The Journal of Family Practice

A 2-year-old boy with atopic dermatitis developed a flare of his eczema after having a bath with mint-scented soap. His mother treated the flare with over-the-counter topical hydrocortisone cream. Two to 3 days later, he developed grouped vesicles on the right side of his neck. Three days after that, he developed a painful generalized vesicular eruption all over his body.

The boy was admitted to a hospital for supportive care and empiric antibiotics, but was discharged when no bacterial infection was found. The patient’s mother was instructed to follow up with his primary care provider in the next 2 weeks.

Three days after his hospitalization, the eruption on the young boy’s body spread and he was uncomfortable. He was brought to our hospital’s pediatric clinic, where physicians examined him and decided to transfer him to the university hospital for further evaluation.

On exam, the boy was afebrile, but uncomfortable and irritable. Diffuse heme-crusted and punched-out erosions covered about 90% of his body (FIGURE). His mucous membranes were not involved. Underneath the heme-crusted erosions, there were lichenified pink plaques on the antecubital fossae, popliteal fossae, periocular face, and buttocks. The patient’s right dorsal foot had a small vesicle; all other vesicles on his body had crusted over.

The patient’s family indicated that the child had received the varicella vaccine without incident at 12 months of age. He had no history of travel, no contact with sick individuals, and no exposure to pets or other animals.

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

Diagnosis: Eczema herpeticum

Eczema herpeticum (EH) was suspected based on the appearance of the lesions. A Tzanck smear came back positive for multinucleated giant cells and a herpes simplex virus (HSV) amplified probe came back positive for HSV-1—confirming the diagnosis.

EH—also known as Kaposi varicelliform eruption—is a superficial generalized viral infection (typically caused by HSV-1; HSV-2 is less common). The infection commonly occurs in patients with underlying atopic dermatitis, but may also occur in those with Darier disease, pemphigus, burns, and other conditions that disrupt the skin barrier. Other viruses, such as Coxsackie virus, can also cause EH. Eczema vaccinatum is a variant that may occur after smallpox vaccination.¹ EH occurs more often in infants and children than in adults,² and is a potentially life-threatening dermatologic emergency.

Eczema herpeticum occurs more often in infants and children than in adults, and is a potentially life-threatening emergency.

Who’s at risk? Patients with underlying chronic skin conditions such as eczema may have impaired cell-mediated immunity, making them more susceptible to a viral infection like EH.¹ In addition, treatment of underlying chronic skin conditions with immunosuppressive therapies often increases susceptibility to superimposed infection.¹ (In this case, the patient’s parents had treated an eczema flare with a topical hydrocortisone cream.) Lastly, increased risk may be associated with mutations in the gene encoding filaggrin.²

Areas affected. EH typically appears in areas of pre-existing dermatitis as monomorphic, discrete, 2- to 3-mm, punched-out, heme-crusted erosions with scalloped borders.² The erosions initially appear as vesicles or pustules, which may appear concurrently with the erosions. The erosions can coalesce to form larger lesions.³ Fever, malaise, and lymphadenopathy may also be present.^2,3

4 factors differentiate EH from other conditions

The differential for eczema herpeticum includes impetigo, bullous impetigo, shingles, chicken pox, scabies, pustular psoriasis, bullous pemphigoid, drug hypersensitivity reactions, and exacerbation of a primary dermatosis or skin condition.^1,4

EH may be differentiated from these by its location, its development in the setting of pre-existing dermatitis, its response to antiviral medications, and the results of laboratory testing. Because of the vast differential, physicians must maintain a high index of suspicion for EH, particularly when a patient with a pre-existing skin condition presents with acute onset cutaneous pain.³

Perform a Tzanck smear to diagnose the underlying infection

If EH is suspected, treatment must be initiated immediately.³ (In our patient’s case, he was started on intravenous acyclovir 10 mg/kg every 8 hours.)

Once treatment is underway, a Tzanck smear of the vesicle base can be performed at the patient’s bedside to narrow the cause of the infection to HSV or varicella zoster virus (VZV). Multinucleated giant keratinocytes (as in our patient’s case) are diagnostic for one of the herpes viruses; concurrent inflammatory cells are also to be expected in an inflammatory skin condition but by themselves are not diagnostic of herpes.

If available in the laboratory, direct fluorescent antibody testing can differentiate between HSV and VZV. Alternatively, a nucleic acid amplified probe test may be used to provide a quick and specific result. The most specific test is a viral culture, but it lacks sensitivity and usually requires 2 to 5 daysfor results.² A bacterial skin swab and blood culture should also be considered to direct antibiotic therapy if superinfection has occurred.

Antivirals and antibiotics should be given until lesions heal

Patients with EH should be admitted to the hospital for at least 24 to 48 hours of intravenous acyclovir.⁴ Antivirals—oral or intravenous—should be given for 10 to 14 days or until all mucocutaneous lesions are healed. Recommended dosing for acyclovir is 15 mg/kg (up to 400 mg) by mouth 3 to 5 times per day or, if severe, 5 mg/kg (if ≥12 years of age) to 10 mg/kg (if <12 years of age) intravenously every 8 hours.² Patients should also receive a 3- to 6-month suppressive course of oral acyclovir, valacyclovir, or famciclovir.⁴

Intravenous antibiotics should also be considered, pending the results of bacterial skin swabs and a blood culture, as the skin of patients with atopic dermatitis is colonized with staphylococcus 90% of the time.⁴

Potential complications. Bacterial sepsis resulting from superinfection and disseminated HSV, although extremely rare, is the main cause of death associated with EH.³ One case in the literature described a 43-year-old woman with extensive EH superimposed on atopic dermatitis, disseminated HSV, and Pseudomonas aeruginosa septicemia. Despite treatment with intravenous acyclovir and antibiotics in a burn center intensive care unit, the patient experienced septic shock and disseminated intravascular coagulation with progression to multiorgan failure and death.³

Our patient’s antiviral regimen was transitioned to a 14-day course of oral acyclovir, which he completed. Topical steroids and an immunosuppressant (tacrolimus ointment) were applied concurrently. He was subsequently prescribed a 6-month suppressive course of acyclovir and was scheduled for follow-up at an outpatient dermatology clinic to discuss resuming therapy for atopic dermatitis.

CORRESPONDENCE
Sahand Rahnama-Moghadam, MD, 7323 Snowden Road #1205, San Antonio, TX 78240; rahnamamogha@uthscsa.edu.

A 2-year-old boy with atopic dermatitis developed a flare of his eczema after having a bath with mint-scented soap. His mother treated the flare with over-the-counter topical hydrocortisone cream. Two to 3 days later, he developed grouped vesicles on the right side of his neck. Three days after that, he developed a painful generalized vesicular eruption all over his body.

The boy was admitted to a hospital for supportive care and empiric antibiotics, but was discharged when no bacterial infection was found. The patient’s mother was instructed to follow up with his primary care provider in the next 2 weeks.

Three days after his hospitalization, the eruption on the young boy’s body spread and he was uncomfortable. He was brought to our hospital’s pediatric clinic, where physicians examined him and decided to transfer him to the university hospital for further evaluation.

On exam, the boy was afebrile, but uncomfortable and irritable. Diffuse heme-crusted and punched-out erosions covered about 90% of his body (FIGURE). His mucous membranes were not involved. Underneath the heme-crusted erosions, there were lichenified pink plaques on the antecubital fossae, popliteal fossae, periocular face, and buttocks. The patient’s right dorsal foot had a small vesicle; all other vesicles on his body had crusted over.

The patient’s family indicated that the child had received the varicella vaccine without incident at 12 months of age. He had no history of travel, no contact with sick individuals, and no exposure to pets or other animals.

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

Diagnosis: Eczema herpeticum

Eczema herpeticum (EH) was suspected based on the appearance of the lesions. A Tzanck smear came back positive for multinucleated giant cells and a herpes simplex virus (HSV) amplified probe came back positive for HSV-1—confirming the diagnosis.

EH—also known as Kaposi varicelliform eruption—is a superficial generalized viral infection (typically caused by HSV-1; HSV-2 is less common). The infection commonly occurs in patients with underlying atopic dermatitis, but may also occur in those with Darier disease, pemphigus, burns, and other conditions that disrupt the skin barrier. Other viruses, such as Coxsackie virus, can also cause EH. Eczema vaccinatum is a variant that may occur after smallpox vaccination.¹ EH occurs more often in infants and children than in adults,² and is a potentially life-threatening dermatologic emergency.

Eczema herpeticum occurs more often in infants and children than in adults, and is a potentially life-threatening emergency.

Who’s at risk? Patients with underlying chronic skin conditions such as eczema may have impaired cell-mediated immunity, making them more susceptible to a viral infection like EH.¹ In addition, treatment of underlying chronic skin conditions with immunosuppressive therapies often increases susceptibility to superimposed infection.¹ (In this case, the patient’s parents had treated an eczema flare with a topical hydrocortisone cream.) Lastly, increased risk may be associated with mutations in the gene encoding filaggrin.²

Areas affected. EH typically appears in areas of pre-existing dermatitis as monomorphic, discrete, 2- to 3-mm, punched-out, heme-crusted erosions with scalloped borders.² The erosions initially appear as vesicles or pustules, which may appear concurrently with the erosions. The erosions can coalesce to form larger lesions.³ Fever, malaise, and lymphadenopathy may also be present.^2,3

4 factors differentiate EH from other conditions

The differential for eczema herpeticum includes impetigo, bullous impetigo, shingles, chicken pox, scabies, pustular psoriasis, bullous pemphigoid, drug hypersensitivity reactions, and exacerbation of a primary dermatosis or skin condition.^1,4

EH may be differentiated from these by its location, its development in the setting of pre-existing dermatitis, its response to antiviral medications, and the results of laboratory testing. Because of the vast differential, physicians must maintain a high index of suspicion for EH, particularly when a patient with a pre-existing skin condition presents with acute onset cutaneous pain.³

Perform a Tzanck smear to diagnose the underlying infection

If EH is suspected, treatment must be initiated immediately.³ (In our patient’s case, he was started on intravenous acyclovir 10 mg/kg every 8 hours.)

Once treatment is underway, a Tzanck smear of the vesicle base can be performed at the patient’s bedside to narrow the cause of the infection to HSV or varicella zoster virus (VZV). Multinucleated giant keratinocytes (as in our patient’s case) are diagnostic for one of the herpes viruses; concurrent inflammatory cells are also to be expected in an inflammatory skin condition but by themselves are not diagnostic of herpes.

If available in the laboratory, direct fluorescent antibody testing can differentiate between HSV and VZV. Alternatively, a nucleic acid amplified probe test may be used to provide a quick and specific result. The most specific test is a viral culture, but it lacks sensitivity and usually requires 2 to 5 daysfor results.² A bacterial skin swab and blood culture should also be considered to direct antibiotic therapy if superinfection has occurred.

Antivirals and antibiotics should be given until lesions heal

Patients with EH should be admitted to the hospital for at least 24 to 48 hours of intravenous acyclovir.⁴ Antivirals—oral or intravenous—should be given for 10 to 14 days or until all mucocutaneous lesions are healed. Recommended dosing for acyclovir is 15 mg/kg (up to 400 mg) by mouth 3 to 5 times per day or, if severe, 5 mg/kg (if ≥12 years of age) to 10 mg/kg (if <12 years of age) intravenously every 8 hours.² Patients should also receive a 3- to 6-month suppressive course of oral acyclovir, valacyclovir, or famciclovir.⁴

Intravenous antibiotics should also be considered, pending the results of bacterial skin swabs and a blood culture, as the skin of patients with atopic dermatitis is colonized with staphylococcus 90% of the time.⁴

Potential complications. Bacterial sepsis resulting from superinfection and disseminated HSV, although extremely rare, is the main cause of death associated with EH.³ One case in the literature described a 43-year-old woman with extensive EH superimposed on atopic dermatitis, disseminated HSV, and Pseudomonas aeruginosa septicemia. Despite treatment with intravenous acyclovir and antibiotics in a burn center intensive care unit, the patient experienced septic shock and disseminated intravascular coagulation with progression to multiorgan failure and death.³

Our patient’s antiviral regimen was transitioned to a 14-day course of oral acyclovir, which he completed. Topical steroids and an immunosuppressant (tacrolimus ointment) were applied concurrently. He was subsequently prescribed a 6-month suppressive course of acyclovir and was scheduled for follow-up at an outpatient dermatology clinic to discuss resuming therapy for atopic dermatitis.

CORRESPONDENCE
Sahand Rahnama-Moghadam, MD, 7323 Snowden Road #1205, San Antonio, TX 78240; rahnamamogha@uthscsa.edu.

A 2-year-old boy with atopic dermatitis developed a flare of his eczema after having a bath with mint-scented soap. His mother treated the flare with over-the-counter topical hydrocortisone cream. Two to 3 days later, he developed grouped vesicles on the right side of his neck. Three days after that, he developed a painful generalized vesicular eruption all over his body.

The boy was admitted to a hospital for supportive care and empiric antibiotics, but was discharged when no bacterial infection was found. The patient’s mother was instructed to follow up with his primary care provider in the next 2 weeks.

Three days after his hospitalization, the eruption on the young boy’s body spread and he was uncomfortable. He was brought to our hospital’s pediatric clinic, where physicians examined him and decided to transfer him to the university hospital for further evaluation.

On exam, the boy was afebrile, but uncomfortable and irritable. Diffuse heme-crusted and punched-out erosions covered about 90% of his body (FIGURE). His mucous membranes were not involved. Underneath the heme-crusted erosions, there were lichenified pink plaques on the antecubital fossae, popliteal fossae, periocular face, and buttocks. The patient’s right dorsal foot had a small vesicle; all other vesicles on his body had crusted over.

The patient’s family indicated that the child had received the varicella vaccine without incident at 12 months of age. He had no history of travel, no contact with sick individuals, and no exposure to pets or other animals.

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

Diagnosis: Eczema herpeticum

Eczema herpeticum (EH) was suspected based on the appearance of the lesions. A Tzanck smear came back positive for multinucleated giant cells and a herpes simplex virus (HSV) amplified probe came back positive for HSV-1—confirming the diagnosis.

EH—also known as Kaposi varicelliform eruption—is a superficial generalized viral infection (typically caused by HSV-1; HSV-2 is less common). The infection commonly occurs in patients with underlying atopic dermatitis, but may also occur in those with Darier disease, pemphigus, burns, and other conditions that disrupt the skin barrier. Other viruses, such as Coxsackie virus, can also cause EH. Eczema vaccinatum is a variant that may occur after smallpox vaccination.¹ EH occurs more often in infants and children than in adults,² and is a potentially life-threatening dermatologic emergency.

Eczema herpeticum occurs more often in infants and children than in adults, and is a potentially life-threatening emergency.

