Clinical Inquiries

Evidence summary

Limiting further evaluation of men with a first UTI to those at increased risk (TABLE) may reduce unnecessary radiological, endoscopic, or urodynamic investigation.

Approximately 20% of all UTIs occur in men,^1-3 and the lifetime prevalence is about 14%.³ The incidence in elderly men is high, often attributable to a bladder outflow obstruction.⁴ (For this review, the definition of UTI is limited to bacterial infections of the kidney, ureter, or bladder, and does not include urethritis, epididymitis, prostatitis, or orchitis.)

TABLE
Conditions that increase risk of urinary tract infection in men^3,7,9,10

Get a urine culture

A urine culture is recommended to reliably diagnose an infection and guide treatment.⁵

• A cohort of 66 men (mean age, 66±13 years) presenting to a VA urology clinic for procedures, dysuria, or bacteriuria had urine samples taken while voiding, as well as directly from the bladder, either via suprapubic aspiration or urethral catheterization. Using bladder cultures as a gold standard, midstream urine culture had a specificity and sensitivity of >97% at a threshold of 1000 CFU/mL.⁶

The usual organisms are colonic bacteria: Escherichia coli (75%), enterococci (20%), and, less commonly, Klebsiella and Proteus.⁴

No need for routine imaging

Consider a workup for men who have no response to antibiotic therapy or have persistent hematuria.

There is little evidence to support routine imaging in low-risk men with a first UTI, whether with or without fever:

• A very small prospective study of 29 heterosexual, circumcised men 16 to 45 years old (those who were sexually active had a steady partner) who were hospitalized with a first febrile UTI failed to find any significant structural or functional urinary tract abnormalities.⁴
• Another small prospective study of 85 men, 18 to 86 years of age, with febrile UTI, concluded that routine imaging of the upper urinary tract was unnecessary, and that, if indicated, further workup should focus on the lower urinary tract.⁷ Abnormalities in this group were suggested by a history of voiding problems, hematuria, or recurrent infection. One limitation of this study was the incomplete urodynamic and endoscopic evaluation of the lower urinary tract.
• Another study enrolled 114 men, 18 to 85 years of age, with proven UTIs, who underwent ultrasonography and plain radiography, as well as an IVP.⁸ (Only 100 had complete data at enrollment.) All men had urinary flow rates measured. The combination of a plain abdominal film and ultrasonography detected more abnormalities than an IVP. (The primary role of the plain film was in detecting urinary calculi.)

Final “clinical” diagnoses were reported, but the study did not report a comparison of clinical and radiological findings. Almost half of the abnormalities were lower tract obstructions (bladder outlet obstruction, underactive detrusor, and chronic retention). There was no comment on the importance or treatment of any abnormalities found.

Recommendations from others

PRODIGY (from the British National Health Service) recommends:

• Men under 45 years with a first UTI who respond well to antibiotic treatment are not likely to have a urologic abnormality.⁹
• Older men who do not respond well to antibiotics or who have recurrent UTIs are likely to have abnormalities and may benefit from further investigation.⁹

Neither the American Academy of Urology, the US Preventive Services Task Force, nor the Agency for Healthcare Research and Quality has published guidelines for evaluation of adult men with a first UTI.

Evidence summary

Limiting further evaluation of men with a first UTI to those at increased risk (TABLE) may reduce unnecessary radiological, endoscopic, or urodynamic investigation.

Approximately 20% of all UTIs occur in men,^1-3 and the lifetime prevalence is about 14%.³ The incidence in elderly men is high, often attributable to a bladder outflow obstruction.⁴ (For this review, the definition of UTI is limited to bacterial infections of the kidney, ureter, or bladder, and does not include urethritis, epididymitis, prostatitis, or orchitis.)

TABLE
Conditions that increase risk of urinary tract infection in men^3,7,9,10

Get a urine culture

A urine culture is recommended to reliably diagnose an infection and guide treatment.⁵

• A cohort of 66 men (mean age, 66±13 years) presenting to a VA urology clinic for procedures, dysuria, or bacteriuria had urine samples taken while voiding, as well as directly from the bladder, either via suprapubic aspiration or urethral catheterization. Using bladder cultures as a gold standard, midstream urine culture had a specificity and sensitivity of >97% at a threshold of 1000 CFU/mL.⁶

The usual organisms are colonic bacteria: Escherichia coli (75%), enterococci (20%), and, less commonly, Klebsiella and Proteus.⁴

No need for routine imaging

Consider a workup for men who have no response to antibiotic therapy or have persistent hematuria.

There is little evidence to support routine imaging in low-risk men with a first UTI, whether with or without fever:

• A very small prospective study of 29 heterosexual, circumcised men 16 to 45 years old (those who were sexually active had a steady partner) who were hospitalized with a first febrile UTI failed to find any significant structural or functional urinary tract abnormalities.⁴
• Another small prospective study of 85 men, 18 to 86 years of age, with febrile UTI, concluded that routine imaging of the upper urinary tract was unnecessary, and that, if indicated, further workup should focus on the lower urinary tract.⁷ Abnormalities in this group were suggested by a history of voiding problems, hematuria, or recurrent infection. One limitation of this study was the incomplete urodynamic and endoscopic evaluation of the lower urinary tract.
• Another study enrolled 114 men, 18 to 85 years of age, with proven UTIs, who underwent ultrasonography and plain radiography, as well as an IVP.⁸ (Only 100 had complete data at enrollment.) All men had urinary flow rates measured. The combination of a plain abdominal film and ultrasonography detected more abnormalities than an IVP. (The primary role of the plain film was in detecting urinary calculi.)

Final “clinical” diagnoses were reported, but the study did not report a comparison of clinical and radiological findings. Almost half of the abnormalities were lower tract obstructions (bladder outlet obstruction, underactive detrusor, and chronic retention). There was no comment on the importance or treatment of any abnormalities found.

Recommendations from others

PRODIGY (from the British National Health Service) recommends:

• Men under 45 years with a first UTI who respond well to antibiotic treatment are not likely to have a urologic abnormality.⁹
• Older men who do not respond well to antibiotics or who have recurrent UTIs are likely to have abnormalities and may benefit from further investigation.⁹

Neither the American Academy of Urology, the US Preventive Services Task Force, nor the Agency for Healthcare Research and Quality has published guidelines for evaluation of adult men with a first UTI.

Evidence summary

Limiting further evaluation of men with a first UTI to those at increased risk (TABLE) may reduce unnecessary radiological, endoscopic, or urodynamic investigation.

Approximately 20% of all UTIs occur in men,^1-3 and the lifetime prevalence is about 14%.³ The incidence in elderly men is high, often attributable to a bladder outflow obstruction.⁴ (For this review, the definition of UTI is limited to bacterial infections of the kidney, ureter, or bladder, and does not include urethritis, epididymitis, prostatitis, or orchitis.)

TABLE
Conditions that increase risk of urinary tract infection in men^3,7,9,10

Get a urine culture

A urine culture is recommended to reliably diagnose an infection and guide treatment.⁵

• A cohort of 66 men (mean age, 66±13 years) presenting to a VA urology clinic for procedures, dysuria, or bacteriuria had urine samples taken while voiding, as well as directly from the bladder, either via suprapubic aspiration or urethral catheterization. Using bladder cultures as a gold standard, midstream urine culture had a specificity and sensitivity of >97% at a threshold of 1000 CFU/mL.⁶

The usual organisms are colonic bacteria: Escherichia coli (75%), enterococci (20%), and, less commonly, Klebsiella and Proteus.⁴

No need for routine imaging

Consider a workup for men who have no response to antibiotic therapy or have persistent hematuria.

There is little evidence to support routine imaging in low-risk men with a first UTI, whether with or without fever:

• A very small prospective study of 29 heterosexual, circumcised men 16 to 45 years old (those who were sexually active had a steady partner) who were hospitalized with a first febrile UTI failed to find any significant structural or functional urinary tract abnormalities.⁴
• Another small prospective study of 85 men, 18 to 86 years of age, with febrile UTI, concluded that routine imaging of the upper urinary tract was unnecessary, and that, if indicated, further workup should focus on the lower urinary tract.⁷ Abnormalities in this group were suggested by a history of voiding problems, hematuria, or recurrent infection. One limitation of this study was the incomplete urodynamic and endoscopic evaluation of the lower urinary tract.
• Another study enrolled 114 men, 18 to 85 years of age, with proven UTIs, who underwent ultrasonography and plain radiography, as well as an IVP.⁸ (Only 100 had complete data at enrollment.) All men had urinary flow rates measured. The combination of a plain abdominal film and ultrasonography detected more abnormalities than an IVP. (The primary role of the plain film was in detecting urinary calculi.)

Final “clinical” diagnoses were reported, but the study did not report a comparison of clinical and radiological findings. Almost half of the abnormalities were lower tract obstructions (bladder outlet obstruction, underactive detrusor, and chronic retention). There was no comment on the importance or treatment of any abnormalities found.

Recommendations from others

PRODIGY (from the British National Health Service) recommends:

• Men under 45 years with a first UTI who respond well to antibiotic treatment are not likely to have a urologic abnormality.⁹
• Older men who do not respond well to antibiotics or who have recurrent UTIs are likely to have abnormalities and may benefit from further investigation.⁹

Neither the American Academy of Urology, the US Preventive Services Task Force, nor the Agency for Healthcare Research and Quality has published guidelines for evaluation of adult men with a first UTI.

Evidence summary

Our Medline search retrieved 1114 English-language studies published from 1960 through October 2006. We limited this set to randomized controlled trials and cohort studies, leaving 212 articles. We then excluded articles that had small sample sizes, did not follow subjects for at least 5 years, did not include original data, included men, did not give prevalence or incidence rate of breast cancer in the subjects, or did not discuss diet assessment tools. Of the remaining articles, we selected the 11 best studies to include in the review.

Early studies evaluating national average dietary fat intake and breast cancer incidence rates showed an almost linear relationship between increased dietary fat and increased breast cancer incidence.¹ However, increased fat intake occurs primarily in industrialized nations, providing multiple possible confounders for increased rates of breast cancer, such as pollutants and increased consumption of preservatives, pesticides, and other chemicals.

Case-control studies have shown some minimally increased risk related to dietary fat consumption, but there is concern about recall bias in these studies.² Since the late 1970s, 7 large, well-designed prospective cohort studies have examined the possible relationship between dietary fat and breast cancer.¹ The findings have been somewhat contradictory, with some studies showing statistically significant associations toward increased risk with higher fat intake.^3-5

Since the late 1990s, several meta-analyses, a systematic review of these cohort studies, and the Women’s Health Initiative Randomized Controlled Diet Initiative have largely concluded that there is no difference in breast cancer incidence between women with a low-fat diet (<20% of total calories from fat) and women with average or high-fat diets (>40% total calories from fat).^1,3,6,7

The meta-analysis performed by Boyd et al did find a statistically significant difference, with relative risks ranging from 1.11 for overall to 1.19 for high-saturated-fat diets.⁸ The upper limit of all confidence intervals was no higher than 1.35, however, suggesting a lack of clinical significance. The best-designed studies also evaluated dietary composition with regard to key types of fat (saturated, mono- and poly-unsaturated; animal vs vegetable vs marine) and found no significant differences based on type of fat consumed.¹

Preliminary evidence indicates that lowering dietary fat consumption may help with secondary prevention of breast cancer, but no large studies have been performed to date.⁹ Recently, a nested study within the Women’s Intervention Nutrition Study did show that women with breast cancer who decreased their fat intake to a median of 33 g/day had a hazard ratio of 0.76 for relapse over 60 months (compared with controls who ate a median of 51 g/day).¹⁰

Recommendations from others

There are no evidence-based or specific recommendations for the primary prevention of postmenopausal breast cancer for women through dietary fat reduction. In particular, neither the American Academy of Family Physicians, American College of Surgeons, National Institutes of Health, American College of Obstetricians and Gynecologists, American College of Physicians, US Preventive Services Task Force, or the Centers for Disease Control and Prevention provide any guidelines on dietary fat restriction for primary prevention of postmenopausal breast cancer.

The American Heart Association does have guidelines for coronary artery disease prevention for women, which include a low-fat diet.¹¹ The USPSTF has no specific guidelines regarding dietary fat consumption for the general population.

Evidence summary

Our Medline search retrieved 1114 English-language studies published from 1960 through October 2006. We limited this set to randomized controlled trials and cohort studies, leaving 212 articles. We then excluded articles that had small sample sizes, did not follow subjects for at least 5 years, did not include original data, included men, did not give prevalence or incidence rate of breast cancer in the subjects, or did not discuss diet assessment tools. Of the remaining articles, we selected the 11 best studies to include in the review.

