Topical Antibacterial Treatments for Acne Vulgaris Comparative Review and Guide to Selection

Transcription

1 Am J Clin Dermatol 2004; 5 (2): THERAPY IN PRACTICE /04/ /$31.00/ Adis Data Information BV. All rights reserved. Topical Antibacterial Treatments for Acne Vulgaris Comparative Review and Guide to Selection Hiok-Hee Tan National Skin Centre, Singapore Contents Abstract Topical Antibacterials Mechanism of Actions Efficacy of Topical Antibacterial Agents Topical Antibacterials versus Benzoyl Peroxide Combination Therapy Erythromycin/Zinc Erythromycin/Tretinoin and Erythromycin/Isotretinoin Erythromycin/Benzoyl Peroxide Clindamycin/Benzoyl Peroxide Propionibacterium acnes Resistance Adverse Reactions of Topical Antibacterials Selection of Topical Antibacterial Agents Conclusion...82 Abstract Topical antibacterial agents are an essential part of the armamentarium for treating acne vulgaris. They are indicated for mild-to-moderate acne, and are a useful alternative for patients who cannot take systemic antibacterials. Topical antibacterials such as clindamycin, erythromycin, and tetracycline are bacteriostatic for Propionibacterium acnes, and have also been demonstrated to have anti-inflammatory activities through inhibition of lipase production by P. acnes, as well as inhibition of leukocyte chemotaxis. Benzoyl peroxide is a non-antibiotic antibacterial agent that is bactericidal against P. acnes and has the distinct advantage that thus far, no resistance has been detected against it. Combined agents such as erythromycin/zinc, erythromycin/tretinoin, erythromycin/isotretinoin, erythromycin/benzoyl peroxide, and clindamycin/benzoyl peroxide are increasingly being used and have been proven to be effective. They generally demonstrate good overall tolerability and are useful in reducing the development of antibacterial resistance in P. acnes. The selection of a topical antibacterial agent should be tailored for specific patients by choosing an agent that matches the patient s skin characteristics and acne type. Topical antibacterial agents should generally not be used for extended periods beyond 3 months, and topical antibacterials should ideally not be combined with systemic antibacterial therapy for acne; in particular, the use of topical and systemic antibacterials is to be avoided as far as possible. Acne vulgaris is a common disorder, affecting virtually every adolescent at some point in time. Many treatment options are available, both topical and systemic. Topical antibacterial agents are a very important component of the anti-acne armamentarium.

2 80 Tan 1. Topical Antibacterials used for acne. [5] However, they had to exclude 33 of these studies from the final analysis because of major deficiencies in study Mild inflammatory acne vulgaris can be treated with topical methods. They also commented that of the remaining trials, almost agents. Topical antibacterials are a currently widely accepted all contained defects either of overall trial design or of reporting. effective and well tolerated treatment for acne. Topical clindamy- The conclusion that they were able to draw was that topical cin and erythromycin are most frequently used. Tetracycline is erythromycin was effective against inflamed lesions in concentraalso available as a topical agent. These are available in a variety of tions of 1 4% with or without the addition of zinc. The reviewers vehicles. These antibacterials are available as liquid, gel, lotion, or compared 15 double-blind, placebo-controlled trials of topical ointment. erythromycin, which involved a total of 731 patients who were Benzoyl peroxide is a topical non-antibiotic antibacterial agent treated with five different erythromycin preparations ranging from that is also widely used in the treatment of acne. In view of the 1% w/v without zinc to 4% w/v with zinc (1.2% zinc acetate). synergistic effects when both benzoyl peroxide and antibacterials They used a variety of statistical tests and determined that signifare used, combination formulations are also becoming increasingicant p-values in favor of erythromycin (derived from total or ly used. inflamed lesion counts) were obtained in all 15 studies. It is 2. Mechanism of Actions obviously difficult to compare all these trials directly as different investigators used different criteria to determine response to treat- Topical antibacterial agents work on inflammatory acne lesions ment, whether it is in actual lesion count or grade of acne. The in several ways. Inflammation