Acne Vulgaris Therapy – Topical antibiotics

INTRODUCTION

Topical antibiotics have been an integral component of the topical armamenta-rium for the treatment of acne vulgaris for approximately four decades and remain commonly prescribed by dermatologists in clinical practice (1,2). Over time, the most common topical antibiotics used for acne treatment have been erythromycin and clindamycin, with the latter being favored over the past several years, primarily due to widespread emergence globally of Propionibacterium acnes strains resistant to erythromycin (3 7). Although clindamycin-resistant P. acnes are also relatively prevalent due to its common use, the clinical efficacy of topical clindamycin in the treatment of acne vulgaris has sustained over several years of usage as compared with topical erythromycin on the basis of review of data from several studies (4 7).

In addition to topical erythromycin and clindamycin, sulfacetamide with or without sulfur has also been used topically for treatment of acne vulgaris; however, data on mechanism and efficacy for this indication are very limited (8). Azelaic acid has also been used for treatment of acne and is discussed later in this post (1).

RATIONALE FOR USE OF TOPICAL ANTIBIOTICS IN ACNE THERAPY

Data on the pharmacologic and antibiotic properties of topical antibiotics related to treatment of acne vulgaris have been evaluated predominantly with eryth-romycin and clindamycin. The principal mechanism of action of these topical antibiotics appears to be through reduction in P. acnes organisms, which reduces the subsequent triggering of inflammatory activities and pathways believed to relate to acne lesion pathogenesis (1 3,6 8). The use of benzoyl peroxide in combination with erythromycin or clindamycin augments reduction in P. acnes, reduces the emergence of resistant P. acnes strains, and may improve efficacy over use of either agent alone (1,2,6). Although a variety of anti-inflammatory properties have been reported with both erythromycin and clindamycin, the relevance of these effects to acne treatment is not definitively known (9).

TOPICAL ANTIBIOTIC USE IN ACNE AND CHANGES IN CUTANEOUS FLORA

Concerns regarding emergence of clinically significant antibiotic-resistant bac-teria primarily focus on systemic antibiotic use. Importantly, topical antibiotic use can also change the cutaneous flora (6,7,10 16).

As application of topical antibiotics for treatment of acne is usually con-tinued over several months to years, the issues of alteration of cutaneous flora, antibiotic selection pressure, and increase in antibiotic resistance are clinically relevant. In fact, changes in cutaneous flora have been reported with both topical and oral antibiotic use (6,17 23). Antibiotics commonly used for the treatment of acne vulgaris have been correlated with the progressive emergence of normal bacterial flora that are less antibiotic sensitive. These include macrolide-resistant Staphylococcus epidermidis and erythromycin- and tetracycline-resistant P. acnes strains, the latter increasing by an estimated prevalence of 40% globally over approximately three decades (6,17 25). Additionally, antibiotic-resistant P. acnes strains have been demonstrated on skin of untreated contacts of acne patients treated with topical antibiotic therapy, supporting interpersonal spread (20). In another study, facial application of topical erythromycin over three months has been shown to affect the bacterial flora of both treated and untreated skin (22). This study confirmed an increase in coagulase-negative staphylococci on treated facial skin, and also at untreated sites such as the back and nares (22).

The clinically relevant effects of the aforementioned changes in normal bacterial flora secondary to antibiotic use are not entirely clear. However, there is evidence for a correlation between antibiotic-resistant P. acnes and a reduction in efficacy with antibiotic therapy (10 12,17,24 27).

COMPARISON OF TOPICAL ANTIBIOTICS IN THE TREATMENT OF ACNE

Erythromycin, a macrolide antibiotic, and clindamycin, a lincosamide antibiotic, have been widely used for the treatment of acne for approximately four decades and represent the vast majority of topical antibiotic prescriptions written by dermatologists for acne. Since 2003, prescribing data indicate that clindamycin is the predominant topical antibiotic used by dermatologists to treat acne in clinical practice, with approximately half of prescriptions written for benzoyl peroxide clindamycin combination formulations (6,17).

An important concern related to use of topical antibiotics, especially with chronic administration for acne, is the emergence of antibiotic-resistant bacterial strains. Potential issues of concern that have been raised in the literature include increased prevalence of P. acnes strains less responsive to antibiotics, alterations in cutaneous flora, decreased therapeutic responsiveness to antibiotic therapy, and promotion of other clinical infections among treated patients and/or their close contacts (6,17,18,21 24,26,27). Although in vitro antibiotic cross-resistance between erythromycin and clindamycin has been reported, a differ-ence in clinical efficacy between these two agents used for acne has been noted over time (5). A report analyzing several monotherapy studies using either topical erythromycin or topical clindamycin for acne vulgaris demonstrated that the efficacy of topical erythromycin in reducing acne lesions has markedly decreased over time; however, the efficacy of topical clindamycin has not diminished on the basis of the same parameters of acne lesion reduction (5). Subsequent studies not analyzed in this report, inclusive of approximately 2000 subjects treated with topical clindamycin in the monotherapy study groups, have demonstrated consistent reduction of inflammatory acne lesions ranging from 45% to 49% and noninflammatory acne lesions ranging from 30% to 41% (4,28 31). Overall, these results support the sustained efficacy of topical clin-damycin for acne, at least on the basis of clinical trials. Factors that may explain the efficacy differences between topical clindamycin and topical erythromycin observed over time may include inherent differences in pharmacologic proper-ties, nonantibiotic activities such as possible anti-inflammatory effects, tissue concentrations achieved by topical administration, which may overcome in vitro resistance, and differences in antibiotic resistance genes. Available data, including well-designed studies or analyses, comparing topical erythromycin and/or clindamycin with other topical antibiotics used to treat acne vulgaris are limited.

