Mycological Considerations in the Topical Treatment of Superficial Fungal Infections

February 2016 | Volume 15 | Issue 2 | Supplement Individual Articles | 49 | Copyright © February 2016


Ted Rosen MD

Baylor College of Medicine, Houston, TX

activity, including low MICs for Pseudomonas aeruginosa, Proteus mirabilis, Escherichia coli, and Klebsiella pneumoniae, as well common Streptococcal and Staphylococcal species.51,52 By contrast, butenafine has no activity against Gram-negative bacteria and Gram-positive activity limited only to Group A beta-hemolytic Streptococcus.52 Despite evidence of antibacterial activity, none of these antifungal agents should be considered drugs of choice when treating either uncomplicated or complicated primary bacterial pyodermas.
Anti-inflammatory properties have been investigated in a variety of ways, including: inhibition of neutrophil chemotaxis, reduction in inflammation-associated skin temperature, reduction of croton oil or arachidonic acid-induced ear edema in a murine model, reduced erythema-wheal formation following intracutaneous histamine injection, direct inhibition of 5-lipoxygenase and/or cyclo-oxygenase activity and inhibition of UV-induced erythema. Although many antifungals possess some degree of inherent anti-inflammatory activity, when tested in a head-to-head manner, ciclopirox olamine, naftifine and terbinafine proved more effective than the any of the azole drugs.53,54 This suggests, but does not prove, that these three antifungal agents might be more effective at reducing erythema and pruritus. An example would be tinea corporis or faciei due to M. canis acquired from a new pet kitten or puppy.

Antifungal Resistance

Candida albicans resistance to antifungal drugs seems to be increasing, and such resistance appears to be related to prolonged exposure to these agents.55,56 Candidal resistance appears primarily related to upregulation of CDR1, CDR2 genes, which enhance efflux (removal) of anti-infective drugs, as well as mutations in ergosterol biosynthesis gene (ERG11) leading to an altered (resistant) form of the azole target enzyme, 14C-lanosterol demethylase.
Dermatophyte resistance has been most widely studied in T. rubrum. Antifungal resistance to allylamines depends mostly upon an altered target enzyme, wherein amino acid substitutions in squalene epoxidase occur in the allylamine binding site.57,58 In addition, there appears to be the potential for inducible upregulation of TruMDR1 and TruMDR2 genes which encode for drug efflux structures.59,60 Finally, T. rubrum may over-express salicylate mono-oxygenase which is capable of degrading allylamines.60 Dermatophyte resistance to azole agents depends on the same efflux mechanisms detailed above, and also to compensatory over-production of the target enzyme, 14C-lanosterol demethylase.61 Despite the foregoing, naturally occurring resistant dermatophytes are exceedingly rare. One study estimated that innately azole resistant T. rubrum occurred in about 1 in 107 organisms and innately terbinafine resistant T. rubrum in about 1 in 109 organisms.62 The same investigators noted that repeated exposures (10 passages) of T. rubrum to subinhibitory concentrations of azole and allylamine antifungal agents led to appearance of resistant strains. Thus, failure of one antifungal agent might be due to acquired resistance, even though innate resistance is rare. Interestingly, despite multiple exposures of T. rubrum to subinhibitory concentrations of ciclopirox olamine, no mutant resistant strains were isolated.62
In reality, most antifungal “resistance” is actually due to: poor patient adherence (either in dosing or treatment duration), or to reinfection following re-exposure.63

CONCLUSION

The ideal topical antifungal agent for superficial mycoses should have broad-spectrum activity, high mycologic and clinical cure rates, efficacy at low concentrations, fungicidal activity with a convenient dosing schedule, keratinophilic and lipophilic properties, a reservoir effect in the stratum corneum, lack of potential for development of antifungal drug resistance, low relapse rate, few to no adverse effects, and a low cost. While this “ideal” agent does not yet exist, many of the FDA-approved topical agents have some of these characteristics.

DISCLOSURES

The author has received honoraria from the following pharmaceutical companies in conjunction with participation in advisory boards: Anacor, Merz, and Valeant.
This article includes discussion of published and/or investigational use of agents that are not indicated by the United States FDA.

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