Shannon Humphrey, MD, FRCPC, FAAD
Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
Propionibacterium acnes (P. acnes) is an anaerobic bacteria implicated in the pathogenesis of acne. The last 30 years have witnessed an alarming increase in resistance to antibiotics commonly employed to treat acne. Antibiotic resistance in acne represents a significant international public health concern because resistance can occur in more pathogenic bacteria than P. acnes, and an increase in pathogenic P. acnes has been reported. Current treatment guidelines offer strategies to limit the potential for resistance while achieving optimal outcome in the management of inflammatory and non-inflammatory acne.
acne vulgaris, antibacterial agents, antibiotic resistance, benzoyl peroxide, topical combination therapy
Antibiotic Resistance in Acne Therapy
Propionibacterium acnes (P. acnes) is an anaerobic bacteria implicated in the pathogenesis of acne vulgaris. There are four primary pathogenic factors: excess sebum production, bacterial colonization, inflammation, and abnormal keratinization.1 Treatment targets as many pathogenic factors as possible and may include a combination of topical and systemic agents.
Although current acne guidelines discourage the use of antibiotics as prolonged monotherapy,1 about 5 million prescriptions for oral antibiotics are written each year for the treatment of acne.2 Antibiotics demonstrate anti-inflammatory and antimicrobial effects and work on two levels: to decrease the presence of P. acnes – a resident of the normal microflora found in abnormally high numbers in the sebaceous follicles of patients with acne and a primary factor in the development of inflammatory acne3 – and to inhibit the production of P. acnes-associated inflammatory mediators.4 Indeed, topical and oral antibiotics have been the mainstay of acne treatment for over 50 years.
In 1976, there was no evidence of antibiotic-resistant propionibacteria on the skin of over 1000 patients with acne.5 By 1979, Crawford and colleagues had detected the first indication of resistance to topical erythromycin and clindamycin,6 which was followed by the emergence of tetracycline-resistant P. acnes in the early eighties.7 Since then, the incidence of antibiotic resistance in acne has continued to rise across the globe, from 20% in 1978 to 72.5% in 1995,8 with combined resistance to erythromycin and clindamycin more prevalent than resistance to tetracycline.9 Evidence suggests that it is the use of topical erythromycin and clindamycin – the most commonly used topical antibiotics in acne – that has contributed to the gradual increase in resistance over the last 20 years.7,8,10-12 In fact, resistant P. acnes strains have been shown to emerge after only 8 weeks of topical antibiotic monotherapy, with the number of resistant strains increasing progressively over subsequent weeks.13
Evidence of Clinical Relevance
Acne does not represent a typical bacterial infection, in which antibiotic resistance directly correlates to treatment failure, because antibiotics demonstrate both antibacterial and anti-inflammatory effects, and P. acnes – existing in the microaerophilic or anaerobic and lipid-rich environment of the pilosebaceous follicle – cannot easily be cultured. However, it is logical to assume that resistance manifests with a reduced clinical response, and this theory is substantiated by the results of several investigations linking resistant strains to higher counts of P. acnes and therapeutic failure.7,10,14,15 A systematic review of 50 clinical trials using topical antibiotics between 1974 and 2003 paints a startling picture: a significant decrease in the efficacy of topical erythromycin on inflammatory and non-inflammatory lesions over time (Figure 1).16
The question remains: what does it matter? While it is true that that the prevalence of life-threatening infections caused by P. acnes has greatly increased in the last twenty-odd years,17 most often in the post-surgical setting in patients with significant medical comorbidities,18 acute propionibacterial infections are never treated with acne medication. Furthermore, it would seem that antibiotic-resistant acne puts neither patients nor the community at risk for resistant propionibacterial infections.
|Figure 1: Impact on acne: efficacy of topical erythromycin over time (empty circles: studies evaluating treatment efficacy after 8 weeks; asterisks: studies evaluating treatment efficacy after 12 weeks).|
Figure from Simonart T, Dramaix M., Treatment of acne with topical antibiotics: lessons from clinical studies. Br J Dermatol. 2005 Aug;153(2):page 399, Figure 1. Reprinted with permission from John Wiley and Sons.
