Mycological Considerations in the Topical Treatment of Superficial Fungal Infections

higher in-vitro MIC when compared to azole antifungals worldwide (studies cited from Brazil, Cuba and Singapore).^36-38

Virtually no cases of pityriasis versicolor are investigated to determine the precise causative Malssezia species. The absence of standardized collection and reporting practices during clinical studies or during routine use, precludes any conclusions to be drawn regarding the relative efficacy of the many approved topical agents with regards to specific Malassezia species.³⁹ In general, topical azoles are felt to be superior to topical allylamines in the management of pityriasis versicolor. However, topical prescription treatments for pityriasis versicolor may be logistically and economically impractical in extensive disease. Several OTC preparations are suitable for treatment of pityriasis versicolor, including zinc pyrithione and selenium sulfide.³² Short courses of generic oral antifungal agents (such as fluconazole, off-label) may actually be more cost effective, not to mention more convenient, than two-eight weeks of topical application of either prescription or OTC agents.³⁹ As another deviation from FDA approvals, both terbinafine and naftifine have been utilized successfully in pityriasis versicolor, although neither is considered a drug of choice for this superficial mycosis.

Perhaps therapeutic decisions could (or should) be based upon in-vitro anti-fungal drug sensitivities of clinical isolates, akin to the manner in which bacterial diseases are treated? Alas, such is not the case. Stringent but cumbersome broth microdilution standards do exist: Clinical Laboratory Standards Institute (CLSI: M38-A1 and M38-A2) in the United States and the European Committee on Antimicrobial Susceptibility Testing (EUCAST: E.DEF 7.2 and 9.1) in Europe. However, even these reference techniques differ in inoculum size, incubation time and medium composition.⁴⁰ They are also designed and validated only for yeasts and molds and, as a consequence, do not directly address the antifungal susceptibility of dermatophyte species. While reference tests can be adapted for dermatophytes, ^41-43 results may vary depending upon exact parameters employed during testing. There are also alternative methods in use, including: macro-dilution, agar-based disk diffusion, colorimetric modifications, bioluminescence assays, flow cytometry, ergosterol quantitation and a number of automated and semiautomated commercial kits.^44,45 The various techniques available for antifungal susceptibility testing do not always correlate with reference techniques or with eachother.^42,45 Finally, as pointed out repeatedly, correlation between in-vitro dermatophyte MICs and in-vivo clinical outcomes remains unclear and yet to be determined.^32,41,42,45 Even when dealing with Candida species, isolates from patients whose condition does not respond to azole therapy may be apparently sensitive based upon standardized in-vitro testing, whereas patients whose condition responds to treatment may have strains that show MIC values consistent with in-vitro resistance.⁴⁶ In short, when it comes to topical therapy for superficial fungal infections, in-vitro laboratory determination of sensitivity is not a “surefire” manner to predict clinical success.

Similarly, whether an agent is considered “fungicidal” or “fungistatic” has minimal real world importance. A high enough concentration of virtually any of the agents listed (except for nystatin and tonaftate) will result in in-vitro fungicidal activity for at least some dermatophytes and yeast. Moreover, as noted by a leading Japanese mycologist, we are far from understanding how to devise accurate, reproducible and standardized methods of determining minimal fungicidal drug concentrations for dermatophytes.⁴⁷ It is, however, generally accepted that, with the exception of luliconazole, sertaconazole, and possibly oxiconazole, the azoles are predominantly fungistatic; by contrast, butenafine, naftifine, terbinafine, and ciclopirox are considered fungicidal.³² The possible benefit to a fungicidal agent is the potential for more rapid onset of action, and therefore somewhat more prompt relief of symptoms.

These properties may influence, to some extent, the choice of specific agents in certain clinical settings. For example, when concurrent bacterial infection is probable, or already present (such as severe interdigital tinea pedis), an antifungal agent which helps eradicate bacterial superinfection might be preferable. In those situations where the inflammatory response to superficial mycoses is extreme and symptoms are overwhelming, an antifungal agent which is inherently anti-inflammatory may be preferable.

Some of the azole antifungal drugs are antibacterial: clotrimazole, econazole, miconazole, oxiconazole, sertaconazole, and sulconazole demonstrate inhibitory activity in vitro and in vivo against some Gram-positive and a few Gram-negative bacteria. ³² In particular, sertaconazole has a lower geometric mean MIC for Streptococcal and Staphylococcal species than other azoles.⁴⁸ Both naftifine and terbinafine have some demonstrable in-vitro and in-vivo anti-bacterial properties according to a German group of investigators.^49,50 Of all the anti-mycotic agents, ciclopirox olamine has the broadest spectrum of antibacterial