Central adverse effects include cognitive impairment, confusion, and delirium; peripheral adverse effects include constipation, urinary retention, dry mouth, blurred vision, peristaltic reduction, and tachycardia.⁹

Anticholinergic drugs are commonly prescribed to elderly patients for cardiovascular (CV) and neurologic disorders. (Medications for the former include ß-blockers, calcium channel blockers, diuretics, and ACE inhibitors; for the latter, amitriptyline, quetiapine, nortriptyline, prochlorperazine, haloperidol, and paroxetine.) An assessment of anticholinergic activity classified most neurologic medications as high activity and most CV medications as low—however, the latter are usually given in conjunction with other anticholinergic medications, increasing their ability to cause ADRs.¹¹

In many cases, patients are prescribed anticholinergic medications to control symptoms of a disease, not to cure it—which means patients may be taking these medications for years. This cumulative exposure is called the anticholinergic burden. Many studies show that the anticholinergic burden is a predictor of cognitive and physical decline; a 2016 study of adults older than 65 who were exposed to 5 mg/d of oxybutynin for more than three years had a 23% increased risk for dementia, compared to low-risk or no exposure groups.⁹

In a retrospective, population-level study conducted in New Zealand, researchers assessed the anticholinergic effects of delirium, urinary retention, and constipation in 2,248 patients (65 and older) who were admitted to the hospital with at least one prescribed medication. Anticholinergic burden was found to be a significant independent predictor; patients taking five anticholinergic medications were more than three times as likely to develop an anticholinergic effect than those taking just one such medication (adjusted odds ratio, 3.21).¹¹

Psychotropic drugs

Another often-prescribed medication group is psychotropic drugs, specifically antipsychotics and benzodiazepines, for agitation and behavioral disturbances in dementia. A year-long study of 851 patients in two long-term care nursing homes in Boston found that risk for ADRs—specifically, falls—was increased in those who had a change (initiation or dose increase) in psychotropic medication (ie, benzodiazepine, antipsychotic, or antidepressant).¹²

Second-generation antipsychotics, which are more commonly prescribed than first-generation agents, work on a postsynaptic blockade of brain dopamine D₂ receptors and have an increased affinity for serotonin 5-HT_2A receptors (see Table 1 for pharmacology of these medications).^13,14 Adverse effects of these drugs include hypotension, sedation, and anticholinergic effects. Second-generation antipsychotics also carry a “black box warning” for increased risk for death in elderly patients with dementia-related psychosis.¹⁵

Benzodiazepines bind to receptors in the gamma-aminobutyric acid receptor complex, which enhances the binding of this inhibitory neurotransmitter (see Table 2 for pharmacology). Of this class of drugs, lorazepam has the highest potency, whereas midazolam and diazepam have lower potencies. Use of benzodiazepines increases risk for delirium and respiratory depression.¹⁶

Diabetes treatment

People with diabetes have an increased risk for ADEs; this risk is elevated in older adults due to comorbidities such as peripheral neuropathy, retinopathy, coronary artery disease, and peripheral vascular disease.¹⁰ Hypoglycemic agents, such as insulin and insulin secretagogues, confer a higher risk for falls due to their hypoglycemic effect.¹⁰ Furthermore, metformin is known to increase risk for cognitive impairment in patients with diabetes.¹⁰

PREVENTING ADEs AND UNNECESSARY POLYPHARMACY

Predicting and preventing ADEs should be a health care provider’s priority when treating an elderly patient taking multiple medications—but it is often overlooked. Electronic medical records (EMRs) are helpful in preventing ADEs, specifically prescription errors, by flagging the patient’s chart when potentially problematic medications are ordered; however, this captures only a portion of ADEs occurring in this popu­lation.⁷

Other options to evaluate a patient for polypharmacy and possible ADRs include the Beers Criteria and the STOPP/START Criteria.^17,18 Additionally, performing thorough and frequent medication reviews helps ensure that patients are prescribed essential medications to treat their comorbidities with the most opportunistic risk-benefit ratio. Patients’ medication lists across settings (eg, hospital, primary care, urgent care) can be accessed more easily, efficiently, and accurately with the integration of EMRs.

Beers Criteria

First published by Dr. Mark Beers in 1991 and endorsed by the American Geriatrics Society, the Beers Criteria identifies possible harmful effects of certain commonly prescribed medications to help guide and modify pharmacologic treatments, particularly in adults older than 65. The Beers Criteria classifies medications into three categories:

1. Drugs that should be avoided or dose-adjusted
2. Drugs that are potentially inappropriate in patients with certain conditions or syndromes
3. Drugs that should be prescribed with caution in older adults.¹⁷

In the most recent update (2015), possible adverse effects of medications based on a patient’s hepatic or renal function, the effectiveness of the medication, and possible drug interactions were added. For example, nitrofurantoin and antiarrhythmics (eg, amiodarone and digoxin) should be avoided at a lower threshold of hepatic and renal impairment than previously recommended. The criteria suggest avoiding use of zolpidem, a nonbenzodiazepine receptor agonist, because of its elevated risk for adverse effects and minimal effectiveness in treating insomnia. More information about the 2015 criteria is available from the American Geriatrics Society (http://online library.wiley.com/doi/10.1111/jgs. 13702/full).¹⁹

The latest update also takes into account recently published evidence of increased ADEs resulting from drugs such as antipsychotics and proton pump inhibitors (PPIs).²⁰ Antipsychotics are associated with an increased risk for morbidity and mortality, and PPIs are now recommended only for treatment duration of up to two months because of the possible increased risk for Clostridium difficile infection, as well as falls and fractures in patients older than 65.²⁰ (PPIs indirectly reduce calcium absorption, which may lead to an increased fracture risk, particularly in postmenopausal women.²⁰)

As with any guideline, the Beers Criteria was designed to supplement, not replace, clinical expertise and judgment. The risks and benefits of a medication should be weighed for the individual patient.

STOPP/START Criteria

Less widely used is the STOPP/START Criteria, an evidence-based set of guidelines consisting of 65 STOPP (Screening Tool of Older Person’s potentially inappropriate Prescriptions) and 22 START (Screening Tool to Alert doctors to the Right Treatment) criteria. Although they may be used individually, STOPP and START are best used together to determine the most appropriate medications for an elderly patient.

The STOPP guidelines help determine when the risks of a medication may outweigh the benefits in a given patient. STOPP includes recommendations for the appropriate length of time to use a medication; for example, PPIs should not be used for more than eight weeks (similar to the Beers recommendation) and benzodiazepines and neuroleptics for more than four weeks.¹⁸

START helps clinicians recognize potential prescribing omissions and to identify when a medication regimen should be implemented based on a patient’s history.¹⁸ Examples of START criteria include suggestions of when to initiate calcium and vitamin D supplementation for prevention of osteoporosis and when to begin statins in patients with diabetes, coronary artery disease, and cardiovascular disease.¹⁸

STOPP/START is organized by physiologic system, which allows for greater usability, and it addresses medications by class rather than specific medications. (The Beers Criteria was criticized for these reasons, as well as its limited transferability outside the United States.) When assessed in systematic reviews, the STOPP/START criteria were found to be fundamentally more sensitive than the Beers Criteria. Overall, it was concluded that the use of the STOPP/START criteria resulted in an absolute risk reduction of 21.2% to 35.7% and greatly improved the appropriateness of prescribing medication to the elderly. Its use also resulted in fewer follow-up appointments with a primary care physician (PCP).¹⁸

iPhone and Android applications such as iGeriatrics and Medstopper provide clinicians with easy access to Beers Criteria and STOPP/START Criteria, respectively.

Medication reconciliation

Medication reconciliation—in which health care providers review a patient’s medication list at hospital admission and discharge, and even at routine office visits—is an increasingly common practice, especially with the implementation of EMRs. The patient’s prescribed and OTC medications, as well as dose, route, frequency, and indication, are updated, with the goal of maintaining the most accurate list. Health care providers can utilize both the Beers Criteria and the STOPP/START criteria in their reconciliation process to help reduce polypharmacy in the elderly. It is an essential step in maintaining communication between providers and ultimately decreasing the incidence of ADEs.¹⁷

IMPROVE … continuity of care

Polypharmacy can decrease patient likelihood to adhere to the regimen, whether due to confusion or intolerance.⁸ Patients should be included, along with caregivers and all medical providers, in a holistic assessment of the patient’s best interests in terms of long-term care and pharmacologic treatment, since those who have a sense of control in their treatment goals and expectations often achieve a better understanding of their medical status.¹⁰

However, educating patients about their medications is time-consuming, and time is often at a premium during a typical office visit. A pilot study of 28 male veterans (ages 85 and older)—the Integrated Management and Polypharmacy Review of Vulnerable Elders (IMPROVE) project—devised a model to combat this problem.²¹ As an adjunct to a visit with the PCP, a clinical pharmacist trained in patient education and medication management performed face-to-face clinical consults with patients and their caregivers. The results indicated that medical management by both the PCP and the pharmacist resulted in better medication management. The pharmacist was able to spend time with the patient and caregiver, resulting in individualized instructions, education, and strategies for safe and effective medication use. The PCP remained involved by cosigning the note with the pharmacist and was available for consultation, if needed.

In IMPROVE, 79% of patients had at least one medication discontinued and 75% had one or more dosing or timing adjustments made. Potentially inappropriate medications were reduced by 14%.²¹ When the researchers compared the six-month period before the trial with the six-month period afterward, they found an average pharmacy cost savings of $64 per veteran per month. There was also a decreasing trend in phone calls and visits to the PCP. Cost savings were comparable to or greater than those reported for similar interventions.²¹ There has not been sufficient long-term follow-up to assess this method’s effects on ADEs, morbidity, and mortality, however.

CONCLUSION

Managing medications in the elderly population is difficult, and polypharmacy is common due to the prevalence of patients with comorbidities. It is important for providers to be aware of possible drug interactions, prescribing cascades, and ADEs. Medications such as anticholinergics and antipsychotics pose an increased risk for ADEs, but the regular implementation of criteria such as Beers or STOPP/START in clinical practice will minimize overprescribing and improve health outcomes. These criteria should be used to supplement the clinical judgment and expertise of providers as a mainstay of patient care in the elderly.

CE/CME No: CR-1802

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Identify patients who are at the greatest risk for the effects of polypharmacy.
• Recognize which medications are most likely to cause adverse drug events (ADEs) in the elderly population.
• Understand the effects of aging on the pharmacokinetics and pharmacodynamics of medications.
• Learn strategies to reduce the risk for polypharmacy and ADEs, including use of the Beers Criteria and the STOPP/START Criteria.

FACULTY
Kelsey Barclay practices in orthopedic surgery at Stanford Medical Center in Palo Alto, California. Amy Frassetto practices in Ob-Gyn at NewYork-Presbyterian in New York City. Julie Robb practices in emergency medicine at South Nassau Communities Hospital in Oceanside, New York. Ellen D. Mandel is a Clinical Professor in the Department of PA Studies at Pace University-Lenox Hill Hospital in New York City.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid through January 31, 2019.

Article begins on next page >>

Managing medications in the elderly can be complicated by the physiologic effects of aging and the prevalence of comorbidities. Consistent use of tools such as the Beers criteria and the STOPP/START criteria, as well as medication reconciliation, can reduce polypharmacy and its adverse drug effects, improving health outcomes in this population.