Resistance in Pathogenic Organisms
Prolonged regimens using either topical or oral antibiotics for the treatment of acne have resulted in selection pressure or the transfer of resistant genes to potentially pathogenic bacteria, such as certain strains of staphylococci or streptococci,4,6 and it is these resistant organisms that could present clinical challenges. Levy and colleagues investigated the effects of topical and/or oral antibiotics on the oropharyngeal flora in patients with acne.19 Patients treated with any antibiotic exhibited a 3-fold greater risk of group A streptococcus colonization by Streptococcus pyogenes (S. pyogenes) compared to patients not using antibiotic therapy. Eighty-five percent of S. pyogenes cultures from those using antibiotics were resistant to at least one tetracycline antibiotic, compared to 20% from those not using antibiotics.
A subgroup analysis of topical versus oral antibiotics found similar prevalence rates, indicating that topical antibiotics have an impact on distant flora and resistance patterns by direct inoculation or systemic absorption. Like their oral counterparts, topical antibiotics may alter the microbial equilibrium through selective elimination of certain bacteria, allowing species like S. pyogenes, which would normally be held in check, to flourish.19
Studies have clearly demonstrated that the use of topical erythromycin increases counts of resistant coagulase-negative staphylococci (CNS) on both local and distant anatomical sites.20-22 Harkaway and colleagues demonstrated aerobic flora dominated by Staphylococcus epidermidis (S. epidermidis) completely resistant to erythromycin and partially resistant to clindamycin and tetracycline after 12 weeks of treatment.20 Vowels and colleagues found that the prevalence and density of resistant organisms persisted and did not return to baseline values until 6 weeks after discontinuation of topical antibiotic therapy.21
The implications are potentially serious. S. epidermidis has been found to be pathogenic in certain patients, predominantly those with indwelling catheters, surgical patients, or premature infants.23-25 More ominously, CNS has been shown to transfer resistance to the more pathogenic S. aureus,26 which tends to thrive and disseminate more widely in conjunction with topical antibiotic therapy. In a 24-week randomized trial of 2% erythromycin gel versus its vehicle, antibiotic therapy led to an increase from 15% to 40% in erythromycin-resistant S. aureus carriage rates in the nose, and resistance increased significantly and substantially in the treated group versus patients receiving vehicle (63% vs. 37%) by the end of the treatment period.22
For all the potentially pathogenic organisms that develop resistance to anti-acne antibiotics, the question remains: does it really matter? Physicians are unlikely to treat S. epidermidis or group A streptococcus with acne medication. However, consider this: first-line systemic agents for community-acquired methecillin-resistant S. aureus (MRSA) include minocycline and trimethoprim-sulfamethoxazole, both of which are used for the treatment of acne. Thus far, resistance to minocycline is not common; the same cannot be said about trimethoprim.27 As multi-drug-resistant organisms emerge, therapeutic options continue to shrink.
Antibiotic Resistance in Acne Treatment: Evidence of Clinical Relevance
- Reduced clinical response to antibiotic therapy
- Potential increase in pathogenicity of P. acnes
- Transfer of resistance to more pathogenic organisms
Strategies to Limit Resistance
Since prescribing practice patterns directly influence the rates of P. acnes resistance in the population (i.e., the levels of resistance correlate to the levels of antibiotic use), and since selection pressure may affect more pathogenic bacteria than P. acnes, it makes sense to implement strategies and guidelines to limit antibiotic resistance.1 The Global Alliance to Improve Outcomes in Acne guidelines recommend the combination of a topical retinoid plus an antimicrobial agent as first-line therapy for most patients with acne.1 When antibiotics are indicated, the guidelines recommend strategies to limit resistance, including the use of oral antibiotics only in moderate and moderately severe cases of acne, and the necessary addition of benzoyl peroxide (BPO) and a topical retinoid to regimens using topical antibiotics in mild-tomoderate cases.
