Maha Dutil, MD, MEd, FRCPC
Division of Dermatology, University of Toronto, Toronto, ON, Canada
Women’s College Hospital, Toronto, ON, Canada
Benzoyl peroxide is one of the most widely used topical agents for acne. It has potent antibacterial and mild anti-inflammatory and comedolytic effects. To treat mild to moderate acne, it can be used alone or in combination with topical antibiotics and topical retinoids. The combination of benzoyl peroxide with either erythromycin or clindamycin is synergistic and well-tolerated. In more severe acne, when oral antibiotics are required, benzoyl peroxide can contribute to suppressing the emergence of resistant strains of Propionibacterium acnes.
acne vulgaris, antibacterial agents, antibiotic resistance, benzoyl peroxide, erythromycin, clindamycin, topical combination therapy
The first description of benzoyl peroxide (BP) in the treatment of acneiform eruptions dates back to 1934, although its use as a topical agent in the management of various skin lesions was pioneered by Loevenhart in 1905.1 In 1958, Fishman was the first to suggest benzoyl peroxide as a viable treatment for acne.2 Pace presented findings of its efficacy before the members of the Canadian Dermatology Association at their meeting in Toronto in June of 1962 (later publishing the findings in 19653) and after a suitable vehicle (it is insoluble in water) was found for the drug, benzoyl peroxide was adopted by clinicians. Its popularity has increased in recent years with the emergence of antibiotic-resistant strains of Propionibacterium acnes (P. acnes).
Benzoyl peroxide is available in various strengths (2.5-20%) and vehicles (gels, lotions, solutions, creams, soap bars, pads, masks, and washes), as well as in combination formulation with the topical antibiotics erythromycin or clindamycin phosphate. It is also combined with the topical retinoid adapalene in a formulation that was US FDA approved in December 2008, but is not yet available in Canada.
Pharmacokinetics and Pharmacodynamics
Benzoyl peroxide is lipophilic and when applied to the skin it is capable of penetrating into the pilosebaceous follicle. Within the skin, benzoyl peroxide releases free radical oxygen and benzoic acid. The free radicals oxidize bacterial proteins. Higher concentrations of benzoyl peroxide applied to the skin result in larger amounts of drug in the skin.4 The benzoic acid is cleared rapidly by the kidneys and excreted unchanged in the urine.5 A second peak of urinary excretion of benzoic acid is detected when the benzoyl peroxide is washed off 24 hours after its application. This was noted especially with higher concentrations of the drug, suggesting that it is retained in the stratum corneum and that hydration increases its penetration.4
Inhibiting Antibiotic Resistance
Since the introduction of topical antibiotics in the mid-1970s, antibiotic-resistant strains of P. acnes have emerged and increased in numbers over the years.6 There is some evidence to suggest that patients with these resistant strains clinically fail to respond to the corresponding oral antibiotic when it is used alone.6,7
Benzoyl peroxide is a very effective broad-spectrum anti-bacterial agent. It was found to be more effective in reducing the concentration of free fatty acids in sebum than was systemic tetracycline, and efficacy was not affected by
P. acnes resistance.8,9 BP has mild anti-inflammatory and comedolytic effects,10 thus, it influences three of the four factors involved in acne pathogenesis. BP was initially thought to have sebo-suppressive effects, but Cunliffe showed that a 5% concentration increased sebum secretion rates by 22.5% after 1-2 months, likely by reducing obstruction in the pilosebaceous follicle and allowing sebum to flow more freely to reach the skin surface rather than affecting the sebaceous gland cells.11
Benzoyl peroxide is effective in controlling antibiotic-sensitive and antibiotic-resistant P. acnes. Significant reductions of P. acnes counts on the skin surface and in the follicle were noted after only 2 days of application of 5% benzoyl peroxide in an aqueous gel, with clinical improvement seen as early as 4 days.12 Benzoyl peroxide 6% cleanser was shown to reduce counts of antibiotic-susceptible and antibiotic-resistant strains of P. acnes equally by at least 2 logs after only 3 weeks of once daily washing for 20 seconds.13
Three double-blind studies that enrolled 153 patients with mild to moderately severe acne compared the efficacy of 2.5%, 5%, and 10% benzoyl peroxide gel formulations with the gel vehicle applied twice daily for 8 weeks. The three strengths were significantly more effective than the gel vehicle. Though the three strengths were deemed similar in their ability to reduce inflammatory lesions, the study was inadequately powered. Consequently, a statistically significant difference between the 2.5% and 5% and the 2.5% and 10% could not be reached. The 2.5% gel was also formulated in a different vehicle than the 5% and 10% gels. Furthermore, the findings showed an increased incidence of irritation related to higher strengths of benzoyl peroxide.14
