image of silk fabric and dry skin

Maha Dutil, MD, MEd, FRCPC

Division of Dermatology, University of Toronto, Toronto, ON, Canada
Women’s College Hospital, Toronto, ON, Canada

ABSTRACT
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.

Key Words:
acne vulgaris, antibacterial agents, antibiotic resistance, benzoyl peroxide, erythromycin, clindamycin, topical combination therapy

Background

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

Safety

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.

Conclusion

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.

References

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STL Volume 15 Number 10
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