in acne can be a direct or indirect reviewers also looked at studies evaluating the effect of topical result of the proliferation of Propionibacterium acnes. It produces erythromycin on non-inflamed lesions, and noted that there were lipases that hydrolyze serum triglycerides to glycerol, which it fewer investigators who had attempted to evaluate this issue. The uses as a growth substrate, and free fatty acids, which have study of topical antibacterial efficacy on non-inflamed lesions is proinflammatory and comedogenic properties. [1] Neutrophils are also complicated by the fact that technically, the enumeration of also attracted to the follicular lumen as a result of chemotactic non-inflamed lesions is much more difficult. They were thus factors produced by the organism. [2] unable to conclude from the published evidence whether topical Topical antibacterials such as clindamycin, erythromycin, and erythromycin had significant activity against non-inflamed letetracycline are bacteriostatic for P. acnes, while benzoyl perox- sions. [5] ide, an oxidizing agent, is bactericidal for P. acnes. Reduction in The effectiveness of topical clindamycin against inflamed le- P. acnes counts therefore results in a reduction of both free fatty sions was also adequately demonstrated. [5] The reviewers found acid production as well as chemotactic factors that cause inflamonly seven evaluable placebo-controlled trials of topical clindamymation to occur. However, drugs such as erythromycin and tetracin. Three of these studies showed that topical clindamycin was cycline have been shown to inhibit lipase production by P. acnes superior in reducing numbers of inflamed lesions, but at one time in vitro, even at concentrations lower than the minimal inhibitory point only. The other four studies showed that topical clindamycin concentrations (MICs) for P. acnes. [3] Topical antibacterials also was consistently superior in reducing inflamed lesion count cominhibit leukocyte chemotaxis; in vivo suppression of neutrophil pared with placebo. There were only three studies that also evaluchemotaxis has been demonstrated with both systemically and ated the effects of topical clindamycin on non-inflamed lesions, topically administered tetracycline. [4] These suggest that topical and found that clindamycin was more effective than placebo antibacterials also exert a direct anti-inflammatory effect in acne, against open but not closed comedones. The reviewers were aside from reduction in the number of P. acnes. At present, it is not unable to determine that topical tetracyclines were superior to clearly evident as to which mechanism is the most important in placebo in their review because none of the nine identified topical terms of the anti-acne activity of these topical agents. tetracycline trials that they had identified were found to be suitable 3. Efficacy of Topical Antibacterial Agents for evaluation based on the reviewers primary criteria of selecting trials that used blinded evaluation, with placebo controls and Many clinical trials have been published on the efficacy of appropriate statistical analysis. There was a study which found that topical antibacterial agents. These include studies comparing topi- topical tetracycline for 1 year failed to reduce the number of cal antibacterials to benzoyl peroxide, and comparative studies comedones or cysts. [6] None of the topical antibacterials used were between different topical antibacterials. In a major review of these shown to be more effective than benzoyl peroxide against instudies in 1990, Eady et al. reviewed a total of 71 papers published flamed lesions. In a later review of the use of topical antibacterials from 1966 to 1989 reporting the efficacy of topical antibacterials in acne, Toyoda and Morohashi commented that there were con-

3 Topical Antibacterial Treatments for Acne Vulgaris 81 siderable variations in patient profile, evaluation of efficacy, con- components. [13] Combined application of the two active ingredicentrations and formulations of the antibacterials, and data analy- ents was demonstrated to be effective and well tolerated, and ses employed. [7] All these confounding factors made interpretation superior product results than if either agent were used alone for the of data difficult. However, after taking these problems into ac- treatment of moderate inflammatory acne. The role of tretinoin is count, they were able to conclude that topical antibacterials were to correct the abnormal desquamation of