Review
Systematic review of antibiotic resistance in acne: an increasing topical and oral threat

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Summary

Topical and oral antibiotics are routinely used to treat acne. However, antibiotic resistance is increasing, with many countries reporting that more than 50% of Propionibacterium acnes strains are resistant to topical macrolides, making them less effective. We reviewed the current scientific literature to enable proposal of recommendations for antibiotic use in acne treatment. References were identified through PubMed searches for articles published from January, 1954, to March 7, 2015, using four multiword searches. Ideally, benzoyl peroxide in combination with a topical retinoid should be used instead of a topical antibiotic to minimise the impact of resistance. Oral antibiotics still have a role in the treatment of moderate-to-severe acne, but only with a topical retinoid, benzoyl peroxide, or their combination, and ideally for no longer than 3 months. To limit resistance, it is recommended that benzoyl peroxide should always be added when long-term oral antibiotic use is deemed necessary. The benefit-to-risk ratio of long-term antibiotic use should be carefully considered and, in particular, use alone avoided where possible. There is a need to treat acne with effective alternatives to antibiotics to reduce the likelihood of resistance.

Introduction

Topical and oral antibiotics are routinely used to treat acne. However, antibiotic resistance is increasing, with many countries reporting that over 50% of Propionibacterium acnes strains are resistant to topical macrolides, making them less effective. Collateral damage to the steady-state microbiome is a major concern, particularly for Staphylococcus aureus and meticillin-resistant S aureus (MRSA), and antibiotic resistance in non-target bacteria promotes the growth of opportunistic pathogens. The Global Alliance to Improve Outcomes in Acne recommends that topical and oral antibiotics are not used as monotherapy or concurrently, and that combination of a topical retinoid and antimicrobial agent (eg, benzoyl peroxide [BPO]) is preferred as first-line therapy for almost all people with acne. To limit antibiotic resistance, BPO should always be added when long-term antibiotic use is deemed necessary. Comprehensive and detailed antibiotic resistance studies and joint recommendations from both dermatologists and microbiologists are long overdue. Here, we discuss the scientific literature and propose recommendations for international implementation and further clinical microbiological studies.

Section snippets

Search strategy and selection criteria

References were identified through searches of PubMed for articles published from January, 1954, to March 7, 2015, using several search terms. 465 publications were identified using the search terms acne (all fields) AND resistance (all fields) NOT insulin, 323 of which were published after 2000. A search using the terms acne (all fields) AND resistance (all fields) AND macrolide (all fields) led to the identification of 83 publications, 45 of which were published after 2000. 77 publications

Causes and pathogenesis of acne

Acne is a chronic inflammatory disorder of the skin associated with comedones, papules, pustules, nodules, and erythema, which can lead to scarring. It is very common, affecting almost 80% of adolescents and young adults aged 11–30 years.5, 6, 7

The pathogenesis is complex, but the pilosebaceous unit is the target organ, which accounts for the distribution of acne primarily on the face, chest, and back—the areas with the highest concentration of pilosebaceous glands.6, 8, 9, 10 The most notable

Antibiotics used in the treatment of acne

Both topical and oral antibiotics are traditionally used in the treatment of acne.17, 21, 22 Erythromycin and clindamycin, two of the longest used and most commonly prescribed topical antibiotics, are still frequently prescribed because side-effects are typically minor.21, 22, 23, 24 Topical antibiotics are usually used in the treatment of mild-to-moderate acne.17 However, despite their modest efficacy, their use continues and antibiotic resistance associated with topical antibiotic use,

Antibiotic use and resistance: a global issue

Although there is an enormous antibiotic load in the dermatology community, quantitative information on the use of antibiotics to specifically treat acne is very limited. In the USA, dermatologists represent 1% or less of the physician population, but prescribe almost 5% of all antibiotics.44 Roughly 8% of all antibiotics prescribed in the UK are thought to be for dermatological indications.45 Crucially, no longitudinal studies of topical or oral antibiotic use in acne exist. The fact that

Antibiotic resistance in acne

In 1976, no evidence of topical or oral antibiotic-resistant P acnes existed in more than 1000 people with acne.63 However, the overall incidence of P acnes resistance increased from 20% in 1978 to 62% in 1996.64, 65, 66, 67 Increases in P acnes resistance have now been reported in all major regions of the world, although the data for different antibiotics used and for different regions and countries remains incomplete.38 Many countries have reported that over 50% of P acnes strains are

