Can topical ketoconazole tip the scales for acne vulgaris?
By Warren R. Heymann, MD
Oct. 21, 2020
Vol. 2, No. 42
“Now trending.” How often have you seen that phrase when you go online? When it comes to trends in treating acne vulgaris (AV), despite the new addition of oral sarecycline and the release of topical minocycline foam, there is an impetus to move away from prolonged antibiotic therapy for managing acne. It has recently been suggested that spironolactone might have superior drug usage survival compared to oral antibiotics for the treatment of female patients with acne. (1)
AV is a cutaneous chronic inflammatory disorder with complex pathogenesis. Four key factors have roles in acne pathogenesis: hyperseborrhea and dysseborrhea, altered keratinization of the pilosebaceous duct, Cutibacterium acnes (C. acnes, formerly Proprionibacterium acnes, P. acnes) and inflammation. The main hormones responsible for the development of acne vulgaris include androgens, insulin, and insulin-like growth factor-1. (2) Available AV treatment modalities include:
Topical medications: antibacterial (benzoyl peroxide, clindamycin, erythromycin), retinoids (tretinoin, adapalene, tazarotene), others (dapsone, azelaic acid);
Oral agents: antibiotics (tetracyclines, macrolides, sulfamethoxazole trimethoprim), hormonal therapy (oral contraceptives, spironolactone);
Procedural therapies (comedone extraction, chemical peels) (3); and
Novel treatments (laser, photodynamic therapy).
Focusing on hormonal therapy, Zaenglein asserts: “Combined oral contraceptive therapy and spironolactone are effective hormonal therapies for inflammatory acne in female patients and may be considered in patients who do not have a response to topical therapies alone.” (4)
Spironolactone is well-tolerated, especially at lower doses. The most common adverse effects include menstrual irregularities (which is diminished with concomitant oral contraceptives), breast tenderness, breast enlargement, fatigue, dizziness, and headache. In young, healthy women, it is no longer necessary to monitor potassium levels. (3)
Could a topical anti-androgen be effective in treating AV? Dermatologists have been using topical ketoconazole for years treating seborrheic dermatitis, psoriasis, and dermatophytosis. Ketoconazole inhibits the biosynthesis of fungal ergosterol and is capable of selectively inhibiting 17,20-desmolase and 17-alpha-hydroxylase at a dose of 400-600 mg/day. Ketoconazole can also inhibit the growth of P. acnes and decrease P. acnes lipase activity in a dose-dependent manner. Although oral ketoconazole has been reported to improve AV (5), because of hepatotoxicity and potential QT prolongation, the drug should not be utilized for this purpose.
Chaottawornsak et al evaluated the efficacy and safety of ketoconazole cream in mild adult female acne (AFA) by conducting a randomized, double-blind, placebo-controlled trial using ketoconazole 2% and placebo cream twice daily for 10 weeks. They assessed the improvement of clinical severity, measured by AFA score graded by investigators and participants, and the change of acne count. Forty-one participants enrolled in the study. The proportion of participants with acne improvement from baseline (42.9% vs 9.5%, P = 0.015) and the success rate (45.0% vs 14.3%, P = 0.043) in the ketoconazole group were significantly higher than that of the placebo group. The most common adverse events were dryness and itching. The percentage change of acne count decreased significantly compared with baseline but did not differ statistically between the two groups. Limitations of this study were its short duration in subjects with only mild AV. The authors concluded that ketoconazole monotherapy showed a plausible effect in improving AFA with an excellent safety profile. They suggested that ketoconazole be considered a viable therapeutic option for patients with AFA treatment. (6)
Oral spironolactone is only prescribed for women with acne and the topical ketoconazole study was only performed in women. Currently, no prescription topical antiandrogen is available for AV. Clascoterone cream (CB-03-01, Cortexolone 17α propionate), a novel topical androgen receptor inhibitor is currently under investigation for AV. (7) I have never hesitated prescribing topical ketoconazole for men with seborrheic dermatitis; I see no need to withhold this treatment if it proves to be efficacious for acne in men or women. More studies are warranted for determining if topical ketoconazole is beneficial in men or women with moderate to severe AV. How ironic it would be if a good option for treating acne has been in front of our noses for years (while using it on the sides of the nose)!
Point to Remember: While data are preliminary, topical ketoconazole cream may prove to be a valuable topical agent for acne vulgaris based on its inhibition of C. acnes lipase and anti-androgenic activity.
Our Experts’ Viewpoints
Joshua Zeichner, MD
Assistant Professor, Department of Dermatology
Mount Sinai Hospital, New York City
Despite being the number one reason that patients visit dermatologists, effective and tolerable acne treatments remain an unmet need. The currently available armamentarium of drugs is effective in the majority of patients, yet tolerability of topical agents like benzoyl peroxide limits their use in those with sensitive skin. Topical ketoconazole has been used for decades to treat both superficial tinea infections as well as seborrheic dermatitis. Besides its antifungal properties, recent data demonstrating antimicrobial effects against P. acnes suggests that ketoconazole is a potential therapeutic option to treat acne. Given its excellent tolerability profile, ketoconazole may be considered an alternative therapy to patients intolerant of traditional topical acne treatments. We are lacking head-to-head studies comparing ketoconazole to the currently available options, but initial studies yielded promising results. Studies are currently underway evaluating the effect of ketoconazole on the microbiome, and more research is needed to assess any impact on the sebaceous gland itself. However, given its historic widespread use in treating seborrhea without the emergence of negative health effects, the use of topical ketoconazole in the treatment of acne is likely safe as well.
Dr. Zeichner had disclosed financial relationships with the following to the AAD at the time of publication:, AbbVie, Galderma Laboratories, L.P., Johnson & Johnson Consumer Products Company, La Roche-Posay Laboratorie Pharmaceutique, L’Oreal USA Inc., Pfizer Inc., Sanofi/Regeneron, Sun Pharmaceutical Industries Ltd., Unilever, and Valeant Pharmaceuticals International. Full disclosure information is available at coi.aad.org.
Barbieri JS, Choi J, James WD, Margolis DJ. Real world drug usage survival of spironolactone versus oral antibiotics for the management of female patients with acne. J Am Acad Dermatol 2019; 81: 848-851.
Cong TX, Hao D, Wen X, Li XH, et al. From pathogenesis of acne vulgaris to anti-acne agents. Arch Dermatol Res 2019; 311: 337-349.
Marson JW, Baldwin HE. An overview of acne therapy, part 2; Hormonal therapy and istotretinoin. Dermatol Clin 2019; 37: 195-203.
Zaenglein AL. Acne vulgaris. N Engl J Med 2018; 379:1343-1352 .
Unno M, Cho O, Sugita T. Inhibition of Propionibacterium acnes lipase activity by the antifungal agent ketoconazole. Microbiol Immunol 2017; 61: 42-44.
Chottawornsak N, Chongpison Y, Asawanonda P, Kumtornut C. Topical 2% ketoconazole cream monotherapy significantly improves adult female acne: A double-blind, randomized placebo-controlled trial. J Dermatol 2019; 46: 1184-1189.
Rosette C, Agan FJ, Mazetti A, Moro L, Geroloni M. Cortexolone 17α-propionate (Clascoteron) Is a Novel Androgen Receptor Antagonist That Inhibits Production of Lipids and Inflammatory Cytokines From Sebocytes In Vitro Drugs Dermatol 2019; 18: 412-418.
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