Who’s at risk? Patients with underlying chronic skin conditions such as eczema may have impaired cell-mediated immunity, making them more susceptible to a viral infection like EH.¹ In addition, treatment of underlying chronic skin conditions with immunosuppressive therapies often increases susceptibility to superimposed infection.¹ (In this case, the patient’s parents had treated an eczema flare with a topical hydrocortisone cream.) Lastly, increased risk may be associated with mutations in the gene encoding filaggrin.²

Areas affected. EH typically appears in areas of pre-existing dermatitis as monomorphic, discrete, 2- to 3-mm, punched-out, heme-crusted erosions with scalloped borders.² The erosions initially appear as vesicles or pustules, which may appear concurrently with the erosions. The erosions can coalesce to form larger lesions.³ Fever, malaise, and lymphadenopathy may also be present.^2,3

4 factors differentiate EH from other conditions

The differential for eczema herpeticum includes impetigo, bullous impetigo, shingles, chicken pox, scabies, pustular psoriasis, bullous pemphigoid, drug hypersensitivity reactions, and exacerbation of a primary dermatosis or skin condition.^1,4

EH may be differentiated from these by its location, its development in the setting of pre-existing dermatitis, its response to antiviral medications, and the results of laboratory testing. Because of the vast differential, physicians must maintain a high index of suspicion for EH, particularly when a patient with a pre-existing skin condition presents with acute onset cutaneous pain.³

Perform a Tzanck smear to diagnose the underlying infection

If EH is suspected, treatment must be initiated immediately.³ (In our patient’s case, he was started on intravenous acyclovir 10 mg/kg every 8 hours.)

Once treatment is underway, a Tzanck smear of the vesicle base can be performed at the patient’s bedside to narrow the cause of the infection to HSV or varicella zoster virus (VZV). Multinucleated giant keratinocytes (as in our patient’s case) are diagnostic for one of the herpes viruses; concurrent inflammatory cells are also to be expected in an inflammatory skin condition but by themselves are not diagnostic of herpes.

If available in the laboratory, direct fluorescent antibody testing can differentiate between HSV and VZV. Alternatively, a nucleic acid amplified probe test may be used to provide a quick and specific result. The most specific test is a viral culture, but it lacks sensitivity and usually requires 2 to 5 daysfor results.² A bacterial skin swab and blood culture should also be considered to direct antibiotic therapy if superinfection has occurred.

Antivirals and antibiotics should be given until lesions heal

Patients with EH should be admitted to the hospital for at least 24 to 48 hours of intravenous acyclovir.⁴ Antivirals—oral or intravenous—should be given for 10 to 14 days or until all mucocutaneous lesions are healed. Recommended dosing for acyclovir is 15 mg/kg (up to 400 mg) by mouth 3 to 5 times per day or, if severe, 5 mg/kg (if ≥12 years of age) to 10 mg/kg (if <12 years of age) intravenously every 8 hours.² Patients should also receive a 3- to 6-month suppressive course of oral acyclovir, valacyclovir, or famciclovir.⁴

Intravenous antibiotics should also be considered, pending the results of bacterial skin swabs and a blood culture, as the skin of patients with atopic dermatitis is colonized with staphylococcus 90% of the time.⁴

Potential complications. Bacterial sepsis resulting from superinfection and disseminated HSV, although extremely rare, is the main cause of death associated with EH.³ One case in the literature described a 43-year-old woman with extensive EH superimposed on atopic dermatitis, disseminated HSV, and Pseudomonas aeruginosa septicemia. Despite treatment with intravenous acyclovir and antibiotics in a burn center intensive care unit, the patient experienced septic shock and disseminated intravascular coagulation with progression to multiorgan failure and death.³

Our patient’s antiviral regimen was transitioned to a 14-day course of oral acyclovir, which he completed. Topical steroids and an immunosuppressant (tacrolimus ointment) were applied concurrently. He was subsequently prescribed a 6-month suppressive course of acyclovir and was scheduled for follow-up at an outpatient dermatology clinic to discuss resuming therapy for atopic dermatitis.

CORRESPONDENCE
Sahand Rahnama-Moghadam, MD, 7323 Snowden Road #1205, San Antonio, TX 78240; rahnamamogha@uthscsa.edu.

Illustrative Case

A 38-year-old woman recently diagnosed with MDD without a seasonal pattern comes to see you for her treatment options. Her Hamilton Depression Rating Scale (HAM-D) is 22, and she is not suicidal. Should you consider bright light therapy in addition to pharmacotherapy?

MDD is one of the most common psychiatric illnesses in the United States, affecting approximately one in 5 adults at some point in their lives.² Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors are considered effective first-line pharmacotherapy options for MDD.^2,3 Despite their effectiveness, however, studies have shown that only about 40% of patients with MDD achieve remission with first- or second-line drugs.² In addition, pharmacologic agents have a higher frequency of treatment-associated adverse effects than fluorescent light therapy.⁴

A Cochrane systematic review of 20 studies (N=620) showed the effectiveness of combined light therapy and pharmacotherapy in treating nonseasonal MDD, but found no benefit to light used as a monotherapy.⁵ However, the majority of the studies were of poor quality, occurred in the inpatient setting, and lasted fewer than 4 weeks.

In a 5-week, controlled, double-blind trial not included in the Cochrane review, 102 patients with nonseasonal MDD were randomized to receive either active treatment (bright light therapy) plus sertraline 50 mg daily or sham light treatment (using a dim red light) plus sertraline 50 mg daily. The investigators found a statistically significant larger reduction in depression score in the active treatment group than in the sham light group, based on the HAM-D, the Hamilton 6-Item Subscale, the Melancholia Scale, and the 7 atypical items from the Structured Interview Guide for the Seasonal Affective Disorder version of the HAM-D.^6,7

Study Summary 

Light therapy improves depression without a seasonal component

This latest study was an 8-week randomized, double-blind, placebo- and sham-controlled clinical trial evaluating the benefit of light therapy with and without pharmacotherapy for nonseasonal MDD.¹ The investigators enrolled 122 adult patients (ages 19-60 years) from outpatient psychiatry clinics with a diagnosis of MDD (as diagnosed by a psychiatrist) and a HAM-D⁸ score of at least 20. Subjects had to be off psychotropic medication for at least 2 weeks prior to the first visit and were subsequently monitored for one week to identify spontaneous responders and to give patients time to better regulate their sleep-wake cycle (with the goal of sleeping only between 10:00 pm and 8:00 am daily).

The investigators randomly assigned patients to one of 4 treatment groups: active light monotherapy (10,000-lux fluorescent white light for 30 min/d early in the morning) plus a placebo pill; fluoxetine 20 mg/d plus sham light therapy; placebo pills with sham light therapy; and combined active light therapy with fluoxetine 20 mg daily. Sham light therapy consisted of the use of an inactivated negative ion generator, used in the same fashion as a light box. All patients were analyzed based on modified intention to treat.

The investigators monitored patients for adherence to active and sham treatment by review of their daily logs of device treatment times. Pill counts were used to assess medication adherence. The primary outcome at 8 weeks was the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item questionnaire with a worst score of 60.⁹ Secondary outcomes were treatment response (≥50% MADRS score reduction) and remission (≤10 MADRS score) at the final 8th-week visit. MADRS scoring was used because of its higher sensitivity to treatment-induced changes and its high correlation with the HAM-D scale.

Seventy-six percent of patients treated with fluoxetine and light therapy saw at least a 50% improvement in their depression scores.

At the end of 8 weeks, the mean (standard deviation [SD]) changes in MADRS scores from baseline were: light monotherapy 13.4 (7.5), fluoxetine monotherapy 8.8 (9.9), combination therapy 16.9 (9.2), and placebo 6.5 (9.6). The improvement was significant in the light monotherapy treatment group vs the placebo group (P=.006), in the combination treatment group vs the vs placebo group (P<.001), and in the combination group vs the fluoxetine treatment group (P=.02), but not for the fluoxetine treatment group vs the placebo group (P=.32). The effect sizes vs placebo were: fluoxetine, d=0.24 (95% confidence interval [CI], −0.27 to 0.74); light monotherapy, 0.80 (95% CI, 0.28 to 1.31); and combination therapy, 1.11 (95% CI, 0.54 to 1.64). Effect sizes of more than 0.8 are often considered large.¹⁰

The treatment response (≥50% MADRS improvement) rate was highest in the combination treatment group (75.9%) with response rates to light monotherapy, placebo, and fluoxetine monotherapy of 50%, 33.3%, and 29%, respectively. There was a significant response effect for the combination vs placebo treatment group (P=.005). Similarly, there was a higher remission rate in the combination treatment group (58.6%) than in the placebo, light monotherapy, or fluoxetine treatment groups (30%, 43.8%, and 19.4%, respectively) with a significant effect for the combination vs placebo treatment group (P=.02).

Combination therapy was superior to placebo in treatment response (≥50% reduction in the MADRS score) and remission (MADRS ≤10) with numbers needed to treat of 2.4 (95% CI, 1.6-5.8) and 3.5 (95% CI, 2.0-29.9), respectively.

By the end of the 8-week study period, 16 of 122 patients had dropped out; 2 reported lack of efficacy, 5 reported adverse effects, and the remainder cited administrative reasons, were lost to follow-up, or withdrew consent.

What’s New? 

New evidence on a not-so-new treatment

We now have evidence that bright light therapy, either alone or in combination with fluoxetine, is efficacious in increasing the remission rate of nonseasonal MDD.

Caveats 

Choice of SSRI, geography, and trial duration may have affected results

A single SSRI (fluoxetine) was used in this study; other more potent SSRIs might work better. This study was conducted in southern Canada, and light therapy may not demonstrate as large a benefit in regions located farther south. The study excluded pregnant and breastfeeding women.

The trial duration was relatively short, and the investigators did not attain their pre-planned sample size for the study, which limited the power to detect clinically significant seasonal treatment effects and differences between the fluoxetine and placebo groups, regardless of whether they received active phototherapy.

Also, it’s worth noting that there were trends for some adverse events (nausea, heartburn, weight gain, agitation, sexual dysfunction, and skin rash) to occur less frequently in the combination group than in the fluoxetine monotherapy group. Possible explanations are that the study had inadequate power, that the sham treatment did not adequately blind patients, or that light therapy can ameliorate some of the adverse effects of fluoxetine.

We now have evidence that bright light therapy, alone or in combination with fluoxetine, is efficacious in increasing the remission rate of nonseasonal major depressive disorder.

Challenges to Implementation

Commercial insurance doesn’t usually cover light therapy

Bright light therapy is fairly safe, and some evidence exists supporting its use in the treatment of nonseasonal MDD; however, the data for its use in this area are limited.¹¹ Since only a few studies have tested light therapy for nonseasonal MDD, significant uncertainty remains about patient selection, as well as optimal dose, timing, and duration of light therapy in the management of nonseasonal MDD.¹² Although the risks associated with bright light therapy are minimal, the therapy can lead to mania or hypomania,³ so clinicians need to monitor for such effects when initiating therapy.

Lastly, commercial insurance does not usually cover light therapy. The average price of the bright light devices, which can be found in medical supply stores and online outlets, ranges between $118 and $237.^4,12 However, such devices are reusable, making the amortized cost almost negligible.¹³

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 38-year-old woman recently diagnosed with MDD without a seasonal pattern comes to see you for her treatment options. Her Hamilton Depression Rating Scale (HAM-D) is 22, and she is not suicidal. Should you consider bright light therapy in addition to pharmacotherapy?

MDD is one of the most common psychiatric illnesses in the United States, affecting approximately one in 5 adults at some point in their lives.² Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors are considered effective first-line pharmacotherapy options for MDD.^2,3 Despite their effectiveness, however, studies have shown that only about 40% of patients with MDD achieve remission with first- or second-line drugs.² In addition, pharmacologic agents have a higher frequency of treatment-associated adverse effects than fluorescent light therapy.⁴

A Cochrane systematic review of 20 studies (N=620) showed the effectiveness of combined light therapy and pharmacotherapy in treating nonseasonal MDD, but found no benefit to light used as a monotherapy.⁵ However, the majority of the studies were of poor quality, occurred in the inpatient setting, and lasted fewer than 4 weeks.

In a 5-week, controlled, double-blind trial not included in the Cochrane review, 102 patients with nonseasonal MDD were randomized to receive either active treatment (bright light therapy) plus sertraline 50 mg daily or sham light treatment (using a dim red light) plus sertraline 50 mg daily. The investigators found a statistically significant larger reduction in depression score in the active treatment group than in the sham light group, based on the HAM-D, the Hamilton 6-Item Subscale, the Melancholia Scale, and the 7 atypical items from the Structured Interview Guide for the Seasonal Affective Disorder version of the HAM-D.^6,7

Study Summary 

Light therapy improves depression without a seasonal component

This latest study was an 8-week randomized, double-blind, placebo- and sham-controlled clinical trial evaluating the benefit of light therapy with and without pharmacotherapy for nonseasonal MDD.¹ The investigators enrolled 122 adult patients (ages 19-60 years) from outpatient psychiatry clinics with a diagnosis of MDD (as diagnosed by a psychiatrist) and a HAM-D⁸ score of at least 20. Subjects had to be off psychotropic medication for at least 2 weeks prior to the first visit and were subsequently monitored for one week to identify spontaneous responders and to give patients time to better regulate their sleep-wake cycle (with the goal of sleeping only between 10:00 pm and 8:00 am daily).

The investigators randomly assigned patients to one of 4 treatment groups: active light monotherapy (10,000-lux fluorescent white light for 30 min/d early in the morning) plus a placebo pill; fluoxetine 20 mg/d plus sham light therapy; placebo pills with sham light therapy; and combined active light therapy with fluoxetine 20 mg daily. Sham light therapy consisted of the use of an inactivated negative ion generator, used in the same fashion as a light box. All patients were analyzed based on modified intention to treat.

The investigators monitored patients for adherence to active and sham treatment by review of their daily logs of device treatment times. Pill counts were used to assess medication adherence. The primary outcome at 8 weeks was the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item questionnaire with a worst score of 60.⁹ Secondary outcomes were treatment response (≥50% MADRS score reduction) and remission (≤10 MADRS score) at the final 8th-week visit. MADRS scoring was used because of its higher sensitivity to treatment-induced changes and its high correlation with the HAM-D scale.

Seventy-six percent of patients treated with fluoxetine and light therapy saw at least a 50% improvement in their depression scores.

At the end of 8 weeks, the mean (standard deviation [SD]) changes in MADRS scores from baseline were: light monotherapy 13.4 (7.5), fluoxetine monotherapy 8.8 (9.9), combination therapy 16.9 (9.2), and placebo 6.5 (9.6). The improvement was significant in the light monotherapy treatment group vs the placebo group (P=.006), in the combination treatment group vs the vs placebo group (P<.001), and in the combination group vs the fluoxetine treatment group (P=.02), but not for the fluoxetine treatment group vs the placebo group (P=.32). The effect sizes vs placebo were: fluoxetine, d=0.24 (95% confidence interval [CI], −0.27 to 0.74); light monotherapy, 0.80 (95% CI, 0.28 to 1.31); and combination therapy, 1.11 (95% CI, 0.54 to 1.64). Effect sizes of more than 0.8 are often considered large.¹⁰

The treatment response (≥50% MADRS improvement) rate was highest in the combination treatment group (75.9%) with response rates to light monotherapy, placebo, and fluoxetine monotherapy of 50%, 33.3%, and 29%, respectively. There was a significant response effect for the combination vs placebo treatment group (P=.005). Similarly, there was a higher remission rate in the combination treatment group (58.6%) than in the placebo, light monotherapy, or fluoxetine treatment groups (30%, 43.8%, and 19.4%, respectively) with a significant effect for the combination vs placebo treatment group (P=.02).