Early studies evaluating national average dietary fat intake and breast cancer incidence rates showed an almost linear relationship between increased dietary fat and increased breast cancer incidence.¹ However, increased fat intake occurs primarily in industrialized nations, providing multiple possible confounders for increased rates of breast cancer, such as pollutants and increased consumption of preservatives, pesticides, and other chemicals.

Case-control studies have shown some minimally increased risk related to dietary fat consumption, but there is concern about recall bias in these studies.² Since the late 1970s, 7 large, well-designed prospective cohort studies have examined the possible relationship between dietary fat and breast cancer.¹ The findings have been somewhat contradictory, with some studies showing statistically significant associations toward increased risk with higher fat intake.^3-5

Since the late 1990s, several meta-analyses, a systematic review of these cohort studies, and the Women’s Health Initiative Randomized Controlled Diet Initiative have largely concluded that there is no difference in breast cancer incidence between women with a low-fat diet (<20% of total calories from fat) and women with average or high-fat diets (>40% total calories from fat).^1,3,6,7

The meta-analysis performed by Boyd et al did find a statistically significant difference, with relative risks ranging from 1.11 for overall to 1.19 for high-saturated-fat diets.⁸ The upper limit of all confidence intervals was no higher than 1.35, however, suggesting a lack of clinical significance. The best-designed studies also evaluated dietary composition with regard to key types of fat (saturated, mono- and poly-unsaturated; animal vs vegetable vs marine) and found no significant differences based on type of fat consumed.¹

Preliminary evidence indicates that lowering dietary fat consumption may help with secondary prevention of breast cancer, but no large studies have been performed to date.⁹ Recently, a nested study within the Women’s Intervention Nutrition Study did show that women with breast cancer who decreased their fat intake to a median of 33 g/day had a hazard ratio of 0.76 for relapse over 60 months (compared with controls who ate a median of 51 g/day).¹⁰

Recommendations from others

There are no evidence-based or specific recommendations for the primary prevention of postmenopausal breast cancer for women through dietary fat reduction. In particular, neither the American Academy of Family Physicians, American College of Surgeons, National Institutes of Health, American College of Obstetricians and Gynecologists, American College of Physicians, US Preventive Services Task Force, or the Centers for Disease Control and Prevention provide any guidelines on dietary fat restriction for primary prevention of postmenopausal breast cancer.

The American Heart Association does have guidelines for coronary artery disease prevention for women, which include a low-fat diet.¹¹ The USPSTF has no specific guidelines regarding dietary fat consumption for the general population.

Evidence summary

Our Medline search retrieved 1114 English-language studies published from 1960 through October 2006. We limited this set to randomized controlled trials and cohort studies, leaving 212 articles. We then excluded articles that had small sample sizes, did not follow subjects for at least 5 years, did not include original data, included men, did not give prevalence or incidence rate of breast cancer in the subjects, or did not discuss diet assessment tools. Of the remaining articles, we selected the 11 best studies to include in the review.

Early studies evaluating national average dietary fat intake and breast cancer incidence rates showed an almost linear relationship between increased dietary fat and increased breast cancer incidence.¹ However, increased fat intake occurs primarily in industrialized nations, providing multiple possible confounders for increased rates of breast cancer, such as pollutants and increased consumption of preservatives, pesticides, and other chemicals.

Case-control studies have shown some minimally increased risk related to dietary fat consumption, but there is concern about recall bias in these studies.² Since the late 1970s, 7 large, well-designed prospective cohort studies have examined the possible relationship between dietary fat and breast cancer.¹ The findings have been somewhat contradictory, with some studies showing statistically significant associations toward increased risk with higher fat intake.^3-5

Since the late 1990s, several meta-analyses, a systematic review of these cohort studies, and the Women’s Health Initiative Randomized Controlled Diet Initiative have largely concluded that there is no difference in breast cancer incidence between women with a low-fat diet (<20% of total calories from fat) and women with average or high-fat diets (>40% total calories from fat).^1,3,6,7

The meta-analysis performed by Boyd et al did find a statistically significant difference, with relative risks ranging from 1.11 for overall to 1.19 for high-saturated-fat diets.⁸ The upper limit of all confidence intervals was no higher than 1.35, however, suggesting a lack of clinical significance. The best-designed studies also evaluated dietary composition with regard to key types of fat (saturated, mono- and poly-unsaturated; animal vs vegetable vs marine) and found no significant differences based on type of fat consumed.¹

Preliminary evidence indicates that lowering dietary fat consumption may help with secondary prevention of breast cancer, but no large studies have been performed to date.⁹ Recently, a nested study within the Women’s Intervention Nutrition Study did show that women with breast cancer who decreased their fat intake to a median of 33 g/day had a hazard ratio of 0.76 for relapse over 60 months (compared with controls who ate a median of 51 g/day).¹⁰

Recommendations from others

There are no evidence-based or specific recommendations for the primary prevention of postmenopausal breast cancer for women through dietary fat reduction. In particular, neither the American Academy of Family Physicians, American College of Surgeons, National Institutes of Health, American College of Obstetricians and Gynecologists, American College of Physicians, US Preventive Services Task Force, or the Centers for Disease Control and Prevention provide any guidelines on dietary fat restriction for primary prevention of postmenopausal breast cancer.

The American Heart Association does have guidelines for coronary artery disease prevention for women, which include a low-fat diet.¹¹ The USPSTF has no specific guidelines regarding dietary fat consumption for the general population.

Evidence summary

Fungal infections of the nail (onychomycosis) are often treated for relief of local symptoms and cosmetic reasons. Griseofulvin, fluconazole, itraconazole, and terbinafine have all been used orally.

A meta-analysis comparing the efficacy of terbinafine (Lamisil), pulse-dosed and continuous-dosed itraconazole (Sporanox), fluconazole (Diflucan), and griseofulvin showed mycological cure rates of varying degrees for each treatment (TABLE).¹ Another meta-analysis of 6 studies comparing terbinafine with itraconazole reported odds ratios ranging from 1.8 (95% confidence interval [CI], 1.1–2.8) to 2.9 (95% CI, 1.9–4.1), indicating an 80% to 190% increased likelihood of clinical cure with terbinafine compared with itraconazole.²

Lower relapse rates with terbinafine

Longer-term mycologic cure and clinical relapse rates have also been reported. A 5-year blinded prospective study found long-term mycologic cures of 46% for terbinafine vs 13% for itraconazole (number needed to treat [NNT]=4.3). This study also showed a lower clinical relapse for terbinafine (21% vs 48%; NNT=3.7).³ A cost-efficacy analysis of terbinafine, itraconazole, and griseofulvin found terbinafine to be the most cost-effective (TABLE).⁴

A randomized, double-blind, controlled trial compared daily terbinafine with pulse-dose terbinafine.⁵ Daily terbinafine (250 mg for 3 months) had a 70.9% mycologic cure, while pulse-dose terbinafine (500 mg daily for 1 week per month for 3 months) had only a 58.7% mycologic cure (relative risk [RR]=1.21 [95% CI, 1.02–1.43]; NNT=8.2). There was no significant difference in tolerability of the regimens.

Terbinafine is well-tolerated by most patients. A telephone survey after treatment with daily terbinafine or pulse-dose itraconazole reported greater ease and convenience, and higher overall satisfaction with continuous terbinafine vs pulse-dose itraconazole.⁶

A multicenter trial of diabetic patients with onychomycosis (mean±SD age, 55.7±11.7 years) revealed that terbinafine had comparable efficacy and caused no hypoglycemic reactions in this group, who were being treated with insulin or oral hypoglycemics.⁷ The terbinafine prescribing information suggests not using the drug for patients with chronic or active liver disease and recommends checking a pretreatment AST and ALT.⁸

TABLE
Efficacy and cost of treating toenail onychomycosis^1,4

Recommendations from others

Guidelines from the British Association of Dermatologists point out that terbinafine is superior to itraconazole, and consider it a first-line treatment because it has a better cure rate and lower relapse rate.⁹ UpToDate suggests oral terbinafine as initial treatment for onychomycosis at a dose of 250 mg daily for 12 weeks.¹⁰

Evidence summary

Fungal infections of the nail (onychomycosis) are often treated for relief of local symptoms and cosmetic reasons. Griseofulvin, fluconazole, itraconazole, and terbinafine have all been used orally.

A meta-analysis comparing the efficacy of terbinafine (Lamisil), pulse-dosed and continuous-dosed itraconazole (Sporanox), fluconazole (Diflucan), and griseofulvin showed mycological cure rates of varying degrees for each treatment (TABLE).¹ Another meta-analysis of 6 studies comparing terbinafine with itraconazole reported odds ratios ranging from 1.8 (95% confidence interval [CI], 1.1–2.8) to 2.9 (95% CI, 1.9–4.1), indicating an 80% to 190% increased likelihood of clinical cure with terbinafine compared with itraconazole.²

Lower relapse rates with terbinafine

Longer-term mycologic cure and clinical relapse rates have also been reported. A 5-year blinded prospective study found long-term mycologic cures of 46% for terbinafine vs 13% for itraconazole (number needed to treat [NNT]=4.3). This study also showed a lower clinical relapse for terbinafine (21% vs 48%; NNT=3.7).³ A cost-efficacy analysis of terbinafine, itraconazole, and griseofulvin found terbinafine to be the most cost-effective (TABLE).⁴

A randomized, double-blind, controlled trial compared daily terbinafine with pulse-dose terbinafine.⁵ Daily terbinafine (250 mg for 3 months) had a 70.9% mycologic cure, while pulse-dose terbinafine (500 mg daily for 1 week per month for 3 months) had only a 58.7% mycologic cure (relative risk [RR]=1.21 [95% CI, 1.02–1.43]; NNT=8.2). There was no significant difference in tolerability of the regimens.

Terbinafine is well-tolerated by most patients. A telephone survey after treatment with daily terbinafine or pulse-dose itraconazole reported greater ease and convenience, and higher overall satisfaction with continuous terbinafine vs pulse-dose itraconazole.⁶

A multicenter trial of diabetic patients with onychomycosis (mean±SD age, 55.7±11.7 years) revealed that terbinafine had comparable efficacy and caused no hypoglycemic reactions in this group, who were being treated with insulin or oral hypoglycemics.⁷ The terbinafine prescribing information suggests not using the drug for patients with chronic or active liver disease and recommends checking a pretreatment AST and ALT.⁸

TABLE
Efficacy and cost of treating toenail onychomycosis^1,4

Recommendations from others

Guidelines from the British Association of Dermatologists point out that terbinafine is superior to itraconazole, and consider it a first-line treatment because it has a better cure rate and lower relapse rate.⁹ UpToDate suggests oral terbinafine as initial treatment for onychomycosis at a dose of 250 mg daily for 12 weeks.¹⁰

Evidence summary

Fungal infections of the nail (onychomycosis) are often treated for relief of local symptoms and cosmetic reasons. Griseofulvin, fluconazole, itraconazole, and terbinafine have all been used orally.

A meta-analysis comparing the efficacy of terbinafine (Lamisil), pulse-dosed and continuous-dosed itraconazole (Sporanox), fluconazole (Diflucan), and griseofulvin showed mycological cure rates of varying degrees for each treatment (TABLE).¹ Another meta-analysis of 6 studies comparing terbinafine with itraconazole reported odds ratios ranging from 1.8 (95% confidence interval [CI], 1.1–2.8) to 2.9 (95% CI, 1.9–4.1), indicating an 80% to 190% increased likelihood of clinical cure with terbinafine compared with itraconazole.²

Lower relapse rates with terbinafine

Longer-term mycologic cure and clinical relapse rates have also been reported. A 5-year blinded prospective study found long-term mycologic cures of 46% for terbinafine vs 13% for itraconazole (number needed to treat [NNT]=4.3). This study also showed a lower clinical relapse for terbinafine (21% vs 48%; NNT=3.7).³ A cost-efficacy analysis of terbinafine, itraconazole, and griseofulvin found terbinafine to be the most cost-effective (TABLE).⁴

A randomized, double-blind, controlled trial compared daily terbinafine with pulse-dose terbinafine.⁵ Daily terbinafine (250 mg for 3 months) had a 70.9% mycologic cure, while pulse-dose terbinafine (500 mg daily for 1 week per month for 3 months) had only a 58.7% mycologic cure (relative risk [RR]=1.21 [95% CI, 1.02–1.43]; NNT=8.2). There was no significant difference in tolerability of the regimens.