Strategies to Limit Antibiotic Resistance in Acne
- Avoid topical or oral antibiotics as monotherapy or maintenance therapy
- Limit duration of antibiotic use and assess response at 6 to 12 weeks
- Use concomitant BPO (leave-on or wash)
- Avoid simultaneous use of oral and topical antibiotics without BPO
- Use topical retinoid +/- BPO as maintenance in lieu of antibiotics
Evidence suggests that BPO, alone or in combination with a topical retinoid, may serve as an effective and well tolerated option for treating acne in patients with resistant P. acnes, while minimizing the development of further antibiotic resistance. Topical retinoids exhibit both anti-inflammatory and anticomedonal activities11 and are highly effective in reducing both inflammatory and non-inflammatory lesions.28,29 BPO is a broad-spectrum antibacterial agent that comes in many formulations and works through the interaction of oxidized intermediates with various constituents of microbial cells.30 Despite its widespread use, bacterial resistance has not been reported.
Leave-on products containing BPO not only suppress existing insensitive strains, but also reduce the emergence of erythromycin- and clindamycin-resistant strains during antibiotic therapy.13,15,30-35 Moreover, the concomitant use of BPO with a topical antibiotic is highly effective in reducing the colony counts of cutaneous P. acnes.20,33,36 Even simple washes containing BPO effectively reduce P. acnes,11,37 including resistant populations.39 Leyden and colleagues assessed the effectiveness of a gel combination treatment containing 0.1% adapalene and 2.5% BPO in healthy patients with high P. acnes populations resistant to erythromycin, tetracycline and clindamycin, and found a significant reduction in resistant strains by week 4.12 Indeed, therapy with a combination of adapalene and BPO eradicated some resistant strains entirely in some patients.
There is some evidence that subantimicrobial doses of antibiotics may reduce inflammation and provide immunomodulatory effects without risk of any resistance. Doxycycline is a secondgeneration tetracycline class antibiotic normally used at a dose of 100 mg to 200 mg/day in the treatment of acne. Skidmore randomized 51 patients with moderate acne to twice daily 20 mg doses of doxycycline or placebo for 6 months.39 Active treatment significantly reduced the number of inflammatory and non-inflammatory lesions by more than 50% and led to a greater overall improvement compared to placebo, with no change in number or severity of resistant pathogens or evidence of antimicrobial effect on the skin flora. Toossi and colleagues compared subantimicrobial doses (20 mg twice daily) with antimicrobial doses (100 mg daily) in a prospective, double-blind, randomized controlled trial of 100 patients with moderate facial acne.40 Both treatments significantly decreased inflammatory lesion counts; subantimicrobial dosing led to an 84% and 90% reduction in the number of papules and pustules, respectively. Although more rigorous trials designed to study the impact on follicular and cutaneous microflora and resistance patterns are warranted, these early results are promising and may represent a future possibility for the management of acne vulgaris.
Although antibiotics play an important role in acne management, the increase in P. acnes resistance should be cause for concern and serve as the impetus for change in prescribing patterns and treatment algorithms. Not only are resistant strains linked to lack or worsening of clinical response to treatment, but the pathogenicity of P. acnes has increased over recent years, and most importantly prolonged regimens of antibiotic therapy have led to the transfer of resistance among non-targeted pathogenic bacteria. Limiting the frequency and duration of antibiotic use and adding the topical antimicrobial agent BPO will minimize the development of resistance while maintaining efficacy in the treatment of inflammatory and non-inflammatory acne lesions.
- Thiboutot D, Gollnick H, Bettoli V, 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 May;60(5 Suppl):S1-50.