the follicular epithelium, more effective for inflammatory acne than for noninflammatory which therefore results in comedolytic activity and subsequently acne, with clinical improvement in inflamed lesions ranging from inhibits the formation of new non-inflamed lesions. Tretinoin 70.6 to 100% with agents such as tetracycline, meclocycline, enhances the penetration of erythromycin when the two are used in erythromycin, and clindamycin. [7] combination, and therefore enhances the efficacy of the topical antibacterial. [14] The formulation is often prepared as a topical 4. Topical Antibacterials versus Benzoyl Peroxide alcohol-based solution, containing 4% erythromycin and 0.025% Toyoda and Morohashi reviewed 11 double-blind clinical trials tretinoin. High efficacy and tolerability has been demonstrated of topical antibacterials compared with 5% benzoyl peroxide, and with topical erythromycin/tretinoin preparation for the treatment none of these studies showed that topical antibacterials were more of acne vulgaris. [15] effective than benzoyl peroxide against inflamed lesions. [7] Some Another commercially available preparation in a gel formulastudies have shown benzoyl peroxide to be significantly more tion is 4% w/w erythromycin combined with 0.1% w/w isotreti- effective in reducing comedones than topical erythromycin [8] or noin. This preparation is used once daily, and does not require clindamycin. [9] These different studies used several means to mixing or storage in a refrigerator. It has been shown to have assess efficacy, such as lesion count and acne grade. However, comparable efficacy with erythromycin/benzoyl peroxide given many of these studies are not directly comparable. The main twice daily in the treatment of mild-to-moderate acne vulgaris. [16] advantages of benzoyl peroxide over topical antibacterials are the lower cost, and the fact that to date, there has been no resistance of 4.4 Erythromycin/Benzoyl Peroxide P. acnes to benzoyl peroxide detected. Erythromycin/benzoyl peroxide combination gel consists of 4.1 Combination Therapy 3% w/w erythromycin and 5% w/w benzoyl peroxide. According to the manufacturer s instructions, this preparation has to be stored Topical antibacterials have been studied in combination with in the refrigerator upon reconstitution, and is stable for up to 3 other agents, such as zinc, benzoyl peroxide, and tretinoin. months from the initial preparation. [17] It has been demonstrated to be effective in the treatment of mild-to-moderate acne vulgaris. [16] 4.2 Erythromycin/Zinc This combination has been shown to impact on the antioxidant A randomized, double-blind comparative study showed that a defense enzymes in patients with inflammatory acne. Levels of combination of erythromycin and zinc was superior to topical superoxide dismutase, glutathione peroxidase, and catalase in erythromycin alone in reducing acne severity grade, comedones, leukocytes were found to be deceased in patients treated with papules, pustules, and total number of inflamed lesions. [10] The erythromycin/benzoyl peroxide combination versus benzoyl per- mechanism by which zinc exerts its effects against acne has not oxide alone. [18] Data also suggest that this combination has greater been fully elucidated. Zinc salts do exert an anti-inflammatory in vivo anti-propionibacterial activity than 3% w/w erythromycin effect by inhibition of chemotaxis in acne patients, [11] as well as alone, and brings about significant clinical improvement in acne modulation of inflammatory cytokines such as tumor necrosis patients with high numbers of erythromycin-resistant P. acnes factor-α and increase activity of superoxide dismutase. [11] It has strains pretreatment. [19] been suggested that the erythromycin/zinc combination exerts some direct bactericidal effect, as evidenced by a decrease in P. 4.5 Clindamycin/Benzoyl Peroxide acnes counts when the combination is used compared with vehicle Benzoyl peroxide formulations have been shown to suppress only. [12] This bactericidal effect was also accompanied by a signifthe follicular population of P. acnes more rapidly and to a greater icant reduction in free fatty acid of the skin surface. [12] degree than clindamycin. [20] Using a clindamycin/benzoyl peroxide 4.3 Erythromycin/Tretinoin and Erythromycin/Isotretinoin gel results in clinical efficacy in the treatment of acne vulgaris through both antibacterial and anti-inflammatory means. [21] There Mills and Kligman were the first to describe the combined have been several clinical trials demonstrating that twice-daily effect of erythromycin/tretinoin compared with the individual application of 1% clindamycin/5% benzoyl peroxide gel for 10 16