Terbinafine is well-tolerated by most patients. A telephone survey after treatment with daily terbinafine or pulse-dose itraconazole reported greater ease and convenience, and higher overall satisfaction with continuous terbinafine vs pulse-dose itraconazole.⁶

A multicenter trial of diabetic patients with onychomycosis (mean±SD age, 55.7±11.7 years) revealed that terbinafine had comparable efficacy and caused no hypoglycemic reactions in this group, who were being treated with insulin or oral hypoglycemics.⁷ The terbinafine prescribing information suggests not using the drug for patients with chronic or active liver disease and recommends checking a pretreatment AST and ALT.⁸

TABLE
Efficacy and cost of treating toenail onychomycosis^1,4

Recommendations from others

Guidelines from the British Association of Dermatologists point out that terbinafine is superior to itraconazole, and consider it a first-line treatment because it has a better cure rate and lower relapse rate.⁹ UpToDate suggests oral terbinafine as initial treatment for onychomycosis at a dose of 250 mg daily for 12 weeks.¹⁰

Evidence summary

All diagnoses of generalized anxiety disorder and panic disorder are clinical; they require the clinician’s judgment of objective findings. This Clinical Inquiry assesses the accuracy of case finding for these disorders, using screening tools, against the reference standard of a structured interview established by the criteria of the DSM-IV.

The TABLE compares the tools discussed here. Sensitivity, specificity, and likelihood ratios are calculated according to the authors’ designated cut points for the tools’ scores.

None of the authors recommend using these tools alone to make a diagnosis; clinicians must combine these instruments with an office interview to establish their diagnosis.

TABLE
How the anxiety and panic disorder screening tools stack up

GAD-7 tool is brief and in the public domain

For diagnosing generalized anxiety disorder, the GAD-7 has the best evidence for its utility. It was studied in a large, primary care–based sample size, is brief, and is in the public domain. It has a positive likelihood ratio of 4.9 (ie, the odds that a person has generalized anxiety disorder are 4.9 times higher if the GAD-7 is positive).¹

The Anxiety Screening Questionnaire (ASQ-15) also has good likelihood ratios, but the sample population was small, selected, and over half of the subjects were from a psychiatric practice.² The QPD has similar likelihood ratios to the GAD-7, but it requires purchase of proprietary software, and the supporting evidence is based on a small, selected, and compensated study group.³

Likelihood ratios are good for QPD and panic disorder

Panic disorder research yielded 3 screening tools: QPD, the Mental Health Index 5 (MHI-5), and the Panic Disorder Self-Report (PDSR).

• The QPD reports an excellent positive likelihood ratio and good negative likelihood ratio for panic disorder. As mentioned above, these results are limited by the quality of its sample size and the expense.³
• The MHI-5 screens for panic disorder with a single item taken from a larger questionnaire for panic disorder and depression. It has 100% sensitivity but a poor positive likelihood ratio. The sample size was very small—only 9 persons with panic disorder were tested.⁴
• The PDSR shows 100% specificity at the recommended cut-off point and a good negative likelihood ratio. Its weaknesses are a small study size, the homogeneity of the study population, who were self-selected, as well as the lengthiness of the questionnaire.⁵

Recommendations from others

A clinical practice guideline from the National Institute for Health and Clinical Excellence (UK) recommends a screening tool and structured interview or clinician consultation to establish a DSM-IV diagnosis for anxiety disorders. It reviews several ratings scales without grading utility or accuracy.⁶

The American Psychiatric Association has one guideline specifically addressing panic disorder, with a short paragraph describing the use of the DSM-IV via a structured interview to establish the diagnosis.⁷

Evidence summary

All diagnoses of generalized anxiety disorder and panic disorder are clinical; they require the clinician’s judgment of objective findings. This Clinical Inquiry assesses the accuracy of case finding for these disorders, using screening tools, against the reference standard of a structured interview established by the criteria of the DSM-IV.

The TABLE compares the tools discussed here. Sensitivity, specificity, and likelihood ratios are calculated according to the authors’ designated cut points for the tools’ scores.

None of the authors recommend using these tools alone to make a diagnosis; clinicians must combine these instruments with an office interview to establish their diagnosis.

TABLE
How the anxiety and panic disorder screening tools stack up

GAD-7 tool is brief and in the public domain

For diagnosing generalized anxiety disorder, the GAD-7 has the best evidence for its utility. It was studied in a large, primary care–based sample size, is brief, and is in the public domain. It has a positive likelihood ratio of 4.9 (ie, the odds that a person has generalized anxiety disorder are 4.9 times higher if the GAD-7 is positive).¹

The Anxiety Screening Questionnaire (ASQ-15) also has good likelihood ratios, but the sample population was small, selected, and over half of the subjects were from a psychiatric practice.² The QPD has similar likelihood ratios to the GAD-7, but it requires purchase of proprietary software, and the supporting evidence is based on a small, selected, and compensated study group.³

Likelihood ratios are good for QPD and panic disorder

Panic disorder research yielded 3 screening tools: QPD, the Mental Health Index 5 (MHI-5), and the Panic Disorder Self-Report (PDSR).

• The QPD reports an excellent positive likelihood ratio and good negative likelihood ratio for panic disorder. As mentioned above, these results are limited by the quality of its sample size and the expense.³
• The MHI-5 screens for panic disorder with a single item taken from a larger questionnaire for panic disorder and depression. It has 100% sensitivity but a poor positive likelihood ratio. The sample size was very small—only 9 persons with panic disorder were tested.⁴
• The PDSR shows 100% specificity at the recommended cut-off point and a good negative likelihood ratio. Its weaknesses are a small study size, the homogeneity of the study population, who were self-selected, as well as the lengthiness of the questionnaire.⁵

Recommendations from others

A clinical practice guideline from the National Institute for Health and Clinical Excellence (UK) recommends a screening tool and structured interview or clinician consultation to establish a DSM-IV diagnosis for anxiety disorders. It reviews several ratings scales without grading utility or accuracy.⁶

The American Psychiatric Association has one guideline specifically addressing panic disorder, with a short paragraph describing the use of the DSM-IV via a structured interview to establish the diagnosis.⁷

Evidence summary

All diagnoses of generalized anxiety disorder and panic disorder are clinical; they require the clinician’s judgment of objective findings. This Clinical Inquiry assesses the accuracy of case finding for these disorders, using screening tools, against the reference standard of a structured interview established by the criteria of the DSM-IV.

The TABLE compares the tools discussed here. Sensitivity, specificity, and likelihood ratios are calculated according to the authors’ designated cut points for the tools’ scores.

None of the authors recommend using these tools alone to make a diagnosis; clinicians must combine these instruments with an office interview to establish their diagnosis.

TABLE
How the anxiety and panic disorder screening tools stack up

GAD-7 tool is brief and in the public domain

For diagnosing generalized anxiety disorder, the GAD-7 has the best evidence for its utility. It was studied in a large, primary care–based sample size, is brief, and is in the public domain. It has a positive likelihood ratio of 4.9 (ie, the odds that a person has generalized anxiety disorder are 4.9 times higher if the GAD-7 is positive).¹

The Anxiety Screening Questionnaire (ASQ-15) also has good likelihood ratios, but the sample population was small, selected, and over half of the subjects were from a psychiatric practice.² The QPD has similar likelihood ratios to the GAD-7, but it requires purchase of proprietary software, and the supporting evidence is based on a small, selected, and compensated study group.³

Likelihood ratios are good for QPD and panic disorder

Panic disorder research yielded 3 screening tools: QPD, the Mental Health Index 5 (MHI-5), and the Panic Disorder Self-Report (PDSR).

• The QPD reports an excellent positive likelihood ratio and good negative likelihood ratio for panic disorder. As mentioned above, these results are limited by the quality of its sample size and the expense.³
• The MHI-5 screens for panic disorder with a single item taken from a larger questionnaire for panic disorder and depression. It has 100% sensitivity but a poor positive likelihood ratio. The sample size was very small—only 9 persons with panic disorder were tested.⁴
• The PDSR shows 100% specificity at the recommended cut-off point and a good negative likelihood ratio. Its weaknesses are a small study size, the homogeneity of the study population, who were self-selected, as well as the lengthiness of the questionnaire.⁵

Recommendations from others

A clinical practice guideline from the National Institute for Health and Clinical Excellence (UK) recommends a screening tool and structured interview or clinician consultation to establish a DSM-IV diagnosis for anxiety disorders. It reviews several ratings scales without grading utility or accuracy.⁶

The American Psychiatric Association has one guideline specifically addressing panic disorder, with a short paragraph describing the use of the DSM-IV via a structured interview to establish the diagnosis.⁷

Evidence summary

Herpes labialis is the most common presentation of herpes simplex virus 1 (HSV-1) infection and generally represents reactivation. The disease progresses quickly; therefore, early treatment is required.

TABLE 1
Antiviral agents for herpes labialis: A comparison

Oral treatments: Shortening episodes by a day

Two RCTs have shown that valacyclovir (the prodrug of acyclovir, which has 3 to 5 times greater bioavailability) at a dosage of 2 g twice in 1 day significantly decreased the episode duration and time to lesion healing compared with placebo. In the first study (n=603), the mean episode duration was decreased by 1.1 days (5.0 vs 6.1 days; 95% confidence interval [CI], –1.6 to –0.6); in the second study (n=615) by 1.0 day (5.3 vs 6.3 days; 95% CI, –1.0 to –0.5).¹

Oral acyclovir has also been shown to be effective in a well-done RCT (TABLE 1). For a subgroup of patients who started acyclovir in the prodrome or erythema stage, the duration decreased (2.5 vs 3.9 days, P=.02), but in the papular stage, it did not decrease significantly (2.5 vs. 3.6 days, P=.36).²

Topical treatments speed healing, reduce pain

Topical penciclovir 1% cream decreases the duration of lesion healing and pain compared with a vehicle control, as shown by 2 RCTs (n=3057, 1573). Patients initiated self-treatment every 2 hours during waking hours for 4 days. In one RCT, the treatment patients lost classic lesions 31% faster than the placebo group. In another trial, healing of classical lesions was faster by 0.7 days (4.8 vs 5.5). Benefits were achieved in both the early (P=.001) and later stages (P=.0055) of recurrence.³

Two RCTs of topical acyclovir 5% cream, 5 times a day for 4 days (n=689, 699) showed that topical acyclovir, compared with placebo, shortened the duration of an outbreak by 0.5 day (4.3 vs 4.8) and 0.6 day (4.6 vs 5.2), respectively.⁴ When it comes to prophylaxis, several studies have shown that oral valacyclovir and sunscreen may be effective for prophylaxis of herpes labialis (TABLE 2).^6-8

TABLE 2
Valacyclovir and sunscreen: Helpful in preventing a herpes labialis outbreak

Recommendations from others

The BMJ Clinical Evidence Guideline reiterates that oral agents (acyclovir or valacyclovir) and topical agents (acyclovir or penciclovir) slightly reduce healing time and duration of pain in treating recurrent attack. As prophylaxis, oral acyclovir or sunscreen are likely to be beneficial.⁹

UpToDate reports that recurrent herpes labialis is usually not treated with antivirals unless a prodromal stage can be identified. In these cases, oral acyclovir or penciclovir cream can be prescribed for 4 days’ duration. Chronic suppressive therapy can be useful in immunocompetent patients with more than 2 episodes in 4 months, and for recurrences associated with systemic complications or those that affect job performance. As prophylaxis, oral acyclovir (200 mg 3–5 times a day) is generally used, but valacyclovir (500 mg once daily) is also effective.¹⁰

Evidence summary

Herpes labialis is the most common presentation of herpes simplex virus 1 (HSV-1) infection and generally represents reactivation. The disease progresses quickly; therefore, early treatment is required.