Older adults (those 65 and older) often have a number of comorbidities requiring pharmacologic intervention, making medication management a complicated but essential part of caring for the elderly. A recent analysis of trends in prescription drug use by community-dwelling adults found that 39% of older adults used five or more prescribed medications.¹ Furthermore, about 72% of older adults also take a nonprescription medication (OTC or supplement); while OTC medication use has declined in this population in recent years, dietary supplement use has increased.²

These patients are also more susceptible to adverse drug events (ADEs)—including adverse drug reactions (ADRs)—resulting from the physiologic changes of aging. By one estimate, ADRs are about seven times more common in those older than 70 than in younger persons.³ One out of every 30 urgent hospital admissions in patients ages 65 and older is related to an ADR.⁴

Providers must therefore be cognizant of drug indications, dosing, and drug interactions when prescribing medications to elderly patients. Fortunately, tools and methods to avoid polypharmacy and the adverse effects of commonly prescribed medications—such as anticholinergics and psychotropic drugs—are available.

POLYPHARMACY AND PRESCRIPTION CASCADING

While there is no specific number of medications required to define polypharmacy, the term is generally used when a nonhospitalized individual is taking five or more medications.⁵ The more medications a patient is taking, the more at risk he or she will be for ADRs, drug interactions, and prescription cascading.

Prescription cascading begins when an ADR is thought to be a new symptom and a new drug is prescribed to control it. Ultimately, a cascade of prescriptions occurs to control avoidable ADRs, resulting in polypharmacy. As many as 57% of women older than 65 in the United States are currently prescribed five or more medications, with 12% prescribed nine or more drugs.⁶ Not only do these medications cause independent ADRs, but there is also increased risk for drug interactions—and potentially, additional avoidable ADRs.

The elderly population is at greater risk for ADEs because these patients are more likely to have multiple comorbidities and chronic diseases, requiring multiple therapies.⁷ Polypharmacy is also more dangerous in the elderly because the physiologic changes that occur during natural aging can affect both the pharmacokinetics and pharmacodynamics of medications. The absorption, distribution, metabolism, and excretion of drugs within the human body changes as a person ages, while certain drug classes can alter the way the body functions. For example, muscle mass naturally declines and the proportion of body fat to muscle increases; this change affects the distribution of drugs such as benzodiazepines or lithium.⁷ If the medication dosage is not corrected, the toxicity of the drug will be increased.⁷

Medication excretion is largely controlled by the kidneys. Renal perfusion and function decline with age, leading to a decrease in glomerular filtration rate—which requires closer monitoring of medication selection and dosing. The risk is heightened when the elderly patient becomes acutely ill. An acute decrease in kidney function results in decreased excretion of medications, leading to an increase in ADRs.⁷

Ultimately, the safety of many medications in the elderly patient is unknown.⁸ But there is a growing body of knowledge on the adverse effects of some classes of medication in this population.

COMMONLY PRESCRIBED MEDICATIONS—AND RISKS

ADEs result from medication errors, ADRs, allergic reactions, and overdoses. The incidence of ADEs—specifically ADRs and medication errors—is elevated in elderly patients who are prescribed certain classes of medications or multiple drugs simultaneously.⁸ Anticholinergic drugs and psychotropic drugs (specifically antipsychotics and benzodiazepines) are among the medications most commonly prescribed to elderly patients—and among the most likely to contribute to ADEs.⁹ Diabetes is a chronic condition whose treatment may also put elderly patients at risk for ADEs.¹⁰

Anticholinergic medications

Anticholinergic drugs—commonly prescribed for Parkinson disease, depression, urinary incontinence, pulmonary disorders, intestinal motility, and muscle spasms—competitively inhibit the binding of acetylcholine to muscarinic acetylcholine receptors.⁹ Because this mechanism tends to be nonselective, the adverse effects may be widespread. Central adverse effects include cognitive impairment, confusion, and delirium; peripheral adverse effects include constipation, urinary retention, dry mouth, blurred vision, peristaltic reduction, and tachycardia.⁹

Anticholinergic drugs are commonly prescribed to elderly patients for cardiovascular (CV) and neurologic disorders. (Medications for the former include ß-blockers, calcium channel blockers, diuretics, and ACE inhibitors; for the latter, amitriptyline, quetiapine, nortriptyline, prochlorperazine, haloperidol, and paroxetine.) An assessment of anticholinergic activity classified most neurologic medications as high activity and most CV medications as low—however, the latter are usually given in conjunction with other anticholinergic medications, increasing their ability to cause ADRs.¹¹

In many cases, patients are prescribed anticholinergic medications to control symptoms of a disease, not to cure it—which means patients may be taking these medications for years. This cumulative exposure is called the anticholinergic burden. Many studies show that the anticholinergic burden is a predictor of cognitive and physical decline; a 2016 study of adults older than 65 who were exposed to 5 mg/d of oxybutynin for more than three years had a 23% increased risk for dementia, compared to low-risk or no exposure groups.⁹

In a retrospective, population-level study conducted in New Zealand, researchers assessed the anticholinergic effects of delirium, urinary retention, and constipation in 2,248 patients (65 and older) who were admitted to the hospital with at least one prescribed medication. Anticholinergic burden was found to be a significant independent predictor; patients taking five anticholinergic medications were more than three times as likely to develop an anticholinergic effect than those taking just one such medication (adjusted odds ratio, 3.21).¹¹

Psychotropic drugs

Another often-prescribed medication group is psychotropic drugs, specifically antipsychotics and benzodiazepines, for agitation and behavioral disturbances in dementia. A year-long study of 851 patients in two long-term care nursing homes in Boston found that risk for ADRs—specifically, falls—was increased in those who had a change (initiation or dose increase) in psychotropic medication (ie, benzodiazepine, antipsychotic, or antidepressant).¹²

Second-generation antipsychotics, which are more commonly prescribed than first-generation agents, work on a postsynaptic blockade of brain dopamine D₂ receptors and have an increased affinity for serotonin 5-HT_2A receptors (see Table 1 for pharmacology of these medications).^13,14 Adverse effects of these drugs include hypotension, sedation, and anticholinergic effects. Second-generation antipsychotics also carry a “black box warning” for increased risk for death in elderly patients with dementia-related psychosis.¹⁵

Benzodiazepines bind to receptors in the gamma-aminobutyric acid receptor complex, which enhances the binding of this inhibitory neurotransmitter (see Table 2 for pharmacology). Of this class of drugs, lorazepam has the highest potency, whereas midazolam and diazepam have lower potencies. Use of benzodiazepines increases risk for delirium and respiratory depression.¹⁶

Diabetes treatment

People with diabetes have an increased risk for ADEs; this risk is elevated in older adults due to comorbidities such as peripheral neuropathy, retinopathy, coronary artery disease, and peripheral vascular disease.¹⁰ Hypoglycemic agents, such as insulin and insulin secretagogues, confer a higher risk for falls due to their hypoglycemic effect.¹⁰ Furthermore, metformin is known to increase risk for cognitive impairment in patients with diabetes.¹⁰

PREVENTING ADEs AND UNNECESSARY POLYPHARMACY

Predicting and preventing ADEs should be a health care provider’s priority when treating an elderly patient taking multiple medications—but it is often overlooked. Electronic medical records (EMRs) are helpful in preventing ADEs, specifically prescription errors, by flagging the patient’s chart when potentially problematic medications are ordered; however, this captures only a portion of ADEs occurring in this popu­lation.⁷

Other options to evaluate a patient for polypharmacy and possible ADRs include the Beers Criteria and the STOPP/START Criteria.^17,18 Additionally, performing thorough and frequent medication reviews helps ensure that patients are prescribed essential medications to treat their comorbidities with the most opportunistic risk-benefit ratio. Patients’ medication lists across settings (eg, hospital, primary care, urgent care) can be accessed more easily, efficiently, and accurately with the integration of EMRs.

Beers Criteria

First published by Dr. Mark Beers in 1991 and endorsed by the American Geriatrics Society, the Beers Criteria identifies possible harmful effects of certain commonly prescribed medications to help guide and modify pharmacologic treatments, particularly in adults older than 65. The Beers Criteria classifies medications into three categories:

1. Drugs that should be avoided or dose-adjusted
2. Drugs that are potentially inappropriate in patients with certain conditions or syndromes
3. Drugs that should be prescribed with caution in older adults.¹⁷

In the most recent update (2015), possible adverse effects of medications based on a patient’s hepatic or renal function, the effectiveness of the medication, and possible drug interactions were added. For example, nitrofurantoin and antiarrhythmics (eg, amiodarone and digoxin) should be avoided at a lower threshold of hepatic and renal impairment than previously recommended. The criteria suggest avoiding use of zolpidem, a nonbenzodiazepine receptor agonist, because of its elevated risk for adverse effects and minimal effectiveness in treating insomnia. More information about the 2015 criteria is available from the American Geriatrics Society (http://online library.wiley.com/doi/10.1111/jgs. 13702/full).¹⁹

The latest update also takes into account recently published evidence of increased ADEs resulting from drugs such as antipsychotics and proton pump inhibitors (PPIs).²⁰ Antipsychotics are associated with an increased risk for morbidity and mortality, and PPIs are now recommended only for treatment duration of up to two months because of the possible increased risk for Clostridium difficile infection, as well as falls and fractures in patients older than 65.²⁰ (PPIs indirectly reduce calcium absorption, which may lead to an increased fracture risk, particularly in postmenopausal women.²⁰)

As with any guideline, the Beers Criteria was designed to supplement, not replace, clinical expertise and judgment. The risks and benefits of a medication should be weighed for the individual patient.

STOPP/START Criteria

Less widely used is the STOPP/START Criteria, an evidence-based set of guidelines consisting of 65 STOPP (Screening Tool of Older Person’s potentially inappropriate Prescriptions) and 22 START (Screening Tool to Alert doctors to the Right Treatment) criteria. Although they may be used individually, STOPP and START are best used together to determine the most appropriate medications for an elderly patient.

The STOPP guidelines help determine when the risks of a medication may outweigh the benefits in a given patient. STOPP includes recommendations for the appropriate length of time to use a medication; for example, PPIs should not be used for more than eight weeks (similar to the Beers recommendation) and benzodiazepines and neuroleptics for more than four weeks.¹⁸

START helps clinicians recognize potential prescribing omissions and to identify when a medication regimen should be implemented based on a patient’s history.¹⁸ Examples of START criteria include suggestions of when to initiate calcium and vitamin D supplementation for prevention of osteoporosis and when to begin statins in patients with diabetes, coronary artery disease, and cardiovascular disease.¹⁸

STOPP/START is organized by physiologic system, which allows for greater usability, and it addresses medications by class rather than specific medications. (The Beers Criteria was criticized for these reasons, as well as its limited transferability outside the United States.) When assessed in systematic reviews, the STOPP/START criteria were found to be fundamentally more sensitive than the Beers Criteria. Overall, it was concluded that the use of the STOPP/START criteria resulted in an absolute risk reduction of 21.2% to 35.7% and greatly improved the appropriateness of prescribing medication to the elderly. Its use also resulted in fewer follow-up appointments with a primary care physician (PCP).¹⁸

iPhone and Android applications such as iGeriatrics and Medstopper provide clinicians with easy access to Beers Criteria and STOPP/START Criteria, respectively.

