Action mechanisms of modern antifungal agents and resulting problems in the management of onychomycosis

Abstract

Successful treatment of onychomycosis in the infection site depends not only on achieving the minimal inhibitory concentration (MIC) of the antifungal agent, usually determined on fresh, proliferating fungal strains, but also on the effectivity against fungal spores dormant in nail keratin. Ciclopiroxolamine and terbinafine were investigated for their fungicidal properties against proliferating and dormant dermatophyte strains. While ciclopiroxolamine was 100% effective against Trichophyton mentagrophytes (50 microg ml(-1)) and Microsporum canis (5 microg ml(-1)) both in the proliferative and dormant phase after 5 days of incubation, the same result was achieved under identical test conditions with 0.002 microg ml(-1) terbinafine using T. mentagrophytes as test organism in the proliferative and 2.0 microg ml-1 in the dormant phase. The terbinafine concentrations of 0.52 microg g(-1) measured in the nail are well below 2.0. This explains the high treatment failure and relapse rates observed under monotherapy of toenail onychomycosis even with modern antifungals. Consequently, combined therapy is recommended, beginning with atraumatic removal of the affected toenails and continuing with an antifungal nail lacquer combined with a systemic antifungal.

Combination of oral terbinafine and topical ciclopirox compared to oral terbinafine for the treatment of onychomycosis

“…Recently, combination antifungal therapies were advocated for onychomycosis treatment (4,6,9,10,12). The rationale is that topical drug penetration into the nail plate will enhance treatment in locations such as the lateral edges of the nail, which are difficult for systemic treatments to reach (13).…”

“…The rationale is that topical drug penetration into the nail plate will enhance treatment in locations such as the lateral edges of the nail, which are difficult for systemic treatments to reach (13). Successful treatment of onychomycosis in the infection site depends not only on achieving the minimal inhibitory concentration (MIC) of the antifungal agent, usually determined on fresh, proliferating fungal strains, but also on the effectivity against fungal spores dormant in nail keratin (9). At standard concentration, terbinafine has limited efficacy against dormant fungal cells, while ciclopirox was 100% effective against both proliferating and dormant fungal cells (9).…”

“…Ciclopirox (6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone) is a synthetic broad-spectrum hydroxypyridone that differs structurally and mechanistically from the other antifungal agents (8). Ciclopirox is a broad-spectrum antifungal agent that exhibits fungicidal activity in vitro against dermatophytes, Candida species and some nondermatophyte moulds (8)(9)(10). It has also antibacterial activity (8) (e.g.…”

Antidermatophyte Activity of the Gentiopicroside-Rich n-Butanol Fraction from <b><i>Gentiana siphonantha</i></b> Maxim. Root on a Guinea Pig Model of Dermatophytosis

“…However, patients often seek complementary and alternative treatments [3,4,5]. Resistance of human pathogens to antifungal drugs and toxicity-related problems have resulted in the need for novel antifungal agents [2,6]. A number of Chinese medicinal plants have shown antimicrobial properties that can protect the human body against dermatophytes.…”

“…Amphotericin B, ketoconazole, fluconazole, terbinafine (TBF), and flucytosine are the drugs of choice for the treatment of dermatophytoses [2]. However, patients often seek complementary and alternative treatments [3,4,5].…”