Pharmacology Consult

Antibiotics for acne — How long is too long?

Acne commonly occurs in the pediatric population, affecting more than 80% of adolescents. The pathophysiology underlying acne is complex, described by the contribution of four factors — sebaceous hyperplasia, changes in follicular growth and differentiation, interactions in the follicular environment by Propionibacterium acnes, and resultant immune and inflammatory responses. The mechanisms of action of the pharmacotherapies used to treat acne target these pathophysiologic characteristics. Topical and oral antibiotics play an important role, providing anti-inflammatory effects, in addition to antibacterial actions. Recently published data have demonstrated that antibiotics may be inappropriately relied upon when treating acne, with treatment durations often exceeding published recommendations.

Acne treatment guidelines

Edward A. Bell

Several acne treatment guidelines have been published, most recently in 2016 (Zaenglein and colleagues) and 2013 (Eichenfield and colleagues). These guidelines define the role of topical and oral antibiotic therapy, recommending combinations of antibiotic therapy with topical benzoyl peroxide (BP) or retinoid product use, or both, in an effort to enhance therapeutic benefit and to reduce bacterial resistance. Topical antibiotics can be used in the treatment of mild, moderate or severe acne, and should not be used as monotherapy in an effort to reduce resistance development (ie, use topical antibiotics only when combined with topical BP and/or a topical retinoid). Orally administered antibiotics are recommended for moderate-severe inflammatory acne. Similarly, oral antibiotics are not recommended as monotherapy and are best used concomitantly with topical BP or a topical retinoid product, or both.

Antibiotic mechanisms and resistance

In addition to the inferred mechanism of providing antibacterial actions, antibiotics likely provide therapeutic anti-inflammatory effects as well, by inhibiting macrophage and neutrophil function and cytokine production. Although the distinct contributions of antibacterial and anti-inflammatory actions are not well-defined, some data suggest that reduction of P. acnes counts by antibiotics reduces local inflammatory response. Additional data have demonstrated clinical improvement from antibiotic therapy, despite no changes in skin P. acnes counts. These and other data have demonstrated a stronger correlation of inflammatory response and P. acnes with acne severity, as compared with a correlation of P. acnes colony count with acne severity.

Despite the ill-defined relative contribution of antibacterial effects derived from antibiotic therapy, concerns about antimicrobial resistance have been raised with topical and oral use of antibiotics when treating acne. Published studies have demonstrated P. acnes resistance rates increasing from 20% to 62% (1978-1996). Global resistance rates of P. acnes to clindamycin and erythromycin have been reported in more than 50% of individuals with acne. Individuals with resistant P. acnes have been shown to have reduced clinical responses to antibiotic therapy. Other data have shown that individuals treated with antibiotics for acne have alterations in bacterial colonization at other anatomical sites (eg, oropharyngeal S. pyogenes) and increases in other clinical infections (eg, upper respiratory infections or pharyngitis).

Topical antibiotics

Topical antibiotics are recommended for treatment of mild, moderate or severe acne, when combined with BP or a retinoid. Many combination products are available and are commonly used (eg, benzoyl peroxide-clindamycin, Duac; tretinoin-clindamycin, Veltin). Clindamycin is preferred over erythromycin because it has demonstrated improved efficacy and lower resistance patterns. Concomitant BP provides useful synergistic therapeutic efficacy when combined with topical and oral antibiotic therapy because it exerts bactericidal effects through release of free oxygen radicals. BP also provides comedolytic actions. Several published controlled trials have compared topical antibiotic with oral antibiotic treatment. Overall, both topical and oral antibiotics have been demonstrated to be effective (Bienenfeld and colleagues, 2017).