Medication reconciliation

Medication reconciliation—in which health care providers review a patient’s medication list at hospital admission and discharge, and even at routine office visits—is an increasingly common practice, especially with the implementation of EMRs. The patient’s prescribed and OTC medications, as well as dose, route, frequency, and indication, are updated, with the goal of maintaining the most accurate list. Health care providers can utilize both the Beers Criteria and the STOPP/START criteria in their reconciliation process to help reduce polypharmacy in the elderly. It is an essential step in maintaining communication between providers and ultimately decreasing the incidence of ADEs.¹⁷

IMPROVE … continuity of care

Polypharmacy can decrease patient likelihood to adhere to the regimen, whether due to confusion or intolerance.⁸ Patients should be included, along with caregivers and all medical providers, in a holistic assessment of the patient’s best interests in terms of long-term care and pharmacologic treatment, since those who have a sense of control in their treatment goals and expectations often achieve a better understanding of their medical status.¹⁰

However, educating patients about their medications is time-consuming, and time is often at a premium during a typical office visit. A pilot study of 28 male veterans (ages 85 and older)—the Integrated Management and Polypharmacy Review of Vulnerable Elders (IMPROVE) project—devised a model to combat this problem.²¹ As an adjunct to a visit with the PCP, a clinical pharmacist trained in patient education and medication management performed face-to-face clinical consults with patients and their caregivers. The results indicated that medical management by both the PCP and the pharmacist resulted in better medication management. The pharmacist was able to spend time with the patient and caregiver, resulting in individualized instructions, education, and strategies for safe and effective medication use. The PCP remained involved by cosigning the note with the pharmacist and was available for consultation, if needed.

In IMPROVE, 79% of patients had at least one medication discontinued and 75% had one or more dosing or timing adjustments made. Potentially inappropriate medications were reduced by 14%.²¹ When the researchers compared the six-month period before the trial with the six-month period afterward, they found an average pharmacy cost savings of $64 per veteran per month. There was also a decreasing trend in phone calls and visits to the PCP. Cost savings were comparable to or greater than those reported for similar interventions.²¹ There has not been sufficient long-term follow-up to assess this method’s effects on ADEs, morbidity, and mortality, however.

CONCLUSION

Managing medications in the elderly population is difficult, and polypharmacy is common due to the prevalence of patients with comorbidities. It is important for providers to be aware of possible drug interactions, prescribing cascades, and ADEs. Medications such as anticholinergics and antipsychotics pose an increased risk for ADEs, but the regular implementation of criteria such as Beers or STOPP/START in clinical practice will minimize overprescribing and improve health outcomes. These criteria should be used to supplement the clinical judgment and expertise of providers as a mainstay of patient care in the elderly.

CE/CME No: CR-1802

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Identify patients who are at the greatest risk for the effects of polypharmacy.
• Recognize which medications are most likely to cause adverse drug events (ADEs) in the elderly population.
• Understand the effects of aging on the pharmacokinetics and pharmacodynamics of medications.
• Learn strategies to reduce the risk for polypharmacy and ADEs, including use of the Beers Criteria and the STOPP/START Criteria.

FACULTY
Kelsey Barclay practices in orthopedic surgery at Stanford Medical Center in Palo Alto, California. Amy Frassetto practices in Ob-Gyn at NewYork-Presbyterian in New York City. Julie Robb practices in emergency medicine at South Nassau Communities Hospital in Oceanside, New York. Ellen D. Mandel is a Clinical Professor in the Department of PA Studies at Pace University-Lenox Hill Hospital in New York City.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid through January 31, 2019.

Article begins on next page >>

Managing medications in the elderly can be complicated by the physiologic effects of aging and the prevalence of comorbidities. Consistent use of tools such as the Beers criteria and the STOPP/START criteria, as well as medication reconciliation, can reduce polypharmacy and its adverse drug effects, improving health outcomes in this population.

Older adults (those 65 and older) often have a number of comorbidities requiring pharmacologic intervention, making medication management a complicated but essential part of caring for the elderly. A recent analysis of trends in prescription drug use by community-dwelling adults found that 39% of older adults used five or more prescribed medications.¹ Furthermore, about 72% of older adults also take a nonprescription medication (OTC or supplement); while OTC medication use has declined in this population in recent years, dietary supplement use has increased.²

These patients are also more susceptible to adverse drug events (ADEs)—including adverse drug reactions (ADRs)—resulting from the physiologic changes of aging. By one estimate, ADRs are about seven times more common in those older than 70 than in younger persons.³ One out of every 30 urgent hospital admissions in patients ages 65 and older is related to an ADR.⁴

Providers must therefore be cognizant of drug indications, dosing, and drug interactions when prescribing medications to elderly patients. Fortunately, tools and methods to avoid polypharmacy and the adverse effects of commonly prescribed medications—such as anticholinergics and psychotropic drugs—are available.

POLYPHARMACY AND PRESCRIPTION CASCADING

While there is no specific number of medications required to define polypharmacy, the term is generally used when a nonhospitalized individual is taking five or more medications.⁵ The more medications a patient is taking, the more at risk he or she will be for ADRs, drug interactions, and prescription cascading.

Prescription cascading begins when an ADR is thought to be a new symptom and a new drug is prescribed to control it. Ultimately, a cascade of prescriptions occurs to control avoidable ADRs, resulting in polypharmacy. As many as 57% of women older than 65 in the United States are currently prescribed five or more medications, with 12% prescribed nine or more drugs.⁶ Not only do these medications cause independent ADRs, but there is also increased risk for drug interactions—and potentially, additional avoidable ADRs.

The elderly population is at greater risk for ADEs because these patients are more likely to have multiple comorbidities and chronic diseases, requiring multiple therapies.⁷ Polypharmacy is also more dangerous in the elderly because the physiologic changes that occur during natural aging can affect both the pharmacokinetics and pharmacodynamics of medications. The absorption, distribution, metabolism, and excretion of drugs within the human body changes as a person ages, while certain drug classes can alter the way the body functions. For example, muscle mass naturally declines and the proportion of body fat to muscle increases; this change affects the distribution of drugs such as benzodiazepines or lithium.⁷ If the medication dosage is not corrected, the toxicity of the drug will be increased.⁷

Medication excretion is largely controlled by the kidneys. Renal perfusion and function decline with age, leading to a decrease in glomerular filtration rate—which requires closer monitoring of medication selection and dosing. The risk is heightened when the elderly patient becomes acutely ill. An acute decrease in kidney function results in decreased excretion of medications, leading to an increase in ADRs.⁷

Ultimately, the safety of many medications in the elderly patient is unknown.⁸ But there is a growing body of knowledge on the adverse effects of some classes of medication in this population.

COMMONLY PRESCRIBED MEDICATIONS—AND RISKS

ADEs result from medication errors, ADRs, allergic reactions, and overdoses. The incidence of ADEs—specifically ADRs and medication errors—is elevated in elderly patients who are prescribed certain classes of medications or multiple drugs simultaneously.⁸ Anticholinergic drugs and psychotropic drugs (specifically antipsychotics and benzodiazepines) are among the medications most commonly prescribed to elderly patients—and among the most likely to contribute to ADEs.⁹ Diabetes is a chronic condition whose treatment may also put elderly patients at risk for ADEs.¹⁰

Anticholinergic medications

Anticholinergic drugs—commonly prescribed for Parkinson disease, depression, urinary incontinence, pulmonary disorders, intestinal motility, and muscle spasms—competitively inhibit the binding of acetylcholine to muscarinic acetylcholine receptors.⁹ Because this mechanism tends to be nonselective, the adverse effects may be widespread. Central adverse effects include cognitive impairment, confusion, and delirium; peripheral adverse effects include constipation, urinary retention, dry mouth, blurred vision, peristaltic reduction, and tachycardia.⁹

Anticholinergic drugs are commonly prescribed to elderly patients for cardiovascular (CV) and neurologic disorders. (Medications for the former include ß-blockers, calcium channel blockers, diuretics, and ACE inhibitors; for the latter, amitriptyline, quetiapine, nortriptyline, prochlorperazine, haloperidol, and paroxetine.) An assessment of anticholinergic activity classified most neurologic medications as high activity and most CV medications as low—however, the latter are usually given in conjunction with other anticholinergic medications, increasing their ability to cause ADRs.¹¹

In many cases, patients are prescribed anticholinergic medications to control symptoms of a disease, not to cure it—which means patients may be taking these medications for years. This cumulative exposure is called the anticholinergic burden. Many studies show that the anticholinergic burden is a predictor of cognitive and physical decline; a 2016 study of adults older than 65 who were exposed to 5 mg/d of oxybutynin for more than three years had a 23% increased risk for dementia, compared to low-risk or no exposure groups.⁹

In a retrospective, population-level study conducted in New Zealand, researchers assessed the anticholinergic effects of delirium, urinary retention, and constipation in 2,248 patients (65 and older) who were admitted to the hospital with at least one prescribed medication. Anticholinergic burden was found to be a significant independent predictor; patients taking five anticholinergic medications were more than three times as likely to develop an anticholinergic effect than those taking just one such medication (adjusted odds ratio, 3.21).¹¹

Psychotropic drugs

Another often-prescribed medication group is psychotropic drugs, specifically antipsychotics and benzodiazepines, for agitation and behavioral disturbances in dementia. A year-long study of 851 patients in two long-term care nursing homes in Boston found that risk for ADRs—specifically, falls—was increased in those who had a change (initiation or dose increase) in psychotropic medication (ie, benzodiazepine, antipsychotic, or antidepressant).¹²

Second-generation antipsychotics, which are more commonly prescribed than first-generation agents, work on a postsynaptic blockade of brain dopamine D₂ receptors and have an increased affinity for serotonin 5-HT_2A receptors (see Table 1 for pharmacology of these medications).^13,14 Adverse effects of these drugs include hypotension, sedation, and anticholinergic effects. Second-generation antipsychotics also carry a “black box warning” for increased risk for death in elderly patients with dementia-related psychosis.¹⁵

Benzodiazepines bind to receptors in the gamma-aminobutyric acid receptor complex, which enhances the binding of this inhibitory neurotransmitter (see Table 2 for pharmacology). Of this class of drugs, lorazepam has the highest potency, whereas midazolam and diazepam have lower potencies. Use of benzodiazepines increases risk for delirium and respiratory depression.¹⁶

Diabetes treatment

People with diabetes have an increased risk for ADEs; this risk is elevated in older adults due to comorbidities such as peripheral neuropathy, retinopathy, coronary artery disease, and peripheral vascular disease.¹⁰ Hypoglycemic agents, such as insulin and insulin secretagogues, confer a higher risk for falls due to their hypoglycemic effect.¹⁰ Furthermore, metformin is known to increase risk for cognitive impairment in patients with diabetes.¹⁰

PREVENTING ADEs AND UNNECESSARY POLYPHARMACY

Predicting and preventing ADEs should be a health care provider’s priority when treating an elderly patient taking multiple medications—but it is often overlooked. Electronic medical records (EMRs) are helpful in preventing ADEs, specifically prescription errors, by flagging the patient’s chart when potentially problematic medications are ordered; however, this captures only a portion of ADEs occurring in this popu­lation.⁷

Other options to evaluate a patient for polypharmacy and possible ADRs include the Beers Criteria and the STOPP/START Criteria.^17,18 Additionally, performing thorough and frequent medication reviews helps ensure that patients are prescribed essential medications to treat their comorbidities with the most opportunistic risk-benefit ratio. Patients’ medication lists across settings (eg, hospital, primary care, urgent care) can be accessed more easily, efficiently, and accurately with the integration of EMRs.