Resistance, cross-resistance, and topical antibiotic failure

The potential negative consequences of antibiotic use to treat acne are numerous (figure 4).17, 27, 76, 77, 78, 79, 80 Resistance in P acnes mainly arises from chromosomal point mutations.34, 74, 81 Non-resistant P acnes are killed or growth is slowed, while resistant P acnes grow and proliferate.33, 52 P acnes does not usually acquire resistance from other bacteria or transfer resistant determinants to other bacteria.27, 74, 82, 83 Resistant P acnes strains can emerge quickly—for example,

Alternatives to antibiotics in the treatment of acne

Antibiotics still form a major part of acne therapy, despite the low availability of evidence-based data and few clinical trials on topical antibiotic monotherapy.23, 45, 98 Importantly, microbiology is not consistently done across all studies.84, 99 Moreover, detailed microbiological investigation, including bacterial counts, typing, and minimum inhibitory concentration levels and molecular analysis, have been rarely done together.84 Many dermatologists might not fully appreciate the role of

Restriction of the use of topical antibiotics

Topical antibiotics should not be used as monotherapy. Their use in treating mild-to-moderate acne must be combined with a topical retinoid, BPO, or a fixed-dose combination of topical retinoid and BPO to provide synergistic, faster clearance, and be limited in duration. To reduce antibiotic resistance, it is recommended that BPO or a topical retinoid should always be added when long-term topical antibiotic use is necessary (panel, figure 5). Topical and oral antibiotics should never be used

Restriction of the use of oral antibiotics

Oral antibiotics still have a role in the treatment of moderate-to-severe acne. However, they must always be combined with a topical retinoid, BPO, or a fixed-dose combination of topical retinoid and BPO, which has the advantage of a larger spectrum of activity. To reduce antibiotic resistance, it is recommended that BPO should always be added when long-term oral antibiotic use is necessary (panel, figure 5).17 Since BPO is bactericidal, it kills the bacteria and reduces the likelihood of

What does the future hold?

Antibiotic resistance in P acnes and other non-target bacteria as a result of topical antibiotics use in the treatment of acne is a major and increasing concern.26, 52, 69, 76 The challenge is to curtail topical macrolide use, either alone or in combination with oral antibiotics. In combination with a topical retinoid, BPO provides a suitable alternative and reduces the likelihood of the emergence of antibiotic resistance.17 Oral antibiotics still have a place in the treatment of more severe

Limitations of current evidence base

So far, very few controlled, detailed clinical and microbiological studies investigating the use of antibiotic regimens, or comparing the outcomes with use of antibiotics for different lengths of time (eg, 1 vs 2 vs 3 vs 4 months) have been done in people with acne, and even fewer studies relating microbiology to clinical outcomes are available. Additionally, little evidence exists on the clinical and microbiological consequences of antibiotic resistance in P acnes and the dermatological and

Summary of treatment recommendations

Topical antibiotics used to treat mild-to-moderate acne should be limited in duration or avoided. Ideally, BPO combined with a topical retinoid should be used instead of a topical antibiotic to stop their use in acne and minimise the impact of resistance. Topical antibiotics should not be used as monotherapy. Topical and oral antibiotics should never be used concurrently. Oral antibiotics still have a role in the treatment of moderate-to-severe acne, but only in combination with a topical

References (119)

  • TS El-Mahdy et al.

    Detection of a new erm(X)-mediated antibiotic resistance in Egyptian cutaneous propionibacteria

    Anaerobe

    (2010)
  • WJ Cunliffe et al.

    A randomized, double-blind comparison of a clindamycin phosphate/benzoyl peroxide gel formulation and a matching clindamycin gel with respect to microbiologic activity and clinical efficacy in the topical treatment of acne vulgaris

    Clin Ther

    (2002)
  • SL Kaplan

    Recent lessons for the management of bone and joint infections

    J Infect

    (2014)
  • HC Williams et al.

    Acne vulgaris

    Lancet

    (2012)
  • M Patel et al.

    The development of antimicrobial resistance due to the antibiotic treatment of acne vulgaris: a review

    J Drugs Dermatol

    (2010)
  • AJ Cooper

    Systematic review of Propionibacterium acnes resistance to systemic antibiotics

    Med J Aust

    (1998)
  • AE Eady et al.

    Is antibiotic resistance in cutaneous propionibacteria clinically relevant?: implications of resistance for acne patients and prescribers

    Am J Clin Dermatol

    (2003)
  • A Andriessen et al.

