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 microg/ml and a minimal fungicidal concentration of 3.1 microg/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 < or = 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.
Clemons
K V
KV
California Institute for Medical Research, Department of Medicine, Santa Clara Valley Medical Center, San Jose, California 95128, USA. id.cimr@juno.com
Stevens
D A
DA
D000617:Aminoglycosides; D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D001759:Blastomycosis / Q000188:drug therapy*; D002687:Chitin Synthase / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017964:Itraconazole / Q000494:pharmacology; D008172:Lung Diseases, Fungal / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D017964:Itraconazole; D000666:Amphotericin B; C011952:nikkomycin; D002687:Chitin Synthase