4 82 Tan weeks was more effective than 5% benzoyl peroxide, 1% clinda- 6. Adverse Reactions of Topical Antibacterials mycin, or vehicle in patients with mild-to-moderate acne. [21] In trials, physician-rated mean global improvement scores, as well as Generally, adverse effects with topical antibacterial agents are patient-rated scores, were significantly greater in the clindamycin/ mostly minor. The most likely adverse effects would include skin benzoyl peroxide group than in the benzoyl peroxide, clindamyand irritation, itching, dryness, erythema, and peeling. Both irritant cin, or vehicle groups. [21] This combination demonstrates good allergic contact dermatitis can occur. overall tolerability and may be useful in treating patients with acne The safety of topical antibacterial agents in pregnancy has not caused by resistant strains of P. acnes. been fully evaluated, but they have thus far not been implicated as teratogens. [27] Topical erythromycin is useful for the treatment of 5. Propionibacterium acnes Resistance acne in pregnant women. Any combination preparation containing retinoids should be avoided in pregnancy. Pseudomembranous colitis, as a result of systemic absorption, Propionibacteria resistant to erythromycin and clindamycin has been reported with the use of topical clindamycin. [28] were first detected in the late 1970s in the US in comedones extracted from acne patients following topical therapy with either drug. [22] The likelihood of overgrowth of resistant P. acnes increases 7. Selection of Topical Antibacterial Agents with duration of therapy. The use of topical antibacterials The choice of a particular antibacterial agent in the treatment of is of particular concern in this respect. An antibacterial once acne should be tailored for specific patients by selecting agents applied actually creates a situation where antibacterial concentra- that match the patient s skin characteristics as well as acne type. A tion progressively declines towards the periphery, from the most summary of currently used antibacterials in the treatment of acne concentrated portion in the center (personal observation). There is, vulgaris is given in table I. therefore, an opportunity for potential development of resistance Topical antibacterial agents should be used in mild-to-moderate as the antibiotic concentration declines. Erythromycin is the most acne. Patients with more severe forms of acne would usually common antibiotic to which P. acnes are resistant. Concerns require systemic therapy, which can be combined with topical regarding this center on the fact that resistance is increasing, and treatment. However, combined use of both oral and topical antithe degree of resistance reaches very high levels. The MICs of bacterials should be discouraged. these strains range from 512 to 2048 µg/ml. This is between Patients with oilier complexions will benefit more from gels or and fold higher than the MIC for sensitive strains. [23] lotions that contain more alcohol and are therefore more drying. Another major concern is that the majority of erythromycin- Patients with dry skin would probably prefer creams or ointments resistant strains also demonstrate some degree of cross-resistance that contain a moisturizing vehicle. Generally, prolonged use of to clindamycin. [24] According to their cross-resistance patterns to a topical antibacterials (more than 3 months) should be avoided, to panel of macrolide-lincosamide-streptogramin type B (MLS) anti- prevent emergence of bacterial resistance in P. acnes. [30] When bacterials, P. acnes strains resistant to erythromycin can be divid- possible, non-antibiotic antibacterials should be the first-line ed into one of the four phenotypic classes. [25] The majority of agents. Topical antibacterials are a useful alternative for patients isolates have a constitutive resistance to erythromycin, clindamy- who cannot or refuse to take oral antibacterials, and combination cin and to all other MLS antibacterials. This implies that the use of preparations or intermittent use of benzoyl peroxide together with topical clindamycin may also encourage resistance to erythro- these agents may reduce the problem of resistance. Issues of costs mycin. The importance is not only that therapeutic failures occur and convenience of use should also be