    Antibiotic resistance: shifting the paradigm in topical acne treatment

    J Drugs Dermatol

    (2014)
  • KK Kraning et al.

    Prevalence, morbidity, and cost of dermatological diseases

    J Invest Dermatol

    (1979)
  • WJ Cunliffe et al.

    Prevalence of facial acne vulgaris in late adolescence and in adults

    BMJ

    (1979)
  • HP Gollnick et al.

    Pathogenesis and pathogenesis related treatment of acne

    J Dermatol

    (1991)
  • WJ Cunliffe et al.

    Acne: diagnosis and management

    (2001)
  • G Plewig et al.

    Acne and rosacea

    (2000)
  • WJ Cunliffe et al.

    Comedogenesis: some new aetiological, clinical and therapeutic strategies

    Br J Dermatol

    (2000)
  • WJ Cunliffe et al.

    Disorders of the sebaceous gland

  • JL Burton et al.

    The relationship between seborrhoea and acne vulgaris

    Br J Dermatol

    (1971)
  • JJ Leyden

    The evolving role of Propionibacterium acnes in acne

    Semin Cutan Med Surg

    (2001)
  • D Thiboutot et al.

    New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acne group

    J Am Acad Dermatol

    (2009)
  • R Skidmore et al.

    Effects of subantimicrobial-dose doxycycline in the treatment of moderate acne

    Arch Dermatol

    (2003)
  • P Toossi et al.

    Subantimicrobial-dose doxycycline in the treatment of moderate facial acne

    J Drugs Dermatol

    (2008)
  • J Kim et al.

    Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses

    J Immunol

    (2002)
  • H Gollnick et al.

    Management of acne: a report from a Global Alliance to Improve Outcomes in Acne

    J Am Acad Dermatol

    (2003)
  • T Rosen

    Antibiotic resistance: an editorial review with recommendations

    J Drugs Dermatol

    (2011)
  • B Dréno et al.

    Antibiotic stewardship in dermatology: limiting antibiotic use in acne

    Eur J Dermatol

    (2014)
  • G Faghihi et al.

    Efficacy of intense pulsed light combined with topical erythromycin solution 2% versus topical erythromycin solution 2% alone in the treatment of persistent facial erythematous acne macules

    Adv Biomed Res

    (2012)
  • NS Abdel Fattah et al.

    In vitro antibiotic susceptibility patterns of Propionibacterium acnes isolated from acne patients: an Egyptian university hospital-based study

    J Eur Acad Dermatol Venereol

    (2013)
  • G Dumont-Wallon et al.

    Bacterial resistance in French acne patients

    Int J Dermatol

    (2010)
  • JI Ross et al.

    Antibiotic-resistant acne: lessons from Europe

    Br J Dermatol

    (2003)

  • Clindamycin 150 mg capsules summary of product characteristics

  • JQ Del Rosso

    Topical therapy for acne in women: is there a role for clindamycin phosphate-benzoyl peroxide gel?

    Cutis

    (2014)
  • LH Kircik

    The role of benzoyl peroxide in the new treatment paradigm for acne

    J Drugs Dermatol

    (2013)
  • AL Zaenglein et al.

    A phase IV, open-label study evaluating the use of triple-combination therapy with minocycline HCl extended-release tablets, a topical antibiotic/retinoid preparation and benzoyl peroxide in patients with moderate to severe acne vulgaris

    J Drugs Dermatol

    (2013)
  • A Nast et al.

    European evidence-based (S3) guidelines for the treatment of acne

    J Eur Acad Dermatol Venereol

    (2012)
  • CW Stratton

    Dead bugs don't mutate: susceptibility issues in the emergence of bacterial resistance

    Emerg Infect Dis

    (2003)
  • EA Eady et al.

    Propionibacterium acnes resistance: a worldwide problem

    Dermatology

    (2003)
  • JQ Del Rosso et al.

    The sequence of inflammation, relevant biomarkers, and the pathogenesis of acne vulgaris: what does recent research show and what does it mean to the clinician?

    J Drugs Dermatol

    (2013)
  • C Beylot et al.

    Propionibacterium acnes: an update on its role in the pathogenesis of acne

    J Eur Acad Dermatol Venereol

    (2014)
  • S Jugeau et al.

    Induction of toll-like receptors by Propionibacterium acnes

    Br J Dermatol

    (2005)
  • J Wolter et al.

    Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial

    Thorax

    (2002)
  • L Saiman et al.

    Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial

    JAMA

    (2003)

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