A call for antifungal stewardship

Dermatophytoses occur in almost one-quarter of the world’s population. Infections are generally treated with either an oral or topical antifungal medication. Griseofulvin has been available since the late 1950s but is no longer obtainable in many countries. Itraconazole and terbinafine were developed for dermatomycoses about 30 years ago and fluconazole has also been used. Until recently, the newer medications, particularly terbinafine, were largely assumed nearly invulnerable to fungal resistance. According to a study reported in this issue of the BJD, fungal resistance poses a dire challenge in the treatment of dermatophyte infections. Sanjay Singh and colleagues conducted the first large trial comparing the efficacy of these four oral antifungals in 200 healthy patients with chronic relapsing dermatophytosis. At week 4, all four drugs appeared equally useless, with cure rates under 10%, and at week 8, only itraconazole exhibited a cure rate over 50%. The 28% cure rate after 8 weeks of oral terbinafine was particularly disturbing. Although the study concludes that itraconazole was the most effective, it can be cost prohibitive. How did these drugs lose their power? Assuming the effectiveness reported in the study, the answer lies in practitioners’ use and misuse of these medications. Antifungal medications, as is true with antibiotics, are overprescribed and often given without confirmatory mycological testing. Unlike bacterial cultures, fungal cultures are more complicated to perform in the office and isolate in the laboratory, and fungal susceptibility testing is not routine. For many years the selection of the antifungal did not alter the clinical course as, with few exceptions, they were equally effective. The current study establishes that these lax practices must change. It is no surprise then that terbinafine-resistant superficial mycoses have emerged. There are documented instances of squalene epoxidase gene mutations in Trichophyton rubrum and Trichophyton mentagrophytes resulting in resistance. Some authors have suggested that the widespread use and availability of inexpensive topical antifungal preparations or corticosteroid–antifungal–antibacterial combinations are a significant contributor to this dilemma. Perhaps suboptimal dosing or incomplete treatment may also have added to the resistance problem. Notably, the study does have limitations. Topical antifungal agents were not included, although they are usually first-line treatment. However, if it is resistant to an oral drug, a fungus likely would not respond to the same topical agent. Another limitation is the lack of positive fungal cultures at baseline and study conclusion in all patients. Despite the study’s limitations, it shines a welcome light on the public health threat posed by treatment-resistant dermatomycosis. In fact, our centre has seen several patients with T. rubrum nonresponsive to all four oral medications, with mycology resistance proven by susceptibility testing and additional patients with clinical response to only itraconazole. While additional antifungal medications indicated for systemic mycoses such as posaconazole and voriconazole are available, they are costly and have concerning side-effects. As the study timely illustrates, we need to take responsibility as antifungal stewards to protect our patients. Dermatologists must stop overprescribing without confirmatory mycology documentation.