Combination therapy was superior to placebo in treatment response (≥50% reduction in the MADRS score) and remission (MADRS ≤10) with numbers needed to treat of 2.4 (95% CI, 1.6-5.8) and 3.5 (95% CI, 2.0-29.9), respectively.

By the end of the 8-week study period, 16 of 122 patients had dropped out; 2 reported lack of efficacy, 5 reported adverse effects, and the remainder cited administrative reasons, were lost to follow-up, or withdrew consent.

What’s New? 

New evidence on a not-so-new treatment

We now have evidence that bright light therapy, either alone or in combination with fluoxetine, is efficacious in increasing the remission rate of nonseasonal MDD.

Caveats 

Choice of SSRI, geography, and trial duration may have affected results

A single SSRI (fluoxetine) was used in this study; other more potent SSRIs might work better. This study was conducted in southern Canada, and light therapy may not demonstrate as large a benefit in regions located farther south. The study excluded pregnant and breastfeeding women.

The trial duration was relatively short, and the investigators did not attain their pre-planned sample size for the study, which limited the power to detect clinically significant seasonal treatment effects and differences between the fluoxetine and placebo groups, regardless of whether they received active phototherapy.

Also, it’s worth noting that there were trends for some adverse events (nausea, heartburn, weight gain, agitation, sexual dysfunction, and skin rash) to occur less frequently in the combination group than in the fluoxetine monotherapy group. Possible explanations are that the study had inadequate power, that the sham treatment did not adequately blind patients, or that light therapy can ameliorate some of the adverse effects of fluoxetine.

We now have evidence that bright light therapy, alone or in combination with fluoxetine, is efficacious in increasing the remission rate of nonseasonal major depressive disorder.

Challenges to Implementation

Commercial insurance doesn’t usually cover light therapy

Bright light therapy is fairly safe, and some evidence exists supporting its use in the treatment of nonseasonal MDD; however, the data for its use in this area are limited.¹¹ Since only a few studies have tested light therapy for nonseasonal MDD, significant uncertainty remains about patient selection, as well as optimal dose, timing, and duration of light therapy in the management of nonseasonal MDD.¹² Although the risks associated with bright light therapy are minimal, the therapy can lead to mania or hypomania,³ so clinicians need to monitor for such effects when initiating therapy.

Lastly, commercial insurance does not usually cover light therapy. The average price of the bright light devices, which can be found in medical supply stores and online outlets, ranges between $118 and $237.^4,12 However, such devices are reusable, making the amortized cost almost negligible.¹³

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 38-year-old woman recently diagnosed with MDD without a seasonal pattern comes to see you for her treatment options. Her Hamilton Depression Rating Scale (HAM-D) is 22, and she is not suicidal. Should you consider bright light therapy in addition to pharmacotherapy?

MDD is one of the most common psychiatric illnesses in the United States, affecting approximately one in 5 adults at some point in their lives.² Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors are considered effective first-line pharmacotherapy options for MDD.^2,3 Despite their effectiveness, however, studies have shown that only about 40% of patients with MDD achieve remission with first- or second-line drugs.² In addition, pharmacologic agents have a higher frequency of treatment-associated adverse effects than fluorescent light therapy.⁴

A Cochrane systematic review of 20 studies (N=620) showed the effectiveness of combined light therapy and pharmacotherapy in treating nonseasonal MDD, but found no benefit to light used as a monotherapy.⁵ However, the majority of the studies were of poor quality, occurred in the inpatient setting, and lasted fewer than 4 weeks.

In a 5-week, controlled, double-blind trial not included in the Cochrane review, 102 patients with nonseasonal MDD were randomized to receive either active treatment (bright light therapy) plus sertraline 50 mg daily or sham light treatment (using a dim red light) plus sertraline 50 mg daily. The investigators found a statistically significant larger reduction in depression score in the active treatment group than in the sham light group, based on the HAM-D, the Hamilton 6-Item Subscale, the Melancholia Scale, and the 7 atypical items from the Structured Interview Guide for the Seasonal Affective Disorder version of the HAM-D.^6,7

Study Summary 

Light therapy improves depression without a seasonal component

This latest study was an 8-week randomized, double-blind, placebo- and sham-controlled clinical trial evaluating the benefit of light therapy with and without pharmacotherapy for nonseasonal MDD.¹ The investigators enrolled 122 adult patients (ages 19-60 years) from outpatient psychiatry clinics with a diagnosis of MDD (as diagnosed by a psychiatrist) and a HAM-D⁸ score of at least 20. Subjects had to be off psychotropic medication for at least 2 weeks prior to the first visit and were subsequently monitored for one week to identify spontaneous responders and to give patients time to better regulate their sleep-wake cycle (with the goal of sleeping only between 10:00 pm and 8:00 am daily).

The investigators randomly assigned patients to one of 4 treatment groups: active light monotherapy (10,000-lux fluorescent white light for 30 min/d early in the morning) plus a placebo pill; fluoxetine 20 mg/d plus sham light therapy; placebo pills with sham light therapy; and combined active light therapy with fluoxetine 20 mg daily. Sham light therapy consisted of the use of an inactivated negative ion generator, used in the same fashion as a light box. All patients were analyzed based on modified intention to treat.

The investigators monitored patients for adherence to active and sham treatment by review of their daily logs of device treatment times. Pill counts were used to assess medication adherence. The primary outcome at 8 weeks was the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item questionnaire with a worst score of 60.⁹ Secondary outcomes were treatment response (≥50% MADRS score reduction) and remission (≤10 MADRS score) at the final 8th-week visit. MADRS scoring was used because of its higher sensitivity to treatment-induced changes and its high correlation with the HAM-D scale.

Seventy-six percent of patients treated with fluoxetine and light therapy saw at least a 50% improvement in their depression scores.

At the end of 8 weeks, the mean (standard deviation [SD]) changes in MADRS scores from baseline were: light monotherapy 13.4 (7.5), fluoxetine monotherapy 8.8 (9.9), combination therapy 16.9 (9.2), and placebo 6.5 (9.6). The improvement was significant in the light monotherapy treatment group vs the placebo group (P=.006), in the combination treatment group vs the vs placebo group (P<.001), and in the combination group vs the fluoxetine treatment group (P=.02), but not for the fluoxetine treatment group vs the placebo group (P=.32). The effect sizes vs placebo were: fluoxetine, d=0.24 (95% confidence interval [CI], −0.27 to 0.74); light monotherapy, 0.80 (95% CI, 0.28 to 1.31); and combination therapy, 1.11 (95% CI, 0.54 to 1.64). Effect sizes of more than 0.8 are often considered large.¹⁰

The treatment response (≥50% MADRS improvement) rate was highest in the combination treatment group (75.9%) with response rates to light monotherapy, placebo, and fluoxetine monotherapy of 50%, 33.3%, and 29%, respectively. There was a significant response effect for the combination vs placebo treatment group (P=.005). Similarly, there was a higher remission rate in the combination treatment group (58.6%) than in the placebo, light monotherapy, or fluoxetine treatment groups (30%, 43.8%, and 19.4%, respectively) with a significant effect for the combination vs placebo treatment group (P=.02).

Combination therapy was superior to placebo in treatment response (≥50% reduction in the MADRS score) and remission (MADRS ≤10) with numbers needed to treat of 2.4 (95% CI, 1.6-5.8) and 3.5 (95% CI, 2.0-29.9), respectively.

By the end of the 8-week study period, 16 of 122 patients had dropped out; 2 reported lack of efficacy, 5 reported adverse effects, and the remainder cited administrative reasons, were lost to follow-up, or withdrew consent.

What’s New? 

New evidence on a not-so-new treatment

We now have evidence that bright light therapy, either alone or in combination with fluoxetine, is efficacious in increasing the remission rate of nonseasonal MDD.

Caveats 

Choice of SSRI, geography, and trial duration may have affected results

A single SSRI (fluoxetine) was used in this study; other more potent SSRIs might work better. This study was conducted in southern Canada, and light therapy may not demonstrate as large a benefit in regions located farther south. The study excluded pregnant and breastfeeding women.

The trial duration was relatively short, and the investigators did not attain their pre-planned sample size for the study, which limited the power to detect clinically significant seasonal treatment effects and differences between the fluoxetine and placebo groups, regardless of whether they received active phototherapy.

Also, it’s worth noting that there were trends for some adverse events (nausea, heartburn, weight gain, agitation, sexual dysfunction, and skin rash) to occur less frequently in the combination group than in the fluoxetine monotherapy group. Possible explanations are that the study had inadequate power, that the sham treatment did not adequately blind patients, or that light therapy can ameliorate some of the adverse effects of fluoxetine.

We now have evidence that bright light therapy, alone or in combination with fluoxetine, is efficacious in increasing the remission rate of nonseasonal major depressive disorder.

Challenges to Implementation

Commercial insurance doesn’t usually cover light therapy

Bright light therapy is fairly safe, and some evidence exists supporting its use in the treatment of nonseasonal MDD; however, the data for its use in this area are limited.¹¹ Since only a few studies have tested light therapy for nonseasonal MDD, significant uncertainty remains about patient selection, as well as optimal dose, timing, and duration of light therapy in the management of nonseasonal MDD.¹² Although the risks associated with bright light therapy are minimal, the therapy can lead to mania or hypomania,³ so clinicians need to monitor for such effects when initiating therapy.

Lastly, commercial insurance does not usually cover light therapy. The average price of the bright light devices, which can be found in medical supply stores and online outlets, ranges between $118 and $237.^4,12 However, such devices are reusable, making the amortized cost almost negligible.¹³

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.

A biopsy was performed and direct immunofluorescence came back negative. This, along with the patient’s history of diabetes, led us to diagnose bullosis diabeticorum.

This condition, also known as bullous disease of diabetes, is characterized by abrupt development of noninflammatory bullae on acral areas in patients with diabetes. The skin appears normal except for the bullae. Bullosis diabeticorum occurs in just .5% of patients with diabetes and is twice as common in men as it is in women.

The etiology of bullosis diabeticorum is unknown. The acral location suggests that trauma may be a contributing factor. Although electron microscopy has suggested an abnormality in anchoring fibrils, this cellular change does not fully explain the development of multiple blisters at varying sites. Glycemic control is not thought to play a role.

The distribution of lesions and the presence—or absence—of systemic symptoms goes a long way toward narrowing the differential of blistering diseases. The presence of generalized blistering and systemic symptoms would suggest conditions related to medication exposure, such as Stevens-Johnson syndrome or toxic epidermal necrolysis; infectious etiologies (eg, staphylococcal scalded skin syndrome); autoimmune causes; or underlying malignancy. Generalized blistering in the absence of systemic symptoms would support diagnoses such as bullous impetigo and pemphigoid.

Lesion distribution provides important clues, too. Sun exposure-related causes typically leave lesions on the hands and forearms, not just the toes. A dermatomal distribution would suggest herpes zoster. A linear distribution of blisters argues for contact dermatitis.

A diagnosis of bullosis diabeticorum can be made when biopsy with immunofluorescence excludes other histologically similar entities such as epidermolysis bullosa, noninflammatory bullous pemphigoid, and porphyria cutanea tarda. And while immunofluorescence findings are typically negative, elevated levels of immunoglobulin M and C3 have, on occasion, been reported. Cultures are warranted only if a secondary infection is suspected.

The bullae of this condition spontaneously resolve over several weeks without treatment, but tend to recur. The lesions typically heal without significant scarring, although they may have a darker pigmentation after the first occurrence. Treatment may be warranted if a patient develops a secondary infection.

In our patient’s case, the bullae resolved within 2 weeks without treatment, although mild hyperpigmentation remained.

Adapted from: Mims L, Savage A, Chessman A. Blisters on an elderly woman's toes. J Fam Pract. 2014;63:273-274.

A biopsy was performed and direct immunofluorescence came back negative. This, along with the patient’s history of diabetes, led us to diagnose bullosis diabeticorum.

This condition, also known as bullous disease of diabetes, is characterized by abrupt development of noninflammatory bullae on acral areas in patients with diabetes. The skin appears normal except for the bullae. Bullosis diabeticorum occurs in just .5% of patients with diabetes and is twice as common in men as it is in women.

The etiology of bullosis diabeticorum is unknown. The acral location suggests that trauma may be a contributing factor. Although electron microscopy has suggested an abnormality in anchoring fibrils, this cellular change does not fully explain the development of multiple blisters at varying sites. Glycemic control is not thought to play a role.

The distribution of lesions and the presence—or absence—of systemic symptoms goes a long way toward narrowing the differential of blistering diseases. The presence of generalized blistering and systemic symptoms would suggest conditions related to medication exposure, such as Stevens-Johnson syndrome or toxic epidermal necrolysis; infectious etiologies (eg, staphylococcal scalded skin syndrome); autoimmune causes; or underlying malignancy. Generalized blistering in the absence of systemic symptoms would support diagnoses such as bullous impetigo and pemphigoid.

Lesion distribution provides important clues, too. Sun exposure-related causes typically leave lesions on the hands and forearms, not just the toes. A dermatomal distribution would suggest herpes zoster. A linear distribution of blisters argues for contact dermatitis.

A diagnosis of bullosis diabeticorum can be made when biopsy with immunofluorescence excludes other histologically similar entities such as epidermolysis bullosa, noninflammatory bullous pemphigoid, and porphyria cutanea tarda. And while immunofluorescence findings are typically negative, elevated levels of immunoglobulin M and C3 have, on occasion, been reported. Cultures are warranted only if a secondary infection is suspected.

The bullae of this condition spontaneously resolve over several weeks without treatment, but tend to recur. The lesions typically heal without significant scarring, although they may have a darker pigmentation after the first occurrence. Treatment may be warranted if a patient develops a secondary infection.

In our patient’s case, the bullae resolved within 2 weeks without treatment, although mild hyperpigmentation remained.

Adapted from: Mims L, Savage A, Chessman A. Blisters on an elderly woman's toes. J Fam Pract. 2014;63:273-274.

A biopsy was performed and direct immunofluorescence came back negative. This, along with the patient’s history of diabetes, led us to diagnose bullosis diabeticorum.

This condition, also known as bullous disease of diabetes, is characterized by abrupt development of noninflammatory bullae on acral areas in patients with diabetes. The skin appears normal except for the bullae. Bullosis diabeticorum occurs in just .5% of patients with diabetes and is twice as common in men as it is in women.

The etiology of bullosis diabeticorum is unknown. The acral location suggests that trauma may be a contributing factor. Although electron microscopy has suggested an abnormality in anchoring fibrils, this cellular change does not fully explain the development of multiple blisters at varying sites. Glycemic control is not thought to play a role.

The distribution of lesions and the presence—or absence—of systemic symptoms goes a long way toward narrowing the differential of blistering diseases. The presence of generalized blistering and systemic symptoms would suggest conditions related to medication exposure, such as Stevens-Johnson syndrome or toxic epidermal necrolysis; infectious etiologies (eg, staphylococcal scalded skin syndrome); autoimmune causes; or underlying malignancy. Generalized blistering in the absence of systemic symptoms would support diagnoses such as bullous impetigo and pemphigoid.

Lesion distribution provides important clues, too. Sun exposure-related causes typically leave lesions on the hands and forearms, not just the toes. A dermatomal distribution would suggest herpes zoster. A linear distribution of blisters argues for contact dermatitis.