Beers Criteria

First published by Dr. Mark Beers in 1991 and endorsed by the American Geriatrics Society, the Beers Criteria identifies possible harmful effects of certain commonly prescribed medications to help guide and modify pharmacologic treatments, particularly in adults older than 65. The Beers Criteria classifies medications into three categories:

1. Drugs that should be avoided or dose-adjusted
2. Drugs that are potentially inappropriate in patients with certain conditions or syndromes
3. Drugs that should be prescribed with caution in older adults.¹⁷

In the most recent update (2015), possible adverse effects of medications based on a patient’s hepatic or renal function, the effectiveness of the medication, and possible drug interactions were added. For example, nitrofurantoin and antiarrhythmics (eg, amiodarone and digoxin) should be avoided at a lower threshold of hepatic and renal impairment than previously recommended. The criteria suggest avoiding use of zolpidem, a nonbenzodiazepine receptor agonist, because of its elevated risk for adverse effects and minimal effectiveness in treating insomnia. More information about the 2015 criteria is available from the American Geriatrics Society (http://online library.wiley.com/doi/10.1111/jgs. 13702/full).¹⁹

The latest update also takes into account recently published evidence of increased ADEs resulting from drugs such as antipsychotics and proton pump inhibitors (PPIs).²⁰ Antipsychotics are associated with an increased risk for morbidity and mortality, and PPIs are now recommended only for treatment duration of up to two months because of the possible increased risk for Clostridium difficile infection, as well as falls and fractures in patients older than 65.²⁰ (PPIs indirectly reduce calcium absorption, which may lead to an increased fracture risk, particularly in postmenopausal women.²⁰)

As with any guideline, the Beers Criteria was designed to supplement, not replace, clinical expertise and judgment. The risks and benefits of a medication should be weighed for the individual patient.

STOPP/START Criteria

Less widely used is the STOPP/START Criteria, an evidence-based set of guidelines consisting of 65 STOPP (Screening Tool of Older Person’s potentially inappropriate Prescriptions) and 22 START (Screening Tool to Alert doctors to the Right Treatment) criteria. Although they may be used individually, STOPP and START are best used together to determine the most appropriate medications for an elderly patient.

The STOPP guidelines help determine when the risks of a medication may outweigh the benefits in a given patient. STOPP includes recommendations for the appropriate length of time to use a medication; for example, PPIs should not be used for more than eight weeks (similar to the Beers recommendation) and benzodiazepines and neuroleptics for more than four weeks.¹⁸

START helps clinicians recognize potential prescribing omissions and to identify when a medication regimen should be implemented based on a patient’s history.¹⁸ Examples of START criteria include suggestions of when to initiate calcium and vitamin D supplementation for prevention of osteoporosis and when to begin statins in patients with diabetes, coronary artery disease, and cardiovascular disease.¹⁸

STOPP/START is organized by physiologic system, which allows for greater usability, and it addresses medications by class rather than specific medications. (The Beers Criteria was criticized for these reasons, as well as its limited transferability outside the United States.) When assessed in systematic reviews, the STOPP/START criteria were found to be fundamentally more sensitive than the Beers Criteria. Overall, it was concluded that the use of the STOPP/START criteria resulted in an absolute risk reduction of 21.2% to 35.7% and greatly improved the appropriateness of prescribing medication to the elderly. Its use also resulted in fewer follow-up appointments with a primary care physician (PCP).¹⁸

iPhone and Android applications such as iGeriatrics and Medstopper provide clinicians with easy access to Beers Criteria and STOPP/START Criteria, respectively.

Medication reconciliation

Medication reconciliation—in which health care providers review a patient’s medication list at hospital admission and discharge, and even at routine office visits—is an increasingly common practice, especially with the implementation of EMRs. The patient’s prescribed and OTC medications, as well as dose, route, frequency, and indication, are updated, with the goal of maintaining the most accurate list. Health care providers can utilize both the Beers Criteria and the STOPP/START criteria in their reconciliation process to help reduce polypharmacy in the elderly. It is an essential step in maintaining communication between providers and ultimately decreasing the incidence of ADEs.¹⁷

IMPROVE … continuity of care

Polypharmacy can decrease patient likelihood to adhere to the regimen, whether due to confusion or intolerance.⁸ Patients should be included, along with caregivers and all medical providers, in a holistic assessment of the patient’s best interests in terms of long-term care and pharmacologic treatment, since those who have a sense of control in their treatment goals and expectations often achieve a better understanding of their medical status.¹⁰

However, educating patients about their medications is time-consuming, and time is often at a premium during a typical office visit. A pilot study of 28 male veterans (ages 85 and older)—the Integrated Management and Polypharmacy Review of Vulnerable Elders (IMPROVE) project—devised a model to combat this problem.²¹ As an adjunct to a visit with the PCP, a clinical pharmacist trained in patient education and medication management performed face-to-face clinical consults with patients and their caregivers. The results indicated that medical management by both the PCP and the pharmacist resulted in better medication management. The pharmacist was able to spend time with the patient and caregiver, resulting in individualized instructions, education, and strategies for safe and effective medication use. The PCP remained involved by cosigning the note with the pharmacist and was available for consultation, if needed.

In IMPROVE, 79% of patients had at least one medication discontinued and 75% had one or more dosing or timing adjustments made. Potentially inappropriate medications were reduced by 14%.²¹ When the researchers compared the six-month period before the trial with the six-month period afterward, they found an average pharmacy cost savings of $64 per veteran per month. There was also a decreasing trend in phone calls and visits to the PCP. Cost savings were comparable to or greater than those reported for similar interventions.²¹ There has not been sufficient long-term follow-up to assess this method’s effects on ADEs, morbidity, and mortality, however.

CONCLUSION

Managing medications in the elderly population is difficult, and polypharmacy is common due to the prevalence of patients with comorbidities. It is important for providers to be aware of possible drug interactions, prescribing cascades, and ADEs. Medications such as anticholinergics and antipsychotics pose an increased risk for ADEs, but the regular implementation of criteria such as Beers or STOPP/START in clinical practice will minimize overprescribing and improve health outcomes. These criteria should be used to supplement the clinical judgment and expertise of providers as a mainstay of patient care in the elderly.

ILLUSTRATIVE CASE

A 24-year-old G2P1 at 24 weeks’ gestation presents to your clinic for a routine prenatal visit. Her older daughter has asthma and she is inquiring as to whether there is anything she can do to lower the risk of her second child developing asthma in the future. What do you recommend?

Asthma is the most common chronic disease in children in resource-rich countries such as the United States.² The Centers for Disease Control and Prevention (CDC) reported that 8.4% of children were diagnosed with asthma in 2015.³

Omega-3 fatty acids, found naturally in fish oil, are thought to confer anti-inflammatory properties that offer protection against asthma. Clinical trials have shown that fish oil supplementation in pregnancy results in higher levels of omega-3 fatty acids, along with anti-inflammatory changes, in offspring.⁴ Previous epidemiologic studies have also found that consumption of omega-3 fatty acids decreased the risk of atopy and asthma in offspring.^5,6

A Cochrane review published in 2015, however, concluded that omega-3 supplementation during pregnancy had no benefit on wheeze or asthma in offspring.⁷ Five RCTs were included in the analysis. The largest trial by Palmer et al, which included 706 women, showed no benefit for omega-3 supplementation.⁸ The second largest by Olsen et al, which included 533 women, did show a benefit (hazard ratio [HR]=0.37; 95% confidence interval [CI], 0.15-0.92; number needed to treat [NNT]=19.6).⁹

These results, however, were limited by heterogeneity in the amount of fish oil supplemented and duration of follow-up. For example, the children in the Palmer study were followed only until 3 years of age, which is around the time that asthma can be formally diagnosed, potentially leading to under-reporting.⁸ In addition, the diagnosis of asthma was based on parent report of 3 episodes of wheezing, use of daily asthma medication, or use of a national registry—all of which can underestimate the incidence of asthma. The reported rate of childhood asthma with IgE-sensitization (they did not report the rate without sensitization) was 1.8% in both arms, which is much lower than the CDC’s rate of 8.4%, suggesting underdiagnosis.^3,8 Due to these biases and other potential confounders, no firm conclusions can be drawn from the Cochrane review.

STUDY SUMMARY

Maternal fish oil supplementation reduces incidence of asthma in children

This single-center, double-blinded RCT of 736 pregnant women evaluated the effect of 2.4 g/d of n-3 long-chain polyunsaturated fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) or placebo (olive oil), starting at an estimated gestational age of 24 to 26 weeks, on wheeze or asthma incidence in their offspring.¹

Eligible women were between 22 and 26 weeks’ pregnant at the time of recruitment. Exclusion criteria included supplementation of 600 IU/d or more of vitamin D, or having any endocrine, cardiac, or renal disorders. The investigators randomized the women in a 1:1 ratio to either fish oil or placebo. Maternal EPA and DHA blood levels were tested at the time of randomization and one week after birth.

The primary outcome was persistent wheeze or asthma (after 3 years of age, the diagnosis of persistent wheeze was termed asthma) based on daily diary recordings of 5 episodes of troublesome lung symptoms within the last 6 months (each lasting for at least 3 consecutive days), rescue use of inhaled beta₂-agonists, and/or relapse after a 3-month course of inhaled glucocorticoids. Secondary outcomes included lower respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization.

In total, 695 offspring were included in the study with 95.5% follow-up at 3 years and 93.1% follow-up at 5 years. The children had scheduled pediatric visits at 1 week; 1, 3, 6, 12, 18, 24, 30, and 36 months; and at 4 and 5 years, and acute visits for any pulmonary, allergic, or dermatologic symptoms that arose.

Results. The investigators found that the children of the mothers who received the fish oil had a lower risk of persistent wheeze or asthma at ages 3 to 5 years compared to those who received placebo (16.9% vs 23.7%; HR=0.69; 95% CI, 0.49-0.97; P=.035; NNT=14.7). But the effect of the fish oil supplementation was significant only in the children of the mothers with baseline EPA and DHA levels in the lowest third (17.5% vs 34.1%; HR=0.46; 95% CI, 0.25-0.83; P=.011; NNT=5.6). Similarly, in mothers who consumed the least EPA and DHA before the start of the study, fish oil supplementation had a greater benefit in terms of decreased wheeze and asthma (18.5% vs 32.4%; HR=0.55; 95% CI, 0.30-0.98; P=.043; NNT=7.2).

As for the secondary outcomes, only a reduction in lower respiratory tract infections was associated with the fish oil supplementation vs the control (38.8% vs 45.5%; HR=0.77; 95% CI, 0.61-0.99; P=.041; NNT=14.9). There was no reduction in asthma exacerbations, eczema, or risk of sensitization in the fish oil group.

WHAT'S NEW?

Study adds fuel to the fire

This study strengthens the case for fish oil supplementation during pregnancy to reduce the risk of asthma in offspring, despite the recent Cochrane review that showed no benefit.^1,7 The Palmer study used a much lower amount of omega-3s (900 mg/d fish oil vs 2400 mg/d in the current trial).^1,8 Olsen et al supplemented with a greater amount of omega-3s (2700 mg/d) and did find a benefit.⁹ The NNT from the Olsen study (19.6) is consistent with that of the current investigation, suggesting that a higher dosage may be necessary to prevent the onset of asthma.

This study strengthens the case for fish oil supplementation during pregnancy to reduce the risk of asthma in children.

Additionally, this study followed children for a longer period than did the Palmer study, which may have led to more accurate diagnoses of asthma.^1,8 Lastly, the diagnosis of asthma in the Palmer study was based on parent survey data and use of daily asthma medicine rather than on daily diary cards, which are often more accurate.

Consider fish consumption. Both this study and the Olsen trial were performed in Denmark.^1,9 While Denmark and the United States have had a relatively similar level of fish consumption since the 1990s, women in Denmark may eat a higher proportion of oily fish than women in the United States, given the more common inclusion of mackerel and herring in their diet.¹⁰ Thus, the effect of supplementation may be more pronounced in women in the United States.

