Clinical Review & Education
JAMA Dermatology Clinical Evidence Synopsis
Antibiotic Resistance in Acne Treatment Brandon L. Adler, MD; Heather Kornmehl, BS; April W. Armstrong, MD, MPH
CLINICAL QUESTION What is the evidence for antibiotic resistance in acne, and how does resistance affect treatment? BOTTOM LINE Use of topical and systemic antibiotics for acne is associated with formation of resistance in Propionibacterium acnes and other bacteria, with clinical consequences. Guidelines recommend resistance reduction strategies including avoidance of antibiotic monotherapy, combination treatment with topical modalities, and limiting the duration of oral antibiotic use.
Introduction Antibiotics are a fundamental component of the treatment of acne owing to the role that Propionibacterium acnes plays in its pathogenesis. Despite a relatively small workforce, dermatologists disproportionately prescribe antibiotics.1 However, antibiotic resistance is a global issue with increasing prevalence over time. The antibiotics most frequently used for acne are topical erythromycin and clindamycin and oral tetracyclines, which are bacteriostatic (inhibiting bacterial growth) rather than bactericidal (killing bacteria). Exposure to bacteriostatic agents may encourage the emergence of antibiotic-resistant strains of P acnes.
Summary of Findings Use of antibiotics for acne is associated with development of resistance in P acnes, mostly via point mutations.1 • Multiple countries report resistance in greater than half of P acnes isolates, predominantly to topical erythromycin and clindamycin, and less so to tetracyclines.1,2
Evidence Profile No. of trials: 5 No. of randomized clinical trials: 0 Study years: 1987-2002, 2007-2008 No. of patients: 120 088 Male: 44.1% Female: 55.9% Race: White (65.6%) (from 2 trials [662 participants])
• The clinical efficacy of topical erythromycin decreased from the 1970s to 2002, attributed to antibiotic resistance.1 • Resistant P acnes is found on the skin of untreated contacts of acne patients prescribed antibiotics.2 Resistant strains of P acnes are reported to cause severe infections1; therefore, current prescribing practices may represent a risk to untreated contacts, especially those with impaired immunity. • After discontinuation of therapy, resistance may persist.1 Although P acnes is not known to acquire resistance from or transfer it to other bacteria,1 using antibiotics for acne leads to off-target effects. • Use of topical antibiotics is associated with resistance in Staphylococcus aureus. This organism, especially when methicillin resistant, is responsible for potentially severe health care– and community-associated infections. Treatment with oral tetracyclines is associated with lower S aureus carriage rates, without increased resistance.3 • In a retrospective cohort of more than 100 000 patients with acne, those treated with topical and/or oral antibiotics for at least 6 weeks were significantly more likely to develop upper respiratory infections during 1 year of follow-up than patients who had not received antibiotics (odds ratio, 2.15; 95% CI, 2.052.23; P < .001).4 • In a prospective cohort of university students (N = 579), those receiving oral antibiotics for acne were more than 4 times more likely to report pharyngitis during 1 year of follow-up than untreated individuals (odds ratio, 4.34; 95% CI, 1.51-12.47).5
Age, mean (range): 22.3 (12-59) years
Discussion
Setting: Outpatient
Current Guidelines
Countries: United States (n = 3), United Kingdom (n = 2), Greece, Hungary, Italy, Spain, Sweden (n = 1 each)
Lack of development of new antibiotics and increasing resistance rates have prompted an emphasis on antibiotic stewardship in acne treatment guidelines (Table). The American Academy of Dermatology’s most recent guidelines6 recommend coadministration of benzoyl peroxide (BP), a topical bactericidal agent not reported to cause resistance, alongside both topical and oral antibiotics. Benzoyl peroxide is comedolytic and kills P acnes by generating free radicals. Added to topical antibiotics, BP may prevent the formation of resistance and increase treatment efficacy. Only indirect evidence supports the ability of BP to limit resistance when used with oral antibiotics.7
