Increase in Resistance to Fluconazole and Itraconazole in Trichophyton rubrum Clinical Isolates by Sequential Passages In Vitro under Drug Pressure

Abstract

Trichophyton rubrum, an anthropophilic dermatophyte fungus, is the predominant causative agent of superficial skin infections in human population. There are only scanty reports on drug susceptibility profiling of T. rubrum. Neither mechanisms for drug resistance development nor correlation between in vitro drug susceptibility and in vivo response to treatment is known for that species. In this study, changes in the in vitro susceptibilities to fluconazole (FLZ) and itraconazole (ITZ) among thirty T. rubrum clinical strains subjected to sequential passages in the presence or absence of the azoles were investigated. Each strain was passaged 12 times at 4-week intervals as three parallel cultures, maintained on a drug-free medium (1), and a medium containing FLZ (2) or ITZ (3) at subinhibitory concentrations. Susceptibility to FLZ and ITZ of the original strain and its 3 subcultures was determined by microdilution method. The MIC values of the two azoles remained unaltered for all T. rubrum strains tested, after 12 passages on a drug-free medium. Among the strains grown with FLZ, an increase in the MICs of FLZ and ITZ was noted in 17 (56.7 %) and 19 (63.3 %) strains, respectively. Increased MICs of ITZ and FLZ were demonstrated for 24 (80 %) and 20 (66.7 %) strains that were propagated with ITZ. The results indicate the capacity of T. rubrum to develop resistance toward the azoles after prolonged exposure to these drugs. Resistance of T. rubrum to azoles plays an important role in therapy failures and consequently contributes to persistence and chronicity of the infections.

Potential of Ergosterol Synthesis Inhibitors To Cause Resistance or Cross-Resistance in Trichophyton rubrum

“…In the presence of ITC, mutants with elevated resistance to ITC were isolated at a higher frequency than was seen with spontaneous mutation. A decreased susceptibility to ITC has already been described for T. rubrum subjected to sequential passages in the presence of the azole compound (17). Our results determined with TRB and AMF indicate that prolonged exposure to subinhibitory concentrations of these drugs also leads to significant loss of susceptibility (resistance frequency, about 10 Ϫ7 to 10 Ϫ8 ).…”

“…However, relapses following cessation of the antifungal therapy may also be due to T. rubrum acquisition of resistance, especially in the case of infections involving prolonged treatment with relatively low drug concentrations (14). Although rare, T. rubrum clinical isolates and in vitro-selected mutants resistant to ITC and TRB have already been described (14,(16)(17)(18).…”

Onychomycosis in diabetic patients in Fako Division of Cameroon: prevalence, causative agents, associated factors and antifungal sensitivity patterns

“…This conflicts report given by Zaias et al and Gupta et al who obtained high clinical and mycological cure rates in patients treated with itraconazole and griseofulvin [29, 31]. The high resistance to itraconazole obtained is similar to that reported by Hryncewicz et al [32], who observed resistance in 80% of isolates tested in Poland. High resistant rates to griseofulvin also conforms to that stated by Elewski who recorded high rates of resistance and patient relapse when treated with griseofulvin [33].…”

In Vivo Synergy of Amphotericin B plus Posaconazole in Murine Aspergillosis

“…An in vitro adaptation experiment (26,27) was carried out to investigate the poor in vivo efficacy of azoles against the strains FMR 7739 and FMR 10528, despite their low MICs. Each strain was passaged 3 times at 1-week intervals on PDA containing PSC or VRC at a concentration corresponding to half of the MIC.…”