CAVEATS

Questions remain: Ideal dose and which women to treat?

The US Food and Drug Administration currently recommends 8 to 12 ounces of fish per week for pregnant women, but there are no guidelines on the ideal amount of fish oil to be consumed.¹¹ The Palmer study,⁸ using 900 mg/d fish oil, did not show a benefit, whereas there did appear to be benefit in this study (2400 mg/d)¹ and the Olsen study (2700 mg/d).⁹ Further research is needed to determine the optimal dosage.

Only women whose blood levels of EPA and DHA are low to begin with will likely benefit from this intervention.

The decreased risk of persistent wheeze or asthma was seen only in the children of the women whose EPA and DHA blood levels were in the lowest third of the study population. Thus, only women whose blood levels are low to begin with will likely benefit from this intervention. Currently, EPA and DHA levels are not routinely checked, but there may be some benefit to doing so.

One proxy for blood levels is maternal intake of fish at baseline. The investigators found that there was an association between dietary intake of fish and blood levels of EPA and DHA (r=0.32; P<.001).¹ Therefore, additional screening questions to determine fish consumption would be useful for identifying women most likely to benefit from supplementation.

CHALLENGES TO IMPLEMENTATION

Multiple pills and additional cost

Since omega-3 fatty acids are relatively safe and the NNT in the general population is low, it may be worth supplementing all pregnant women, even without a commercially-available blood test for EPA or DHA. Nevertheless, some women may find it challenging to take up to an additional 4 pills/d for 13 or more weeks. Also, there is an associated cost with these supplements, although it is low.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 24-year-old G2P1 at 24 weeks’ gestation presents to your clinic for a routine prenatal visit. Her older daughter has asthma and she is inquiring as to whether there is anything she can do to lower the risk of her second child developing asthma in the future. What do you recommend?

Asthma is the most common chronic disease in children in resource-rich countries such as the United States.² The Centers for Disease Control and Prevention (CDC) reported that 8.4% of children were diagnosed with asthma in 2015.³

Omega-3 fatty acids, found naturally in fish oil, are thought to confer anti-inflammatory properties that offer protection against asthma. Clinical trials have shown that fish oil supplementation in pregnancy results in higher levels of omega-3 fatty acids, along with anti-inflammatory changes, in offspring.⁴ Previous epidemiologic studies have also found that consumption of omega-3 fatty acids decreased the risk of atopy and asthma in offspring.^5,6

A Cochrane review published in 2015, however, concluded that omega-3 supplementation during pregnancy had no benefit on wheeze or asthma in offspring.⁷ Five RCTs were included in the analysis. The largest trial by Palmer et al, which included 706 women, showed no benefit for omega-3 supplementation.⁸ The second largest by Olsen et al, which included 533 women, did show a benefit (hazard ratio [HR]=0.37; 95% confidence interval [CI], 0.15-0.92; number needed to treat [NNT]=19.6).⁹

These results, however, were limited by heterogeneity in the amount of fish oil supplemented and duration of follow-up. For example, the children in the Palmer study were followed only until 3 years of age, which is around the time that asthma can be formally diagnosed, potentially leading to under-reporting.⁸ In addition, the diagnosis of asthma was based on parent report of 3 episodes of wheezing, use of daily asthma medication, or use of a national registry—all of which can underestimate the incidence of asthma. The reported rate of childhood asthma with IgE-sensitization (they did not report the rate without sensitization) was 1.8% in both arms, which is much lower than the CDC’s rate of 8.4%, suggesting underdiagnosis.^3,8 Due to these biases and other potential confounders, no firm conclusions can be drawn from the Cochrane review.

STUDY SUMMARY

Maternal fish oil supplementation reduces incidence of asthma in children

This single-center, double-blinded RCT of 736 pregnant women evaluated the effect of 2.4 g/d of n-3 long-chain polyunsaturated fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) or placebo (olive oil), starting at an estimated gestational age of 24 to 26 weeks, on wheeze or asthma incidence in their offspring.¹

Eligible women were between 22 and 26 weeks’ pregnant at the time of recruitment. Exclusion criteria included supplementation of 600 IU/d or more of vitamin D, or having any endocrine, cardiac, or renal disorders. The investigators randomized the women in a 1:1 ratio to either fish oil or placebo. Maternal EPA and DHA blood levels were tested at the time of randomization and one week after birth.

The primary outcome was persistent wheeze or asthma (after 3 years of age, the diagnosis of persistent wheeze was termed asthma) based on daily diary recordings of 5 episodes of troublesome lung symptoms within the last 6 months (each lasting for at least 3 consecutive days), rescue use of inhaled beta₂-agonists, and/or relapse after a 3-month course of inhaled glucocorticoids. Secondary outcomes included lower respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization.

In total, 695 offspring were included in the study with 95.5% follow-up at 3 years and 93.1% follow-up at 5 years. The children had scheduled pediatric visits at 1 week; 1, 3, 6, 12, 18, 24, 30, and 36 months; and at 4 and 5 years, and acute visits for any pulmonary, allergic, or dermatologic symptoms that arose.

Results. The investigators found that the children of the mothers who received the fish oil had a lower risk of persistent wheeze or asthma at ages 3 to 5 years compared to those who received placebo (16.9% vs 23.7%; HR=0.69; 95% CI, 0.49-0.97; P=.035; NNT=14.7). But the effect of the fish oil supplementation was significant only in the children of the mothers with baseline EPA and DHA levels in the lowest third (17.5% vs 34.1%; HR=0.46; 95% CI, 0.25-0.83; P=.011; NNT=5.6). Similarly, in mothers who consumed the least EPA and DHA before the start of the study, fish oil supplementation had a greater benefit in terms of decreased wheeze and asthma (18.5% vs 32.4%; HR=0.55; 95% CI, 0.30-0.98; P=.043; NNT=7.2).

As for the secondary outcomes, only a reduction in lower respiratory tract infections was associated with the fish oil supplementation vs the control (38.8% vs 45.5%; HR=0.77; 95% CI, 0.61-0.99; P=.041; NNT=14.9). There was no reduction in asthma exacerbations, eczema, or risk of sensitization in the fish oil group.

WHAT'S NEW?

Study adds fuel to the fire

This study strengthens the case for fish oil supplementation during pregnancy to reduce the risk of asthma in offspring, despite the recent Cochrane review that showed no benefit.^1,7 The Palmer study used a much lower amount of omega-3s (900 mg/d fish oil vs 2400 mg/d in the current trial).^1,8 Olsen et al supplemented with a greater amount of omega-3s (2700 mg/d) and did find a benefit.⁹ The NNT from the Olsen study (19.6) is consistent with that of the current investigation, suggesting that a higher dosage may be necessary to prevent the onset of asthma.

This study strengthens the case for fish oil supplementation during pregnancy to reduce the risk of asthma in children.

Additionally, this study followed children for a longer period than did the Palmer study, which may have led to more accurate diagnoses of asthma.^1,8 Lastly, the diagnosis of asthma in the Palmer study was based on parent survey data and use of daily asthma medicine rather than on daily diary cards, which are often more accurate.

Consider fish consumption. Both this study and the Olsen trial were performed in Denmark.^1,9 While Denmark and the United States have had a relatively similar level of fish consumption since the 1990s, women in Denmark may eat a higher proportion of oily fish than women in the United States, given the more common inclusion of mackerel and herring in their diet.¹⁰ Thus, the effect of supplementation may be more pronounced in women in the United States.

CAVEATS

Questions remain: Ideal dose and which women to treat?

The US Food and Drug Administration currently recommends 8 to 12 ounces of fish per week for pregnant women, but there are no guidelines on the ideal amount of fish oil to be consumed.¹¹ The Palmer study,⁸ using 900 mg/d fish oil, did not show a benefit, whereas there did appear to be benefit in this study (2400 mg/d)¹ and the Olsen study (2700 mg/d).⁹ Further research is needed to determine the optimal dosage.

Only women whose blood levels of EPA and DHA are low to begin with will likely benefit from this intervention.

The decreased risk of persistent wheeze or asthma was seen only in the children of the women whose EPA and DHA blood levels were in the lowest third of the study population. Thus, only women whose blood levels are low to begin with will likely benefit from this intervention. Currently, EPA and DHA levels are not routinely checked, but there may be some benefit to doing so.

One proxy for blood levels is maternal intake of fish at baseline. The investigators found that there was an association between dietary intake of fish and blood levels of EPA and DHA (r=0.32; P<.001).¹ Therefore, additional screening questions to determine fish consumption would be useful for identifying women most likely to benefit from supplementation.

CHALLENGES TO IMPLEMENTATION

Multiple pills and additional cost

Since omega-3 fatty acids are relatively safe and the NNT in the general population is low, it may be worth supplementing all pregnant women, even without a commercially-available blood test for EPA or DHA. Nevertheless, some women may find it challenging to take up to an additional 4 pills/d for 13 or more weeks. Also, there is an associated cost with these supplements, although it is low.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 24-year-old G2P1 at 24 weeks’ gestation presents to your clinic for a routine prenatal visit. Her older daughter has asthma and she is inquiring as to whether there is anything she can do to lower the risk of her second child developing asthma in the future. What do you recommend?

Asthma is the most common chronic disease in children in resource-rich countries such as the United States.² The Centers for Disease Control and Prevention (CDC) reported that 8.4% of children were diagnosed with asthma in 2015.³

Omega-3 fatty acids, found naturally in fish oil, are thought to confer anti-inflammatory properties that offer protection against asthma. Clinical trials have shown that fish oil supplementation in pregnancy results in higher levels of omega-3 fatty acids, along with anti-inflammatory changes, in offspring.⁴ Previous epidemiologic studies have also found that consumption of omega-3 fatty acids decreased the risk of atopy and asthma in offspring.^5,6

A Cochrane review published in 2015, however, concluded that omega-3 supplementation during pregnancy had no benefit on wheeze or asthma in offspring.⁷ Five RCTs were included in the analysis. The largest trial by Palmer et al, which included 706 women, showed no benefit for omega-3 supplementation.⁸ The second largest by Olsen et al, which included 533 women, did show a benefit (hazard ratio [HR]=0.37; 95% confidence interval [CI], 0.15-0.92; number needed to treat [NNT]=19.6).⁹

These results, however, were limited by heterogeneity in the amount of fish oil supplemented and duration of follow-up. For example, the children in the Palmer study were followed only until 3 years of age, which is around the time that asthma can be formally diagnosed, potentially leading to under-reporting.⁸ In addition, the diagnosis of asthma was based on parent report of 3 episodes of wheezing, use of daily asthma medication, or use of a national registry—all of which can underestimate the incidence of asthma. The reported rate of childhood asthma with IgE-sensitization (they did not report the rate without sensitization) was 1.8% in both arms, which is much lower than the CDC’s rate of 8.4%, suggesting underdiagnosis.^3,8 Due to these biases and other potential confounders, no firm conclusions can be drawn from the Cochrane review.

STUDY SUMMARY

Maternal fish oil supplementation reduces incidence of asthma in children

This single-center, double-blinded RCT of 736 pregnant women evaluated the effect of 2.4 g/d of n-3 long-chain polyunsaturated fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) or placebo (olive oil), starting at an estimated gestational age of 24 to 26 weeks, on wheeze or asthma incidence in their offspring.¹

Eligible women were between 22 and 26 weeks’ pregnant at the time of recruitment. Exclusion criteria included supplementation of 600 IU/d or more of vitamin D, or having any endocrine, cardiac, or renal disorders. The investigators randomized the women in a 1:1 ratio to either fish oil or placebo. Maternal EPA and DHA blood levels were tested at the time of randomization and one week after birth.