ECOLOGIC MISCHIEF AND TOPICAL ANTIBIOTIC USE FOR ACNE

Chronic facial application of antibiotics used to treat acne does alter cutaneous and anterior nasal flora (6,15,17). Topical erythromycin or clindamycin appli-cation does promote emergence of less sensitive strains of P. acnes, with con-comitant use of benzoyl peroxide reducing both the emergence of less sensitive P. acnes strains and the proliferation of preexistent antibiotic-resistant strains (17,23,32).

Pharyngeal colonization with Streptococcus pyogenes has been associated with chronic use of antibiotics for acne, including topical agents. A cross‑sectional study evaluated 39 subjects with acne treated chronically with oral and/ or topical antibiotics versus 63 control subjects not treated with antibiotic therapy (18). The results demonstrated that 33% of antibiotic-treated subjects exhibited S. pyogenes on oropharyngeal culture, as compared with 10% in the control group (18). Importantly, 85% of S. pyogenes cultures obtained from antibiotic-treated subjects demonstrated resistance to at least one tetracycline antibiotic as compared with 20% in control subjects. In this same study, 10 subjects used only topical therapy without an oral antibiotic for acne. Four of these 10 subjects who were treated only with a topical antibiotic exhibited a positive oropharyngeal culture for S. pyogenes, with resistance to at least one tetracycline antibiotic observed in 3 of the 4 subjects. Despite the small study size, these results raise questions regarding the potential clinical significance of oropharyngeal carriage of pathogenic streptococci related to antibiotic use for acne, including topical agents.

In an additional study using retrospective cohort analysis of a large patient database, potential clinical implications of chronic oral and/or topical antibiotic therapy for acne vulgaris were analyzed (26). The topical antibiotics included in the evaluation were erythromycin and clindamycin. Antibiotic therapy needed to be used for a duration of at least six weeks. Among the antibiotic-treated group, 6.1% used topical therapy only and 92.6% used a combination of oral and topical agents. The United Kingdom General Practice Research Database was used, identifying 118,496 patients with a diagnosis of acne vulgaris between the ages of 15 and 35 years. Among this acne patient group, 71.7% (n = 84,977) received an oral and/or topical antibiotic, with 28.3% (n = 33,519) not receiving antibiotic therapy. It was shown within the first observation year on the basis of chart review that the odds of an antibiotic-treated patient developing an upper respi-ratory tract infection (URTI) was 2.15 times greater than patients not treated with antibiotic therapy. Individually, the odds ratios were 2.37, 1.88, and 2.75 for topical therapy only, combined use of topical and oral agents, and oral antibiotic therapy only, respectively. Identified limitations of this analysis include retro-spective evaluation based on diagnosis coding, lack of exclusion of other anti-biotics for disorders other than acne vulgaris, dependence on diagnosis codes only for documentation of URTI, and failure to differentiate the etiology of URTI. Despite the questions raised by this report, further study is needed to determine clinical relevance.

INTEGRATION OF TOPICAL ANTIBIOTICS IN ACNE TREATMENT

Topical antibiotics have long been an integral component of the combination therapy approach to acne therapy, including use with benzoyl peroxide and/or a topical retinoid (1 6,17,28 34). Importantly, topical antibiotics are best combined with benzoyl peroxide to optimize acne lesion reduction and reduce emergence of antibiotic-resistant P. acnes strains (7,17,23,32 35). Benzoyl peroxide may be used concurrently as either a “leave-on” formulation or a wash/cleanser (35,36). Data supporting the therapeutic benefits of the combination use of benzoyl per-oxide with antibiotics are based on studies using specific brand vehicle for-mulations, including both leave-on and wash/cleanser products (37,38). As vehicle formulation can influence several factors such as percutaneous drug penetration and tolerability, results from a given study cannot be automatically assumed to apply to unstudied formulations, including generic products.

