Introduction.
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 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.
Methods.
Mice were challenged intravenously, with low or high arthroconidial inocula. Fluconazole, clinically the most commonly used anti-coccidioidal 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.
Results.
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, spleen) than fluconazole. Oral nikZ doses ≥200 mg/kg/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.
Summary
. 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.