A diagnosis of bullosis diabeticorum can be made when biopsy with immunofluorescence excludes other histologically similar entities such as epidermolysis bullosa, noninflammatory bullous pemphigoid, and porphyria cutanea tarda. And while immunofluorescence findings are typically negative, elevated levels of immunoglobulin M and C3 have, on occasion, been reported. Cultures are warranted only if a secondary infection is suspected.

The bullae of this condition spontaneously resolve over several weeks without treatment, but tend to recur. The lesions typically heal without significant scarring, although they may have a darker pigmentation after the first occurrence. Treatment may be warranted if a patient develops a secondary infection.

In our patient’s case, the bullae resolved within 2 weeks without treatment, although mild hyperpigmentation remained.

Adapted from: Mims L, Savage A, Chessman A. Blisters on an elderly woman's toes. J Fam Pract. 2014;63:273-274.

A 31-year-old incarcerated man sought care for one crusted ulcer and one adjacent open ulcer with granulation tissue on his left malleolus. The ulcers were caused by chronic venous insufficiency—the result of previous trauma to the ankle. Concerned that the ulcers would become infected, the physician prescribed one double-strength tablet twice a day of trimethoprim-sulfamethoxazole (TMP-SMX). The patient took 2 doses of the antibiotic and one dose of naproxen.

When the patient awoke the next morning, he had a generalized skin eruption on his chin, trunk, buttocks, glans penis, and extremities (FIGURE). The rash began as red edematous plaques that became itchy and painful with dark, violaceous dusky centers surrounded by redness. The patient was treated with topical hydrocortisone 2.5% twice a day and oral diphenhydramine 25 mg followed by 50 mg, but the rash didn’t improve.

The patient was transported to the local emergency department where physicians noted that the patient had about 30 to 40 well-demarcated papules and plaques of various sizes that were haphazardly located over the patient’s chin, chest, back, upper and lower extremities, and genitalia. There was one lesion on the chest with central vesiculation. There were no lesions on the mucous membranes of his eyes, ears, nose, mouth, or anus.

The patient, whose vital signs were within normal limits, was empirically treated with one dose of methylprednisolone (125 mg intravenous [IV]) and started on IV piperacillin-tazobactam and vancomycin. Lab work revealed no elevation in his white blood cell count, creatinine, liver function enzymes, or C-reactive protein.

The patient subsequently revealed that he’d had a similar experience a year earlier after being treated with TMP-SMX for cellulitis. He noted that during the previous episode, the lesions were located on the exact same areas of his glans penis and chin.

Diagnosis: Disseminated fixed-drug eruption

The diagnosis was based on the morphologic characteristics of the eruption and the patient’s history of similar lesions that appeared in the exact same initial locations (chin and glans penis) following previous treatment with TMP-SMX.

A fixed-drug eruption is an adverse cutaneous reaction to a drug that is defined by a dusky red or violaceous macule, which evolves into a patch, and eventually, an edematous plaque. Fixed-drug eruptions are typically solitary, but may be generalized (as was the case with our patient).

The pathophysiology of the disease involves resident intra-epidermal CD8+ T-cells resembling effector memory T-cells. These T-cells are increased in number at the dermoepidermal junction of normal appearing skin; their aberrant activation leads to an inflammatory response, stimulating tissue destruction and formation of the classic fixed-drug lesion.¹

The diagnosis is usually made based on a history of similar lesions recurring at the same location in response to a specific drug² and the classic physical exam findings of well-demarcated, edematous, and violaceous plaques. To confirm a fixed-drug eruption in the case of clinical equipoise, a skin biopsy may be performed.

Classic histologic findings of a fixed-drug eruption include:

• band-like lichenoid lymphocytic infiltrates with vacuolar changes at the dermoepidermal junction,
• mixed cellular infiltrates, including eosinophils, throughout the dermis and occasional superficial and deep mixed cellular perivascular infiltrates, and
• abundant melanophages suggesting pigment incontinence.

There are several reports of similar TMP-SMX–induced generalized fixed-drug eruptions in the literature.³ One study of 64 cases of fixed-drug eruption found that TMP-SMX was the most common offender, causing 75% of fixed-drug eruption cases; naproxen sodium came in second with 12.5%.³ Other common culprits include the antipyretic metamizole and other pyrazolone derivatives such as tetracycline, metronidazole, ciprofloxacin, and phenytoin sodium.⁴ There is evidence supporting a correlation between the offending drug and the subsequent site of reaction; TMP-SMX is associated with mucosal junction and genital involvement.^4,5 This finding may aid physicians in the investigation of provoking agents.

Distinguish fixed-drug eruptions from serious bullous diseases

Fixed-drug eruptions occasionally exhibit bullae and erosions and must be differentiated from more serious generalized bullous diseases, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The differential diagnosis also includes erythema multiforme, early bullous drug eruption, and bullous arthropod assault, which may leave similar hyperpigmented patches. Fixed-drug eruptions can be distinguished by the lack of simultaneous involvement of 2 mucosal surfaces, lack of generalized desquamation, and normal vital signs and lab values, including white blood cell count and erythrocyte sedimentation rate/C-reactive protein.

A subset of fixed-drug eruption, generalized bullous fixed-drug eruption (which has been defined as blistering on >10% of the body’s surface area at 3 different anatomic sites), may be particularly hard to distinguish from SJS and TEN. Generalized bullous fixed-drug eruption generally has a shorter latency period than SJS or TEN (usually <3 days compared to 7-10 days) and has less mucosal involvement.⁶

Symptomatic therapy includes antihistamines, glucocorticoid ointment

Management of a disseminated fixed-drug eruption requires a thorough history to identify the causative agent (including over-the-counter drugs, herbals, topicals, and eye drops). Most patients are asymptomatic, but some (like our patient) are symptomatic and experience generalized pruritus, cutaneous burning, and/or pain. Symptomatic therapy includes oral antihistamines and potent topical glucocorticoid ointment for non-eroded lesions. Additionally, if not medically contraindicated, oral steroids may be used for generalized or extremely painful mucosal lesions at a dose of 0.5 mg/kg daily for 3 to 5 days. Be advised, however, that these therapies are based on case report level data.²

Local wound care of eroded lesions includes keeping the site moist with a bland emollient and bandaging. The inciting agent must be added to the patient’s allergy list and avoided in the future. In equivocal cases, it is prudent to admit the patient for observation to ensure that the eruption is not a nascent SJS or TEN eruption.

Our patient was admitted to the observation unit overnight to monitor for the appearance of systemic symptoms and to assess the evolution of the rash for further mucosal involvement that could have indicated SJS. Upon reassessment the next day, his older lesions had evolved into vesiculated and necrotic areas as per the natural history of severe fixed-drug eruption.

He was prescribed prednisone 40 mg/d for 3 days to help with local inflammation, pain, and itching. TMP-SMX was added to his allergy list and he was given local wound care instructions. He was told to return if he developed any systemic symptoms.

CORRESPONDENCE
Jackie Bucher, MD, 7733 Louis Pasteur Drive Apt. 209, San Antonio, TX 78229; bucher@uthscsa.edu.

A 31-year-old incarcerated man sought care for one crusted ulcer and one adjacent open ulcer with granulation tissue on his left malleolus. The ulcers were caused by chronic venous insufficiency—the result of previous trauma to the ankle. Concerned that the ulcers would become infected, the physician prescribed one double-strength tablet twice a day of trimethoprim-sulfamethoxazole (TMP-SMX). The patient took 2 doses of the antibiotic and one dose of naproxen.

When the patient awoke the next morning, he had a generalized skin eruption on his chin, trunk, buttocks, glans penis, and extremities (FIGURE). The rash began as red edematous plaques that became itchy and painful with dark, violaceous dusky centers surrounded by redness. The patient was treated with topical hydrocortisone 2.5% twice a day and oral diphenhydramine 25 mg followed by 50 mg, but the rash didn’t improve.

The patient was transported to the local emergency department where physicians noted that the patient had about 30 to 40 well-demarcated papules and plaques of various sizes that were haphazardly located over the patient’s chin, chest, back, upper and lower extremities, and genitalia. There was one lesion on the chest with central vesiculation. There were no lesions on the mucous membranes of his eyes, ears, nose, mouth, or anus.

The patient, whose vital signs were within normal limits, was empirically treated with one dose of methylprednisolone (125 mg intravenous [IV]) and started on IV piperacillin-tazobactam and vancomycin. Lab work revealed no elevation in his white blood cell count, creatinine, liver function enzymes, or C-reactive protein.

The patient subsequently revealed that he’d had a similar experience a year earlier after being treated with TMP-SMX for cellulitis. He noted that during the previous episode, the lesions were located on the exact same areas of his glans penis and chin.

Diagnosis: Disseminated fixed-drug eruption

The diagnosis was based on the morphologic characteristics of the eruption and the patient’s history of similar lesions that appeared in the exact same initial locations (chin and glans penis) following previous treatment with TMP-SMX.

A fixed-drug eruption is an adverse cutaneous reaction to a drug that is defined by a dusky red or violaceous macule, which evolves into a patch, and eventually, an edematous plaque. Fixed-drug eruptions are typically solitary, but may be generalized (as was the case with our patient).

The pathophysiology of the disease involves resident intra-epidermal CD8+ T-cells resembling effector memory T-cells. These T-cells are increased in number at the dermoepidermal junction of normal appearing skin; their aberrant activation leads to an inflammatory response, stimulating tissue destruction and formation of the classic fixed-drug lesion.¹

The diagnosis is usually made based on a history of similar lesions recurring at the same location in response to a specific drug² and the classic physical exam findings of well-demarcated, edematous, and violaceous plaques. To confirm a fixed-drug eruption in the case of clinical equipoise, a skin biopsy may be performed.

Classic histologic findings of a fixed-drug eruption include:

• band-like lichenoid lymphocytic infiltrates with vacuolar changes at the dermoepidermal junction,
• mixed cellular infiltrates, including eosinophils, throughout the dermis and occasional superficial and deep mixed cellular perivascular infiltrates, and
• abundant melanophages suggesting pigment incontinence.

There are several reports of similar TMP-SMX–induced generalized fixed-drug eruptions in the literature.³ One study of 64 cases of fixed-drug eruption found that TMP-SMX was the most common offender, causing 75% of fixed-drug eruption cases; naproxen sodium came in second with 12.5%.³ Other common culprits include the antipyretic metamizole and other pyrazolone derivatives such as tetracycline, metronidazole, ciprofloxacin, and phenytoin sodium.⁴ There is evidence supporting a correlation between the offending drug and the subsequent site of reaction; TMP-SMX is associated with mucosal junction and genital involvement.^4,5 This finding may aid physicians in the investigation of provoking agents.

Distinguish fixed-drug eruptions from serious bullous diseases

Fixed-drug eruptions occasionally exhibit bullae and erosions and must be differentiated from more serious generalized bullous diseases, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The differential diagnosis also includes erythema multiforme, early bullous drug eruption, and bullous arthropod assault, which may leave similar hyperpigmented patches. Fixed-drug eruptions can be distinguished by the lack of simultaneous involvement of 2 mucosal surfaces, lack of generalized desquamation, and normal vital signs and lab values, including white blood cell count and erythrocyte sedimentation rate/C-reactive protein.

A subset of fixed-drug eruption, generalized bullous fixed-drug eruption (which has been defined as blistering on >10% of the body’s surface area at 3 different anatomic sites), may be particularly hard to distinguish from SJS and TEN. Generalized bullous fixed-drug eruption generally has a shorter latency period than SJS or TEN (usually <3 days compared to 7-10 days) and has less mucosal involvement.⁶

Symptomatic therapy includes antihistamines, glucocorticoid ointment

Management of a disseminated fixed-drug eruption requires a thorough history to identify the causative agent (including over-the-counter drugs, herbals, topicals, and eye drops). Most patients are asymptomatic, but some (like our patient) are symptomatic and experience generalized pruritus, cutaneous burning, and/or pain. Symptomatic therapy includes oral antihistamines and potent topical glucocorticoid ointment for non-eroded lesions. Additionally, if not medically contraindicated, oral steroids may be used for generalized or extremely painful mucosal lesions at a dose of 0.5 mg/kg daily for 3 to 5 days. Be advised, however, that these therapies are based on case report level data.²

Local wound care of eroded lesions includes keeping the site moist with a bland emollient and bandaging. The inciting agent must be added to the patient’s allergy list and avoided in the future. In equivocal cases, it is prudent to admit the patient for observation to ensure that the eruption is not a nascent SJS or TEN eruption.

Our patient was admitted to the observation unit overnight to monitor for the appearance of systemic symptoms and to assess the evolution of the rash for further mucosal involvement that could have indicated SJS. Upon reassessment the next day, his older lesions had evolved into vesiculated and necrotic areas as per the natural history of severe fixed-drug eruption.

He was prescribed prednisone 40 mg/d for 3 days to help with local inflammation, pain, and itching. TMP-SMX was added to his allergy list and he was given local wound care instructions. He was told to return if he developed any systemic symptoms.

CORRESPONDENCE
Jackie Bucher, MD, 7733 Louis Pasteur Drive Apt. 209, San Antonio, TX 78229; bucher@uthscsa.edu.

A 31-year-old incarcerated man sought care for one crusted ulcer and one adjacent open ulcer with granulation tissue on his left malleolus. The ulcers were caused by chronic venous insufficiency—the result of previous trauma to the ankle. Concerned that the ulcers would become infected, the physician prescribed one double-strength tablet twice a day of trimethoprim-sulfamethoxazole (TMP-SMX). The patient took 2 doses of the antibiotic and one dose of naproxen.

When the patient awoke the next morning, he had a generalized skin eruption on his chin, trunk, buttocks, glans penis, and extremities (FIGURE). The rash began as red edematous plaques that became itchy and painful with dark, violaceous dusky centers surrounded by redness. The patient was treated with topical hydrocortisone 2.5% twice a day and oral diphenhydramine 25 mg followed by 50 mg, but the rash didn’t improve.

The patient was transported to the local emergency department where physicians noted that the patient had about 30 to 40 well-demarcated papules and plaques of various sizes that were haphazardly located over the patient’s chin, chest, back, upper and lower extremities, and genitalia. There was one lesion on the chest with central vesiculation. There were no lesions on the mucous membranes of his eyes, ears, nose, mouth, or anus.

The patient, whose vital signs were within normal limits, was empirically treated with one dose of methylprednisolone (125 mg intravenous [IV]) and started on IV piperacillin-tazobactam and vancomycin. Lab work revealed no elevation in his white blood cell count, creatinine, liver function enzymes, or C-reactive protein.

The patient subsequently revealed that he’d had a similar experience a year earlier after being treated with TMP-SMX for cellulitis. He noted that during the previous episode, the lesions were located on the exact same areas of his glans penis and chin.

Diagnosis: Disseminated fixed-drug eruption

The diagnosis was based on the morphologic characteristics of the eruption and the patient’s history of similar lesions that appeared in the exact same initial locations (chin and glans penis) following previous treatment with TMP-SMX.

A fixed-drug eruption is an adverse cutaneous reaction to a drug that is defined by a dusky red or violaceous macule, which evolves into a patch, and eventually, an edematous plaque. Fixed-drug eruptions are typically solitary, but may be generalized (as was the case with our patient).