- Stern RS. Medication and medical service utilization for acne 1995-1998. J Am Acad Dermatol. 2000 Dec;43(6):1042-8.
- Webster GF. Acne vulgaris. BMJ. 2002 Aug 31;325(7362):475-9.
- Leyden JJ, Del Rosso JQ, Webster GF. Clinical considerations in the treatment of acne vulgaris and other inflammatory skin disorders: focus on antibiotic resistance. Cutis. 2007 Jun;79(6 Supp™l):9-25.
- Leyden JJ. Antibiotic resistant acne. Cutis. 1976 Mar;17(3):593-606.
- Crawford WW, Crawford IP, Stoughton RB, et al. Laboratory induction and clinical occurrence of combined clindamycin and erythromycin resistance in Corynebacterium acnes. J Invest Dermatol. 1979 Apr;72(4):187-90.
- Leyden JJ, McGinley KJ, Cavalieri S, et al. Propionibacterium acnes resistance to antibiotics in acne patients. J Am Acad Dermatol. 1983 Jan;8(1):41-5.
- Cooper AJ. Systematic review of Propionibacterium acnes resistance to systemic antibiotics. Med J Aust. 1998 Sep 7;169(5):259-61.
- Ross JI, Snelling AM, Carnegie E, et al. Antibiotic-resistant acne: lessons from Europe. Br J Dermatol. 2003 Mar;148(3):467-78.
- Eady EA, Cove JH, Holland KT, et al. Erythromycin resistant propionibacteria in antibiotic treated acne patients: association with therapeutic failure. Br J Dermatol. 1989 Jul;121(1):51-7.
- Gollnick H, Cunliffe W, Berson D, et al. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2003 Jul;49(1 Suppl):S1-37.
- Leyden JJ, Preston N, Osborn C, et al. In-vivo effectiveness of adapalene 0.1%/benzoyl peroxide 2.5% gel on antibiotic-sensitive and resistant Propionibacterium acnes. J Clin Aesthet Dermatol. 2011 May;4(5):22-6.
- Cunliffe WJ, Holland KT, Bojar R, 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 Jul;24(7):1117-33.
- Eady EA, Gloor M, Leyden JJ. Propionibacterium acnes resistance: a worldwide problem. Dermatology. 2003;206(1):54-6.
- Ozolins M, Eady EA, Avery AJ, et al. Comparison of five antimicrobial regimens for treatment of mild to moderate inflammatory facial acne vulgaris in the community: randomised controlled trial. Lancet. 2004 Dec 18-31;364(9452):2188-95.
- Simonart T, Dramaix M. Treatment of acne with topical antibiotics: lessons from clinical studies. Br J Dermatol. 2005 Aug;153(2):395-403.
- Jakab E, Zbinden R, Gubler J, et al. Severe infections caused by Propionibacterium acnes: an underestimated pathogen in late postoperative infections. Yale J Biol Med. 1996 Nov-Dec;69(6):477-82.
- Oprica C, Nord CE. European surveillance study on the antibiotic susceptibility of Propionibacterium acnes. Clin Microbiol Infect. 2005 Mar;11(3):204-13.
- Levy RM, Huang EY, Roling D, et al. Effect of antibiotics on the oropharyngeal flora in patients with acne. Arch Dermatol. 2003 Apr;139(4):467-71.
- Harkaway KS, McGinley KJ, Foglia AN, et al. Antibiotic resistance patterns in coagulase-negative staphylococci after treatment with topical erythromycin, benzoyl peroxide, and combination therapy. Br J Dermatol. 1992 Jun;126(6):586-90.
- Vowels BR, Feingold DS, Sloughfy C, et al. Effects of topical erythromycin on ecology of aerobic cutaneous bacterial flora. Antimicrob Agents Chemother. 1996 Nov;40(11):2598-604.
- Mills O, Jr., Thornsberry C, Cardin CW, et al. Bacterial resistance and therapeutic outcome following three months of topical acne therapy with 2% erythromycin gel versus its vehicle. Acta Derm Venereol. 2002;82(4):260-5.