TABLE 1
Antiviral agents for herpes labialis: A comparison

Oral treatments: Shortening episodes by a day

Two RCTs have shown that valacyclovir (the prodrug of acyclovir, which has 3 to 5 times greater bioavailability) at a dosage of 2 g twice in 1 day significantly decreased the episode duration and time to lesion healing compared with placebo. In the first study (n=603), the mean episode duration was decreased by 1.1 days (5.0 vs 6.1 days; 95% confidence interval [CI], –1.6 to –0.6); in the second study (n=615) by 1.0 day (5.3 vs 6.3 days; 95% CI, –1.0 to –0.5).¹

Oral acyclovir has also been shown to be effective in a well-done RCT (TABLE 1). For a subgroup of patients who started acyclovir in the prodrome or erythema stage, the duration decreased (2.5 vs 3.9 days, P=.02), but in the papular stage, it did not decrease significantly (2.5 vs. 3.6 days, P=.36).²

Topical treatments speed healing, reduce pain

Topical penciclovir 1% cream decreases the duration of lesion healing and pain compared with a vehicle control, as shown by 2 RCTs (n=3057, 1573). Patients initiated self-treatment every 2 hours during waking hours for 4 days. In one RCT, the treatment patients lost classic lesions 31% faster than the placebo group. In another trial, healing of classical lesions was faster by 0.7 days (4.8 vs 5.5). Benefits were achieved in both the early (P=.001) and later stages (P=.0055) of recurrence.³

Two RCTs of topical acyclovir 5% cream, 5 times a day for 4 days (n=689, 699) showed that topical acyclovir, compared with placebo, shortened the duration of an outbreak by 0.5 day (4.3 vs 4.8) and 0.6 day (4.6 vs 5.2), respectively.⁴ When it comes to prophylaxis, several studies have shown that oral valacyclovir and sunscreen may be effective for prophylaxis of herpes labialis (TABLE 2).^6-8

TABLE 2
Valacyclovir and sunscreen: Helpful in preventing a herpes labialis outbreak

Recommendations from others

The BMJ Clinical Evidence Guideline reiterates that oral agents (acyclovir or valacyclovir) and topical agents (acyclovir or penciclovir) slightly reduce healing time and duration of pain in treating recurrent attack. As prophylaxis, oral acyclovir or sunscreen are likely to be beneficial.⁹

UpToDate reports that recurrent herpes labialis is usually not treated with antivirals unless a prodromal stage can be identified. In these cases, oral acyclovir or penciclovir cream can be prescribed for 4 days’ duration. Chronic suppressive therapy can be useful in immunocompetent patients with more than 2 episodes in 4 months, and for recurrences associated with systemic complications or those that affect job performance. As prophylaxis, oral acyclovir (200 mg 3–5 times a day) is generally used, but valacyclovir (500 mg once daily) is also effective.¹⁰

Evidence summary

Herpes labialis is the most common presentation of herpes simplex virus 1 (HSV-1) infection and generally represents reactivation. The disease progresses quickly; therefore, early treatment is required.

TABLE 1
Antiviral agents for herpes labialis: A comparison

Oral treatments: Shortening episodes by a day

Two RCTs have shown that valacyclovir (the prodrug of acyclovir, which has 3 to 5 times greater bioavailability) at a dosage of 2 g twice in 1 day significantly decreased the episode duration and time to lesion healing compared with placebo. In the first study (n=603), the mean episode duration was decreased by 1.1 days (5.0 vs 6.1 days; 95% confidence interval [CI], –1.6 to –0.6); in the second study (n=615) by 1.0 day (5.3 vs 6.3 days; 95% CI, –1.0 to –0.5).¹

Oral acyclovir has also been shown to be effective in a well-done RCT (TABLE 1). For a subgroup of patients who started acyclovir in the prodrome or erythema stage, the duration decreased (2.5 vs 3.9 days, P=.02), but in the papular stage, it did not decrease significantly (2.5 vs. 3.6 days, P=.36).²

Topical treatments speed healing, reduce pain

Topical penciclovir 1% cream decreases the duration of lesion healing and pain compared with a vehicle control, as shown by 2 RCTs (n=3057, 1573). Patients initiated self-treatment every 2 hours during waking hours for 4 days. In one RCT, the treatment patients lost classic lesions 31% faster than the placebo group. In another trial, healing of classical lesions was faster by 0.7 days (4.8 vs 5.5). Benefits were achieved in both the early (P=.001) and later stages (P=.0055) of recurrence.³

Two RCTs of topical acyclovir 5% cream, 5 times a day for 4 days (n=689, 699) showed that topical acyclovir, compared with placebo, shortened the duration of an outbreak by 0.5 day (4.3 vs 4.8) and 0.6 day (4.6 vs 5.2), respectively.⁴ When it comes to prophylaxis, several studies have shown that oral valacyclovir and sunscreen may be effective for prophylaxis of herpes labialis (TABLE 2).^6-8

TABLE 2
Valacyclovir and sunscreen: Helpful in preventing a herpes labialis outbreak

Recommendations from others

The BMJ Clinical Evidence Guideline reiterates that oral agents (acyclovir or valacyclovir) and topical agents (acyclovir or penciclovir) slightly reduce healing time and duration of pain in treating recurrent attack. As prophylaxis, oral acyclovir or sunscreen are likely to be beneficial.⁹

UpToDate reports that recurrent herpes labialis is usually not treated with antivirals unless a prodromal stage can be identified. In these cases, oral acyclovir or penciclovir cream can be prescribed for 4 days’ duration. Chronic suppressive therapy can be useful in immunocompetent patients with more than 2 episodes in 4 months, and for recurrences associated with systemic complications or those that affect job performance. As prophylaxis, oral acyclovir (200 mg 3–5 times a day) is generally used, but valacyclovir (500 mg once daily) is also effective.¹⁰

Evidence summary

The prevalence of infertility in the US is approximately 15% to 17%.^2,3 Secondary infertility may comprise 80% of these cases, though reports vary.² Begin the evaluation of secondary infertility with a thorough history and physical, as outlined in the TABLE), followed by semen analysis and evaluation of ovulation.^1,3,4

TABLE
Secondary infertility? Here’s what to cover in the history and exam

Evaluate the male partner for varicoceles

The semen sample can be taken after the patient abstains from ejaculation for 2 to 6 days. Analyze the sample for volume, pH, sperm concentration, motility, and total number. If the sample is abnormal, repeat the analysis within 3 months.^1,5

Evaluate the male for varicoceles. A retrospective chart review compared 285 men with secondary infertility with 285 men with primary infertility. Varicoceles were the cause of secondary infertility in 177 (69%) of men with secondary infertility compared with 128 (50%) of men with primary infertility (P<.0001).⁶

Order tests to evaluate ovulation

To evaluate ovulation, look at menstrual history, serum progesterone, and urine luteinizing hormone (LH).^1,3,4 If the woman has signs of androgenic dysfunction, draw tests for LH, thyroid-stimulating hormone, follicle-stimulating hormone (FSH), testosterone, prolactin, and 17-hydroxyprogesterone. A woman with irregular menses should have her LH and FSH checked.¹

A hysterosalpingogram is an effective first test in the evaluation of the uterine cavity and tubal patency.^1,7,8 If the woman has comorbidities—such as a history of pelvic inflammatory disease, previous ectopic pregnancy, or endometriosis—then laparoscopy should be the initial test.^1,3 One study demonstrated increased diagnostic yield with a combined approach of hysteroscopy and laparoscopy, in communities where the risk of pelvic infection was great.⁹

Routine postcoital testing is unnecessary.¹⁰ A randomized controlled trial compared 227 couples who received the postcoital test with 217 couples who did not. Routine use of the postcoital test led to more tests and more treatments but had no significant effect on the pregnancy rate.

Recommendations from others

According to the Royal College of Obstetricians and Gynecologists:¹

1. The use of basal body temperature charts to confirm ovulation does not reliably predict ovulation and is not recommended.
2. The routine measurement of thyroid function should not be offered.
3. Women should not be offered an endometrial biopsy to evaluate the luteal phase because there is no evidence that medical treatment of luteal phase defect improves pregnancy rates.
4. Women who are not known to have comorbidities (such as pelvic inflammatory disease, previous ectopic pregnancy, or endometriosis) should be offered hysterosalpingography to screen for tubal occlusion.
5. Women who are thought to have comorbidities should be offered laparoscopy and dye so that tubal and other pelvic pathology can be assessed at the same time.

Evidence summary

The prevalence of infertility in the US is approximately 15% to 17%.^2,3 Secondary infertility may comprise 80% of these cases, though reports vary.² Begin the evaluation of secondary infertility with a thorough history and physical, as outlined in the TABLE), followed by semen analysis and evaluation of ovulation.^1,3,4

TABLE
Secondary infertility? Here’s what to cover in the history and exam

Evaluate the male partner for varicoceles

The semen sample can be taken after the patient abstains from ejaculation for 2 to 6 days. Analyze the sample for volume, pH, sperm concentration, motility, and total number. If the sample is abnormal, repeat the analysis within 3 months.^1,5

Evaluate the male for varicoceles. A retrospective chart review compared 285 men with secondary infertility with 285 men with primary infertility. Varicoceles were the cause of secondary infertility in 177 (69%) of men with secondary infertility compared with 128 (50%) of men with primary infertility (P<.0001).⁶

Order tests to evaluate ovulation

To evaluate ovulation, look at menstrual history, serum progesterone, and urine luteinizing hormone (LH).^1,3,4 If the woman has signs of androgenic dysfunction, draw tests for LH, thyroid-stimulating hormone, follicle-stimulating hormone (FSH), testosterone, prolactin, and 17-hydroxyprogesterone. A woman with irregular menses should have her LH and FSH checked.¹

A hysterosalpingogram is an effective first test in the evaluation of the uterine cavity and tubal patency.^1,7,8 If the woman has comorbidities—such as a history of pelvic inflammatory disease, previous ectopic pregnancy, or endometriosis—then laparoscopy should be the initial test.^1,3 One study demonstrated increased diagnostic yield with a combined approach of hysteroscopy and laparoscopy, in communities where the risk of pelvic infection was great.⁹

Routine postcoital testing is unnecessary.¹⁰ A randomized controlled trial compared 227 couples who received the postcoital test with 217 couples who did not. Routine use of the postcoital test led to more tests and more treatments but had no significant effect on the pregnancy rate.

Recommendations from others

According to the Royal College of Obstetricians and Gynecologists:¹

1. The use of basal body temperature charts to confirm ovulation does not reliably predict ovulation and is not recommended.
2. The routine measurement of thyroid function should not be offered.
3. Women should not be offered an endometrial biopsy to evaluate the luteal phase because there is no evidence that medical treatment of luteal phase defect improves pregnancy rates.
4. Women who are not known to have comorbidities (such as pelvic inflammatory disease, previous ectopic pregnancy, or endometriosis) should be offered hysterosalpingography to screen for tubal occlusion.
5. Women who are thought to have comorbidities should be offered laparoscopy and dye so that tubal and other pelvic pathology can be assessed at the same time.

Evidence summary

The prevalence of infertility in the US is approximately 15% to 17%.^2,3 Secondary infertility may comprise 80% of these cases, though reports vary.² Begin the evaluation of secondary infertility with a thorough history and physical, as outlined in the TABLE), followed by semen analysis and evaluation of ovulation.^1,3,4

TABLE
Secondary infertility? Here’s what to cover in the history and exam

Evaluate the male partner for varicoceles

The semen sample can be taken after the patient abstains from ejaculation for 2 to 6 days. Analyze the sample for volume, pH, sperm concentration, motility, and total number. If the sample is abnormal, repeat the analysis within 3 months.^1,5

Evaluate the male for varicoceles. A retrospective chart review compared 285 men with secondary infertility with 285 men with primary infertility. Varicoceles were the cause of secondary infertility in 177 (69%) of men with secondary infertility compared with 128 (50%) of men with primary infertility (P<.0001).⁶

Order tests to evaluate ovulation

To evaluate ovulation, look at menstrual history, serum progesterone, and urine luteinizing hormone (LH).^1,3,4 If the woman has signs of androgenic dysfunction, draw tests for LH, thyroid-stimulating hormone, follicle-stimulating hormone (FSH), testosterone, prolactin, and 17-hydroxyprogesterone. A woman with irregular menses should have her LH and FSH checked.¹

A hysterosalpingogram is an effective first test in the evaluation of the uterine cavity and tubal patency.^1,7,8 If the woman has comorbidities—such as a history of pelvic inflammatory disease, previous ectopic pregnancy, or endometriosis—then laparoscopy should be the initial test.^1,3 One study demonstrated increased diagnostic yield with a combined approach of hysteroscopy and laparoscopy, in communities where the risk of pelvic infection was great.⁹

Routine postcoital testing is unnecessary.¹⁰ A randomized controlled trial compared 227 couples who received the postcoital test with 217 couples who did not. Routine use of the postcoital test led to more tests and more treatments but had no significant effect on the pregnancy rate.