The pathophysiology of the disease involves resident intra-epidermal CD8+ T-cells resembling effector memory T-cells. These T-cells are increased in number at the dermoepidermal junction of normal appearing skin; their aberrant activation leads to an inflammatory response, stimulating tissue destruction and formation of the classic fixed-drug lesion.¹

The diagnosis is usually made based on a history of similar lesions recurring at the same location in response to a specific drug² and the classic physical exam findings of well-demarcated, edematous, and violaceous plaques. To confirm a fixed-drug eruption in the case of clinical equipoise, a skin biopsy may be performed.

Classic histologic findings of a fixed-drug eruption include:

• band-like lichenoid lymphocytic infiltrates with vacuolar changes at the dermoepidermal junction,
• mixed cellular infiltrates, including eosinophils, throughout the dermis and occasional superficial and deep mixed cellular perivascular infiltrates, and
• abundant melanophages suggesting pigment incontinence.

There are several reports of similar TMP-SMX–induced generalized fixed-drug eruptions in the literature.³ One study of 64 cases of fixed-drug eruption found that TMP-SMX was the most common offender, causing 75% of fixed-drug eruption cases; naproxen sodium came in second with 12.5%.³ Other common culprits include the antipyretic metamizole and other pyrazolone derivatives such as tetracycline, metronidazole, ciprofloxacin, and phenytoin sodium.⁴ There is evidence supporting a correlation between the offending drug and the subsequent site of reaction; TMP-SMX is associated with mucosal junction and genital involvement.^4,5 This finding may aid physicians in the investigation of provoking agents.

Distinguish fixed-drug eruptions from serious bullous diseases

Fixed-drug eruptions occasionally exhibit bullae and erosions and must be differentiated from more serious generalized bullous diseases, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The differential diagnosis also includes erythema multiforme, early bullous drug eruption, and bullous arthropod assault, which may leave similar hyperpigmented patches. Fixed-drug eruptions can be distinguished by the lack of simultaneous involvement of 2 mucosal surfaces, lack of generalized desquamation, and normal vital signs and lab values, including white blood cell count and erythrocyte sedimentation rate/C-reactive protein.

A subset of fixed-drug eruption, generalized bullous fixed-drug eruption (which has been defined as blistering on >10% of the body’s surface area at 3 different anatomic sites), may be particularly hard to distinguish from SJS and TEN. Generalized bullous fixed-drug eruption generally has a shorter latency period than SJS or TEN (usually <3 days compared to 7-10 days) and has less mucosal involvement.⁶

Symptomatic therapy includes antihistamines, glucocorticoid ointment

Management of a disseminated fixed-drug eruption requires a thorough history to identify the causative agent (including over-the-counter drugs, herbals, topicals, and eye drops). Most patients are asymptomatic, but some (like our patient) are symptomatic and experience generalized pruritus, cutaneous burning, and/or pain. Symptomatic therapy includes oral antihistamines and potent topical glucocorticoid ointment for non-eroded lesions. Additionally, if not medically contraindicated, oral steroids may be used for generalized or extremely painful mucosal lesions at a dose of 0.5 mg/kg daily for 3 to 5 days. Be advised, however, that these therapies are based on case report level data.²

Local wound care of eroded lesions includes keeping the site moist with a bland emollient and bandaging. The inciting agent must be added to the patient’s allergy list and avoided in the future. In equivocal cases, it is prudent to admit the patient for observation to ensure that the eruption is not a nascent SJS or TEN eruption.

Our patient was admitted to the observation unit overnight to monitor for the appearance of systemic symptoms and to assess the evolution of the rash for further mucosal involvement that could have indicated SJS. Upon reassessment the next day, his older lesions had evolved into vesiculated and necrotic areas as per the natural history of severe fixed-drug eruption.

He was prescribed prednisone 40 mg/d for 3 days to help with local inflammation, pain, and itching. TMP-SMX was added to his allergy list and he was given local wound care instructions. He was told to return if he developed any systemic symptoms.

CORRESPONDENCE
Jackie Bucher, MD, 7733 Louis Pasteur Drive Apt. 209, San Antonio, TX 78229; bucher@uthscsa.edu.

In December 2015, the United States Preventive Services Task Force updated its recommendation on screening for abnormal blood glucose and diabetes to say that clinicians should screen all adults ages 40 to 70 years who are overweight or obese as part of a cardiovascular risk assessment.¹ This recommendation carries a B grade signifying a moderate certainty that a moderate net benefit will be gained by detecting impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or diabetes, and by implementing intensive lifestyle interventions. In this article, as in the Task Force recommendation, the term diabetes means type 2 diabetes. Obesity is defined as a body mass index (BMI) of ≥30 kg/m², and overweight as a BMI >25.

How the Task Force recommendation evolved

The previous Task Force recommendation on this topic, made in 2008, advised screening only adults with hypertension because there was no evidence that any other group benefited from screening. In subsequent years, there were calls for the Task Force to revise its recommendation to bring it more in line with that of the American Diabetes Association (ADA).² While this new recommendation does add more adults to the cohort of those the Task Force believes should be screened, it is still not totally in concert with the ADA, which recommends screening all adults 45 years or older and those who are younger if they have multiple risk factors.³

Both the Task Force and the ADA acknowledge there is no direct evidence for any benefit in screening for diabetes in the general, asymptomatic population. The Task Force, with its standard of making recommendations only when good evidence supports them, has opted to address screening for abnormal glucose levels in the context of cardiovascular risk reduction and persuasive evidence that lifestyle interventions can reduce cardiovascular risks and slow progression to diabetes.

The ADA is willing to rely on less rigorous evidence of benefit in screening, diagnosing, and treating undetected diabetes. It believes that morbidity and mortality from this pervasive chronic disease can be reduced with early detection and treatment.

Still the Task Force and ADA agree more than they differ

While it appears that significant differences exist between the recommendations of the Task Force and the ADA, a closer look shows they actually have much in common; and, as they pertain to daily practice, any remaining differences are primarily ones of emphasis. For instance, the Clinical Considerations section of the Task Force recommendation acknowledges that certain people are at increased risk for diabetes at younger ages and at a lower BMI, and that clinicians should “consider” screening them earlier than at age 40 years. The risks listed include a family history of diabetes or a personal history of gestational diabetes or polycystic ovarian syndrome; or being African American, Hispanic, Asian American, American Indian, Alaskan Native, or Native Hawaiian.

The Task Force statement seems to imply—although this is not entirely clear—that those who have these risks should also be screened if they are older than age 40 years even if they are not obese. So, although the ADA would screen everyone ages 45 and older, the Task Force would screen everyone ages 40 and older, except for non-Hispanic whites who are not overweight or obese, and who have no other risk factors. TABLE 1^1,3 details the Task Force and the ADA screening criteria and how they differ.

The Task Force and the ADA also agree on the 3 tests acceptable for screening and the test values that define normal glucose, IGT, IFG, and diabetes (TABLE 2).^1,3 The tests are a randomly measured glycated hemoglobin level, a fasting plasma glucose level, and an oral glucose tolerance test performed in the morning after an overnight fast, with glucose measured 2 hours after a 75-g oral glucose load. If a screening result is abnormal, confirmation should be sought by repeating the same test. And both organizations suggest that, following a normal test result, the optimal interval for retesting is 3 years.

Intervening to delay progression to diabetes

For anyone with a confirmed abnormal blood glucose level, the Task Force advises referral for intensive behavioral interventions—ie, multiple counseling sessions over an extended period on a healthy diet and optimal physical activity. These types of interventions can reduce blood glucose levels and lower the risk of progression to diabetes, and can help with lowering weight, blood pressure, and lipid levels. The evidence report that preceded the recommendation pooled the results from 10 studies on lifestyle modification.⁴ The length of follow-up in these studies ranged from 3 to 23 years, and the number needed to treat to prevent one case of progression to diabetes ranged from about 5 to 20.⁴

Medications such as metformin, thiazolidinediones, and alpha-glucosidase inhibitors can also reduce blood glucose levels and slow progression to diabetes. However, the Task Force says there is insufficient evidence that pharmacologic interventions have the same multifactorial benefits—weight loss or reductions in glucose levels, blood pressure, and lipid levels—as behavioral interventions.¹

As for the other modifiable risk factors for cardiovascular disease—obesity, lack of physical activity, high lipid levels, high blood pressure, and smoking—the Task Force has developed recommendations on screening for and treating each of them,⁵ which supplement the recommendations discussed in this article.

In December 2015, the United States Preventive Services Task Force updated its recommendation on screening for abnormal blood glucose and diabetes to say that clinicians should screen all adults ages 40 to 70 years who are overweight or obese as part of a cardiovascular risk assessment.¹ This recommendation carries a B grade signifying a moderate certainty that a moderate net benefit will be gained by detecting impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or diabetes, and by implementing intensive lifestyle interventions. In this article, as in the Task Force recommendation, the term diabetes means type 2 diabetes. Obesity is defined as a body mass index (BMI) of ≥30 kg/m², and overweight as a BMI >25.

How the Task Force recommendation evolved

The previous Task Force recommendation on this topic, made in 2008, advised screening only adults with hypertension because there was no evidence that any other group benefited from screening. In subsequent years, there were calls for the Task Force to revise its recommendation to bring it more in line with that of the American Diabetes Association (ADA).² While this new recommendation does add more adults to the cohort of those the Task Force believes should be screened, it is still not totally in concert with the ADA, which recommends screening all adults 45 years or older and those who are younger if they have multiple risk factors.³

Both the Task Force and the ADA acknowledge there is no direct evidence for any benefit in screening for diabetes in the general, asymptomatic population. The Task Force, with its standard of making recommendations only when good evidence supports them, has opted to address screening for abnormal glucose levels in the context of cardiovascular risk reduction and persuasive evidence that lifestyle interventions can reduce cardiovascular risks and slow progression to diabetes.

The ADA is willing to rely on less rigorous evidence of benefit in screening, diagnosing, and treating undetected diabetes. It believes that morbidity and mortality from this pervasive chronic disease can be reduced with early detection and treatment.

Still the Task Force and ADA agree more than they differ

While it appears that significant differences exist between the recommendations of the Task Force and the ADA, a closer look shows they actually have much in common; and, as they pertain to daily practice, any remaining differences are primarily ones of emphasis. For instance, the Clinical Considerations section of the Task Force recommendation acknowledges that certain people are at increased risk for diabetes at younger ages and at a lower BMI, and that clinicians should “consider” screening them earlier than at age 40 years. The risks listed include a family history of diabetes or a personal history of gestational diabetes or polycystic ovarian syndrome; or being African American, Hispanic, Asian American, American Indian, Alaskan Native, or Native Hawaiian.

The Task Force statement seems to imply—although this is not entirely clear—that those who have these risks should also be screened if they are older than age 40 years even if they are not obese. So, although the ADA would screen everyone ages 45 and older, the Task Force would screen everyone ages 40 and older, except for non-Hispanic whites who are not overweight or obese, and who have no other risk factors. TABLE 1^1,3 details the Task Force and the ADA screening criteria and how they differ.

The Task Force and the ADA also agree on the 3 tests acceptable for screening and the test values that define normal glucose, IGT, IFG, and diabetes (TABLE 2).^1,3 The tests are a randomly measured glycated hemoglobin level, a fasting plasma glucose level, and an oral glucose tolerance test performed in the morning after an overnight fast, with glucose measured 2 hours after a 75-g oral glucose load. If a screening result is abnormal, confirmation should be sought by repeating the same test. And both organizations suggest that, following a normal test result, the optimal interval for retesting is 3 years.

Intervening to delay progression to diabetes

For anyone with a confirmed abnormal blood glucose level, the Task Force advises referral for intensive behavioral interventions—ie, multiple counseling sessions over an extended period on a healthy diet and optimal physical activity. These types of interventions can reduce blood glucose levels and lower the risk of progression to diabetes, and can help with lowering weight, blood pressure, and lipid levels. The evidence report that preceded the recommendation pooled the results from 10 studies on lifestyle modification.⁴ The length of follow-up in these studies ranged from 3 to 23 years, and the number needed to treat to prevent one case of progression to diabetes ranged from about 5 to 20.⁴

Medications such as metformin, thiazolidinediones, and alpha-glucosidase inhibitors can also reduce blood glucose levels and slow progression to diabetes. However, the Task Force says there is insufficient evidence that pharmacologic interventions have the same multifactorial benefits—weight loss or reductions in glucose levels, blood pressure, and lipid levels—as behavioral interventions.¹

As for the other modifiable risk factors for cardiovascular disease—obesity, lack of physical activity, high lipid levels, high blood pressure, and smoking—the Task Force has developed recommendations on screening for and treating each of them,⁵ which supplement the recommendations discussed in this article.

In December 2015, the United States Preventive Services Task Force updated its recommendation on screening for abnormal blood glucose and diabetes to say that clinicians should screen all adults ages 40 to 70 years who are overweight or obese as part of a cardiovascular risk assessment.¹ This recommendation carries a B grade signifying a moderate certainty that a moderate net benefit will be gained by detecting impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or diabetes, and by implementing intensive lifestyle interventions. In this article, as in the Task Force recommendation, the term diabetes means type 2 diabetes. Obesity is defined as a body mass index (BMI) of ≥30 kg/m², and overweight as a BMI >25.

How the Task Force recommendation evolved

The previous Task Force recommendation on this topic, made in 2008, advised screening only adults with hypertension because there was no evidence that any other group benefited from screening. In subsequent years, there were calls for the Task Force to revise its recommendation to bring it more in line with that of the American Diabetes Association (ADA).² While this new recommendation does add more adults to the cohort of those the Task Force believes should be screened, it is still not totally in concert with the ADA, which recommends screening all adults 45 years or older and those who are younger if they have multiple risk factors.³

Both the Task Force and the ADA acknowledge there is no direct evidence for any benefit in screening for diabetes in the general, asymptomatic population. The Task Force, with its standard of making recommendations only when good evidence supports them, has opted to address screening for abnormal glucose levels in the context of cardiovascular risk reduction and persuasive evidence that lifestyle interventions can reduce cardiovascular risks and slow progression to diabetes.

The ADA is willing to rely on less rigorous evidence of benefit in screening, diagnosing, and treating undetected diabetes. It believes that morbidity and mortality from this pervasive chronic disease can be reduced with early detection and treatment.

Still the Task Force and ADA agree more than they differ

While it appears that significant differences exist between the recommendations of the Task Force and the ADA, a closer look shows they actually have much in common; and, as they pertain to daily practice, any remaining differences are primarily ones of emphasis. For instance, the Clinical Considerations section of the Task Force recommendation acknowledges that certain people are at increased risk for diabetes at younger ages and at a lower BMI, and that clinicians should “consider” screening them earlier than at age 40 years. The risks listed include a family history of diabetes or a personal history of gestational diabetes or polycystic ovarian syndrome; or being African American, Hispanic, Asian American, American Indian, Alaskan Native, or Native Hawaiian.

The Task Force statement seems to imply—although this is not entirely clear—that those who have these risks should also be screened if they are older than age 40 years even if they are not obese. So, although the ADA would screen everyone ages 45 and older, the Task Force would screen everyone ages 40 and older, except for non-Hispanic whites who are not overweight or obese, and who have no other risk factors. TABLE 1^1,3 details the Task Force and the ADA screening criteria and how they differ.