- Lowy FD, Hammer SM. Staphylococcus epidermidis infections. Ann Intern Med. 1983 Dec;99(6):834-9.
- Gemmell CG. Coagulase-negative staphylococci. Med Microbiol. 1986 Dec;22(4):285-95.
- Stillman RI, Wenzel RP, Donowitz LC. Emergence of coagulase negative staphylococci as major nosocomial bloodstream pathogens. Infect Control. 1987 Mar;8(3):108-12.
- Naidoo J, Noble WC. Skin as a source of transferable antibiotic resistance in coagulase-negative staphylococci. Zentralblatt Bakt Suppl. 1987;16:225-34.
- Eady EA, Jones CE, Gardner KJ, et al. Tetracycline-resistant propionibacteria from acne patients are cross-resistant to doxycycline, but sensitive to minocycline. Br J Dermatol. 1993 May;128(5):556-60.
- Thiboutot DM, Shalita AR, Yamauchi PS, et al. Adapalene gel, 0.1%, as maintenance therapy for acne vulgaris: a randomized, controlled, investigatorblind follow-up of a recent combination study. Arch Dermatol. 2006 May;142(5):597-602.
- Leyden J, Thiboutot DM, Shalita AR, et al. Comparison of tazarotene and minocycline maintenance therapies in acne vulgaris: a multicenter, doubleblind, randomized, parallel-group study. Arch Dermatol. 2006 May;142(5): 605-12.
- Eady EA, Farmery MR, Ross JI, et al. Effects of benzoyl peroxide and erythromycin alone and in combination against antibiotic-sensitive and -resistant skin bacteria from acne patients. Br J Dermatol. 1994 Sep;131(3):331-6.
- Bojar RA, Cunliffe WJ, Holland KT. The short-term treatment of acne vulgaris with benzoyl peroxide: effects on the surface and follicular cutaneous microflora. Br J Dermatol. 1995 Feb;132(2):204-8.
- Eady EA, Bojar RA, Jones CE, et al. The effects of acne treatment with a combination of benzoyl peroxide and erythromycin on skin carriage of erythromycin-resistant propionibacteria. Br J Dermatol. 1996 Jan;134(1): 107-13.
- Lookingbill DP, Chalker DK, Lindholm JS, et al. Treatment of acne with a combination clindamycin/benzoyl peroxide gel compared with clindamycin gel, benzoyl peroxide gel and vehicle gel: combined results of two double-blind investigations. J Am Acad Dermatol. 1997 Oct;37(4):590-5.
- Leyden J, Levy S. The development of antibiotic resistance in Propionibacterium acnes. Cutis. 2001 Feb;67(2 Suppl):21-4.
- Thiboutot D. Acne: 1991-2001. J Am Acad Dermatol. 2002 Jul;47(1):109-17.
- Leyden JJ. Current issues in antimicrobial therapy for the treatment of acne. J Eur Acad Dermatol Venereol. 2001;15 Suppl 3:51-5.
- Gans EH, Kligman AM. Comparative efficacy of clindamycin and benzoyl peroxide for in vivo suppression of Propionibacterium acnes. J Dermatolog Treat. 2002 Sep;13(3):107-10.
- Leyden JJ, Wortzman M, Baldwin EK. Antibiotic-resistant Propionibacterium acnes suppressed by a benzoyl peroxide cleanser 6%. Cutis. 2008 Dec;82(6): 417-21.
- Skidmore R, Kovach R, Walker C, et al. Effects of subantimicrobial-dose doxycycline in the treatment of moderate acne. Arch Dermatol. 2003 Apr;139(4):459-64.
- Toossi P, Farshchian M, Malekzad F, et al. Subantimicrobial-dose doxycycline in the treatment of moderate facial acne. J Drugs Dermatol. 2008 Dec;7(12): 1149-52.