Recommendations from others

According to the Royal College of Obstetricians and Gynecologists:¹

1. The use of basal body temperature charts to confirm ovulation does not reliably predict ovulation and is not recommended.
2. The routine measurement of thyroid function should not be offered.
3. Women should not be offered an endometrial biopsy to evaluate the luteal phase because there is no evidence that medical treatment of luteal phase defect improves pregnancy rates.
4. Women who are not known to have comorbidities (such as pelvic inflammatory disease, previous ectopic pregnancy, or endometriosis) should be offered hysterosalpingography to screen for tubal occlusion.
5. Women who are thought to have comorbidities should be offered laparoscopy and dye so that tubal and other pelvic pathology can be assessed at the same time.

Evidence summary

Clinical diagnosis of scabies begins with pruritus, typical lesions in a distribution consistent with scabies—finger webs, wrists, axillae, elbows, buttocks, genitalia of men, breasts of women—and possible exposure. Clinical diagnosis can be confirmed by skin scrapings from characteristic lesions, such as burrows. When these scrapings are examined under light microscopy, they can show mites, eggs, or feces from the mites (FIGURE). However, this technique depends greatly on operator experience and skill, and a lack of light microscopy findings does not rule out scabies.¹

The only study we found that investigated the sensitivity of clinical features in diagnosing scabies was done in sub-Saharan Africa.² In this study, the presence of diffuse itching, plus lesions in at least 2 locations typical with scabies or a household member with itch, had 100% sensitivity and 96.9% specificity for scabies infection. This study used the evaluation of a dermatologist as a gold standard. The authors propose that treatment based on clinical findings with or without microscopic confirmation is appropriate; however, it is not clear how these data translate to a primary care population with a lower prevalence of scabies.

FIGURE
The “Oh, wow!” test

It is reassuring to know that evidence exists for opting to treat without confirmation. It also saves the patient the cost of the skin scraping and microscopy—important for the increasing numbers of cash-paying, uninsured patients.
—Barbara Walker, Do

Long stretches without symptoms play role in treatment

To date, no controlled trials address whether empiric treatment of asymptomatic contacts or family members of those with scabies decreases its spread. However, it is known that an initial infestation with scabies will not lead to pruritus for up to 4 to 6 weeks.¹ Asymptomatic contacts can be infected with scabies, and can transmit this infection to others before symptoms even occur.

Given the long period of asymptomatic infestation, prevention of epidemics in institutions such as hospitals, nursing homes, and residential facilities is of particular importance. One case-control study, performed at a large tertiary-care teaching hospital, demonstrated that health care workers on a service having a patient with undiagnosed scabies were 5.3 times more likely to develop a pruritic rash than those in other units.³

Health care workers with more skin-to-skin contact with the patients (nurses, nursing students, and physical therapists) were 4.5 times more likely to develop scabies compared with those in less physical contact (physicians, medical students, and occupational therapists). Among the symptomatic health care workers, 17% of their household contacts developed scabies, too.

Permethrin vs lindane? Which is better?

A 2000 Cochrane review, updated in 2002, concluded that permethrin was superior to lindane for topical treatment of scabies.^4,5 Combining 4 trials with 718 patients, permethrin 5% appeared better than lindane 1% (odds ratio=0.66; 95% confidence interval, 0.46–0.95). However, there was significant heterogeneity between the studies, and the largest trial (n=467) found no difference.

Oral ivermectin, though costly, is an effective alternative for those who do not tolerate topical treatment. See the TABLE for a summary of treatment recommendations.

TABLE
Recommended treatment for scabies infection

Recommendations from others

Guidelines released by the Centers for Disease Control and Prevention in 2002 regarding the treatment of sexually transmitted diseases state that both sexual and close personal or household contacts of patients diagnosed with scabies within the preceding month should be examined and treated.⁶

Another guideline, developed by the British Association of Sexual Health and HIV, recommends empiric treatment of sexual, household, and institutional contacts of those with scabies. This guideline recommends treating those who were in contact with the scabies patient within 2 months of his diagnosis; this time frame, though, is arbitrary.⁷ No evidence grading was given for these recommendations, which are based on expert opinion.

Evidence summary

Clinical diagnosis of scabies begins with pruritus, typical lesions in a distribution consistent with scabies—finger webs, wrists, axillae, elbows, buttocks, genitalia of men, breasts of women—and possible exposure. Clinical diagnosis can be confirmed by skin scrapings from characteristic lesions, such as burrows. When these scrapings are examined under light microscopy, they can show mites, eggs, or feces from the mites (FIGURE). However, this technique depends greatly on operator experience and skill, and a lack of light microscopy findings does not rule out scabies.¹

The only study we found that investigated the sensitivity of clinical features in diagnosing scabies was done in sub-Saharan Africa.² In this study, the presence of diffuse itching, plus lesions in at least 2 locations typical with scabies or a household member with itch, had 100% sensitivity and 96.9% specificity for scabies infection. This study used the evaluation of a dermatologist as a gold standard. The authors propose that treatment based on clinical findings with or without microscopic confirmation is appropriate; however, it is not clear how these data translate to a primary care population with a lower prevalence of scabies.

FIGURE
The “Oh, wow!” test

It is reassuring to know that evidence exists for opting to treat without confirmation. It also saves the patient the cost of the skin scraping and microscopy—important for the increasing numbers of cash-paying, uninsured patients.
—Barbara Walker, Do

Long stretches without symptoms play role in treatment

To date, no controlled trials address whether empiric treatment of asymptomatic contacts or family members of those with scabies decreases its spread. However, it is known that an initial infestation with scabies will not lead to pruritus for up to 4 to 6 weeks.¹ Asymptomatic contacts can be infected with scabies, and can transmit this infection to others before symptoms even occur.

Given the long period of asymptomatic infestation, prevention of epidemics in institutions such as hospitals, nursing homes, and residential facilities is of particular importance. One case-control study, performed at a large tertiary-care teaching hospital, demonstrated that health care workers on a service having a patient with undiagnosed scabies were 5.3 times more likely to develop a pruritic rash than those in other units.³

Health care workers with more skin-to-skin contact with the patients (nurses, nursing students, and physical therapists) were 4.5 times more likely to develop scabies compared with those in less physical contact (physicians, medical students, and occupational therapists). Among the symptomatic health care workers, 17% of their household contacts developed scabies, too.

Permethrin vs lindane? Which is better?

A 2000 Cochrane review, updated in 2002, concluded that permethrin was superior to lindane for topical treatment of scabies.^4,5 Combining 4 trials with 718 patients, permethrin 5% appeared better than lindane 1% (odds ratio=0.66; 95% confidence interval, 0.46–0.95). However, there was significant heterogeneity between the studies, and the largest trial (n=467) found no difference.

Oral ivermectin, though costly, is an effective alternative for those who do not tolerate topical treatment. See the TABLE for a summary of treatment recommendations.

TABLE
Recommended treatment for scabies infection

Recommendations from others

Guidelines released by the Centers for Disease Control and Prevention in 2002 regarding the treatment of sexually transmitted diseases state that both sexual and close personal or household contacts of patients diagnosed with scabies within the preceding month should be examined and treated.⁶

Another guideline, developed by the British Association of Sexual Health and HIV, recommends empiric treatment of sexual, household, and institutional contacts of those with scabies. This guideline recommends treating those who were in contact with the scabies patient within 2 months of his diagnosis; this time frame, though, is arbitrary.⁷ No evidence grading was given for these recommendations, which are based on expert opinion.

Evidence summary

Clinical diagnosis of scabies begins with pruritus, typical lesions in a distribution consistent with scabies—finger webs, wrists, axillae, elbows, buttocks, genitalia of men, breasts of women—and possible exposure. Clinical diagnosis can be confirmed by skin scrapings from characteristic lesions, such as burrows. When these scrapings are examined under light microscopy, they can show mites, eggs, or feces from the mites (FIGURE). However, this technique depends greatly on operator experience and skill, and a lack of light microscopy findings does not rule out scabies.¹

The only study we found that investigated the sensitivity of clinical features in diagnosing scabies was done in sub-Saharan Africa.² In this study, the presence of diffuse itching, plus lesions in at least 2 locations typical with scabies or a household member with itch, had 100% sensitivity and 96.9% specificity for scabies infection. This study used the evaluation of a dermatologist as a gold standard. The authors propose that treatment based on clinical findings with or without microscopic confirmation is appropriate; however, it is not clear how these data translate to a primary care population with a lower prevalence of scabies.

FIGURE
The “Oh, wow!” test

It is reassuring to know that evidence exists for opting to treat without confirmation. It also saves the patient the cost of the skin scraping and microscopy—important for the increasing numbers of cash-paying, uninsured patients.
—Barbara Walker, Do

Long stretches without symptoms play role in treatment

To date, no controlled trials address whether empiric treatment of asymptomatic contacts or family members of those with scabies decreases its spread. However, it is known that an initial infestation with scabies will not lead to pruritus for up to 4 to 6 weeks.¹ Asymptomatic contacts can be infected with scabies, and can transmit this infection to others before symptoms even occur.

Given the long period of asymptomatic infestation, prevention of epidemics in institutions such as hospitals, nursing homes, and residential facilities is of particular importance. One case-control study, performed at a large tertiary-care teaching hospital, demonstrated that health care workers on a service having a patient with undiagnosed scabies were 5.3 times more likely to develop a pruritic rash than those in other units.³

Health care workers with more skin-to-skin contact with the patients (nurses, nursing students, and physical therapists) were 4.5 times more likely to develop scabies compared with those in less physical contact (physicians, medical students, and occupational therapists). Among the symptomatic health care workers, 17% of their household contacts developed scabies, too.

Permethrin vs lindane? Which is better?

A 2000 Cochrane review, updated in 2002, concluded that permethrin was superior to lindane for topical treatment of scabies.^4,5 Combining 4 trials with 718 patients, permethrin 5% appeared better than lindane 1% (odds ratio=0.66; 95% confidence interval, 0.46–0.95). However, there was significant heterogeneity between the studies, and the largest trial (n=467) found no difference.

Oral ivermectin, though costly, is an effective alternative for those who do not tolerate topical treatment. See the TABLE for a summary of treatment recommendations.

TABLE
Recommended treatment for scabies infection

Recommendations from others

Guidelines released by the Centers for Disease Control and Prevention in 2002 regarding the treatment of sexually transmitted diseases state that both sexual and close personal or household contacts of patients diagnosed with scabies within the preceding month should be examined and treated.⁶

Another guideline, developed by the British Association of Sexual Health and HIV, recommends empiric treatment of sexual, household, and institutional contacts of those with scabies. This guideline recommends treating those who were in contact with the scabies patient within 2 months of his diagnosis; this time frame, though, is arbitrary.⁷ No evidence grading was given for these recommendations, which are based on expert opinion.

Evidence summary

Night sweats are a common complaint in the ambulatory primary care setting: Of 2267 patients in 1 cross-sectional study, 41% reported night sweats, defined as “sweating at night even when it isn’t excessively hot in your bedroom” within the previous month.¹ Because the peak prevalence in both men and women occurred in the group ages 41 to 55 years, there was concern that menopausal hot flashes were a confounding factor, at least for women. In a subsequent study of 795 patients older than 64 years, 10% still reported being bothered by night sweats.²

The more common causes are not widely studied

Few studies look at the causes of night sweats. Although they have been associated with tuberculosis, lymphoma, and HIV infection, these are not common causes of night sweats in outpatient care.

In the only study that specifically addressed the causes of night sweats in an ambulatory population, Reynolds³ interviewed 200 consecutive patients, 70% from a primary care practice and 30% from a gastroenterology practice. Of the 81 patients who reported having an episode of night sweats at least once a week, esophageal reflux and menopause were the most frequent causes.

Several authors agree that certain medications are frequently associated with night sweats, although the exact incidence is unknown due to a lack of published epidemiologic data.^4-6 Antidepressants and antipyretics are among the more commonly cited offenders (TABLE 1).⁴

TABLE 1
Medications that may cause sweating or flushing

Finding the right diagnosis requires thorough history & exam

With such a long differential diagnosis (TABLE 2),^4-6 night sweats should initially be evaluated with a thorough history and physical examination (according to a consensus opinion of various authors). If these don’t elicit possible causes, the appropriate next step in the work-up can vary. Some authors recommend multiple laboratory and imaging studies, while others advise against any routine tests. None of these approaches is evidence-based.