The Task Force and the ADA also agree on the 3 tests acceptable for screening and the test values that define normal glucose, IGT, IFG, and diabetes (TABLE 2).^1,3 The tests are a randomly measured glycated hemoglobin level, a fasting plasma glucose level, and an oral glucose tolerance test performed in the morning after an overnight fast, with glucose measured 2 hours after a 75-g oral glucose load. If a screening result is abnormal, confirmation should be sought by repeating the same test. And both organizations suggest that, following a normal test result, the optimal interval for retesting is 3 years.

Intervening to delay progression to diabetes

For anyone with a confirmed abnormal blood glucose level, the Task Force advises referral for intensive behavioral interventions—ie, multiple counseling sessions over an extended period on a healthy diet and optimal physical activity. These types of interventions can reduce blood glucose levels and lower the risk of progression to diabetes, and can help with lowering weight, blood pressure, and lipid levels. The evidence report that preceded the recommendation pooled the results from 10 studies on lifestyle modification.⁴ The length of follow-up in these studies ranged from 3 to 23 years, and the number needed to treat to prevent one case of progression to diabetes ranged from about 5 to 20.⁴

Medications such as metformin, thiazolidinediones, and alpha-glucosidase inhibitors can also reduce blood glucose levels and slow progression to diabetes. However, the Task Force says there is insufficient evidence that pharmacologic interventions have the same multifactorial benefits—weight loss or reductions in glucose levels, blood pressure, and lipid levels—as behavioral interventions.¹

As for the other modifiable risk factors for cardiovascular disease—obesity, lack of physical activity, high lipid levels, high blood pressure, and smoking—the Task Force has developed recommendations on screening for and treating each of them,⁵ which supplement the recommendations discussed in this article.

Despite encouraging data that antibiotic prescribing is on the decline, patients are still prescribed antibiotics frequently, making these agents the 12th most frequently used drug class.¹ At the same time, prescribers are caring for patients with increasingly complex drug regimens that provide fertile ground for drug interactions with these antibiotics. And, of course, lifestyle factors such as alcohol consumption are a consideration when any prescription is written.

As pharmacists, we find that certain questions about antibiotic prescribing and interactions come up with frequency. These questions often pertain to the use of warfarin, oral contraceptives, drugs that prolong the QT interval, and alcohol. But conflicting reports about issues such as monitoring international normalized ratio (INR) in patients taking warfarin and antibiotics, and whether (or which) antibiotics decrease the efficacy of oral contraceptives (OCs) can make decision-making challenging.

This review provides evidence-based answers to questions you may have. It also details some reliable sources of information you can consult (TABLE 1^2-7) when discussing treatment options with other members of the health care team.

1. Which antibiotics are preferable when a patient is taking warfarin, and are preemptive warfarin dose reductions advisable?

The simple answer is that agents with a lower likelihood of affecting the INR, such as penicillin G, clindamycin, and 1st- and 4th-generation cephalosporins, are a good place to start, and whether to preemptively reduce the warfarin dose hinges on the antibiotic being prescribed.

The more detailed answer. The fundamental mechanisms of interaction between warfarin and antibiotics are two-fold:⁸

• Antimicrobial agents disrupt gastrointestinal flora that synthesize vitamin K.
• Antimicrobials inhibit cytochrome p450 (CYP450) enzymes (primarily CYP2C9 and 3A4), which are responsible for the metabolism of warfarin.

The antibiotics most likely to interfere with warfarin are TMP/SMX, ciprofloxacin, levofloxacin, metronidazole, fluconazole, azithromycin, and clarithromycin (TABLE 2).^9,10 Low-risk agents include clindamycin, cephalexin, and penicillin G. When prescribing an antibiotic for a patient taking warfarin, it is important not only to be aware of the agents that should be avoided, but also the agents that do not require more frequent monitoring of INR.

Preemptive warfarin dose reductions? Some physicians make preemptive warfarin dose reductions in an attempt to avoid supratherapeutic INRs in patients being prescribed antibiotics. But the evidence suggests that this step should be considered only in the presence of the antibiotics TMP/SMX and metronidazole.^9,11

A 2008 study investigated the anticoagulation effects of a 10% to 20% preemptive warfarin dose reduction vs no dosing change in patients taking TMP/SMX or levofloxacin. The investigators found that the preemptive warfarin dose reduction (intervention) significantly decreased the number of supratherapeutic INR values above 4 when compared to controls (2 of 8 vs 8 of 9).¹²

In the dose-reduction group, no patients receiving TMP/SMX developed a subtherapeutic INR, whereas 40% (4 of 10 patients) who received levofloxacin developed a subtherapeutic INR.¹² The authors of the study concluded that a prophylactic warfarin dose reduction of 10% to 20% is effective in maintaining therapeutic anticoagulation in patients receiving TMP/SMX. They added that while no change in warfarin dosing is necessary with levofloxacin, short-term INR follow-up is a prudent approach to prevent subtherapeutic INRs. Others recommend INR monitoring when antibiotic therapy is started and stopped and whenever the dose is changed.⁹

A 2010 retrospective, single-center, cohort study looked at patients who were taking metronidazole and warfarin. Researchers compared those who received a preemptive dose reduction of warfarin (mean reduction was 34.6% ± 13.4%) to those who did not and found a statistically significant mean difference in INR of 1.28 (P=.01).¹³

Almost half (46%) of the patients who did not receive a warfarin dose reduction had an INR >4, whereas none of the patients in the warfarin dose reduction group did (P=.05). Although this secondary outcome was not statistically significant (most likely due to the small sample population [N=20]), the implication is clinically significant. Two patients who reduced their dose had a subtherapeutic INR compared to none of the patients in the control group, which was also not a statistically significant difference.

The authors concluded that a 30% to 35% reduction in mean daily warfarin dose is effective in maintaining therapeutic anticoagulation in patients started on metronidazole.

Significant bleeding events. A retrospective cohort study of slightly more than 22,000 veterans who were prescribed warfarin for ≥30 uninterrupted days and given antibiotics with either a high or low risk for interaction with warfarin were studied for significant bleeding events for one month.¹⁰ Ninety-three significant bleeding events occurred in the high-risk group and 36 occurred in the low-risk group over the course of the study. The agent associated with the greatest increased risk of bleeding was TMP/SMX (hazard ratio [HR]=2.09; 95% CI, 1.45-3.02). Of note, metronidazole was not included in this study endpoint.

When TMP/SMX or metronidazole can’t be avoided, consider reducing the patient’s warfarin dose by 10% to 35% and rechecking the INR 5 days after starting the antibiotic.

The study’s secondary endpoint of INR >4 found that 10% of patients taking metronidazole and 8% of patients taking TMP/SMX in addition to warfarin had INRs >4. Almost 10% (9.7%) of patients prescribed fluconazole had a peak INR value >6. Patients taking low-risk antibiotics (clindamycin or cephalexin) had no increased risk of bleeding. Monitoring INR within 3 to 14 days of starting patients on antibiotics was found to decrease the risk of serious bleeding events (HR=0.61; 95% CI, 0.42-0.88). More frequent INR monitoring by itself (without preemptive warfarin dose reductions) is appropriate for other antibiotics, including macrolides, tetracyclines, and some cephalosporins (2nd and 3rd generation).⁹

THE BOTTOM LINE When prescribing antibiotics for patients taking warfarin, try to choose agents with a lower likelihood of affecting INR such as penicillin G, clindamycin, and 1st- and 4th-generation cephalosporins. With these agents, there is no need for more frequent INR testing or preemptive reductions in warfarin dose. In patients for whom the use of TMP/SMX or metronidazole can’t be avoided, consider reducing the patient’s warfarin dose by 10% to 35% and rechecking the INR 5 days after starting the antibiotic.^9,11,12 When prescribing agents such as fluoroquinolones, macrolides, and tetracyclines, do not reduce the patient’s warfarin dose preemptively and recheck INR 5 days after starting therapy.

2. Do antibiotics decrease the efficacy of oral contraceptives?

It’s unlikely, but antibiotics may reduce the efficacy of OCs.

There have been few, but well documented, reports of women using OCs who became pregnant after taking antimicrobials.¹⁴ It is recognized that rifampin, an inducer of enzymes that metabolize estrogens, decreases the efficacy of OCs.¹⁵ Ketoconazole’s interaction seems less well documented, but combining the agent with low-estrogen (low-dose) OCs warrants caution.¹⁶ What is not well understood is whether more common or broad-spectrum antibiotics also increase the risk of OC failure.

Three mechanisms have been proposed:¹⁶

• Antimicrobials affect hepatic enzyme induction, which increases metabolism of hormones.
• Broad-spectrum antibiotics reduce gut bacteria, which alters enterohepatic circulation and reduces plasma hormone concentrations.
• Antibiotics increase gastrointestinal motility, which decreases absorption (and reabsorption) of OCs.

A 2007 study found that when physicians and pharmacists were surveyed and asked if broad-spectrum antibiotics have a clinically significant interaction with OCs, 83% of physicians and 89% of pharmacists answered “Yes;”¹⁷ however, a large epidemiologic study performed in the United States showed no association between antibiotic use and OC failure.¹⁸

After this report, investigators in the Netherlands completed a similar cross-over analysis and found that there was a relationship between the use of antibiotics and breakthrough pregnancy in a population-based prescription database, but that the results didn’t hold for broad-spectrum antibiotics or in a sensitivity analysis.¹⁹ Pharmacokinetic studies are also conflicting, as some have shown an effect on serum hormone levels, while others have not.^15,20-22

High- vs low-risk agents. Ciprofloxacin did not affect hormone levels in 2 studies.^20,21 Rifampin and voriconazole may enhance systemic exposure to OCs.^15,22 And erythromycin and azithromycin may interact with OCs, but the clinical significance of this interaction is still unknown.¹⁶

Short-courses of TMP/SMX are generally thought to be safe;¹⁶ a small study looked at cotrimoxazole 1 g twice daily in 9 women taking long-term OC steroids and found that short courses of the drug were unlikely to cause any adverse effects on contraceptive control.²³ Tetracyclines and penicillins were the antibiotics most frequently involved in case reports of pregnancy from the United Kingdom (TABLE 3²).¹⁶

When prescribing fluoroquinolones, macrolides, and tetracyclines, do not reduce the patient's warfarin dose preemptively.

It is hypothesized that some women may have a higher risk of OC failure than others due to how they metabolize ethinyl estradiol.²⁴ Another hypothesis is that some women have gut flora that is more susceptible to the antibiotic being used. And still another possibility is that lower doses of hormones are being used in OCs than were studied for this interaction.¹⁵ Anything that decreases the concentration of these lower-dose OCs is concerning, especially in patients with a higher body mass index (BMI). The few pharmacokinetic studies that have been conducted show that it takes longer for OCs to reach a steady state in obese women and that they have a lower area under the curve (AUC) and maximum estrogen concentration than women with a normal BMI.²⁵

THE BOTTOM LINE Because the degree of variability between patients is unknown and obesity rates are increasing, concern that low-dose OCs may lose efficacy when combined with antibiotics is warranted. While the absolute risk of breakthrough pregnancy seems small, the most conservative approach is to advise patients to use a back-up method of contraception during times of antibiotic use.

3. Which drugs prolong QT intervals?

Macrolides and fluoroquinolones are 2 classes of antibiotics associated with prolonged QT intervals, but other drugs and risk factors are important to consider, as well.

Physicians often receive phone calls from pharmacists warning about drug-drug interactions when they prescribe macrolides or fluoroquinolones for patients already taking medications known to prolong QT intervals or inhibit cytochrome P450 enzymes. Long QT syndrome increases the risk of TdP, a life-threatening arrhythmia. While TdP is rare, its severity warrants a discussion of risk factors and the likelihood of occurrence.

Anything that decreases the concentration of lower-dose OCs is concerning, especially in patients with a higher body mass index.

Two QT interval prolonging medications used together in healthy individuals does not warrant a change in therapy. TdP is most likely to occur when 2 or more QT interval prolonging medications are used in a patient who is already at high risk for arrhythmia because of risk factors such as prolonged QT interval at baseline, family history of prolonged QT intervals, female gender, age >60 years, electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia), underlying comorbid diseases (eg, chronic heart failure, left ventricular hypertrophy, atrial fibrillation), hypertension, bradycardia, and genetic (ion channel) polymorphisms.^26,27

Antiarrhythmics and antipsychotics are most commonly associated with drug-induced prolonged QT interval, with most case reports and research being linked to antiarrhythmics (TABLE 4²).²⁸ But macrolide and fluoroquinolone antibiotics also have been associated with TdP, although to a lesser extent. In a retrospective analysis of case reports of TdP involving macrolides, erythromycin was present (with or without other medications thought to prolong QT) in 53% of the cases and clarithromycin was involved in 36% of the reports.²⁹

An analysis of 2 studies by the US Food and Drug Administration estimated an occurrence rate of serious cardiac arrhythmias of 46 to 85 per 100,000 users with cardiovascular disease, compared to 5 to 44 per 100,000 users without cardiovascular disease.³⁰ And this may underestimate the actual incidence because spontaneous reporting of adverse effects declines the longer a drug is on the market. Ciprofloxacin is associated with less risk than levofloxacin and gatifloxacin (the latter of which is no longer available in the United States).²⁶

Using 2 drugs that may increase the QT interval is likely safe in the absence of certain risk factors.

A recent population-based study using data on over 10.6 million people from the Taiwan National Health Insurance Database examined the risk of cardiovascular death among patients using new-generation macrolides, fluoroquinolones, and β-lactam/β-lactamase inhibitors.³¹ The absolute risk of cardiovascular death per 1000 individuals was 0.06 for clarithromycin, 0.12 for ciprofloxacin, 0.13 for amoxicillin-clavulanate, 0.36 for azithromycin, 0.39 for levofloxacin, and 0.46 for moxifloxacin. The mean interval between first antibiotic use and the adverse cardiac event was <4 days. Not surprisingly, the highest risk was seen in patients with underlying cardiovascular disease.

Patients don't need to avoid alcohol while taking metronidazole.

Another population-based study, this time conducted in Hong Kong, evaluated the cardiovascular safety of clarithromycin compared to that of amoxicillin. Clarithromycin was found to increase the incidence of myocardial infarction, arrhythmia, and cardiac mortality in the short term, with the risk returning to baseline after treatment concluded.³² A binational cohort study of Danish and Swedish adults confirmed that fluoroquinolones (especially ciprofloxacin) do not increase the risk of a serious arrhythmia compared to penicillins.³³

THE BOTTOM LINE For patients taking other QT interval prolonging medications or who are at a higher risk for TdP, consider using clarithromycin over erythromycin or azithromycin for a macrolide antibiotic or ciprofloxacin over levofloxacin or moxifloxacin if a fluoroquinolone is warranted. Using 2 drugs that may increase the QT interval is likely safe in the absence of certain risk factors.

4. Should patients avoid alcohol while taking metronidazole?

Probably not.

