Nikkomycins X and Z (NZ), competitive inhibitors of fungal
chitin synthetase, were combined with
azoles in a series of in vitro checkerboard assays to test for synergism against Candida spp. All combinations of nikkomycins and
azoles tested resulted in marked synergistic activity against an isolate of Candida albicans, with fractional inhibitory concentration indices ranging from 0.016 to 0.28. No synergistic effect was demonstrable with isolates of C. tropicalis, C. parapsilosis, or C. krusei, though results for the latter two were suggestive of an additive effect. In survival models of mice infected intravenously with C. albicans, NZ administered singly in doses ranging from 5 to 50 mg/kg of
body weight twice a day was able to delay the onset of mortality but showed no dose-response effect. The combination of NZ and the
azole R 3783 administered orally in a ratio of 8:1 to 40:1 or greater (wt/wt) enhanced survival better than did the drugs given individually, but this effect was less evident for combinations involving
fluconazole. In short-term organ load assays with outbred mice infected intravenously with C. albicans, high ratios of NZ to R 3783 reduced the CFU per gram in kidneys more significantly than did the drugs individually. Statistically significant reductions were not seen for short-term fungal burden assays using combinations of NZ and
fluconazole in outbred mice or in inbred mice more susceptible to
candidiasis. In a model of rat vaginal
candidiasis, the combination of NZ and R 3783 administered either orally or vaginally was more effective than the drugs used singly. Thus, under certain conditions, combination
therapy with
nikkomycin and select
azoles may offer promise for an increased
therapeutic effect in
candidiasis.