Oral antibiotics

Recently published treatment guidelines recommend oral antibiotics for moderate-severe inflammatory acne. Although several classes of antibiotics have been demonstrated to be effective, including tetracyclines, macrolides/azolides and trimethoprim/sulfamethoxazole, the tetracycline class, notably second-generation tetracyclines (eg, doxycycline, minocycline), are recommended as first-line therapy. No evidence from published controlled trials exists to support differences in therapeutic efficacy among these different antibiotic classes, nor differences in efficacy within the tetracycline class (ie, no differences in efficacy between minocycline, doxycycline or tetracycline). Thus, product choice is guided by adverse effect profiles, dosing schedule differences and cost considerations. Recently published treatment guidelines recommend second-generation tetracycline products doxycycline or minocycline as first-line oral treatment choices because of improved dosing schedules and lower resistance patterns. Oral antibiotics are best used with concomitant BP or topical retinoids.

The oral antibiotics most commonly used when treating acne include doxycycline and minocycline. Each of these tetracycline-class antibiotics possess unique adverse effect profiles. Doxycycline use may result in gastrointestinal upset (so-called pill esophagitis) or a hypersensitivity syndrome. Patients are best counseled to take doxycycline with at least 8 ounces of fluid and to remain upright for 60 minutes following administration (ie, do not take at bedtime). Fluid choices may include milk because doxycycline is less susceptible to reduced oral absorption when taken with milk as compared with tetracycline. Additionally, minocycline may result in vertigo or dizziness. More serious adverse effects from minocycline include hypersensitivity reactions, lupus-like syndrome and hepatitis. Patient counseling and monitoring for these potential adverse effects are of paramount importance when doxycycline and minocycline are used. Doxycycline is available as numerous specific brand and generic products. Brand products generally are more expensive, at nearly $50 per capsule or tablet for some products. Less expensive doxycycline products include generic hyclate and monohydrate salt forms, as capsule or tablet products.

Both doxycycline and minocycline are commonly dosed as 50 to 100 mg once or twice daily. Despite the publication of several dose-ranging studies, the most effective doxycycline or minocycline dose has not been determined.

An additional consideration when using oral antibiotic therapy is treatment duration. Several recently published studies have demonstrated that oral antibiotics may be commonly given for treatment durations significantly longer than recommended. When individuals respond to oral antibiotic therapy, clinical efficacy is often noticed within 4 to 8 weeks of treatment initiation. Guideline recommendations include use of 12-to-16 week treatment durations, or less (ie, discontinue 4 to 8 weeks after new lesion formation). Treatment durations of up to 24 weeks may be appropriate if clinical improvement is continuing. Treatment durations beyond 24 weeks are not recommended to limit the potential for resistance development. Concomitant and continued maintenance therapy should include BP or a topical retinoid, or both.

Studies of oral antibiotic treatment duration

A retrospective chart review of 31,634 courses of antibiotics for subjects 9 to 21 years of age was conducted from 2008-2010 and published in 2014 (Lee). Subject use information in this study was obtained from the MarketScan Commercial Claims and Encounters database (claims for employees of more than 250 national companies). Most antibiotic course durations (93%) were shorter than 9 months, although 5,547 course durations (17.53%) were longer than 6 months; 18,280 courses (57.8%) did not include concomitant retinoid therapy. Use of concomitant topical BP was not evaluated in this study. Nagler and colleagues conducted a retrospective single-site chart view of individuals 12 years of age and older receiving an oral antibiotic for acne (N = 137) over a 10-year period (2005-2014) at an academic center dermatology practice. The study population evaluated individuals who eventually required isotretinoin. The average duration of antibiotic use was 331.3 days, with 64.2% receiving an antibiotic for 6 months or longer and 33.6% receiving an antibiotic for 12 months or longer.

Conclusions

Acne commonly affects the adolescent population and often requires combination pharmacotherapy. Oral antibiotics are often used, with some recent data suggesting that antibiotics may be inappropriately prescribed for long durations. Recommendations from several published guidelines include limiting oral antibiotic use duration to 24 weeks or less, and combining oral antibiotic therapy with a topical retinoid or BP product. Oral antibiotics should not be used as monotherapy. Similarly, topical antibiotics should always be combined with a retinoid or BP, with many combination products available for this use.

Disclosure: Bell reports no relevant financial disclosures.