Primary outcomes: • Prevalence of antibiotic-resistant Propionibacterium acnes among patients and untreated contacts • Nasal/pharyngeal colonization with Staphylococcus aureus and antibiotic susceptibility patterns • Diagnosis of upper respiratory or urinary tract infection • Self-reported pharyngitis Secondary outcomes: Genotypic/phenotypic analysis of resistant P acnes
jamadermatology.com
(Reprinted) JAMA Dermatology Published online June 21, 2017
© 2017 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/pdfaccess.ashx?url=/data/journals/derm/0/ on 06/21/2017
E1
Clinical Review & Education JAMA Dermatology Clinical Evidence Synopsis
Table. Guidelines for Treatment of Acne With Antibiotics Strength of Recommendation
Treatment American Academy of Dermatology Guidelines6 Mild-to-moderate acne BP
A
Topical retinoid
A
BP + topical retinoid
A
BP + topical antibiotic
A
BP + topical retinoid + topical antibiotic
A
Moderate-to-severe acne Oral antibiotic + BP + topical retinoid
A
Oral antibiotic + BP + topical antibiotic
A
Oral antibiotic + BP + topical retinoid + topical antibiotic
A
European Guidelines7 Mild-to-moderate acne Fixed-dose BP/topical retinoid
High
Fixed-dose BP/topical antibiotic
High
BP
Medium
Topical retinoid
Medium
Fixed-dose topical antibiotic/retinoid
Medium
Azelaic acid
Medium
Moderate-to-severe acne Oral antibiotic + topical retinoid
Medium
Oral antibiotic + fixed-dose BP/retinoid
Medium
Oral antibiotic + azelaic acid
Medium
Limitations and Areas in Need of Further Study
Oral antibiotic + BP
Low
The body of data on antibiotic resistance in acne is limited in scope and quality. Additional studies are needed to address multiple evidence gaps. Reduction of resistance through use of BP and fixeddose topical formulations should be quantified by susceptibility testing and genomic studies to more completely elucidate the benefits of combination therapy. It is unclear how effectively adding BP to systemic antibiotics impedes resistance formation, contrasting the limited application of BP with the antibiotic’s distribution throughout the body. Subantimicrobial antibiotic dosing, which may discourage resistance, is still poorly understood and merits further inquiry.
Abbreviation: BP, benzoyl peroxide.
For mild-to-moderate acne, first-line treatment is with BP, topical retinoids, or combination therapy, which may incorporate a topical antibiotic (BP + antibiotic, BP + retinoid, BP + antibiotic + retinoid). Topical antibiotic monotherapy is not recommended. In patients who benefit from topical antibiotic treatment, available fixed-combination antibiotic/BP formulations simplify the regimen and potentially improve patient adherence. ARTICLE INFORMATION Author Affiliations: Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles (Adler, Armstrong); Drexel University College of Medicine, Philadelphia, Pennsylvania (Kornmehl). Corresponding Author: April W. Armstrong, MD, MPH, Department of Dermatology, Keck School of Medicine, University of Southern California, 1975 Zonal Ave, KAM 510, MC 9034, Los Angeles, CA 90089 ([email protected]). Published Online: June 21, 2017. doi:10.1001/jamadermatol.2017.1297 Conflict of Interest Disclosures: Dr Armstrong’s disclosures include serving as an investigator and consultant/advisor to AbbVie, Celgene, Janssen,
E2
For moderate-to-severe acne, first-line treatment is with oral antibiotics combined with BP and a topical retinoid. Oral antibiotic monotherapy is not recommended. Topical antibiotics may also be included in the regimen, provided BP is used concomitantly. The first-line oral antibiotics are doxycycline and minocycline, which exert anti-inflammatory as well as antimicrobial effects. Because of associated resistance, systemic erythromycin should be avoided, except in patients unable to tolerate tetracycline therapy (eg, pregnant women and children
JAMA Dermatology Clinical Evidence Synopsis
Antibiotic Resistance in Acne Treatment Brandon L. Adler, MD; Heather Kornmehl, BS; April W. Armstrong, MD, MPH
CLINICAL QUESTION What is the evidence for antibiotic resistance in acne, and how does resistance affect treatment? BOTTOM LINE Use of topical and systemic antibiotics for acne is associated with formation of resistance in Propionibacterium acnes and other bacteria, with clinical consequences. Guidelines recommend resistance reduction strategies including avoidance of antibiotic monotherapy, combination treatment with topical modalities, and limiting the duration of oral antibiotic use.