discussed with the patient. in acne, but also that antibiotic resistance can be transmitted to other organisms, notably Staphylococcus. Combination therapy with benzoyl peroxide and topical erythromycin seems not to 8. Conclusion promote resistant strains, and therefore, this may be a valuable Topical antibacterial agents are useful in the treatment of mildalternative in patients who develop resistant strains but need to to-moderate acne. Single agent antibacterials work better for inremain on topical treatment. [26] It has also been suggested that flammatory acne than noninflammatory acne. The most commonintermittent use of benzoyl peroxide, rather than continuous use in ly used agents are benzoyl peroxide, which is a non-antibiotic combination with an antibacterial, may also be useful in removing antibacterial, and erythromycin and clindamycin. Combination antibiotic-resistant strains of P. acnes. The duration of use of formulations are more recently available and are effective and well topical antibacterials should probably be restricted to about 3 tolerated, but cost more. While these agents are a useful part of the months to reduce the emergence of antibacterial-resistant strains. anti-acne armamentarium, attention must be focused on issues

5 Topical Antibacterial Treatments for Acne Vulgaris 83 Table I. Commonly used topical antibacterial agents in the treatment of acne vulgaris Antibacterial agent Benzoyl peroxide Clindamycin Erythromycin Tetracycline Erythromycin/zinc combination Erythromycin/retinoid combination Erythromycin/benzoyl peroxide combination Clindamycin/benzoyl peroxide combination Comments Non-antibiotic antibacterial Wide variety of formulations cream, gel, or lotion Available as 2.5%, 4%, 5%, and 10% preparations No Propionibacterium acnes resistance detected to this agent May cause discoloration to clothes Available over the counter Can be used once or twice daily Available as 1% gel, lotion and solution Can be used once or twice daily Cross-resistance to erythromycin in antibacterial resistant P. acnes Rare cases of pseudomembranous colitis and systemic absorption from topical use have been reported [28] Available as 2% or 4% preparations Most common antibacterial to which P. acnes develops resistance Cross-resistance to clindamycin common Most antibacterial resistance to erythromycin in P. acnes is high level May be useful in treatment of acne in pregnancy Less commonly used Available in some countries as a powder which is reconstituted into a solution, and as an ointment Should not be used in pregnancy and in children who have not developed permanent teeth [29] Available as a solution after reconstitution Erythromycin 40mg, zinc acetate 12 mg/ml after reconstitution with solvent containing ethanol Used once or twice daily 4% w/w erythromycin/0.025% w/w tretinoin solution 2% w/w erythromycin/0.05% w/w isotretinoin gel 4% w/w erythromycin/0.1% w/w isotretinoin gel Used at night, avoid sun exposure Avoid in pregnancy 3% w/w erythromycin/5% w/w benzoyl peroxide gel Needs reconstitution and refrigeration Useful for topical treatment of patients with antibacterial-resistant P. acnes Once or twice daily application Has been evaluated as a combination gel containing 1% w/w clindamycin and 5% w/w benzoyl peroxide Useful for topical treatment of patients with antibacterial-resistant P. acnes such as emergence of antibacterial resistance and cost effective- Acknowledgments ness. Generally, prolonged treatment (more than 3 months) with The authors have provided no information on sources of funding or on topical antibacterials should be avoided, and a combination of both conflicts of interest directly relevant to the content of this review. topical and systemic antibacterials for the treatment of acne is discouraged. If a patient has previously responded well to a particular topical agent, that agent should be reused if the acne References 1. Shalita AR, Lee WL. Inflammatory acne. Dermatol Clin 1983; 1: relapses. Non-antibiotic antibacterial agents can be combined with 2. Puhvel SM, Sakamato M. The chemoattractant properties of comedonal compontopical antibacterials to reduce the possibility of resistance. ents. J Invest Dermatol 1978; 71: 324-9