Acne commonly occurs in the pediatric population, affecting more than 80% of adolescents. The pathophysiology underlying acne is complex, described by the contribution of four factors — sebaceous hyperplasia, changes in follicular growth and differentiation, interactions in the follicular environment by Propionibacterium acnes, and resultant immune and inflammatory responses. The mechanisms of action of the pharmacotherapies used to treat acne target these pathophysiologic characteristics. Topical and oral antibiotics play an important role, providing anti-inflammatory effects, in addition to antibacterial actions. Recently published data have demonstrated that antibiotics may be inappropriately relied upon when treating acne, with treatment durations often exceeding published recommendations.

Acne treatment guidelines

Edward A. Bell

Several acne treatment guidelines have been published, most recently in 2016 (Zaenglein and colleagues) and 2013 (Eichenfield and colleagues). These guidelines define the role of topical and oral antibiotic therapy, recommending combinations of antibiotic therapy with topical benzoyl peroxide (BP) or retinoid product use, or both, in an effort to enhance therapeutic benefit and to reduce bacterial resistance. Topical antibiotics can be used in the treatment of mild, moderate or severe acne, and should not be used as monotherapy in an effort to reduce resistance development (ie, use topical antibiotics only when combined with topical BP and/or a topical retinoid). Orally administered antibiotics are recommended for moderate-severe inflammatory acne. Similarly, oral antibiotics are not recommended as monotherapy and are best used concomitantly with topical BP or a topical retinoid product, or both.

Antibiotic mechanisms and resistance

In addition to the inferred mechanism of providing antibacterial actions, antibiotics likely provide therapeutic anti-inflammatory effects as well, by inhibiting macrophage and neutrophil function and cytokine production. Although the distinct contributions of antibacterial and anti-inflammatory actions are not well-defined, some data suggest that reduction of P. acnes counts by antibiotics reduces local inflammatory response. Additional data have demonstrated clinical improvement from antibiotic therapy, despite no changes in skin P. acnes counts. These and other data have demonstrated a stronger correlation of inflammatory response and P. acnes with acne severity, as compared with a correlation of P. acnes colony count with acne severity.

Despite the ill-defined relative contribution of antibacterial effects derived from antibiotic therapy, concerns about antimicrobial resistance have been raised with topical and oral use of antibiotics when treating acne. Published studies have demonstrated P. acnes resistance rates increasing from 20% to 62% (1978-1996). Global resistance rates of P. acnes to clindamycin and erythromycin have been reported in more than 50% of individuals with acne. Individuals with resistant P. acnes have been shown to have reduced clinical responses to antibiotic therapy. Other data have shown that individuals treated with antibiotics for acne have alterations in bacterial colonization at other anatomical sites (eg, oropharyngeal S. pyogenes) and increases in other clinical infections (eg, upper respiratory infections or pharyngitis).

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Topical antibiotics

Topical antibiotics are recommended for treatment of mild, moderate or severe acne, when combined with BP or a retinoid. Many combination products are available and are commonly used (eg, benzoyl peroxide-clindamycin, Duac; tretinoin-clindamycin, Veltin). Clindamycin is preferred over erythromycin because it has demonstrated improved efficacy and lower resistance patterns. Concomitant BP provides useful synergistic therapeutic efficacy when combined with topical and oral antibiotic therapy because it exerts bactericidal effects through release of free oxygen radicals. BP also provides comedolytic actions. Several published controlled trials have compared topical antibiotic with oral antibiotic treatment. Overall, both topical and oral antibiotics have been demonstrated to be effective (Bienenfeld and colleagues, 2017).