Introduction Antibiotics are a fundamental component of the treatment of acne owing to the role that Propionibacterium acnes plays in its pathogenesis. Despite a relatively small workforce, dermatologists disproportionately prescribe antibiotics.1 However, antibiotic resistance is a global issue with increasing prevalence over time. The antibiotics most frequently used for acne are topical erythromycin and clindamycin and oral tetracyclines, which are bacteriostatic (inhibiting bacterial growth) rather than bactericidal (killing bacteria). Exposure to bacteriostatic agents may encourage the emergence of antibiotic-resistant strains of P acnes.
Summary of Findings Use of antibiotics for acne is associated with development of resistance in P acnes, mostly via point mutations.1 • Multiple countries report resistance in greater than half of P acnes isolates, predominantly to topical erythromycin and clindamycin, and less so to tetracyclines.1,2
Evidence Profile No. of trials: 5 No. of randomized clinical trials: 0 Study years: 1987-2002, 2007-2008 No. of patients: 120 088 Male: 44.1% Female: 55.9% Race: White (65.6%) (from 2 trials [662 participants])
• The clinical efficacy of topical erythromycin decreased from the 1970s to 2002, attributed to antibiotic resistance.1 • Resistant P acnes is found on the skin of untreated contacts of acne patients prescribed antibiotics.2 Resistant strains of P acnes are reported to cause severe infections1; therefore, current prescribing practices may represent a risk to untreated contacts, especially those with impaired immunity. • After discontinuation of therapy, resistance may persist.1 Although P acnes is not known to acquire resistance from or transfer it to other bacteria,1 using antibiotics for acne leads to off-target effects. • Use of topical antibiotics is associated with resistance in Staphylococcus aureus. This organism, especially when methicillin resistant, is responsible for potentially severe health care– and community-associated infections. Treatment with oral tetracyclines is associated with lower S aureus carriage rates, without increased resistance.3 • In a retrospective cohort of more than 100 000 patients with acne, those treated with topical and/or oral antibiotics for at least 6 weeks were significantly more likely to develop upper respiratory infections during 1 year of follow-up than patients who had not received antibiotics (odds ratio, 2.15; 95% CI, 2.052.23; P < .001).4 • In a prospective cohort of university students (N = 579), those receiving oral antibiotics for acne were more than 4 times more likely to report pharyngitis during 1 year of follow-up than untreated individuals (odds ratio, 4.34; 95% CI, 1.51-12.47).5
Age, mean (range): 22.3 (12-59) years
Discussion
Setting: Outpatient
Current Guidelines
Countries: United States (n = 3), United Kingdom (n = 2), Greece, Hungary, Italy, Spain, Sweden (n = 1 each)
Lack of development of new antibiotics and increasing resistance rates have prompted an emphasis on antibiotic stewardship in acne treatment guidelines (Table). The American Academy of Dermatology’s most recent guidelines6 recommend coadministration of benzoyl peroxide (BP), a topical bactericidal agent not reported to cause resistance, alongside both topical and oral antibiotics. Benzoyl peroxide is comedolytic and kills P acnes by generating free radicals. Added to topical antibiotics, BP may prevent the formation of resistance and increase treatment efficacy. Only indirect evidence supports the ability of BP to limit resistance when used with oral antibiotics.7