One reasonable algorithm recommends an initial work-up including a complete blood count, thyroid-stimulating hormone (TSH) and erythrocyte sedimentation rate (ESR) level, a purified protein derivative (PPD) and HIV test, and a chest x-ray.⁵ If the results are unrevealing, a trial of antireflux medication is recommended. If the patient does not improve, consider a diary of nocturnal temperatures to help discern the presence or absence of febrile pulses and further evaluate for suspected endocarditis or lymphoma.

TABLE 2
Differential diagnosis for night sweats

Evidence is scant for symptom relief

Very few clinical trials have directly studied symptomatic relief of night sweats. A large Cochrane meta-analysis found that oral hormone therapy—estrogens alone or estrogens with progesterone—reduced the frequency of night sweats associated with hot flashes among menopausal women by 75% when compared with placebo alone.⁷ Neither primrose oil nor foot reflexology proved effective.⁸

A cohort study found that 80% of the patients with frequent night sweats responded to antireflux therapy.³ One author suggests using therapies aimed at relieving hyperhydrosis.⁶ These include local treatment with aluminum chloride hexahydrate (Drysol), antiperspirants, scopolamine, or phenoxybenzamine hydrochloride (Dibenzyline).

Recommendations from others

A thorough literature search through Cochrane Database Systematic Reviews, AHRQ, National Guideline Clearing-house, and Medline did not yield any guidelines or consensus statements from other organizations or specialty groups on the evaluation or treatment of night sweats.

Evidence summary

Night sweats are a common complaint in the ambulatory primary care setting: Of 2267 patients in 1 cross-sectional study, 41% reported night sweats, defined as “sweating at night even when it isn’t excessively hot in your bedroom” within the previous month.¹ Because the peak prevalence in both men and women occurred in the group ages 41 to 55 years, there was concern that menopausal hot flashes were a confounding factor, at least for women. In a subsequent study of 795 patients older than 64 years, 10% still reported being bothered by night sweats.²

The more common causes are not widely studied

Few studies look at the causes of night sweats. Although they have been associated with tuberculosis, lymphoma, and HIV infection, these are not common causes of night sweats in outpatient care.

In the only study that specifically addressed the causes of night sweats in an ambulatory population, Reynolds³ interviewed 200 consecutive patients, 70% from a primary care practice and 30% from a gastroenterology practice. Of the 81 patients who reported having an episode of night sweats at least once a week, esophageal reflux and menopause were the most frequent causes.

Several authors agree that certain medications are frequently associated with night sweats, although the exact incidence is unknown due to a lack of published epidemiologic data.^4-6 Antidepressants and antipyretics are among the more commonly cited offenders (TABLE 1).⁴

TABLE 1
Medications that may cause sweating or flushing

Finding the right diagnosis requires thorough history & exam

With such a long differential diagnosis (TABLE 2),^4-6 night sweats should initially be evaluated with a thorough history and physical examination (according to a consensus opinion of various authors). If these don’t elicit possible causes, the appropriate next step in the work-up can vary. Some authors recommend multiple laboratory and imaging studies, while others advise against any routine tests. None of these approaches is evidence-based.

One reasonable algorithm recommends an initial work-up including a complete blood count, thyroid-stimulating hormone (TSH) and erythrocyte sedimentation rate (ESR) level, a purified protein derivative (PPD) and HIV test, and a chest x-ray.⁵ If the results are unrevealing, a trial of antireflux medication is recommended. If the patient does not improve, consider a diary of nocturnal temperatures to help discern the presence or absence of febrile pulses and further evaluate for suspected endocarditis or lymphoma.

TABLE 2
Differential diagnosis for night sweats

Evidence is scant for symptom relief

Very few clinical trials have directly studied symptomatic relief of night sweats. A large Cochrane meta-analysis found that oral hormone therapy—estrogens alone or estrogens with progesterone—reduced the frequency of night sweats associated with hot flashes among menopausal women by 75% when compared with placebo alone.⁷ Neither primrose oil nor foot reflexology proved effective.⁸

A cohort study found that 80% of the patients with frequent night sweats responded to antireflux therapy.³ One author suggests using therapies aimed at relieving hyperhydrosis.⁶ These include local treatment with aluminum chloride hexahydrate (Drysol), antiperspirants, scopolamine, or phenoxybenzamine hydrochloride (Dibenzyline).

Recommendations from others

A thorough literature search through Cochrane Database Systematic Reviews, AHRQ, National Guideline Clearing-house, and Medline did not yield any guidelines or consensus statements from other organizations or specialty groups on the evaluation or treatment of night sweats.

Evidence summary

Night sweats are a common complaint in the ambulatory primary care setting: Of 2267 patients in 1 cross-sectional study, 41% reported night sweats, defined as “sweating at night even when it isn’t excessively hot in your bedroom” within the previous month.¹ Because the peak prevalence in both men and women occurred in the group ages 41 to 55 years, there was concern that menopausal hot flashes were a confounding factor, at least for women. In a subsequent study of 795 patients older than 64 years, 10% still reported being bothered by night sweats.²

The more common causes are not widely studied

Few studies look at the causes of night sweats. Although they have been associated with tuberculosis, lymphoma, and HIV infection, these are not common causes of night sweats in outpatient care.

In the only study that specifically addressed the causes of night sweats in an ambulatory population, Reynolds³ interviewed 200 consecutive patients, 70% from a primary care practice and 30% from a gastroenterology practice. Of the 81 patients who reported having an episode of night sweats at least once a week, esophageal reflux and menopause were the most frequent causes.

Several authors agree that certain medications are frequently associated with night sweats, although the exact incidence is unknown due to a lack of published epidemiologic data.^4-6 Antidepressants and antipyretics are among the more commonly cited offenders (TABLE 1).⁴

TABLE 1
Medications that may cause sweating or flushing

Finding the right diagnosis requires thorough history & exam

With such a long differential diagnosis (TABLE 2),^4-6 night sweats should initially be evaluated with a thorough history and physical examination (according to a consensus opinion of various authors). If these don’t elicit possible causes, the appropriate next step in the work-up can vary. Some authors recommend multiple laboratory and imaging studies, while others advise against any routine tests. None of these approaches is evidence-based.

One reasonable algorithm recommends an initial work-up including a complete blood count, thyroid-stimulating hormone (TSH) and erythrocyte sedimentation rate (ESR) level, a purified protein derivative (PPD) and HIV test, and a chest x-ray.⁵ If the results are unrevealing, a trial of antireflux medication is recommended. If the patient does not improve, consider a diary of nocturnal temperatures to help discern the presence or absence of febrile pulses and further evaluate for suspected endocarditis or lymphoma.

TABLE 2
Differential diagnosis for night sweats

Evidence is scant for symptom relief

Very few clinical trials have directly studied symptomatic relief of night sweats. A large Cochrane meta-analysis found that oral hormone therapy—estrogens alone or estrogens with progesterone—reduced the frequency of night sweats associated with hot flashes among menopausal women by 75% when compared with placebo alone.⁷ Neither primrose oil nor foot reflexology proved effective.⁸

A cohort study found that 80% of the patients with frequent night sweats responded to antireflux therapy.³ One author suggests using therapies aimed at relieving hyperhydrosis.⁶ These include local treatment with aluminum chloride hexahydrate (Drysol), antiperspirants, scopolamine, or phenoxybenzamine hydrochloride (Dibenzyline).

Recommendations from others

A thorough literature search through Cochrane Database Systematic Reviews, AHRQ, National Guideline Clearing-house, and Medline did not yield any guidelines or consensus statements from other organizations or specialty groups on the evaluation or treatment of night sweats.

Evidence summary

Little research has been performed on sulfonamide antibiotic and sulfonamide diuretic allergic cross-reactivity. What we do know is that there are 2 classes of sulfonamides—those with an aromatic amine (the antimicrobial sulfonamides) and those without (eg, the diuretics acetazolamide, furosemide, hydrochlorothiazide, and indapamide). Hypersensitivity reactions occur when the aromatic amine group is oxidized into hydroxylamine metabolites by the liver. Sulfonamides that do not contain this aromatic amine group undergo different metabolic pathways, suggesting that allergic reactions that do occur in this group are not due to cross-reactivity in sulfa-allergic patients. But that point is far from settled by the research.

On one side, a large cohort study shows some cross-reactivity

A large retrospective cohort study using Britain’s General Practice Research Database identified 20,226 patients seen from 1987 through March 1999 who were prescribed a systemic sulfonamide antibiotic, and then at least 60 days later received a nonantibiotic sulfonamide (eg, thiazide diuretic, furosemide, oral hypoglycemic).¹ Researchers reviewed records to determine whether patients described as having an allergic reaction to a sulfonamide antibiotic were at increased risk of having a subsequent allergic reaction to a sulfonamide nonantibiotic.

Patients were identified as being allergic using both narrow definitions (anaphylaxis, bronchospasm, urticaria, laryngospasm, or angioedema) and broad ones. As only 18 patients out of the 20,226 patients were reported as having an allergic reaction using the narrow definition, analysis was based on the broad definition. Added to the broad category were asthma, eczema, and other “adverse” drug effects that were not specified by the author.

Using this broad definition, researchers identified allergies to sulfonamide antibiotics in 969 patients. Of this group, 96 patients (9.9%) had a subsequent reaction to a sulfonamide nonantibiotic, which included drugs from the loop and thiazide diuretic classes (including bumetanide, chlorothiazide, furosemide, hydrochlorothiazide, indapamide, and torsemide). It was unclear if any patients taking a carbonic anhydrase inhibitor experienced an allergic reaction. For comparison purposes, of the 19,257 patients who were not identified as having an allergy to a sulfonamide antibiotic, again using the broad definition, 315 (1.6%), had a subsequent allergic reaction to a sulfonamide nonantibiotic, for an unadjusted odds ratio of 6.6 (95% confidence interval [CI], 5.2–8.4).

When the results were adjusted for age, sex, history of asthma, use of medications for asthma or corticosteroids, the adjusted odds ratio for individuals experiencing an allergy to a nonantibiotic sulfonamide in those persons with a history of allergy to a sulfonamide antibiotic was 2.8 (95 % CI, 2.1–3.7). Of note, the adjusted odds ratio for the occurrence of a penicillin allergy in a patient with a history of sulfonamide antibiotic allergy was significantly higher at 3.9 (95% CI, 3.5–4.3).

Some limitations of the study included uncertainty of cause and effect of prescribed medications and subsequent reactions, possible inconsistency of physician diagnosis and coding, and lack of precision in the diagnosis of allergic reactions. There is also the possibility of “suspicion bias,” where patients with a history of allergies may be more closely monitored for subsequent reactions than nonallergic patients.

On the other side, small studies reveal little risk of cross-reaction

Researchers involved in a retrospective study of 363 hospital charts examined 34 patients with a self-reported history of sulfa allergy who were subsequently given acetazolamide (a carbonic anhydrase inhibitor), furosemide (a loop diuretic), or both.² The nature of the self-reported sulfa allergic reaction was documented in 79% of the 34 patients. These reported reactions included urticarial rash, nonspecified rash, dyspnea, swelling, nausea or vomiting, throat swelling, red eyes, and bullae. Two patients who were given acetazolamide developed urticaria. No allergic reactions occurred for those patients given furosemide.

The researchers concluded that there was little clinical or pharmacological evidence to suggest that a self-reported sulfa allergy was likely to produce a life-threatening cross-reaction with acetazolamide or furosemide. Small numbers and the lack of a standard definition for an allergic reaction limited the strength of their conclusion.

A small single-blind study of 28 patients with a history of fixed drug eruption to sulfonamide antibiotics examined the usefulness of patch testing as an alternative to controlled oral challenge testing.³ Before patch testing, a sulfonamide antibiotic allergy was confirmed by each patient with an oral challenge of sulfamethoxazole, sulfadiazine, or sulfamethazole. Potential cross-reactivity to several nonantibiotic sulfonamides (including furosemide) was also investigated using controlled oral challenge testing of these agents. Every patient tolerated a subsequent oral challenge with furosemide.

Literature reviews limited by small numbers

Two literature reviews examined the small number of case series, case reports, and “other articles” and concluded little evidence supports the presence of cross-reactivity between sulfonamide antibiotics and non-sulfonamide antibiotics.^3,4 These reviews were limited by their search criteria and lack of explicit critical appraisal.

A literature review of Medline from 1966 to early 2004 revealed 21 case series, case reports, and “other articles” that evaluated the presence of cross-reactivity.³ When the authors of this literature reviewed drilled down to diuretics, they found 5 case reports for cross-reactivity to acetazolamide, 2 case reports for furosemide, 1 case series, and 2 case reports for indapamide (a thiazide diuretic). After reviewing the studies, the authors concluded that little evidence suggested a problem with cross-reactivity either with acetazolamide or furosemide and that there may be an association of cross-reactivity between sulfonamide antibiotics and indapamide. This study was limited by its small numbers and lack of explicit critical appraisal.