Oral antibiotics

Recently published treatment guidelines recommend oral antibiotics for moderate-severe inflammatory acne. Although several classes of antibiotics have been demonstrated to be effective, including tetracyclines, macrolides/azolides and trimethoprim/sulfamethoxazole, the tetracycline class, notably second-generation tetracyclines (eg, doxycycline, minocycline), are recommended as first-line therapy. No evidence from published controlled trials exists to support differences in therapeutic efficacy among these different antibiotic classes, nor differences in efficacy within the tetracycline class (ie, no differences in efficacy between minocycline, doxycycline or tetracycline). Thus, product choice is guided by adverse effect profiles, dosing schedule differences and cost considerations. Recently published treatment guidelines recommend second-generation tetracycline products doxycycline or minocycline as first-line oral treatment choices because of improved dosing schedules and lower resistance patterns. Oral antibiotics are best used with concomitant BP or topical retinoids.

The oral antibiotics most commonly used when treating acne include doxycycline and minocycline. Each of these tetracycline-class antibiotics possess unique adverse effect profiles. Doxycycline use may result in gastrointestinal upset (so-called pill esophagitis) or a hypersensitivity syndrome. Patients are best counseled to take doxycycline with at least 8 ounces of fluid and to remain upright for 60 minutes following administration (ie, do not take at bedtime). Fluid choices may include milk because doxycycline is less susceptible to reduced oral absorption when taken with milk as compared with tetracycline. Additionally, minocycline may result in vertigo or dizziness. More serious adverse effects from minocycline include hypersensitivity reactions, lupus-like syndrome and hepatitis. Patient counseling and monitoring for these potential adverse effects are of paramount importance when doxycycline and minocycline are used. Doxycycline is available as numerous specific brand and generic products. Brand products generally are more expensive, at nearly $50 per capsule or tablet for some products. Less expensive doxycycline products include generic hyclate and monohydrate salt forms, as capsule or tablet products.

PAGE BREAK

Both doxycycline and minocycline are commonly dosed as 50 to 100 mg once or twice daily. Despite the publication of several dose-ranging studies, the most effective doxycycline or minocycline dose has not been determined.

An additional consideration when using oral antibiotic therapy is treatment duration. Several recently published studies have demonstrated that oral antibiotics may be commonly given for treatment durations significantly longer than recommended. When individuals respond to oral antibiotic therapy, clinical efficacy is often noticed within 4 to 8 weeks of treatment initiation. Guideline recommendations include use of 12-to-16 week treatment durations, or less (ie, discontinue 4 to 8 weeks after new lesion formation). Treatment durations of up to 24 weeks may be appropriate if clinical improvement is continuing. Treatment durations beyond 24 weeks are not recommended to limit the potential for resistance development. Concomitant and continued maintenance therapy should include BP or a topical retinoid, or both.

Studies of oral antibiotic treatment duration

A retrospective chart review of 31,634 courses of antibiotics for subjects 9 to 21 years of age was conducted from 2008-2010 and published in 2014 (Lee). Subject use information in this study was obtained from the MarketScan Commercial Claims and Encounters database (claims for employees of more than 250 national companies). Most antibiotic course durations (93%) were shorter than 9 months, although 5,547 course durations (17.53%) were longer than 6 months; 18,280 courses (57.8%) did not include concomitant retinoid therapy. Use of concomitant topical BP was not evaluated in this study. Nagler and colleagues conducted a retrospective single-site chart view of individuals 12 years of age and older receiving an oral antibiotic for acne (N = 137) over a 10-year period (2005-2014) at an academic center dermatology practice. The study population evaluated individuals who eventually required isotretinoin. The average duration of antibiotic use was 331.3 days, with 64.2% receiving an antibiotic for 6 months or longer and 33.6% receiving an antibiotic for 12 months or longer.

Conclusions

Acne commonly affects the adolescent population and often requires combination pharmacotherapy. Oral antibiotics are often used, with some recent data suggesting that antibiotics may be inappropriately prescribed for long durations. Recommendations from several published guidelines include limiting oral antibiotic use duration to 24 weeks or less, and combining oral antibiotic therapy with a topical retinoid or BP product. Oral antibiotics should not be used as monotherapy. Similarly, topical antibiotics should always be combined with a retinoid or BP, with many combination products available for this use.

Disclosure: Bell reports no relevant financial disclosures.