Warning patients against drinking alcohol while taking metronidazole has been a common practice for years. The mechanism for this theorized interaction was thought to be similar to the interaction between disulfiram and ethanol.³⁴ Disulfiram inhibits hepatic aldehyde dehydrogenase (ALDH) when combined with alcohol, which leads to increased levels of acetaldehyde in the blood and symptoms of flushing, palpitations, nausea, vomiting, headache, and visual disturbances.³⁵ However, multiple studies using rats have found that metronidazole does not inhibit ALDH or increase acetaldehyde concentrations like disulfiram does.³⁴

A 2000 review article discussed 6 cases involving serious metronidazole-ethanol interactions. Ethanol alone was found to explain the reaction in 2 of the cases, and the remaining 4 could be linked to the use of other drugs or disease states.³⁵ A 2002 Finnish study found no statistically significant differences in objective or subjective signs of a disulfiram-like interaction.³⁴ When considering the symptoms associated with the interaction, it is important to remember that many of the symptoms can result from metronidazole therapy alone, regardless of whether other medications or alcohol are used.³⁵

THE BOTTOM LINE Researchers have failed to identify a clinically significant interaction between metronidazole and alcohol. Avoiding alcohol while taking metronidazole does not appear to be necessary.

CORRESPONDENCE
Mary Onysko, PharmD, BCPS, University of Wyoming, School of Pharmacy Health Sciences Center, Room 292, 1000 E. University Avenue, Laramie, WY 82071; monysko@uwyo.edu.

Despite encouraging data that antibiotic prescribing is on the decline, patients are still prescribed antibiotics frequently, making these agents the 12th most frequently used drug class.¹ At the same time, prescribers are caring for patients with increasingly complex drug regimens that provide fertile ground for drug interactions with these antibiotics. And, of course, lifestyle factors such as alcohol consumption are a consideration when any prescription is written.

As pharmacists, we find that certain questions about antibiotic prescribing and interactions come up with frequency. These questions often pertain to the use of warfarin, oral contraceptives, drugs that prolong the QT interval, and alcohol. But conflicting reports about issues such as monitoring international normalized ratio (INR) in patients taking warfarin and antibiotics, and whether (or which) antibiotics decrease the efficacy of oral contraceptives (OCs) can make decision-making challenging.

This review provides evidence-based answers to questions you may have. It also details some reliable sources of information you can consult (TABLE 1^2-7) when discussing treatment options with other members of the health care team.

1. Which antibiotics are preferable when a patient is taking warfarin, and are preemptive warfarin dose reductions advisable?

The simple answer is that agents with a lower likelihood of affecting the INR, such as penicillin G, clindamycin, and 1st- and 4th-generation cephalosporins, are a good place to start, and whether to preemptively reduce the warfarin dose hinges on the antibiotic being prescribed.

The more detailed answer. The fundamental mechanisms of interaction between warfarin and antibiotics are two-fold:⁸

• Antimicrobial agents disrupt gastrointestinal flora that synthesize vitamin K.
• Antimicrobials inhibit cytochrome p450 (CYP450) enzymes (primarily CYP2C9 and 3A4), which are responsible for the metabolism of warfarin.

The antibiotics most likely to interfere with warfarin are TMP/SMX, ciprofloxacin, levofloxacin, metronidazole, fluconazole, azithromycin, and clarithromycin (TABLE 2).^9,10 Low-risk agents include clindamycin, cephalexin, and penicillin G. When prescribing an antibiotic for a patient taking warfarin, it is important not only to be aware of the agents that should be avoided, but also the agents that do not require more frequent monitoring of INR.

Preemptive warfarin dose reductions? Some physicians make preemptive warfarin dose reductions in an attempt to avoid supratherapeutic INRs in patients being prescribed antibiotics. But the evidence suggests that this step should be considered only in the presence of the antibiotics TMP/SMX and metronidazole.^9,11

A 2008 study investigated the anticoagulation effects of a 10% to 20% preemptive warfarin dose reduction vs no dosing change in patients taking TMP/SMX or levofloxacin. The investigators found that the preemptive warfarin dose reduction (intervention) significantly decreased the number of supratherapeutic INR values above 4 when compared to controls (2 of 8 vs 8 of 9).¹²

In the dose-reduction group, no patients receiving TMP/SMX developed a subtherapeutic INR, whereas 40% (4 of 10 patients) who received levofloxacin developed a subtherapeutic INR.¹² The authors of the study concluded that a prophylactic warfarin dose reduction of 10% to 20% is effective in maintaining therapeutic anticoagulation in patients receiving TMP/SMX. They added that while no change in warfarin dosing is necessary with levofloxacin, short-term INR follow-up is a prudent approach to prevent subtherapeutic INRs. Others recommend INR monitoring when antibiotic therapy is started and stopped and whenever the dose is changed.⁹

A 2010 retrospective, single-center, cohort study looked at patients who were taking metronidazole and warfarin. Researchers compared those who received a preemptive dose reduction of warfarin (mean reduction was 34.6% ± 13.4%) to those who did not and found a statistically significant mean difference in INR of 1.28 (P=.01).¹³

Almost half (46%) of the patients who did not receive a warfarin dose reduction had an INR >4, whereas none of the patients in the warfarin dose reduction group did (P=.05). Although this secondary outcome was not statistically significant (most likely due to the small sample population [N=20]), the implication is clinically significant. Two patients who reduced their dose had a subtherapeutic INR compared to none of the patients in the control group, which was also not a statistically significant difference.

The authors concluded that a 30% to 35% reduction in mean daily warfarin dose is effective in maintaining therapeutic anticoagulation in patients started on metronidazole.

Significant bleeding events. A retrospective cohort study of slightly more than 22,000 veterans who were prescribed warfarin for ≥30 uninterrupted days and given antibiotics with either a high or low risk for interaction with warfarin were studied for significant bleeding events for one month.¹⁰ Ninety-three significant bleeding events occurred in the high-risk group and 36 occurred in the low-risk group over the course of the study. The agent associated with the greatest increased risk of bleeding was TMP/SMX (hazard ratio [HR]=2.09; 95% CI, 1.45-3.02). Of note, metronidazole was not included in this study endpoint.

When TMP/SMX or metronidazole can’t be avoided, consider reducing the patient’s warfarin dose by 10% to 35% and rechecking the INR 5 days after starting the antibiotic.

The study’s secondary endpoint of INR >4 found that 10% of patients taking metronidazole and 8% of patients taking TMP/SMX in addition to warfarin had INRs >4. Almost 10% (9.7%) of patients prescribed fluconazole had a peak INR value >6. Patients taking low-risk antibiotics (clindamycin or cephalexin) had no increased risk of bleeding. Monitoring INR within 3 to 14 days of starting patients on antibiotics was found to decrease the risk of serious bleeding events (HR=0.61; 95% CI, 0.42-0.88). More frequent INR monitoring by itself (without preemptive warfarin dose reductions) is appropriate for other antibiotics, including macrolides, tetracyclines, and some cephalosporins (2nd and 3rd generation).⁹

THE BOTTOM LINE When prescribing antibiotics for patients taking warfarin, try to choose agents with a lower likelihood of affecting INR such as penicillin G, clindamycin, and 1st- and 4th-generation cephalosporins. With these agents, there is no need for more frequent INR testing or preemptive reductions in warfarin dose. In patients for whom the use of TMP/SMX or metronidazole can’t be avoided, consider reducing the patient’s warfarin dose by 10% to 35% and rechecking the INR 5 days after starting the antibiotic.^9,11,12 When prescribing agents such as fluoroquinolones, macrolides, and tetracyclines, do not reduce the patient’s warfarin dose preemptively and recheck INR 5 days after starting therapy.

2. Do antibiotics decrease the efficacy of oral contraceptives?

It’s unlikely, but antibiotics may reduce the efficacy of OCs.

There have been few, but well documented, reports of women using OCs who became pregnant after taking antimicrobials.¹⁴ It is recognized that rifampin, an inducer of enzymes that metabolize estrogens, decreases the efficacy of OCs.¹⁵ Ketoconazole’s interaction seems less well documented, but combining the agent with low-estrogen (low-dose) OCs warrants caution.¹⁶ What is not well understood is whether more common or broad-spectrum antibiotics also increase the risk of OC failure.

Three mechanisms have been proposed:¹⁶

• Antimicrobials affect hepatic enzyme induction, which increases metabolism of hormones.
• Broad-spectrum antibiotics reduce gut bacteria, which alters enterohepatic circulation and reduces plasma hormone concentrations.
• Antibiotics increase gastrointestinal motility, which decreases absorption (and reabsorption) of OCs.

A 2007 study found that when physicians and pharmacists were surveyed and asked if broad-spectrum antibiotics have a clinically significant interaction with OCs, 83% of physicians and 89% of pharmacists answered “Yes;”¹⁷ however, a large epidemiologic study performed in the United States showed no association between antibiotic use and OC failure.¹⁸

After this report, investigators in the Netherlands completed a similar cross-over analysis and found that there was a relationship between the use of antibiotics and breakthrough pregnancy in a population-based prescription database, but that the results didn’t hold for broad-spectrum antibiotics or in a sensitivity analysis.¹⁹ Pharmacokinetic studies are also conflicting, as some have shown an effect on serum hormone levels, while others have not.^15,20-22

High- vs low-risk agents. Ciprofloxacin did not affect hormone levels in 2 studies.^20,21 Rifampin and voriconazole may enhance systemic exposure to OCs.^15,22 And erythromycin and azithromycin may interact with OCs, but the clinical significance of this interaction is still unknown.¹⁶

Short-courses of TMP/SMX are generally thought to be safe;¹⁶ a small study looked at cotrimoxazole 1 g twice daily in 9 women taking long-term OC steroids and found that short courses of the drug were unlikely to cause any adverse effects on contraceptive control.²³ Tetracyclines and penicillins were the antibiotics most frequently involved in case reports of pregnancy from the United Kingdom (TABLE 3²).¹⁶

When prescribing fluoroquinolones, macrolides, and tetracyclines, do not reduce the patient's warfarin dose preemptively.

It is hypothesized that some women may have a higher risk of OC failure than others due to how they metabolize ethinyl estradiol.²⁴ Another hypothesis is that some women have gut flora that is more susceptible to the antibiotic being used. And still another possibility is that lower doses of hormones are being used in OCs than were studied for this interaction.¹⁵ Anything that decreases the concentration of these lower-dose OCs is concerning, especially in patients with a higher body mass index (BMI). The few pharmacokinetic studies that have been conducted show that it takes longer for OCs to reach a steady state in obese women and that they have a lower area under the curve (AUC) and maximum estrogen concentration than women with a normal BMI.²⁵

THE BOTTOM LINE Because the degree of variability between patients is unknown and obesity rates are increasing, concern that low-dose OCs may lose efficacy when combined with antibiotics is warranted. While the absolute risk of breakthrough pregnancy seems small, the most conservative approach is to advise patients to use a back-up method of contraception during times of antibiotic use.

3. Which drugs prolong QT intervals?

Macrolides and fluoroquinolones are 2 classes of antibiotics associated with prolonged QT intervals, but other drugs and risk factors are important to consider, as well.

Physicians often receive phone calls from pharmacists warning about drug-drug interactions when they prescribe macrolides or fluoroquinolones for patients already taking medications known to prolong QT intervals or inhibit cytochrome P450 enzymes. Long QT syndrome increases the risk of TdP, a life-threatening arrhythmia. While TdP is rare, its severity warrants a discussion of risk factors and the likelihood of occurrence.

Anything that decreases the concentration of lower-dose OCs is concerning, especially in patients with a higher body mass index.

Two QT interval prolonging medications used together in healthy individuals does not warrant a change in therapy. TdP is most likely to occur when 2 or more QT interval prolonging medications are used in a patient who is already at high risk for arrhythmia because of risk factors such as prolonged QT interval at baseline, family history of prolonged QT intervals, female gender, age >60 years, electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia), underlying comorbid diseases (eg, chronic heart failure, left ventricular hypertrophy, atrial fibrillation), hypertension, bradycardia, and genetic (ion channel) polymorphisms.^26,27

Antiarrhythmics and antipsychotics are most commonly associated with drug-induced prolonged QT interval, with most case reports and research being linked to antiarrhythmics (TABLE 4²).²⁸ But macrolide and fluoroquinolone antibiotics also have been associated with TdP, although to a lesser extent. In a retrospective analysis of case reports of TdP involving macrolides, erythromycin was present (with or without other medications thought to prolong QT) in 53% of the cases and clarithromycin was involved in 36% of the reports.²⁹

An analysis of 2 studies by the US Food and Drug Administration estimated an occurrence rate of serious cardiac arrhythmias of 46 to 85 per 100,000 users with cardiovascular disease, compared to 5 to 44 per 100,000 users without cardiovascular disease.³⁰ And this may underestimate the actual incidence because spontaneous reporting of adverse effects declines the longer a drug is on the market. Ciprofloxacin is associated with less risk than levofloxacin and gatifloxacin (the latter of which is no longer available in the United States).²⁶

Using 2 drugs that may increase the QT interval is likely safe in the absence of certain risk factors.

A recent population-based study using data on over 10.6 million people from the Taiwan National Health Insurance Database examined the risk of cardiovascular death among patients using new-generation macrolides, fluoroquinolones, and β-lactam/β-lactamase inhibitors.³¹ The absolute risk of cardiovascular death per 1000 individuals was 0.06 for clarithromycin, 0.12 for ciprofloxacin, 0.13 for amoxicillin-clavulanate, 0.36 for azithromycin, 0.39 for levofloxacin, and 0.46 for moxifloxacin. The mean interval between first antibiotic use and the adverse cardiac event was <4 days. Not surprisingly, the highest risk was seen in patients with underlying cardiovascular disease.

Patients don't need to avoid alcohol while taking metronidazole.

Another population-based study, this time conducted in Hong Kong, evaluated the cardiovascular safety of clarithromycin compared to that of amoxicillin. Clarithromycin was found to increase the incidence of myocardial infarction, arrhythmia, and cardiac mortality in the short term, with the risk returning to baseline after treatment concluded.³² A binational cohort study of Danish and Swedish adults confirmed that fluoroquinolones (especially ciprofloxacin) do not increase the risk of a serious arrhythmia compared to penicillins.³³

THE BOTTOM LINE For patients taking other QT interval prolonging medications or who are at a higher risk for TdP, consider using clarithromycin over erythromycin or azithromycin for a macrolide antibiotic or ciprofloxacin over levofloxacin or moxifloxacin if a fluoroquinolone is warranted. Using 2 drugs that may increase the QT interval is likely safe in the absence of certain risk factors.

4. Should patients avoid alcohol while taking metronidazole?

Probably not.

Warning patients against drinking alcohol while taking metronidazole has been a common practice for years. The mechanism for this theorized interaction was thought to be similar to the interaction between disulfiram and ethanol.³⁴ Disulfiram inhibits hepatic aldehyde dehydrogenase (ALDH) when combined with alcohol, which leads to increased levels of acetaldehyde in the blood and symptoms of flushing, palpitations, nausea, vomiting, headache, and visual disturbances.³⁵ However, multiple studies using rats have found that metronidazole does not inhibit ALDH or increase acetaldehyde concentrations like disulfiram does.³⁴

A 2000 review article discussed 6 cases involving serious metronidazole-ethanol interactions. Ethanol alone was found to explain the reaction in 2 of the cases, and the remaining 4 could be linked to the use of other drugs or disease states.³⁵ A 2002 Finnish study found no statistically significant differences in objective or subjective signs of a disulfiram-like interaction.³⁴ When considering the symptoms associated with the interaction, it is important to remember that many of the symptoms can result from metronidazole therapy alone, regardless of whether other medications or alcohol are used.³⁵

THE BOTTOM LINE Researchers have failed to identify a clinically significant interaction between metronidazole and alcohol. Avoiding alcohol while taking metronidazole does not appear to be necessary.