The rise of resistant strains of P. acnes has been associated with a failure to respond to antibiotic therapy. This resistance was first reported with the topical antibiotics, clindamycin and erythromycin.15 The combination of benzoyl peroxide and topical antibiotic should prevent the selection of antibiotic-resistant propionibacteria, as well as reduce the number of strains of existing antibiotic-resistant bacteria on the skin. Benzoyl peroxide has also been shown to reduce the amount of erythromycin required to inhibit sensitive propionibacteria by up to 50% less than if erythromycin was used alone.16
Additionally, benzoyl peroxide can prevent the selection of erythromycin-resistant Staphylococcus epidermidis (S. epidermidis). During a 16-week study,17 three groups of 20 patients were treated with benzoyl peroxide alone, BP in combination with 3% erythromycin (BP/E), or erythromycin alone. After 12 weeks of treatment with erythromycin alone, the S. epidermidis isolated was completely resistant to erythromycin. There was also an increase in resistance to clindamycin and tetracycline. Those treated with BP or BP/E showed no change in resistance patterns to erythromycin or other antibiotics. These results are of major significance as S. epidermidis can cause infections in immunosuppressed and hospitalized patients and can transfer resistance to Staphylococcus aureus.17
In a double-blind study, 37 patients with mild to moderate acne were treated with 5% benzoyl peroxide in combination with 3% erythromycin (BP/E) gel or 3% erythromycin gel alone for 12 weeks. The combination therapy resulted in a greater than 3 log reduction in total P. acnes counts and significantly reduced the number of erythromycin-resistant strains by 6 weeks. Erythromycin alone, however, produced less than a 1.5 log reduction in total P. acnes counts and did not reduce the number of resistant strains after the same amount of time.18 Of concern, five patients in each group developed erythromycin-resistant strains de novo at 6 and 12 weeks. In an open study of 21 patients with erythromycin-resistant strains of P. acnes, the total count and number of resistant strains were reduced by greater than 2.5 logs after
6 weeks of treatment with the BP/E gel.18
The combination of benzoyl peroxide and antibiotics has also been shown to have superior efficacy to either product alone. In two double-blind randomized, parallel, vehicle-controlled trials, patients were treated nightly with a combination 5% benzoyl peroxide + 1% clindamycin gel (BP/C), benzoyl peroxide, clindamycin, or vehicle gel. The combination gel was significantly superior to the two individual agents in global improvement and reduction of inflammatory lesions.19
In a ten week study, the combination of BP/C was more efficacious than benzoyl peroxide alone and statistically comparable to the BP/E combination.20
Benzoyl peroxide can induce an irritant contact dermatitis that is related to the amount and type of product, its concentration, and its vehicle formulation. Reactivity may be more commonly seen in patients with atopic dermatitis. In combination with a topical antibiotic, BP produces less erythema than when used alone.21 The rates reported of true allergic contact dermatitis vary in the literature from 0.2% to 1%.21,22 Patch testing to benzoyl peroxide can be difficult to interpret because of its irritant properties.23
The carcinogenicity and photocarcinogenicity of benzoyl peroxide have been questioned for many years. An article reviewing two case-control epidemiological studies and 23 carcinogenicity studies in rodents concluded that there was no evidence to support an association between skin cancer in humans and the use of benzoyl peroxide.24 Current data suggests that benzoyl peroxide is considered safe in humans and does not accelerate photocarcinogenesis, though more data is needed.25
Benzoyl peroxide is assigned a Category C by the US FDA, and no studies on its use in pregnant women have been published. However, its metabolism and excretion would suggest that it should have no effect on the fetus.26
Other Treatment Considerations
Benzoyl peroxide bleaches clothing and hair, and thus, patients should be warned accordingly when the drug is prescribed. Practical suggestions for patient management may include limiting use on the chest and back to nighttime due to its bleaching effect on clothing, or recommending that the patient wear a white T-shirt under clothing for daytime application.
Benzoyl peroxide is one of the most commonly used and efficacious topical acne agents. It is equally effective against antibiotic-resistant and antibiotic-sensitive strains of
P. acnes. To avoid antibiotic resistance, the prolonged use of topical or oral antibiotic monotherapy for acne is strongly discouraged without concomitant treatment with benzoyl peroxide. For topical acne therapy benzoyl peroxide can be used as a combination formulation with an antibiotic, and for systemic antibiotic therapy it can be used daily as a wash or leave-on product.27 If found to be too irritating for daily use, even as a wash, a short course (5-7 days) of benzoyl peroxide used monthly may be effective in reducing resistant strains of
P. acnes. Limitations of benzoyl peroxide include an irritant contact dermatitis and, much less frequently, an allergic contact dermatitis.