Primary outcomes: • Prevalence of antibiotic-resistant Propionibacterium acnes among patients and untreated contacts • Nasal/pharyngeal colonization with Staphylococcus aureus and antibiotic susceptibility patterns • Diagnosis of upper respiratory or urinary tract infection • Self-reported pharyngitis Secondary outcomes: Genotypic/phenotypic analysis of resistant P acnes
jamadermatology.com
(Reprinted) JAMA Dermatology Published online June 21, 2017
© 2017 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/pdfaccess.ashx?url=/data/journals/derm/0/ on 06/21/2017
E1
Clinical Review & Education JAMA Dermatology Clinical Evidence Synopsis
Table. Guidelines for Treatment of Acne With Antibiotics Strength of Recommendation
Treatment American Academy of Dermatology Guidelines6 Mild-to-moderate acne BP
A
Topical retinoid
A
BP + topical retinoid
A
BP + topical antibiotic
A
BP + topical retinoid + topical antibiotic
A
Moderate-to-severe acne Oral antibiotic + BP + topical retinoid
A
Oral antibiotic + BP + topical antibiotic
A
Oral antibiotic + BP + topical retinoid + topical antibiotic
A
European Guidelines7 Mild-to-moderate acne Fixed-dose BP/topical retinoid
High
Fixed-dose BP/topical antibiotic
High
BP
Medium
Topical retinoid
Medium
Fixed-dose topical antibiotic/retinoid
Medium
Azelaic acid
Medium
Moderate-to-severe acne Oral antibiotic + topical retinoid
Medium
Oral antibiotic + fixed-dose BP/retinoid
Medium
Oral antibiotic + azelaic acid
Medium
Limitations and Areas in Need of Further Study
Oral antibiotic + BP
Low
The body of data on antibiotic resistance in acne is limited in scope and quality. Additional studies are needed to address multiple evidence gaps. Reduction of resistance through use of BP and fixeddose topical formulations should be quantified by susceptibility testing and genomic studies to more completely elucidate the benefits of combination therapy. It is unclear how effectively adding BP to systemic antibiotics impedes resistance formation, contrasting the limited application of BP with the antibiotic’s distribution throughout the body. Subantimicrobial antibiotic dosing, which may discourage resistance, is still poorly understood and merits further inquiry.
Abbreviation: BP, benzoyl peroxide.
For mild-to-moderate acne, first-line treatment is with BP, topical retinoids, or combination therapy, which may incorporate a topical antibiotic (BP + antibiotic, BP + retinoid, BP + antibiotic + retinoid). Topical antibiotic monotherapy is not recommended. In patients who benefit from topical antibiotic treatment, available fixed-combination antibiotic/BP formulations simplify the regimen and potentially improve patient adherence. ARTICLE INFORMATION Author Affiliations: Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles (Adler, Armstrong); Drexel University College of Medicine, Philadelphia, Pennsylvania (Kornmehl). Corresponding Author: April W. Armstrong, MD, MPH, Department of Dermatology, Keck School of Medicine, University of Southern California, 1975 Zonal Ave, KAM 510, MC 9034, Los Angeles, CA 90089 ([email protected]). Published Online: June 21, 2017. doi:10.1001/jamadermatol.2017.1297 Conflict of Interest Disclosures: Dr Armstrong’s disclosures include serving as an investigator and consultant/advisor to AbbVie, Celgene, Janssen,
E2
For moderate-to-severe acne, first-line treatment is with oral antibiotics combined with BP and a topical retinoid. Oral antibiotic monotherapy is not recommended. Topical antibiotics may also be included in the regimen, provided BP is used concomitantly. The first-line oral antibiotics are doxycycline and minocycline, which exert anti-inflammatory as well as antimicrobial effects. Because of associated resistance, systemic erythromycin should be avoided, except in patients unable to tolerate tetracycline therapy (eg, pregnant women and children
