Background: Terbinafine (TERB) inhibits squalene epoxidase, a key enzyme in ergosterol biosynthesis, being active in vitro against Aspergillus spp. We investigated its in vitro interaction with itraconazole (ITZ), fluconazole (FCZ), amphotericin B (AMB) and 5-flucytosine (FCY), against 3 clinical isolates of A. fumigatus (one of them itraconazole resistant in vivo - AF72), and 2 each of A. flavus, A. niger and A. terreus. Methods: Drug interactions were assessed employing a broth microdilution-based method with casitone+2% glucose or RPMI-1640+2% glucose (for ITZ only). The final inoculum was 5 x 104 CFU/ml. The MICs were read visually as no growth after 48 hours incubation at 37Â°C. We studied the effect of the combination on the MICs by calculation of the fractional inhibitory concentration (FIC) and on the minimum fungicidal concentrations (99.99% kill) (MFCs). Results: ITZ and TERB were synergistic or additive in all strains (FIC = 0.28-1.0). FCZ and TERB were synergistic with A. fumigatus, A. terreus and A. flavus (FIC = 0.3-0.5) and indifferent with A. niger isolates (FIC = 2). AMB and TERB were mostly indifferent or antagonistic (FIC = 1.0-4.02). FCY and TERB were usually indifferent or antagonistic (FIC = 0.63-8.5). MFCs of combinations were generally in accord with MICs, although AMB and TERB killing of A. fumigatus was enhanced in combination, in contrast to the MICs. Conclusion: The potential use of TERB in combination with azoles (but not amphotericin B or flucytosine) seems promising for the treatment of aspergillosis.
Full conference title:
- ICAAC 41st