- Merker PC. Benzoyl peroxide: a history of early research and researchers. Int J Dermatol 41(3):185-8 (2002 Mar).
- Fishman IM. Benzoyl peroxide in acne: reply. J Am Acad Dermatol 20(3):518 (1989 Mar).
- Pace WE. A benzoyl peroxide-sulfur cream for acne vulgaris. Can Med Assoc J 93:252-4 (1965 Aug 7).
- Yeung D, Nacht S, Bucks D, et al. Benzoyl peroxide: percutaneous penetration and metabolic disposition. II. Effect of concentration. J Am Acad Dermatol 9(6):920-4 (1983 Dec).
- Nacht S, Yeung D, Beasley JN, et al. Benzoyl peroxide: percutaneous penetration and metabolic disposition. J Am Acad Dermatol 4(1):31-7 (1981 Jan).
- Leyden JJ, McGinley KJ, Cavalieri S, et al. Propionibacterium acnes resistance to antibiotics in acne patients. J Am Acad Dermatol 8(1):41-5 (1983 Jan).
- Eady EA, Cove JH, Holland KT, et al. Erythromycin resistant propionibacteria in antibiotic treated acne patients: association with therapeutic failure. Br J Dermatol 121(1):51-7 (1989 Jul).
- Fulton JE Jr, Farzad-Bakshandeh A, Bradley S. Studies on the mechanism of action to topical benzoyl peroxide and vitamin A acid in acne vulgaris. J Cutan Pathol 1(5):191-200 (1974).
- 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 364(9452):2188-95 (2004 Dec 18-31).
- Burkhart CK. A re-examination of the function of benzoyl peroxide in acne. J Dermatol Allergy 5:23-6 (1982).
- Cunliffe WJ, Stainton C, Forster RA. Topical benzoyl peroxide increases the sebum excretion rate in patients with acne. Br J Dermatol 109(5):577-9 (1983 Nov).
- Bojar RA., Cunliffe WJ, Holland KT, et al. The short-term treatment of acne vulgaris with benzoyl peroxide: effects on the surface and follicular cutaneous microflora. Br J Dermatol 132(2):204-8 (1995 Feb).
- Leyden JJ, Wortzman M, Baldwin EK. Antibiotic-resistant Propionibacterium acnes suppressed by a benzoyl peroxide cleanser 6%. Cutis 82(6):417-21 (2008 Dec).
- Mills OH Jr, Kligman AM, Pochi P, et al. Comparing 2.5%, 5%, and 10% benzoyl peroxide on inflammatory acne vulgaris. Int J Dermatol 25(10):664-7 (1986 Dec).
- 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 72(4):187-90 (1979 Apr).
- Eady EA, Farmery MR, Ross JE, 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 131(3):331-6 (1994 Sep).
- 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 126(6):586-90 (1992 Jun).
- 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 134(1):107-13 (1996 Jan).
- 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 37(4):590-5 (1997 Oct).
- Leyden JJ, Hickman JG, Jarratt MT, et al. The efficacy and safety of a combination benzoyl peroxide/clindamycin topical gel compared with benzoyl peroxide alone and a benzoyl peroxide/erythromycin combination product. J Cutan Med Surg 5(1):37-42 (2001 Jan-Feb).
- Cunliffe WJ, Burke B. Benzoyl peroxide: lack of sensitization. Acta Derm Venereol 62(5):458-9 (1982).
- Fulton JE Jr, Bradley S. The choice of vitamin A acid, erythromycin, or benzoyl peroxide for the topical treatment of acne. Cutis 17(3):560-4 (1976 Mar).
- Ockenfels HM, Uter W, Lessmann H, et al. Patch testing with benzoyl peroxide: reaction profile and interpretation of positive patch test reactions. Contact Dermatitis 61(4):209-16 (2009 Oct).
- Kraus AL, Munro IC, Orr JC, et al. Benzoyl peroxide: an integrated human safety assessment for carcinogenicity. Regul Toxicol Pharmacol 21(1):87-107 (1995 Feb).
- Lerche CM, Philipsen PA, Poulsen T, et al. Photocarcinogenesis and toxicity of benzoyl peroxide in hairless mice after simulated solar radiation. Exp Dermatol 19(4):381-6 (2010 Apr).
- Rothman KF, Pochi PE. Use of oral and topical agents for acne in pregnancy. J Am Acad Dermatol 19(3):431-42 (1988 Sep).
- Del Rosso JQ. Benzoyl peroxide cleansers for the treatment of acne vulgaris: status report on available data. Cutis 82(5):336-42 (2008 Nov).