In another literature review—in which the main focus was cross-reactivity between sulfonamide antibiotics and celecoxib—the authors concluded that little evidence supported definitive cross-reactivity between sulfonamide antibiotics and diuretics.⁴ The limitations of this study were similar to those of the previous study.

Recommendations from others

The manufacturer insert for furosemide states, under the heading “General Precautions,” that “patients allergic to sulfonamides may also be allergic to furosemide.”⁵ A similar warning occurs for hydrochlorothiazide under the heading “Contraindications.”⁶

Evidence summary

Little research has been performed on sulfonamide antibiotic and sulfonamide diuretic allergic cross-reactivity. What we do know is that there are 2 classes of sulfonamides—those with an aromatic amine (the antimicrobial sulfonamides) and those without (eg, the diuretics acetazolamide, furosemide, hydrochlorothiazide, and indapamide). Hypersensitivity reactions occur when the aromatic amine group is oxidized into hydroxylamine metabolites by the liver. Sulfonamides that do not contain this aromatic amine group undergo different metabolic pathways, suggesting that allergic reactions that do occur in this group are not due to cross-reactivity in sulfa-allergic patients. But that point is far from settled by the research.

On one side, a large cohort study shows some cross-reactivity

A large retrospective cohort study using Britain’s General Practice Research Database identified 20,226 patients seen from 1987 through March 1999 who were prescribed a systemic sulfonamide antibiotic, and then at least 60 days later received a nonantibiotic sulfonamide (eg, thiazide diuretic, furosemide, oral hypoglycemic).¹ Researchers reviewed records to determine whether patients described as having an allergic reaction to a sulfonamide antibiotic were at increased risk of having a subsequent allergic reaction to a sulfonamide nonantibiotic.

Patients were identified as being allergic using both narrow definitions (anaphylaxis, bronchospasm, urticaria, laryngospasm, or angioedema) and broad ones. As only 18 patients out of the 20,226 patients were reported as having an allergic reaction using the narrow definition, analysis was based on the broad definition. Added to the broad category were asthma, eczema, and other “adverse” drug effects that were not specified by the author.

Using this broad definition, researchers identified allergies to sulfonamide antibiotics in 969 patients. Of this group, 96 patients (9.9%) had a subsequent reaction to a sulfonamide nonantibiotic, which included drugs from the loop and thiazide diuretic classes (including bumetanide, chlorothiazide, furosemide, hydrochlorothiazide, indapamide, and torsemide). It was unclear if any patients taking a carbonic anhydrase inhibitor experienced an allergic reaction. For comparison purposes, of the 19,257 patients who were not identified as having an allergy to a sulfonamide antibiotic, again using the broad definition, 315 (1.6%), had a subsequent allergic reaction to a sulfonamide nonantibiotic, for an unadjusted odds ratio of 6.6 (95% confidence interval [CI], 5.2–8.4).

When the results were adjusted for age, sex, history of asthma, use of medications for asthma or corticosteroids, the adjusted odds ratio for individuals experiencing an allergy to a nonantibiotic sulfonamide in those persons with a history of allergy to a sulfonamide antibiotic was 2.8 (95 % CI, 2.1–3.7). Of note, the adjusted odds ratio for the occurrence of a penicillin allergy in a patient with a history of sulfonamide antibiotic allergy was significantly higher at 3.9 (95% CI, 3.5–4.3).

Some limitations of the study included uncertainty of cause and effect of prescribed medications and subsequent reactions, possible inconsistency of physician diagnosis and coding, and lack of precision in the diagnosis of allergic reactions. There is also the possibility of “suspicion bias,” where patients with a history of allergies may be more closely monitored for subsequent reactions than nonallergic patients.

On the other side, small studies reveal little risk of cross-reaction

Researchers involved in a retrospective study of 363 hospital charts examined 34 patients with a self-reported history of sulfa allergy who were subsequently given acetazolamide (a carbonic anhydrase inhibitor), furosemide (a loop diuretic), or both.² The nature of the self-reported sulfa allergic reaction was documented in 79% of the 34 patients. These reported reactions included urticarial rash, nonspecified rash, dyspnea, swelling, nausea or vomiting, throat swelling, red eyes, and bullae. Two patients who were given acetazolamide developed urticaria. No allergic reactions occurred for those patients given furosemide.

The researchers concluded that there was little clinical or pharmacological evidence to suggest that a self-reported sulfa allergy was likely to produce a life-threatening cross-reaction with acetazolamide or furosemide. Small numbers and the lack of a standard definition for an allergic reaction limited the strength of their conclusion.

A small single-blind study of 28 patients with a history of fixed drug eruption to sulfonamide antibiotics examined the usefulness of patch testing as an alternative to controlled oral challenge testing.³ Before patch testing, a sulfonamide antibiotic allergy was confirmed by each patient with an oral challenge of sulfamethoxazole, sulfadiazine, or sulfamethazole. Potential cross-reactivity to several nonantibiotic sulfonamides (including furosemide) was also investigated using controlled oral challenge testing of these agents. Every patient tolerated a subsequent oral challenge with furosemide.

Literature reviews limited by small numbers

Two literature reviews examined the small number of case series, case reports, and “other articles” and concluded little evidence supports the presence of cross-reactivity between sulfonamide antibiotics and non-sulfonamide antibiotics.^3,4 These reviews were limited by their search criteria and lack of explicit critical appraisal.

A literature review of Medline from 1966 to early 2004 revealed 21 case series, case reports, and “other articles” that evaluated the presence of cross-reactivity.³ When the authors of this literature reviewed drilled down to diuretics, they found 5 case reports for cross-reactivity to acetazolamide, 2 case reports for furosemide, 1 case series, and 2 case reports for indapamide (a thiazide diuretic). After reviewing the studies, the authors concluded that little evidence suggested a problem with cross-reactivity either with acetazolamide or furosemide and that there may be an association of cross-reactivity between sulfonamide antibiotics and indapamide. This study was limited by its small numbers and lack of explicit critical appraisal.

In another literature review—in which the main focus was cross-reactivity between sulfonamide antibiotics and celecoxib—the authors concluded that little evidence supported definitive cross-reactivity between sulfonamide antibiotics and diuretics.⁴ The limitations of this study were similar to those of the previous study.

Recommendations from others

The manufacturer insert for furosemide states, under the heading “General Precautions,” that “patients allergic to sulfonamides may also be allergic to furosemide.”⁵ A similar warning occurs for hydrochlorothiazide under the heading “Contraindications.”⁶

Evidence summary

Little research has been performed on sulfonamide antibiotic and sulfonamide diuretic allergic cross-reactivity. What we do know is that there are 2 classes of sulfonamides—those with an aromatic amine (the antimicrobial sulfonamides) and those without (eg, the diuretics acetazolamide, furosemide, hydrochlorothiazide, and indapamide). Hypersensitivity reactions occur when the aromatic amine group is oxidized into hydroxylamine metabolites by the liver. Sulfonamides that do not contain this aromatic amine group undergo different metabolic pathways, suggesting that allergic reactions that do occur in this group are not due to cross-reactivity in sulfa-allergic patients. But that point is far from settled by the research.

On one side, a large cohort study shows some cross-reactivity

A large retrospective cohort study using Britain’s General Practice Research Database identified 20,226 patients seen from 1987 through March 1999 who were prescribed a systemic sulfonamide antibiotic, and then at least 60 days later received a nonantibiotic sulfonamide (eg, thiazide diuretic, furosemide, oral hypoglycemic).¹ Researchers reviewed records to determine whether patients described as having an allergic reaction to a sulfonamide antibiotic were at increased risk of having a subsequent allergic reaction to a sulfonamide nonantibiotic.

Patients were identified as being allergic using both narrow definitions (anaphylaxis, bronchospasm, urticaria, laryngospasm, or angioedema) and broad ones. As only 18 patients out of the 20,226 patients were reported as having an allergic reaction using the narrow definition, analysis was based on the broad definition. Added to the broad category were asthma, eczema, and other “adverse” drug effects that were not specified by the author.

Using this broad definition, researchers identified allergies to sulfonamide antibiotics in 969 patients. Of this group, 96 patients (9.9%) had a subsequent reaction to a sulfonamide nonantibiotic, which included drugs from the loop and thiazide diuretic classes (including bumetanide, chlorothiazide, furosemide, hydrochlorothiazide, indapamide, and torsemide). It was unclear if any patients taking a carbonic anhydrase inhibitor experienced an allergic reaction. For comparison purposes, of the 19,257 patients who were not identified as having an allergy to a sulfonamide antibiotic, again using the broad definition, 315 (1.6%), had a subsequent allergic reaction to a sulfonamide nonantibiotic, for an unadjusted odds ratio of 6.6 (95% confidence interval [CI], 5.2–8.4).

When the results were adjusted for age, sex, history of asthma, use of medications for asthma or corticosteroids, the adjusted odds ratio for individuals experiencing an allergy to a nonantibiotic sulfonamide in those persons with a history of allergy to a sulfonamide antibiotic was 2.8 (95 % CI, 2.1–3.7). Of note, the adjusted odds ratio for the occurrence of a penicillin allergy in a patient with a history of sulfonamide antibiotic allergy was significantly higher at 3.9 (95% CI, 3.5–4.3).

Some limitations of the study included uncertainty of cause and effect of prescribed medications and subsequent reactions, possible inconsistency of physician diagnosis and coding, and lack of precision in the diagnosis of allergic reactions. There is also the possibility of “suspicion bias,” where patients with a history of allergies may be more closely monitored for subsequent reactions than nonallergic patients.

On the other side, small studies reveal little risk of cross-reaction

Researchers involved in a retrospective study of 363 hospital charts examined 34 patients with a self-reported history of sulfa allergy who were subsequently given acetazolamide (a carbonic anhydrase inhibitor), furosemide (a loop diuretic), or both.² The nature of the self-reported sulfa allergic reaction was documented in 79% of the 34 patients. These reported reactions included urticarial rash, nonspecified rash, dyspnea, swelling, nausea or vomiting, throat swelling, red eyes, and bullae. Two patients who were given acetazolamide developed urticaria. No allergic reactions occurred for those patients given furosemide.

The researchers concluded that there was little clinical or pharmacological evidence to suggest that a self-reported sulfa allergy was likely to produce a life-threatening cross-reaction with acetazolamide or furosemide. Small numbers and the lack of a standard definition for an allergic reaction limited the strength of their conclusion.

A small single-blind study of 28 patients with a history of fixed drug eruption to sulfonamide antibiotics examined the usefulness of patch testing as an alternative to controlled oral challenge testing.³ Before patch testing, a sulfonamide antibiotic allergy was confirmed by each patient with an oral challenge of sulfamethoxazole, sulfadiazine, or sulfamethazole. Potential cross-reactivity to several nonantibiotic sulfonamides (including furosemide) was also investigated using controlled oral challenge testing of these agents. Every patient tolerated a subsequent oral challenge with furosemide.

Literature reviews limited by small numbers

Two literature reviews examined the small number of case series, case reports, and “other articles” and concluded little evidence supports the presence of cross-reactivity between sulfonamide antibiotics and non-sulfonamide antibiotics.^3,4 These reviews were limited by their search criteria and lack of explicit critical appraisal.

A literature review of Medline from 1966 to early 2004 revealed 21 case series, case reports, and “other articles” that evaluated the presence of cross-reactivity.³ When the authors of this literature reviewed drilled down to diuretics, they found 5 case reports for cross-reactivity to acetazolamide, 2 case reports for furosemide, 1 case series, and 2 case reports for indapamide (a thiazide diuretic). After reviewing the studies, the authors concluded that little evidence suggested a problem with cross-reactivity either with acetazolamide or furosemide and that there may be an association of cross-reactivity between sulfonamide antibiotics and indapamide. This study was limited by its small numbers and lack of explicit critical appraisal.

In another literature review—in which the main focus was cross-reactivity between sulfonamide antibiotics and celecoxib—the authors concluded that little evidence supported definitive cross-reactivity between sulfonamide antibiotics and diuretics.⁴ The limitations of this study were similar to those of the previous study.

