Nikkomycin Z (nikZ) is a
chitin synthase inhibitor. Efficacy against Coccidioides has been demonstrated in animal models of pulmonary or brain
infection. Its short half-life in mice and in humans would necessitate divided daily dosing. We assayed nikZ efficacy in disseminated
coccidioidomycosis (in a reduction of CFU design) and whether sustained release might be useful. Mice were challenged intravenously with low or high arthroconidial inocula.
Fluconazole, clinically the most commonly used anticoccidioidal
drug, was compared (gavage) at high dose to a dose range of nikZ administered intraperitoneally or, to mimic sustained release, administered continuously in
drinking water.
Therapy was given for 5 days. In vitro, both
fluconazole and nikZ inhibited the isolate studied; nikZ was fungicidal. Oral nikZ
therapy gave similar results to intraperitoneal nikZ and sterilized
infection in most animals after low-inoculum challenge. In both challenges, oral nikZ produced greater reduction of CFU in organs (lung, liver, and spleen) than
fluconazole. Oral nikZ doses of ≥200 mg/kg of
body weight/day were particularly effective in all organs and were well tolerated. This efficacy occurred even though, after severe challenge, mice had reduced water intake, resulting in ingesting less than the desired dose, particularly initially after
infection. This study shows, for the first time, efficacy of nikZ against disseminated
coccidioidomycosis. Efficacy was shown after challenges producing different levels of severity of disease. This study also suggests the likely benefits of developing an
extended release formulation supplying continuous systemic concentrations of nikZ.