The primary outcome was persistent wheeze or asthma (after 3 years of age, the diagnosis of persistent wheeze was termed asthma) based on daily diary recordings of 5 episodes of troublesome lung symptoms within the last 6 months (each lasting for at least 3 consecutive days), rescue use of inhaled beta₂-agonists, and/or relapse after a 3-month course of inhaled glucocorticoids. Secondary outcomes included lower respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization.

In total, 695 offspring were included in the study with 95.5% follow-up at 3 years and 93.1% follow-up at 5 years. The children had scheduled pediatric visits at 1 week; 1, 3, 6, 12, 18, 24, 30, and 36 months; and at 4 and 5 years, and acute visits for any pulmonary, allergic, or dermatologic symptoms that arose.

Results. The investigators found that the children of the mothers who received the fish oil had a lower risk of persistent wheeze or asthma at ages 3 to 5 years compared to those who received placebo (16.9% vs 23.7%; HR=0.69; 95% CI, 0.49-0.97; P=.035; NNT=14.7). But the effect of the fish oil supplementation was significant only in the children of the mothers with baseline EPA and DHA levels in the lowest third (17.5% vs 34.1%; HR=0.46; 95% CI, 0.25-0.83; P=.011; NNT=5.6). Similarly, in mothers who consumed the least EPA and DHA before the start of the study, fish oil supplementation had a greater benefit in terms of decreased wheeze and asthma (18.5% vs 32.4%; HR=0.55; 95% CI, 0.30-0.98; P=.043; NNT=7.2).

As for the secondary outcomes, only a reduction in lower respiratory tract infections was associated with the fish oil supplementation vs the control (38.8% vs 45.5%; HR=0.77; 95% CI, 0.61-0.99; P=.041; NNT=14.9). There was no reduction in asthma exacerbations, eczema, or risk of sensitization in the fish oil group.

WHAT'S NEW?

Study adds fuel to the fire

This study strengthens the case for fish oil supplementation during pregnancy to reduce the risk of asthma in offspring, despite the recent Cochrane review that showed no benefit.^1,7 The Palmer study used a much lower amount of omega-3s (900 mg/d fish oil vs 2400 mg/d in the current trial).^1,8 Olsen et al supplemented with a greater amount of omega-3s (2700 mg/d) and did find a benefit.⁹ The NNT from the Olsen study (19.6) is consistent with that of the current investigation, suggesting that a higher dosage may be necessary to prevent the onset of asthma.

This study strengthens the case for fish oil supplementation during pregnancy to reduce the risk of asthma in children.

Additionally, this study followed children for a longer period than did the Palmer study, which may have led to more accurate diagnoses of asthma.^1,8 Lastly, the diagnosis of asthma in the Palmer study was based on parent survey data and use of daily asthma medicine rather than on daily diary cards, which are often more accurate.

Consider fish consumption. Both this study and the Olsen trial were performed in Denmark.^1,9 While Denmark and the United States have had a relatively similar level of fish consumption since the 1990s, women in Denmark may eat a higher proportion of oily fish than women in the United States, given the more common inclusion of mackerel and herring in their diet.¹⁰ Thus, the effect of supplementation may be more pronounced in women in the United States.

CAVEATS

Questions remain: Ideal dose and which women to treat?

The US Food and Drug Administration currently recommends 8 to 12 ounces of fish per week for pregnant women, but there are no guidelines on the ideal amount of fish oil to be consumed.¹¹ The Palmer study,⁸ using 900 mg/d fish oil, did not show a benefit, whereas there did appear to be benefit in this study (2400 mg/d)¹ and the Olsen study (2700 mg/d).⁹ Further research is needed to determine the optimal dosage.

Only women whose blood levels of EPA and DHA are low to begin with will likely benefit from this intervention.

The decreased risk of persistent wheeze or asthma was seen only in the children of the women whose EPA and DHA blood levels were in the lowest third of the study population. Thus, only women whose blood levels are low to begin with will likely benefit from this intervention. Currently, EPA and DHA levels are not routinely checked, but there may be some benefit to doing so.

One proxy for blood levels is maternal intake of fish at baseline. The investigators found that there was an association between dietary intake of fish and blood levels of EPA and DHA (r=0.32; P<.001).¹ Therefore, additional screening questions to determine fish consumption would be useful for identifying women most likely to benefit from supplementation.

CHALLENGES TO IMPLEMENTATION

Multiple pills and additional cost

Since omega-3 fatty acids are relatively safe and the NNT in the general population is low, it may be worth supplementing all pregnant women, even without a commercially-available blood test for EPA or DHA. Nevertheless, some women may find it challenging to take up to an additional 4 pills/d for 13 or more weeks. Also, there is an associated cost with these supplements, although it is low.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

EVIDENCE SUMMARY

A 25-week double-blind, placebo-controlled RCT of 51 nursing home patients (mean age 76 years, range 50 to 95 years; 96% men) in 2000 found no difference in all-cause mortality between the MA treatment group and the placebo group (absolute risk reduction [ARR]=13.4%; 95% confidence interval [CI], -12.9% to 37.3%; number needed to harm [NNH]=7; 95% CI, -8 to 3).¹

A 2007 case-control study of 17,328 nursing home residents (mean age 84 years [standard deviation, 9]; 71% women) found increased mortality for residents treated with at least 6 days of MA (median survival=23.9 months; 95% CI, 20.2-27.5) compared with untreated residents (median survival=31.2 months; 95% CI, 27.8-35.9).² The decrease in median survival remained after adjusting for demographic variables, medical diagnoses, and cognitive and physical functioning (hazard ratio=1.37; 95% CI, 1.17-1.59). Follow-up ranged from 30 days to 44 months.

Risks related to megestrol acetate include deep vein thrombosis

The 2000 double-blind, placebo-controlled RCT of 51 nursing home patients found no difference in adverse events between the MA group and the placebo group (absolute risk increase=6.3%; 95% CI, -14.7% to 27.3%).¹ No DVTs were reported as adverse events.

A 2003 retrospective chart review of 246 nursing home residents (mean age 87 years, 77% women) who were given MA 400 mg/d found an overall incidence of DVT of 4.1% (10 residents); 3.2% (8) residents were on MA at the time of DVT occurrence.³

A 2000 retrospective chart review of 19 nursing home residents who were prescribed MA (mean age 83 years, range 66 to 92 years; 84% women) found 32% (6) who developed Doppler-confirmed DVT after 50 days of therapy.⁴ DVT was not associated with known risk factors, age, body mass index, numbers of medications, or other medical diagnoses. The authors didn’t report MA dosage.

Patients on megestrol acetate don’t gain weight...

The 2000 double-blind, placebo-controlled RCT of 51 nursing home patients found no difference between the MA (800 mg/d for 12 weeks) and placebo groups in percentage of patients who gained ≥1.82 kg (ARR=-6.6%; 95% CI, -30.2% to 18.2%).¹ At the 25-week follow-up (after the MA patients had been off the therapy for 13 weeks), a statistically, but not clinically, significant difference was observed in the number of MA patients who gained ≥1.82 kg (absolute benefit increase=40.2%; 95% CI, 13.4%-66.9%; number needed to treat [NNT]=2; 95% CI, 1-8). Of note, the authors based their statistics on a weight gain of ≥1.82 kg whereas 5 kg or 5% weight gain is the more commonly used definition for clinical significance.⁵

Megestrol acetate is neither safe nor effective for stimulating appetite in malnourished nursing home residents.

The 2007 case-control cohort study of 17,328 nursing home residents, who had lost 5% of total body weight in 3 months or 10% of total body weight in 6 months, also found no significant difference in weight gain between MA-treated patients (median dose=486 mg, range 20 to 2400 mg; median duration=90 days, range 7 to 934 days; median change=1 lb, interquartile range [IQR]=-8 to 10) and controls (median change=2 lb, IQR=-4 to 9) after 6 months of treatment.²

In a 2005 prospective case series of 17 nursing home residents (mean age 92 years [standard deviation, 6], 88% women), MA (400 mg/d for 63 days) was associated with weight loss (mean=-2.13±9.32 lb).⁶ Nine patients (53%) lost weight (mean=9.3±5.4 lb), and 8 patients (47%) gained weight (mean=5.9±4.9 lb).

A retrospective chart review in 2000 of 14 nursing home residents (mean age 84 years, range 74 to 97 years; 85% women) who received MA 40 to 800 mg/d for one to 15 weeks showed that 43% gained weight (mean=3.1 kg), 43% lost weight (mean=2.0 kg), and 14% had no weight change.⁷

A 2002 retrospective chart review of 50 nursing home residents (mean age 79 years, range 31 to 93 years; 74% women) who were treated with MA 200 to 2400 mg/d for at least 6 months found a mean weight loss of 1.1 to 2.2 kg.⁸ In the 6 months after MA discontinuation, weight gain for available subjects (5 to 16 patients) varied (mean monthly change=-0.17 kg to 3.07 kg). The study had a high attrition rate (26 patients were lost 6 months after MA initiation; 39 were lost 6 months after MA discontinuation).

RECOMMENDATIONS

The 2015 American Geriatrics Society Beers Criteria for potentially inappropriate medication use in older adults strongly advises against the use of MA because of limited increases in weight and increased risk of thrombotic events.⁹

EVIDENCE SUMMARY

A 25-week double-blind, placebo-controlled RCT of 51 nursing home patients (mean age 76 years, range 50 to 95 years; 96% men) in 2000 found no difference in all-cause mortality between the MA treatment group and the placebo group (absolute risk reduction [ARR]=13.4%; 95% confidence interval [CI], -12.9% to 37.3%; number needed to harm [NNH]=7; 95% CI, -8 to 3).¹

A 2007 case-control study of 17,328 nursing home residents (mean age 84 years [standard deviation, 9]; 71% women) found increased mortality for residents treated with at least 6 days of MA (median survival=23.9 months; 95% CI, 20.2-27.5) compared with untreated residents (median survival=31.2 months; 95% CI, 27.8-35.9).² The decrease in median survival remained after adjusting for demographic variables, medical diagnoses, and cognitive and physical functioning (hazard ratio=1.37; 95% CI, 1.17-1.59). Follow-up ranged from 30 days to 44 months.

Risks related to megestrol acetate include deep vein thrombosis

The 2000 double-blind, placebo-controlled RCT of 51 nursing home patients found no difference in adverse events between the MA group and the placebo group (absolute risk increase=6.3%; 95% CI, -14.7% to 27.3%).¹ No DVTs were reported as adverse events.

A 2003 retrospective chart review of 246 nursing home residents (mean age 87 years, 77% women) who were given MA 400 mg/d found an overall incidence of DVT of 4.1% (10 residents); 3.2% (8) residents were on MA at the time of DVT occurrence.³

A 2000 retrospective chart review of 19 nursing home residents who were prescribed MA (mean age 83 years, range 66 to 92 years; 84% women) found 32% (6) who developed Doppler-confirmed DVT after 50 days of therapy.⁴ DVT was not associated with known risk factors, age, body mass index, numbers of medications, or other medical diagnoses. The authors didn’t report MA dosage.

Patients on megestrol acetate don’t gain weight...