CORRESPONDENCE
Mary Onysko, PharmD, BCPS, University of Wyoming, School of Pharmacy Health Sciences Center, Room 292, 1000 E. University Avenue, Laramie, WY 82071; monysko@uwyo.edu.

Despite encouraging data that antibiotic prescribing is on the decline, patients are still prescribed antibiotics frequently, making these agents the 12th most frequently used drug class.¹ At the same time, prescribers are caring for patients with increasingly complex drug regimens that provide fertile ground for drug interactions with these antibiotics. And, of course, lifestyle factors such as alcohol consumption are a consideration when any prescription is written.

As pharmacists, we find that certain questions about antibiotic prescribing and interactions come up with frequency. These questions often pertain to the use of warfarin, oral contraceptives, drugs that prolong the QT interval, and alcohol. But conflicting reports about issues such as monitoring international normalized ratio (INR) in patients taking warfarin and antibiotics, and whether (or which) antibiotics decrease the efficacy of oral contraceptives (OCs) can make decision-making challenging.

This review provides evidence-based answers to questions you may have. It also details some reliable sources of information you can consult (TABLE 1^2-7) when discussing treatment options with other members of the health care team.

1. Which antibiotics are preferable when a patient is taking warfarin, and are preemptive warfarin dose reductions advisable?

The simple answer is that agents with a lower likelihood of affecting the INR, such as penicillin G, clindamycin, and 1st- and 4th-generation cephalosporins, are a good place to start, and whether to preemptively reduce the warfarin dose hinges on the antibiotic being prescribed.

The more detailed answer. The fundamental mechanisms of interaction between warfarin and antibiotics are two-fold:⁸

• Antimicrobial agents disrupt gastrointestinal flora that synthesize vitamin K.
• Antimicrobials inhibit cytochrome p450 (CYP450) enzymes (primarily CYP2C9 and 3A4), which are responsible for the metabolism of warfarin.

The antibiotics most likely to interfere with warfarin are TMP/SMX, ciprofloxacin, levofloxacin, metronidazole, fluconazole, azithromycin, and clarithromycin (TABLE 2).^9,10 Low-risk agents include clindamycin, cephalexin, and penicillin G. When prescribing an antibiotic for a patient taking warfarin, it is important not only to be aware of the agents that should be avoided, but also the agents that do not require more frequent monitoring of INR.

Preemptive warfarin dose reductions? Some physicians make preemptive warfarin dose reductions in an attempt to avoid supratherapeutic INRs in patients being prescribed antibiotics. But the evidence suggests that this step should be considered only in the presence of the antibiotics TMP/SMX and metronidazole.^9,11

A 2008 study investigated the anticoagulation effects of a 10% to 20% preemptive warfarin dose reduction vs no dosing change in patients taking TMP/SMX or levofloxacin. The investigators found that the preemptive warfarin dose reduction (intervention) significantly decreased the number of supratherapeutic INR values above 4 when compared to controls (2 of 8 vs 8 of 9).¹²

In the dose-reduction group, no patients receiving TMP/SMX developed a subtherapeutic INR, whereas 40% (4 of 10 patients) who received levofloxacin developed a subtherapeutic INR.¹² The authors of the study concluded that a prophylactic warfarin dose reduction of 10% to 20% is effective in maintaining therapeutic anticoagulation in patients receiving TMP/SMX. They added that while no change in warfarin dosing is necessary with levofloxacin, short-term INR follow-up is a prudent approach to prevent subtherapeutic INRs. Others recommend INR monitoring when antibiotic therapy is started and stopped and whenever the dose is changed.⁹

A 2010 retrospective, single-center, cohort study looked at patients who were taking metronidazole and warfarin. Researchers compared those who received a preemptive dose reduction of warfarin (mean reduction was 34.6% ± 13.4%) to those who did not and found a statistically significant mean difference in INR of 1.28 (P=.01).¹³

Almost half (46%) of the patients who did not receive a warfarin dose reduction had an INR >4, whereas none of the patients in the warfarin dose reduction group did (P=.05). Although this secondary outcome was not statistically significant (most likely due to the small sample population [N=20]), the implication is clinically significant. Two patients who reduced their dose had a subtherapeutic INR compared to none of the patients in the control group, which was also not a statistically significant difference.

The authors concluded that a 30% to 35% reduction in mean daily warfarin dose is effective in maintaining therapeutic anticoagulation in patients started on metronidazole.

Significant bleeding events. A retrospective cohort study of slightly more than 22,000 veterans who were prescribed warfarin for ≥30 uninterrupted days and given antibiotics with either a high or low risk for interaction with warfarin were studied for significant bleeding events for one month.¹⁰ Ninety-three significant bleeding events occurred in the high-risk group and 36 occurred in the low-risk group over the course of the study. The agent associated with the greatest increased risk of bleeding was TMP/SMX (hazard ratio [HR]=2.09; 95% CI, 1.45-3.02). Of note, metronidazole was not included in this study endpoint.

When TMP/SMX or metronidazole can’t be avoided, consider reducing the patient’s warfarin dose by 10% to 35% and rechecking the INR 5 days after starting the antibiotic.

The study’s secondary endpoint of INR >4 found that 10% of patients taking metronidazole and 8% of patients taking TMP/SMX in addition to warfarin had INRs >4. Almost 10% (9.7%) of patients prescribed fluconazole had a peak INR value >6. Patients taking low-risk antibiotics (clindamycin or cephalexin) had no increased risk of bleeding. Monitoring INR within 3 to 14 days of starting patients on antibiotics was found to decrease the risk of serious bleeding events (HR=0.61; 95% CI, 0.42-0.88). More frequent INR monitoring by itself (without preemptive warfarin dose reductions) is appropriate for other antibiotics, including macrolides, tetracyclines, and some cephalosporins (2nd and 3rd generation).⁹

THE BOTTOM LINE When prescribing antibiotics for patients taking warfarin, try to choose agents with a lower likelihood of affecting INR such as penicillin G, clindamycin, and 1st- and 4th-generation cephalosporins. With these agents, there is no need for more frequent INR testing or preemptive reductions in warfarin dose. In patients for whom the use of TMP/SMX or metronidazole can’t be avoided, consider reducing the patient’s warfarin dose by 10% to 35% and rechecking the INR 5 days after starting the antibiotic.^9,11,12 When prescribing agents such as fluoroquinolones, macrolides, and tetracyclines, do not reduce the patient’s warfarin dose preemptively and recheck INR 5 days after starting therapy.

2. Do antibiotics decrease the efficacy of oral contraceptives?

It’s unlikely, but antibiotics may reduce the efficacy of OCs.

There have been few, but well documented, reports of women using OCs who became pregnant after taking antimicrobials.¹⁴ It is recognized that rifampin, an inducer of enzymes that metabolize estrogens, decreases the efficacy of OCs.¹⁵ Ketoconazole’s interaction seems less well documented, but combining the agent with low-estrogen (low-dose) OCs warrants caution.¹⁶ What is not well understood is whether more common or broad-spectrum antibiotics also increase the risk of OC failure.

Three mechanisms have been proposed:¹⁶

• Antimicrobials affect hepatic enzyme induction, which increases metabolism of hormones.
• Broad-spectrum antibiotics reduce gut bacteria, which alters enterohepatic circulation and reduces plasma hormone concentrations.
• Antibiotics increase gastrointestinal motility, which decreases absorption (and reabsorption) of OCs.

A 2007 study found that when physicians and pharmacists were surveyed and asked if broad-spectrum antibiotics have a clinically significant interaction with OCs, 83% of physicians and 89% of pharmacists answered “Yes;”¹⁷ however, a large epidemiologic study performed in the United States showed no association between antibiotic use and OC failure.¹⁸

After this report, investigators in the Netherlands completed a similar cross-over analysis and found that there was a relationship between the use of antibiotics and breakthrough pregnancy in a population-based prescription database, but that the results didn’t hold for broad-spectrum antibiotics or in a sensitivity analysis.¹⁹ Pharmacokinetic studies are also conflicting, as some have shown an effect on serum hormone levels, while others have not.^15,20-22

High- vs low-risk agents. Ciprofloxacin did not affect hormone levels in 2 studies.^20,21 Rifampin and voriconazole may enhance systemic exposure to OCs.^15,22 And erythromycin and azithromycin may interact with OCs, but the clinical significance of this interaction is still unknown.¹⁶

Short-courses of TMP/SMX are generally thought to be safe;¹⁶ a small study looked at cotrimoxazole 1 g twice daily in 9 women taking long-term OC steroids and found that short courses of the drug were unlikely to cause any adverse effects on contraceptive control.²³ Tetracyclines and penicillins were the antibiotics most frequently involved in case reports of pregnancy from the United Kingdom (TABLE 3²).¹⁶

When prescribing fluoroquinolones, macrolides, and tetracyclines, do not reduce the patient's warfarin dose preemptively.

It is hypothesized that some women may have a higher risk of OC failure than others due to how they metabolize ethinyl estradiol.²⁴ Another hypothesis is that some women have gut flora that is more susceptible to the antibiotic being used. And still another possibility is that lower doses of hormones are being used in OCs than were studied for this interaction.¹⁵ Anything that decreases the concentration of these lower-dose OCs is concerning, especially in patients with a higher body mass index (BMI). The few pharmacokinetic studies that have been conducted show that it takes longer for OCs to reach a steady state in obese women and that they have a lower area under the curve (AUC) and maximum estrogen concentration than women with a normal BMI.²⁵

THE BOTTOM LINE Because the degree of variability between patients is unknown and obesity rates are increasing, concern that low-dose OCs may lose efficacy when combined with antibiotics is warranted. While the absolute risk of breakthrough pregnancy seems small, the most conservative approach is to advise patients to use a back-up method of contraception during times of antibiotic use.

3. Which drugs prolong QT intervals?

Macrolides and fluoroquinolones are 2 classes of antibiotics associated with prolonged QT intervals, but other drugs and risk factors are important to consider, as well.

Physicians often receive phone calls from pharmacists warning about drug-drug interactions when they prescribe macrolides or fluoroquinolones for patients already taking medications known to prolong QT intervals or inhibit cytochrome P450 enzymes. Long QT syndrome increases the risk of TdP, a life-threatening arrhythmia. While TdP is rare, its severity warrants a discussion of risk factors and the likelihood of occurrence.

Anything that decreases the concentration of lower-dose OCs is concerning, especially in patients with a higher body mass index.

Two QT interval prolonging medications used together in healthy individuals does not warrant a change in therapy. TdP is most likely to occur when 2 or more QT interval prolonging medications are used in a patient who is already at high risk for arrhythmia because of risk factors such as prolonged QT interval at baseline, family history of prolonged QT intervals, female gender, age >60 years, electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia), underlying comorbid diseases (eg, chronic heart failure, left ventricular hypertrophy, atrial fibrillation), hypertension, bradycardia, and genetic (ion channel) polymorphisms.^26,27

Antiarrhythmics and antipsychotics are most commonly associated with drug-induced prolonged QT interval, with most case reports and research being linked to antiarrhythmics (TABLE 4²).²⁸ But macrolide and fluoroquinolone antibiotics also have been associated with TdP, although to a lesser extent. In a retrospective analysis of case reports of TdP involving macrolides, erythromycin was present (with or without other medications thought to prolong QT) in 53% of the cases and clarithromycin was involved in 36% of the reports.²⁹

An analysis of 2 studies by the US Food and Drug Administration estimated an occurrence rate of serious cardiac arrhythmias of 46 to 85 per 100,000 users with cardiovascular disease, compared to 5 to 44 per 100,000 users without cardiovascular disease.³⁰ And this may underestimate the actual incidence because spontaneous reporting of adverse effects declines the longer a drug is on the market. Ciprofloxacin is associated with less risk than levofloxacin and gatifloxacin (the latter of which is no longer available in the United States).²⁶

Using 2 drugs that may increase the QT interval is likely safe in the absence of certain risk factors.

A recent population-based study using data on over 10.6 million people from the Taiwan National Health Insurance Database examined the risk of cardiovascular death among patients using new-generation macrolides, fluoroquinolones, and β-lactam/β-lactamase inhibitors.³¹ The absolute risk of cardiovascular death per 1000 individuals was 0.06 for clarithromycin, 0.12 for ciprofloxacin, 0.13 for amoxicillin-clavulanate, 0.36 for azithromycin, 0.39 for levofloxacin, and 0.46 for moxifloxacin. The mean interval between first antibiotic use and the adverse cardiac event was <4 days. Not surprisingly, the highest risk was seen in patients with underlying cardiovascular disease.

Patients don't need to avoid alcohol while taking metronidazole.

Another population-based study, this time conducted in Hong Kong, evaluated the cardiovascular safety of clarithromycin compared to that of amoxicillin. Clarithromycin was found to increase the incidence of myocardial infarction, arrhythmia, and cardiac mortality in the short term, with the risk returning to baseline after treatment concluded.³² A binational cohort study of Danish and Swedish adults confirmed that fluoroquinolones (especially ciprofloxacin) do not increase the risk of a serious arrhythmia compared to penicillins.³³

THE BOTTOM LINE For patients taking other QT interval prolonging medications or who are at a higher risk for TdP, consider using clarithromycin over erythromycin or azithromycin for a macrolide antibiotic or ciprofloxacin over levofloxacin or moxifloxacin if a fluoroquinolone is warranted. Using 2 drugs that may increase the QT interval is likely safe in the absence of certain risk factors.

4. Should patients avoid alcohol while taking metronidazole?

Probably not.

Warning patients against drinking alcohol while taking metronidazole has been a common practice for years. The mechanism for this theorized interaction was thought to be similar to the interaction between disulfiram and ethanol.³⁴ Disulfiram inhibits hepatic aldehyde dehydrogenase (ALDH) when combined with alcohol, which leads to increased levels of acetaldehyde in the blood and symptoms of flushing, palpitations, nausea, vomiting, headache, and visual disturbances.³⁵ However, multiple studies using rats have found that metronidazole does not inhibit ALDH or increase acetaldehyde concentrations like disulfiram does.³⁴

A 2000 review article discussed 6 cases involving serious metronidazole-ethanol interactions. Ethanol alone was found to explain the reaction in 2 of the cases, and the remaining 4 could be linked to the use of other drugs or disease states.³⁵ A 2002 Finnish study found no statistically significant differences in objective or subjective signs of a disulfiram-like interaction.³⁴ When considering the symptoms associated with the interaction, it is important to remember that many of the symptoms can result from metronidazole therapy alone, regardless of whether other medications or alcohol are used.³⁵

THE BOTTOM LINE Researchers have failed to identify a clinically significant interaction between metronidazole and alcohol. Avoiding alcohol while taking metronidazole does not appear to be necessary.

CORRESPONDENCE
Mary Onysko, PharmD, BCPS, University of Wyoming, School of Pharmacy Health Sciences Center, Room 292, 1000 E. University Avenue, Laramie, WY 82071; monysko@uwyo.edu.