Recommendations from others

The manufacturer insert for furosemide states, under the heading “General Precautions,” that “patients allergic to sulfonamides may also be allergic to furosemide.”⁵ A similar warning occurs for hydrochlorothiazide under the heading “Contraindications.”⁶

Evidence summary

Elevated LDL-C is an independent risk factor for coronary heart disease (CHD),³ the leading cause of death in the US.⁴ Lowering LDL-C by 60 mg/dL reduces CHD events by 50% after 2 years.⁵ Although medications successfully lower LDL-C and decrease CHD risk, therapeutic lifestyle changes remain the initial therapy for most adult patients.^3,6

Our search located evidence about alcohol consumption, counseling, exercise, weight loss, alternative lifestyle measures, and smoking cessation. The TABLE summarizes the evidence for each.

TABLE
A- and B-level evidence points to effectiveness of lifestyle interventions

1 to 2 drinks daily reduced LDL-C

One 5-year-long cohort study (N=933) showed that alcohol was associated with LDL-C reduction in a dose-dependent manner.⁷ Two crossover trials (4–6 weeks in duration) conducted among heavy drinkers showed that LDL-C increased when alcohol intake decreased. Two randomized crossover trials (8–12 weeks in duration) found a statistically significant decrease in LDL-C with consumption of 1 to 2 drinks daily.

Counseling improves medication adherence

An RCT (N=167) with 8 years of follow-up found that patient education and counseling effectively improved medication adherence.⁸ Another RCT (N=1162) lasting 1 year, however, found that nutrition counseling by primary care physicians resulted in no significant change in LDL-C compared with usual care.⁹

Studies focused on enhancing dietary compliance did not find consistent post-intervention improvement. Greater medication adherence or improved dietary compliance did result in consistent significant improvements in LDL-C.

Exercise lowers LDL; weight loss a factor

Aerobic exercise effectively lowers LDL-C. This reduction is enhanced by weight loss and diet and mitigated by weight gain.¹⁰ An analysis of 4 RCTs showed that LDL-C also decreased with resistance training.

A higher body-mass index is associated with higher LDL-C. However, the effect of weight loss perse on LDL-C remains unclear. Multiple short-term studies have found that a modest amount of weight loss (5%–10%) is associated with a significant reduction in LDL-C.¹¹ A meta-analysis found a 0.8 mg/dL LDL-C decrease for every kg of weight lost. Long-term follow-up, however, showed that LDL-C returned to baseline even when weight loss was maintained. Eight clinical trials failed to demonstrate a reduction in LDL-C postintervention with up to 10 kg of weight loss. Studies using weight-loss drugs (Sibutramine, Orlistat) found more significant weight loss during treatment, along with greater decrease in LDL-C, when compared with studies using only lifestyle modifications.

Other measures have mixed results

High-quality RCTs (N=267) with yoga or tai chi as the exercise intervention showed a statistically significant decrease in LDL-C over 12 to 14 weeks.¹² Two RCTs investigated the effect of meditation on LDL-C with mixed results. One (N=16) showed a significant decrease in LDL-C over 8 weeks, while a second (N=60) showed no difference in LDL-C. A high-quality RCT (N=91) with a combined intervention (counseling, exercise, and meditation over 1 year) showed a significant decrease in LDL-C.

In cross-sectional surveys, LDL-C does not appear to differ between smokers and nonsmokers. One meta-analysis found a dose-dependent relationship between smoking and LDL-C, with overall LDL-C 1.7% higher for smokers compared with nonsmokers.¹³ Two RCTs investigated the effect of smoking cessation on LDL-C with mixed results. One (N=935) showed a decrease in nonfasting LDL-C while a second (N=140) showed no difference in LDL-C.

Recommendations from others

According to ATP III guidelines,³ all adults with LDL-C above goal should be treated with therapeutic lifestyle changes for primary and secondary prevention of CHD. These include a diet intervention, increased physical activity, and weight loss. Physicians are encouraged to refer patients to a nutritionist. If LDL-C is not at goal after 6 weeks, changes are intensified; physicians should consider pharmacologic therapy if a patient is still unable to attain his or her goal. ACP III guidelines recommend an office visit every 4 to 6 months to monitor adherence.

American Heart Association guidelines recommend that physicians counsel smokers at every office visit to stop smoking. The American College of Cardiology recommends abstinence from alcohol for patients with suspected alcoholic cardiomyopathy. For patients with heart failure from any other cause, alcohol consumption is usually limited to 1 drink per day.

Evidence summary

Elevated LDL-C is an independent risk factor for coronary heart disease (CHD),³ the leading cause of death in the US.⁴ Lowering LDL-C by 60 mg/dL reduces CHD events by 50% after 2 years.⁵ Although medications successfully lower LDL-C and decrease CHD risk, therapeutic lifestyle changes remain the initial therapy for most adult patients.^3,6

Our search located evidence about alcohol consumption, counseling, exercise, weight loss, alternative lifestyle measures, and smoking cessation. The TABLE summarizes the evidence for each.

TABLE
A- and B-level evidence points to effectiveness of lifestyle interventions

1 to 2 drinks daily reduced LDL-C

One 5-year-long cohort study (N=933) showed that alcohol was associated with LDL-C reduction in a dose-dependent manner.⁷ Two crossover trials (4–6 weeks in duration) conducted among heavy drinkers showed that LDL-C increased when alcohol intake decreased. Two randomized crossover trials (8–12 weeks in duration) found a statistically significant decrease in LDL-C with consumption of 1 to 2 drinks daily.

Counseling improves medication adherence

An RCT (N=167) with 8 years of follow-up found that patient education and counseling effectively improved medication adherence.⁸ Another RCT (N=1162) lasting 1 year, however, found that nutrition counseling by primary care physicians resulted in no significant change in LDL-C compared with usual care.⁹

Studies focused on enhancing dietary compliance did not find consistent post-intervention improvement. Greater medication adherence or improved dietary compliance did result in consistent significant improvements in LDL-C.

Exercise lowers LDL; weight loss a factor

Aerobic exercise effectively lowers LDL-C. This reduction is enhanced by weight loss and diet and mitigated by weight gain.¹⁰ An analysis of 4 RCTs showed that LDL-C also decreased with resistance training.

A higher body-mass index is associated with higher LDL-C. However, the effect of weight loss perse on LDL-C remains unclear. Multiple short-term studies have found that a modest amount of weight loss (5%–10%) is associated with a significant reduction in LDL-C.¹¹ A meta-analysis found a 0.8 mg/dL LDL-C decrease for every kg of weight lost. Long-term follow-up, however, showed that LDL-C returned to baseline even when weight loss was maintained. Eight clinical trials failed to demonstrate a reduction in LDL-C postintervention with up to 10 kg of weight loss. Studies using weight-loss drugs (Sibutramine, Orlistat) found more significant weight loss during treatment, along with greater decrease in LDL-C, when compared with studies using only lifestyle modifications.

Other measures have mixed results

High-quality RCTs (N=267) with yoga or tai chi as the exercise intervention showed a statistically significant decrease in LDL-C over 12 to 14 weeks.¹² Two RCTs investigated the effect of meditation on LDL-C with mixed results. One (N=16) showed a significant decrease in LDL-C over 8 weeks, while a second (N=60) showed no difference in LDL-C. A high-quality RCT (N=91) with a combined intervention (counseling, exercise, and meditation over 1 year) showed a significant decrease in LDL-C.

In cross-sectional surveys, LDL-C does not appear to differ between smokers and nonsmokers. One meta-analysis found a dose-dependent relationship between smoking and LDL-C, with overall LDL-C 1.7% higher for smokers compared with nonsmokers.¹³ Two RCTs investigated the effect of smoking cessation on LDL-C with mixed results. One (N=935) showed a decrease in nonfasting LDL-C while a second (N=140) showed no difference in LDL-C.

Recommendations from others

According to ATP III guidelines,³ all adults with LDL-C above goal should be treated with therapeutic lifestyle changes for primary and secondary prevention of CHD. These include a diet intervention, increased physical activity, and weight loss. Physicians are encouraged to refer patients to a nutritionist. If LDL-C is not at goal after 6 weeks, changes are intensified; physicians should consider pharmacologic therapy if a patient is still unable to attain his or her goal. ACP III guidelines recommend an office visit every 4 to 6 months to monitor adherence.

American Heart Association guidelines recommend that physicians counsel smokers at every office visit to stop smoking. The American College of Cardiology recommends abstinence from alcohol for patients with suspected alcoholic cardiomyopathy. For patients with heart failure from any other cause, alcohol consumption is usually limited to 1 drink per day.

Evidence summary

Elevated LDL-C is an independent risk factor for coronary heart disease (CHD),³ the leading cause of death in the US.⁴ Lowering LDL-C by 60 mg/dL reduces CHD events by 50% after 2 years.⁵ Although medications successfully lower LDL-C and decrease CHD risk, therapeutic lifestyle changes remain the initial therapy for most adult patients.^3,6

Our search located evidence about alcohol consumption, counseling, exercise, weight loss, alternative lifestyle measures, and smoking cessation. The TABLE summarizes the evidence for each.

TABLE
A- and B-level evidence points to effectiveness of lifestyle interventions

1 to 2 drinks daily reduced LDL-C

One 5-year-long cohort study (N=933) showed that alcohol was associated with LDL-C reduction in a dose-dependent manner.⁷ Two crossover trials (4–6 weeks in duration) conducted among heavy drinkers showed that LDL-C increased when alcohol intake decreased. Two randomized crossover trials (8–12 weeks in duration) found a statistically significant decrease in LDL-C with consumption of 1 to 2 drinks daily.

Counseling improves medication adherence

An RCT (N=167) with 8 years of follow-up found that patient education and counseling effectively improved medication adherence.⁸ Another RCT (N=1162) lasting 1 year, however, found that nutrition counseling by primary care physicians resulted in no significant change in LDL-C compared with usual care.⁹

Studies focused on enhancing dietary compliance did not find consistent post-intervention improvement. Greater medication adherence or improved dietary compliance did result in consistent significant improvements in LDL-C.

Exercise lowers LDL; weight loss a factor

Aerobic exercise effectively lowers LDL-C. This reduction is enhanced by weight loss and diet and mitigated by weight gain.¹⁰ An analysis of 4 RCTs showed that LDL-C also decreased with resistance training.

A higher body-mass index is associated with higher LDL-C. However, the effect of weight loss perse on LDL-C remains unclear. Multiple short-term studies have found that a modest amount of weight loss (5%–10%) is associated with a significant reduction in LDL-C.¹¹ A meta-analysis found a 0.8 mg/dL LDL-C decrease for every kg of weight lost. Long-term follow-up, however, showed that LDL-C returned to baseline even when weight loss was maintained. Eight clinical trials failed to demonstrate a reduction in LDL-C postintervention with up to 10 kg of weight loss. Studies using weight-loss drugs (Sibutramine, Orlistat) found more significant weight loss during treatment, along with greater decrease in LDL-C, when compared with studies using only lifestyle modifications.

Other measures have mixed results

High-quality RCTs (N=267) with yoga or tai chi as the exercise intervention showed a statistically significant decrease in LDL-C over 12 to 14 weeks.¹² Two RCTs investigated the effect of meditation on LDL-C with mixed results. One (N=16) showed a significant decrease in LDL-C over 8 weeks, while a second (N=60) showed no difference in LDL-C. A high-quality RCT (N=91) with a combined intervention (counseling, exercise, and meditation over 1 year) showed a significant decrease in LDL-C.

In cross-sectional surveys, LDL-C does not appear to differ between smokers and nonsmokers. One meta-analysis found a dose-dependent relationship between smoking and LDL-C, with overall LDL-C 1.7% higher for smokers compared with nonsmokers.¹³ Two RCTs investigated the effect of smoking cessation on LDL-C with mixed results. One (N=935) showed a decrease in nonfasting LDL-C while a second (N=140) showed no difference in LDL-C.

Recommendations from others

According to ATP III guidelines,³ all adults with LDL-C above goal should be treated with therapeutic lifestyle changes for primary and secondary prevention of CHD. These include a diet intervention, increased physical activity, and weight loss. Physicians are encouraged to refer patients to a nutritionist. If LDL-C is not at goal after 6 weeks, changes are intensified; physicians should consider pharmacologic therapy if a patient is still unable to attain his or her goal. ACP III guidelines recommend an office visit every 4 to 6 months to monitor adherence.

American Heart Association guidelines recommend that physicians counsel smokers at every office visit to stop smoking. The American College of Cardiology recommends abstinence from alcohol for patients with suspected alcoholic cardiomyopathy. For patients with heart failure from any other cause, alcohol consumption is usually limited to 1 drink per day.