The 2000 double-blind, placebo-controlled RCT of 51 nursing home patients found no difference between the MA (800 mg/d for 12 weeks) and placebo groups in percentage of patients who gained ≥1.82 kg (ARR=-6.6%; 95% CI, -30.2% to 18.2%).¹ At the 25-week follow-up (after the MA patients had been off the therapy for 13 weeks), a statistically, but not clinically, significant difference was observed in the number of MA patients who gained ≥1.82 kg (absolute benefit increase=40.2%; 95% CI, 13.4%-66.9%; number needed to treat [NNT]=2; 95% CI, 1-8). Of note, the authors based their statistics on a weight gain of ≥1.82 kg whereas 5 kg or 5% weight gain is the more commonly used definition for clinical significance.⁵

Megestrol acetate is neither safe nor effective for stimulating appetite in malnourished nursing home residents.

The 2007 case-control cohort study of 17,328 nursing home residents, who had lost 5% of total body weight in 3 months or 10% of total body weight in 6 months, also found no significant difference in weight gain between MA-treated patients (median dose=486 mg, range 20 to 2400 mg; median duration=90 days, range 7 to 934 days; median change=1 lb, interquartile range [IQR]=-8 to 10) and controls (median change=2 lb, IQR=-4 to 9) after 6 months of treatment.²

In a 2005 prospective case series of 17 nursing home residents (mean age 92 years [standard deviation, 6], 88% women), MA (400 mg/d for 63 days) was associated with weight loss (mean=-2.13±9.32 lb).⁶ Nine patients (53%) lost weight (mean=9.3±5.4 lb), and 8 patients (47%) gained weight (mean=5.9±4.9 lb).

A retrospective chart review in 2000 of 14 nursing home residents (mean age 84 years, range 74 to 97 years; 85% women) who received MA 40 to 800 mg/d for one to 15 weeks showed that 43% gained weight (mean=3.1 kg), 43% lost weight (mean=2.0 kg), and 14% had no weight change.⁷

A 2002 retrospective chart review of 50 nursing home residents (mean age 79 years, range 31 to 93 years; 74% women) who were treated with MA 200 to 2400 mg/d for at least 6 months found a mean weight loss of 1.1 to 2.2 kg.⁸ In the 6 months after MA discontinuation, weight gain for available subjects (5 to 16 patients) varied (mean monthly change=-0.17 kg to 3.07 kg). The study had a high attrition rate (26 patients were lost 6 months after MA initiation; 39 were lost 6 months after MA discontinuation).

RECOMMENDATIONS

The 2015 American Geriatrics Society Beers Criteria for potentially inappropriate medication use in older adults strongly advises against the use of MA because of limited increases in weight and increased risk of thrombotic events.⁹

EVIDENCE SUMMARY

A 25-week double-blind, placebo-controlled RCT of 51 nursing home patients (mean age 76 years, range 50 to 95 years; 96% men) in 2000 found no difference in all-cause mortality between the MA treatment group and the placebo group (absolute risk reduction [ARR]=13.4%; 95% confidence interval [CI], -12.9% to 37.3%; number needed to harm [NNH]=7; 95% CI, -8 to 3).¹

A 2007 case-control study of 17,328 nursing home residents (mean age 84 years [standard deviation, 9]; 71% women) found increased mortality for residents treated with at least 6 days of MA (median survival=23.9 months; 95% CI, 20.2-27.5) compared with untreated residents (median survival=31.2 months; 95% CI, 27.8-35.9).² The decrease in median survival remained after adjusting for demographic variables, medical diagnoses, and cognitive and physical functioning (hazard ratio=1.37; 95% CI, 1.17-1.59). Follow-up ranged from 30 days to 44 months.

Risks related to megestrol acetate include deep vein thrombosis

The 2000 double-blind, placebo-controlled RCT of 51 nursing home patients found no difference in adverse events between the MA group and the placebo group (absolute risk increase=6.3%; 95% CI, -14.7% to 27.3%).¹ No DVTs were reported as adverse events.

A 2003 retrospective chart review of 246 nursing home residents (mean age 87 years, 77% women) who were given MA 400 mg/d found an overall incidence of DVT of 4.1% (10 residents); 3.2% (8) residents were on MA at the time of DVT occurrence.³

A 2000 retrospective chart review of 19 nursing home residents who were prescribed MA (mean age 83 years, range 66 to 92 years; 84% women) found 32% (6) who developed Doppler-confirmed DVT after 50 days of therapy.⁴ DVT was not associated with known risk factors, age, body mass index, numbers of medications, or other medical diagnoses. The authors didn’t report MA dosage.

Patients on megestrol acetate don’t gain weight...

The 2000 double-blind, placebo-controlled RCT of 51 nursing home patients found no difference between the MA (800 mg/d for 12 weeks) and placebo groups in percentage of patients who gained ≥1.82 kg (ARR=-6.6%; 95% CI, -30.2% to 18.2%).¹ At the 25-week follow-up (after the MA patients had been off the therapy for 13 weeks), a statistically, but not clinically, significant difference was observed in the number of MA patients who gained ≥1.82 kg (absolute benefit increase=40.2%; 95% CI, 13.4%-66.9%; number needed to treat [NNT]=2; 95% CI, 1-8). Of note, the authors based their statistics on a weight gain of ≥1.82 kg whereas 5 kg or 5% weight gain is the more commonly used definition for clinical significance.⁵

Megestrol acetate is neither safe nor effective for stimulating appetite in malnourished nursing home residents.

The 2007 case-control cohort study of 17,328 nursing home residents, who had lost 5% of total body weight in 3 months or 10% of total body weight in 6 months, also found no significant difference in weight gain between MA-treated patients (median dose=486 mg, range 20 to 2400 mg; median duration=90 days, range 7 to 934 days; median change=1 lb, interquartile range [IQR]=-8 to 10) and controls (median change=2 lb, IQR=-4 to 9) after 6 months of treatment.²

In a 2005 prospective case series of 17 nursing home residents (mean age 92 years [standard deviation, 6], 88% women), MA (400 mg/d for 63 days) was associated with weight loss (mean=-2.13±9.32 lb).⁶ Nine patients (53%) lost weight (mean=9.3±5.4 lb), and 8 patients (47%) gained weight (mean=5.9±4.9 lb).

A retrospective chart review in 2000 of 14 nursing home residents (mean age 84 years, range 74 to 97 years; 85% women) who received MA 40 to 800 mg/d for one to 15 weeks showed that 43% gained weight (mean=3.1 kg), 43% lost weight (mean=2.0 kg), and 14% had no weight change.⁷

A 2002 retrospective chart review of 50 nursing home residents (mean age 79 years, range 31 to 93 years; 74% women) who were treated with MA 200 to 2400 mg/d for at least 6 months found a mean weight loss of 1.1 to 2.2 kg.⁸ In the 6 months after MA discontinuation, weight gain for available subjects (5 to 16 patients) varied (mean monthly change=-0.17 kg to 3.07 kg). The study had a high attrition rate (26 patients were lost 6 months after MA initiation; 39 were lost 6 months after MA discontinuation).

RECOMMENDATIONS

The 2015 American Geriatrics Society Beers Criteria for potentially inappropriate medication use in older adults strongly advises against the use of MA because of limited increases in weight and increased risk of thrombotic events.⁹

EVIDENCE SUMMARY

A Cochrane review of 16 RCTs (2144 patients) compared pain relief and return to function with oral NSAIDs and other oral analgesics (acetaminophen, opioids, or opioids plus acetaminophen) in patients who had suffered a soft tissue injury within the past 48 hours.¹ No differences between NSAIDs and acetaminophen were seen in pain relief at fewer than 24 hours on a 100-point visual analog scale (VAS) (4 trials; 359 patients; mean difference [MD]=1.56; 95% confidence interval [CI], -3.9 to 7.0). Nor were differences observed in return to function at 7 days (3 trials, 386 patients; risk ratio [RR]=0.99; 95% CI, 0.90-1.09).

No differences in pain relief between NSAIDs and oral opioids were seen at fewer than 24 hours (2 trials, 757 patients; MD=-0.02; 95% CI, -3.71 to 3.68) nor at days 4 to 6 (one trial, 706 patients; MD=-2.9; 95% CI, -6.06 to 0.26). Compared with NSAIDs, opioids showed a small increase in return to function at 7 days (2 trials, 749 patients; RR=1.13; 95% CI, 1.03-1.25), but the combination of acetaminophen and opioids didn’t show a difference (one trial, 89 patients; RR= 1.28; 95% CI, 0.90-1.81).

Adverse gastrointestinal events (not defined) were no different between NSAIDs and acetaminophen (7 trials, 627 patients; RR=1.76; 95% CI, 0.99-3.14) and occurred less often with NSAIDs than with oral opioids (2 trials, 769 patients; RR=0.51; 95% CI, 0.37-0.69). Overall, the authors concluded that low-quality evidence consistently showed NSAIDs were at least equal to other oral analgesics in efficacy of pain relief and return to function.

Naproxen vs oxycodone: The opioid has more adverse effects

A double-blind, noninferiority, randomized trial (published after the Cochrane review search date) compared the effects of treatment with a single dose of oxycodone with a single dose of naproxen in 150 adult emergency department (ED) patients in a tertiary care academic center who had acute soft tissue injury and pain scores between 3 and 7 (on a 1-to-10 scale).² Injuries included sprains, strains, contusions, low-back injury, and intervertebral disk problems. The authors didn’t clearly define “acute” with regard to time from injury.

Patients were randomized and given a single dose of oxycodone 10 mg or naproxen 250 mg with water. Pain scores and adverse effects were reassessed at 30 minutes and 60 minutes after administration, and a follow-up phone call was placed at 24 hours to evaluate further need for analgesics and adverse effects.

Baseline pain scores before medication administration were similar in the 2 groups (6.21 for the oxycodone group, 6 for the naproxen group). No difference in pain scores between oxycodone and naproxen was seen at 30 minutes (4.5 vs 4.4; P=.76) or 60 minutes (2.5 vs 2.6; P=.45). The number of patients who required more analgesics within 24 hours after administration didn’t differ significantly between the oxycodone group and the naproxen group (12 patients vs 5 patients; P=.07).

The study evaluated adverse effects, including nausea, vomiting, dizziness, drowsiness, pruritus, and epigastric pain. Overall, 22% of patients (33) from both groups combined experienced at least one adverse effect. The oxycodone group reported more adverse effects overall (36% vs 8%; RR=4.5; 95% CI, 2.0-10.2;). Ten patients experienced nausea, 6 vomiting, 4 dizziness, 3 drowsiness, and 2 pruritis. In the naproxen group, 4 patients experienced nausea; no other adverse effects were reported.

A double-blind RCT in a university hospital ED in Hong Kong compared patients older than 16 years with “isolated painful limb injury” after trauma who received combinations of analgesics or placebo.³ Patients were recruited during typical work-week hours (Monday to Friday, 9 am to 5 pm) and randomized into 4 groups: acetaminophen 1 g plus placebo (66 patients), placebo plus indomethacin 25 mg (71 patients), placebo plus diclofenac 25 mg (69 patients), or acetaminophen 1 g plus diclofenac 25 mg (94 patients).

Each patient was given the group’s designated combination of analgesics in the ED and asked to rate pain on a 0-to-100 visual analog pain scale (VAPS) at 0, 30, 60, 90, and 120 minutes after administration. Patients then left the ED with a 3-day course of their analgesic combination and were instructed to take the medication 4 times daily on the first day and 3 times daily thereafter. Patients recorded pain scores on the VAPS 3 times daily after discharge and at follow-up 5 to 8 days after initial presentation. Intention-to-treat analysis was done for patients lost to follow-up. A change in VAPS of 13 was considered clinically significant.

NSAIDs are at least as effective as opioids and acetaminophen in relieving pain from acute musculoskeletal injury.