6 84 Tan 3. Webster GF, McGinley KJ, Leyden JJ. Inhibition of lipase production in propion- 18. Basak PY, Gultekin F, Kiline I, et al. The effect of benzoyl peroxide and benzoyl ibacterium acnes by sub-minimal-inhibitory concentrations of tetracycline and peroxide/erythromycin combination on the antioxidative defence system in erythromycin. Br J Dermatol 1981; 104: papulopustular acne. Eur J Dermatol 2002; 12 (1): Elewski BE, Sam M, Gammon WR. In vivo suppression of neutrophil chemotaxis 19. Eady EA, Bojar RA, Jones CE, et al. The effects of acne treatment with a by systemically and topically administered tetracycline. J Am Acad Dermatol combination of benzoyl peroxide and erythromycin on skin carriage of erythro- 1983; 8: mycin-resistant propionibacteria. Br J Dermatol 1996; 134: Eady EA, Cove JH, Joanes DN, et al. Topical antibiotics for the treatment of acne 20. Gans EH, Kligman AM. Comparative efficacy of clindamycin and benzoyl peroxvulgaris: a critical evaluation of literature on their clinical benefit and compara- ide for in vivo suppression of propionibacterium acnes. J Dermatolog Treat tive efficacy. J Dermatolog Treat 1990; 1: ; 13: Wechsler HL, Kirk J, Slone J. Acne treated with a topical tetracycline preparation: 21. Warner GT, Plosker GL. Clindamycin/benzoyl peroxide gel: a review of its use in results of a one-year multi-group study. Int J Dermatol 1978; 17: the management of acne. Am J Clin Dermatol 2002; 3 (5): Toyoda M, Morohashi M. An overview of topical antibiotics for acne treatment. 22. Crawford WW, Crawford IP, Stoughton RB, et al. Laboratory induction and Dermatology 1998; 196: clinical occurrence of combined clindamycin and erythromycin resistance in 8. Burke B, Eady EA, Cunliffe WJ. Benzoyl peroxide versus topical erythromycin in corynebacterium acnes. J Invest Dermatol 1979; 72: the treatment of acne vulgaris. Br J Dermatol 1983; 108: Bojar RA, Eady EA, Jones CE, et al. Inhibition of erythromycin resistant 9. Swinyer LJ, Baker MD, Swinyer TA, et al. A comparative study of benzoyl propionibacteria on the skin of acne patients by topical erythromycin with and peroxide and clindamycin phosphate for treating acne vulgaris. Br J Dermatol without zinc. Br J Dermatol 1994; 130 (3): ; 119: Eady EA, Cove JH, Holland KT, et al. Erythromycin resistant propionibacteria in 10. Habbema L, Koopmans B, Menke HE, et al. A 4% erythromycin and zinc antibiotic treated patients: association with therapeutic failures. Br J Dermatol combination (Zineryt) versus 2% erythromycin (Eryderm) in acne vulgaris: a 1989; 121: 51-7 randomized, double-blind comparative study. Br J Dermatol 1989; 121: Eady EA, Ross JI, Cove JH. Macrolide-lincosamide-streptogramin B (MLS) resistance in cutaneous propionibacteria: definition of phenotypes. J An- 11. Dreno B, Trossaert M, Boiteau HL, et al. Zinc salts effects on granulocyte zinc timicrob Chemother 1989; 23: concentration and chemotaxis in acne patients. Acta Derm Venereol 1992; 72 (4): Eady EA, Farmery MR, Ross JI, et al. Effects of erythromycin and benzoyl peroxide alone and in combination against antibiotic-sensitive and resistant skin 12. Strauss JS, Stranieri AM. Acne treatment with topical erythromycin and zinc: bacteria from acne patients. Br J Dermatol 1994; 131: effect on Propionibacterium acnes and free fatty acid composition. J Am Acad Dermatol 1984; 11: Rothman KF, Pochi PE. Use of oral and topical agents for acne in pregnancy. J Am 13. Mills OH, Kligman AM. Treatment of acne vulgaris with topically applied erythro- Acad Dermatol 1988; 19: mycin and tretinoin. Acta Derm Venereol (Stockh) 1978; 58: Parry MF, Rha CK. Pseudomembranous colitis caused by topical clindamycin 14. Brisaert M, Gabriels M, Plaizier-Vercammen J. Investigation of the chemical phosphate. Arch Dermatol 1986; 122: stability of an erythromycin-tretinoin lotion by the use of an optimization 29. Tan HH. Antibacterial therapy for acne: a guide to selection and use of systemic system. Int J Pharm 2000; 197: agents. Am J Clin Dermatol 2003; 4 (5): Korting HC, Braun-Falco O. Efficacy and tolerability of combined topical treat- 30. Gollnick H, Cunliffe W, Berson D, et al. Management of acne: a report from a ment of acne vulgaris with tretinoin and erythromycin in general practice. Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol 2003 Jul; Drugs Exp Clin Res 1989; 15: (1 Suppl.): S1-S Marazzi P, Boorman GC, Donald AE, et al. Clinical evaluation of double strength Isotrexin versus Benzamycin in the topical treatment of mild to moderate acne vulgaris. J Dermatolog Treat 2002; 13: Correspondence and offprints: Dr Hiok-Hee Tan, National Skin Centre, Dermik Laboratories. Prescribing information as of December 2002 (a): Mandalay Road, , Singapore. Benzamycin topical gel. Berwyn (PA): Aventis Pharmaceuticals, [email protected]