OTHER TOPICAL ANTIBIOTICS AND ACNE TREATMENT

As mentioned above, despite availability for several years, data on the use of topical sodium sulfacetamide, with or without sulfur, for the treatment of acne vulgaris are limited. One study (n = 60) demonstrated a marked decrease in total acne lesion count, primarily a reduction in inflammatory lesions, in women with acne vulgaris treated with sulfacetamide 10% and sulfur 5% lotion for 12 weeks (8).

Azelaic acid has been shown to exhibit antibiotic properties and has been used for the treatment of acne vulgaris, primarily as a 20% cream formulation (1,34). The use of the 15% gel formulation for acne treatment has also been studied with reductions in acne lesions reported to be comparable to benzoyl peroxide or topical clindamycin (39). Overall, the position of azelaic acid in the treatment algorithm of acne vulgaris has been as an alternative to other topical agents (1,34). Initial improvement in acne with topical azelaic acid has been reported to be observed in 4 to 8 weeks, with maximum benefit generally noted after approximately 16 weeks of use (40 42). Symptoms of tingling, stinging, or burning have been reported to occur in 10% to 20% of patients treated with azelaic acid, usually within the first one to two weeks, with most cases noted as transient and without necessitation of discontinuation of therapy (40 42).

Topical metronidazole is well established as a therapeutic option for papulopustular rosacea. A study evaluating the use of topical metronidazole 0.75% gel for the treatment of acne vulgaris did not demonstrate therapeutic benefit (43).

SAFETY CONSIDERATIONS WITH TOPICAL ANTIBIOTICS USE FOR ACNE

Overall, the safety profile related to the use of topical antibiotics for treatment of acne vulgaris has been very favorable (1 4,8,17,28 31,34,39 42). The majority of adverse events reported in association with topical antibiotic use for acne have been signs and/or symptoms of cutaneous intolerability at sites of application, such as erythema, scaling, stinging, burning, and/or pruritus in some patients; true allergy to the conventional topical antibiotics used to treat acne vulgaris are rare (44). The frequency and intensity of local cutaneous side effects have been relatively infrequent overall and are often dependent on the vehicle formulation.

Importantly, there has been a conspicuous absence of significant systemic safety signals associated with topical antibiotic use for acne, especially con-sidering the plethora of clinical trials and the extensive clinical use worldwide over several years (44). A warning regarding possible association of topical clindamycin use and development of pseudomembranous colitis has been noted on the basis of a few older case reports, with only one involving proprietary formulations (44 46). Considering the availability of this agent for approxi-mately four decades and its widespread use over long durations of time, the risk of association with pseudomembranous colitis appears to be very small (44). Although the actual risk is unclear, it is prudent to avoid topical application of a formulation containing sulfacetamide in patients with a true sulfonamide allergy (47).

With regard to the safety of topical antibiotics during pregnancy, it is very difficult to make definitive statements as recommendations are determined indirectly on the basis of clinical observation, results from animal studies, lim-ited data in humans from clinical trials, sporadic reports from community experience, and information collected from pregnancy exposure databases. Overall, the topical use of erythromycin, clindamycin, sulfacetamide, and azelaic acid appears to be safe; there are no formal contraindications during pregnancy mandated with these agents; teratogenicity does not appear to be associated with their use; and topical erythromycin is generally considered safe in a pregnant female patient (48). However, absolute safety of topical antibiotic use during pregnancy cannot be definitively stated, especially as application is typically for a prolonged duration. Because of the risk of kernicterus potentially associated with sulfonamide exposure in pregnancy, especially during the third trimester, it appears prudent to avoid application of a formulation containing sodium sulfa-cetamide in a pregnant female patient. It is important for clinicians to recognize that despite apparent and anticipated safety during pregnancy based on published general guidelines and Pregnancy Category listings (classified as B or C depending on the topical agent), some product monographs of topical antibiotics contain pregnancy “disclaimers” stated by the manufacturer (48). Such dis-claimers typically imply that data may be too limited to assess safety in preg-nancy and/or that the true risk is unknown.

The potential concerns related to emergence of antibiotic-resistant bacterial strains or changes in microbial flora have been discussed above. Although these concerns are valid and of likely clinical relevance, their true clinical significance remains somewhat controversial. Additional study and dedicated sur-veillance are definitely warranted in this very important area related to antibiotic use for acne.

CONCLUSION

Topical antibiotics remain an important part of acne treatment and are recom-mended as a component of combination topical therapy; monotherapy with a topical antibiotic for acne is not recommended (1,7,17,34). At present, topical clindamycin remains the predominant topical antibiotic used for acne treatment; however, other agents such as erythromycin, sulfacetamide with or without sulfur, and azelaic acid are also options (1,6,7,17,34). Importantly, data suggest that the efficacy of topical erythromycin in acne has diminished over time since its inception (5). Concerns regarding development of antibiotic resistance and changes in cutaneous flora associated with topical antibiotic use, especially chronic application, may be clinically relevant and warrant additional study. Overall, the tolerability and safety profiles of topical antibiotics discussed in this post are very favorable.

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Jean-Paul Marat

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