All groups started with similar pain scores (30 at rest and 70 with activity) and didn’t achieve clinically significant pain relief within the first hour (mean change in VAPS <13). At 90 minutes, all groups achieved a mean change in VAPS >13, with no statistically significant difference between the groups. Adverse effects were rare (7% total), and none were severe (no gastrointestinal hemorrhage or renal damage).

Outside the ED, the acetaminophen-diclofenac combination group showed the greatest pain score reduction at every time point at rest and with activity, but none of the reductions were statistically or clinically significant (results presented graphically). No difference was found between the groups in number of patients who completed the course of analgesics, took additional analgesia, tried Chinese medicine, or returned to the ED within 30 days.

Limitations to the study included that the medication dosages may be much lower than typical dosages given in the United States and therefore lack applicability. The study also didn’t include a true placebo arm.

EVIDENCE SUMMARY

A Cochrane review of 16 RCTs (2144 patients) compared pain relief and return to function with oral NSAIDs and other oral analgesics (acetaminophen, opioids, or opioids plus acetaminophen) in patients who had suffered a soft tissue injury within the past 48 hours.¹ No differences between NSAIDs and acetaminophen were seen in pain relief at fewer than 24 hours on a 100-point visual analog scale (VAS) (4 trials; 359 patients; mean difference [MD]=1.56; 95% confidence interval [CI], -3.9 to 7.0). Nor were differences observed in return to function at 7 days (3 trials, 386 patients; risk ratio [RR]=0.99; 95% CI, 0.90-1.09).

No differences in pain relief between NSAIDs and oral opioids were seen at fewer than 24 hours (2 trials, 757 patients; MD=-0.02; 95% CI, -3.71 to 3.68) nor at days 4 to 6 (one trial, 706 patients; MD=-2.9; 95% CI, -6.06 to 0.26). Compared with NSAIDs, opioids showed a small increase in return to function at 7 days (2 trials, 749 patients; RR=1.13; 95% CI, 1.03-1.25), but the combination of acetaminophen and opioids didn’t show a difference (one trial, 89 patients; RR= 1.28; 95% CI, 0.90-1.81).

Adverse gastrointestinal events (not defined) were no different between NSAIDs and acetaminophen (7 trials, 627 patients; RR=1.76; 95% CI, 0.99-3.14) and occurred less often with NSAIDs than with oral opioids (2 trials, 769 patients; RR=0.51; 95% CI, 0.37-0.69). Overall, the authors concluded that low-quality evidence consistently showed NSAIDs were at least equal to other oral analgesics in efficacy of pain relief and return to function.

Naproxen vs oxycodone: The opioid has more adverse effects

A double-blind, noninferiority, randomized trial (published after the Cochrane review search date) compared the effects of treatment with a single dose of oxycodone with a single dose of naproxen in 150 adult emergency department (ED) patients in a tertiary care academic center who had acute soft tissue injury and pain scores between 3 and 7 (on a 1-to-10 scale).² Injuries included sprains, strains, contusions, low-back injury, and intervertebral disk problems. The authors didn’t clearly define “acute” with regard to time from injury.

Patients were randomized and given a single dose of oxycodone 10 mg or naproxen 250 mg with water. Pain scores and adverse effects were reassessed at 30 minutes and 60 minutes after administration, and a follow-up phone call was placed at 24 hours to evaluate further need for analgesics and adverse effects.

Baseline pain scores before medication administration were similar in the 2 groups (6.21 for the oxycodone group, 6 for the naproxen group). No difference in pain scores between oxycodone and naproxen was seen at 30 minutes (4.5 vs 4.4; P=.76) or 60 minutes (2.5 vs 2.6; P=.45). The number of patients who required more analgesics within 24 hours after administration didn’t differ significantly between the oxycodone group and the naproxen group (12 patients vs 5 patients; P=.07).

The study evaluated adverse effects, including nausea, vomiting, dizziness, drowsiness, pruritus, and epigastric pain. Overall, 22% of patients (33) from both groups combined experienced at least one adverse effect. The oxycodone group reported more adverse effects overall (36% vs 8%; RR=4.5; 95% CI, 2.0-10.2;). Ten patients experienced nausea, 6 vomiting, 4 dizziness, 3 drowsiness, and 2 pruritis. In the naproxen group, 4 patients experienced nausea; no other adverse effects were reported.

A double-blind RCT in a university hospital ED in Hong Kong compared patients older than 16 years with “isolated painful limb injury” after trauma who received combinations of analgesics or placebo.³ Patients were recruited during typical work-week hours (Monday to Friday, 9 am to 5 pm) and randomized into 4 groups: acetaminophen 1 g plus placebo (66 patients), placebo plus indomethacin 25 mg (71 patients), placebo plus diclofenac 25 mg (69 patients), or acetaminophen 1 g plus diclofenac 25 mg (94 patients).

Each patient was given the group’s designated combination of analgesics in the ED and asked to rate pain on a 0-to-100 visual analog pain scale (VAPS) at 0, 30, 60, 90, and 120 minutes after administration. Patients then left the ED with a 3-day course of their analgesic combination and were instructed to take the medication 4 times daily on the first day and 3 times daily thereafter. Patients recorded pain scores on the VAPS 3 times daily after discharge and at follow-up 5 to 8 days after initial presentation. Intention-to-treat analysis was done for patients lost to follow-up. A change in VAPS of 13 was considered clinically significant.

NSAIDs are at least as effective as opioids and acetaminophen in relieving pain from acute musculoskeletal injury.

All groups started with similar pain scores (30 at rest and 70 with activity) and didn’t achieve clinically significant pain relief within the first hour (mean change in VAPS <13). At 90 minutes, all groups achieved a mean change in VAPS >13, with no statistically significant difference between the groups. Adverse effects were rare (7% total), and none were severe (no gastrointestinal hemorrhage or renal damage).

Outside the ED, the acetaminophen-diclofenac combination group showed the greatest pain score reduction at every time point at rest and with activity, but none of the reductions were statistically or clinically significant (results presented graphically). No difference was found between the groups in number of patients who completed the course of analgesics, took additional analgesia, tried Chinese medicine, or returned to the ED within 30 days.

Limitations to the study included that the medication dosages may be much lower than typical dosages given in the United States and therefore lack applicability. The study also didn’t include a true placebo arm.

EVIDENCE SUMMARY

A Cochrane review of 16 RCTs (2144 patients) compared pain relief and return to function with oral NSAIDs and other oral analgesics (acetaminophen, opioids, or opioids plus acetaminophen) in patients who had suffered a soft tissue injury within the past 48 hours.¹ No differences between NSAIDs and acetaminophen were seen in pain relief at fewer than 24 hours on a 100-point visual analog scale (VAS) (4 trials; 359 patients; mean difference [MD]=1.56; 95% confidence interval [CI], -3.9 to 7.0). Nor were differences observed in return to function at 7 days (3 trials, 386 patients; risk ratio [RR]=0.99; 95% CI, 0.90-1.09).

No differences in pain relief between NSAIDs and oral opioids were seen at fewer than 24 hours (2 trials, 757 patients; MD=-0.02; 95% CI, -3.71 to 3.68) nor at days 4 to 6 (one trial, 706 patients; MD=-2.9; 95% CI, -6.06 to 0.26). Compared with NSAIDs, opioids showed a small increase in return to function at 7 days (2 trials, 749 patients; RR=1.13; 95% CI, 1.03-1.25), but the combination of acetaminophen and opioids didn’t show a difference (one trial, 89 patients; RR= 1.28; 95% CI, 0.90-1.81).

Adverse gastrointestinal events (not defined) were no different between NSAIDs and acetaminophen (7 trials, 627 patients; RR=1.76; 95% CI, 0.99-3.14) and occurred less often with NSAIDs than with oral opioids (2 trials, 769 patients; RR=0.51; 95% CI, 0.37-0.69). Overall, the authors concluded that low-quality evidence consistently showed NSAIDs were at least equal to other oral analgesics in efficacy of pain relief and return to function.

Naproxen vs oxycodone: The opioid has more adverse effects

A double-blind, noninferiority, randomized trial (published after the Cochrane review search date) compared the effects of treatment with a single dose of oxycodone with a single dose of naproxen in 150 adult emergency department (ED) patients in a tertiary care academic center who had acute soft tissue injury and pain scores between 3 and 7 (on a 1-to-10 scale).² Injuries included sprains, strains, contusions, low-back injury, and intervertebral disk problems. The authors didn’t clearly define “acute” with regard to time from injury.

Patients were randomized and given a single dose of oxycodone 10 mg or naproxen 250 mg with water. Pain scores and adverse effects were reassessed at 30 minutes and 60 minutes after administration, and a follow-up phone call was placed at 24 hours to evaluate further need for analgesics and adverse effects.

Baseline pain scores before medication administration were similar in the 2 groups (6.21 for the oxycodone group, 6 for the naproxen group). No difference in pain scores between oxycodone and naproxen was seen at 30 minutes (4.5 vs 4.4; P=.76) or 60 minutes (2.5 vs 2.6; P=.45). The number of patients who required more analgesics within 24 hours after administration didn’t differ significantly between the oxycodone group and the naproxen group (12 patients vs 5 patients; P=.07).

The study evaluated adverse effects, including nausea, vomiting, dizziness, drowsiness, pruritus, and epigastric pain. Overall, 22% of patients (33) from both groups combined experienced at least one adverse effect. The oxycodone group reported more adverse effects overall (36% vs 8%; RR=4.5; 95% CI, 2.0-10.2;). Ten patients experienced nausea, 6 vomiting, 4 dizziness, 3 drowsiness, and 2 pruritis. In the naproxen group, 4 patients experienced nausea; no other adverse effects were reported.

A double-blind RCT in a university hospital ED in Hong Kong compared patients older than 16 years with “isolated painful limb injury” after trauma who received combinations of analgesics or placebo.³ Patients were recruited during typical work-week hours (Monday to Friday, 9 am to 5 pm) and randomized into 4 groups: acetaminophen 1 g plus placebo (66 patients), placebo plus indomethacin 25 mg (71 patients), placebo plus diclofenac 25 mg (69 patients), or acetaminophen 1 g plus diclofenac 25 mg (94 patients).

Each patient was given the group’s designated combination of analgesics in the ED and asked to rate pain on a 0-to-100 visual analog pain scale (VAPS) at 0, 30, 60, 90, and 120 minutes after administration. Patients then left the ED with a 3-day course of their analgesic combination and were instructed to take the medication 4 times daily on the first day and 3 times daily thereafter. Patients recorded pain scores on the VAPS 3 times daily after discharge and at follow-up 5 to 8 days after initial presentation. Intention-to-treat analysis was done for patients lost to follow-up. A change in VAPS of 13 was considered clinically significant.

NSAIDs are at least as effective as opioids and acetaminophen in relieving pain from acute musculoskeletal injury.

All groups started with similar pain scores (30 at rest and 70 with activity) and didn’t achieve clinically significant pain relief within the first hour (mean change in VAPS <13). At 90 minutes, all groups achieved a mean change in VAPS >13, with no statistically significant difference between the groups. Adverse effects were rare (7% total), and none were severe (no gastrointestinal hemorrhage or renal damage).

Outside the ED, the acetaminophen-diclofenac combination group showed the greatest pain score reduction at every time point at rest and with activity, but none of the reductions were statistically or clinically significant (results presented graphically). No difference was found between the groups in number of patients who completed the course of analgesics, took additional analgesia, tried Chinese medicine, or returned to the ED within 30 days.

Limitations to the study included that the medication dosages may be much lower than typical dosages given in the United States and therefore lack applicability. The study also didn’t include a true placebo arm.