Efficacy of nikkomycin Z against experimental pulmonary blastomycosis.

Nikkomycin Z is a chitin synthetase inhibitor. In vitro, nikkomycin Z had good activity against Blastomyces dermatitidis, with an MIC of 0.78 mg/ml and a minimal fungicidal concentration of 3.1 mg/ml. The efficacies of various treatment durations (3, 5, or 10 days) and doses (200, 400, or 1,000 mg/kg of body weight) of nikkomycin Z given twice daily were compared with those of itraconazole at 200 mg/kg given twice daily and amphotericin B at 6.25 mg/kg in a murine model of pulmonary blastomycosis. All treatments prolonged survival compared with untreated controls (P < 0.05 to 0.01); 100% survival was achieved with 5 or 10 days of any nikkomycin Z dose or with amphotericin B. Amphotericin B and nikkomycin Z, but not itraconazole, reduced infection compared with controls. Amphotericin B and the 10-day regimens of all nikkomycin Z doses were equivalent and superior to itraconazole or nikkomycin Z for <5 days at any dose (P < 0.05 to 0.01). Increased duration and/or dosage improved the efficacy of nikkomycin Z, with 10 days of each dose curing 50 to 90% of the animals. Only a 1,000-mg/kg/day dose of nikkomycin Z was curative when treatment lasted less than 10 days. In contrast, itraconazole cured no mice, while amphotericin B cured all mice. Based on the total amount of drug given, amphotericin B was estimated to be 32 times as active as nikkomycin Z and nikkomycin Z was estimated to be 3 times as active as itraconazole. Overall, nikkomycin Z given orally was well tolerated, had good activity against blastomycosis, and could result in biological cure, thus producing results equivalent to those of parenteral amphotericin B. Antifungal chemotherapies currently in use have modes of action directed primarily against fungal cell membranes and ergosterol synthesis. Another specific fungal target is the cell wall, and one class of compounds that specifically inhibit cell wall synthesis are chitin synthetase inhibitors (2). Nikkomycin Z and polyoxin D, compounds similar in structure to N-acetylglucosamine, belong to this class (2, 6, 7) and have been shown to be competitive inhibitors of chitin synthetases 1 and 2 (2). Previous studies have reported that nikkomycin Z has in vitro activity against the spherule form of Coccidioides immitis and more limited activity against Blastomyces dermatitidis (7); significantly less activity was demonstrated against several yeasts. In vivo, nikkomycin Z has been shown to be efficacious and superior to azoles in murine models of systemic coccidioidomycosis and blastomycosis (7). Because mammalian cells have no chitin, this polymer is an ideal target for antifungal therapy, and no toxicity has been demonstrated in mice at doses of up to 400 mg/kg of body weight per day for 28 days (7). However, orally administered nikkomycin Z has been shown to have a relatively short half-life in serum, about 1 h (7). In the present study we compared the efficacy of nikkomycin Z with those of amphotericin B and itraconazole in a murine model of pulmonary blastomycosis. Because previous studies have indicated that nikkomycin Z at dosages of 50 mg/kg for 10 days was highly efficacious, we designed the present study to examine the effects of both treatment duration and dose escalation on therapeutic efficacy. In this study, doses of 200, 400, and 1,000 mg/kg/day were used to examine the possibility that high dosages given for short periods would prove efficacious.