Abstract
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.
Full Text
The Full Text of this article is available as a PDF (173.8 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Arathoon E. G., Brummer E., Stevens D. A. Efficacy of itraconazole in blastomycosis in a murine model and comparison with ketoconazole. Mycoses. 1989;32 (Suppl 1):109–112. doi: 10.1111/j.1439-0507.1989.tb02300.x. [DOI] [PubMed] [Google Scholar]
- Cabib E. Differential inhibition of chitin synthetases 1 and 2 from Saccharomyces cerevisiae by polyoxin D and nikkomycins. Antimicrob Agents Chemother. 1991 Jan;35(1):170–173. doi: 10.1128/aac.35.1.170. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Clemons K. V., Hanson L. H., Stevens D. A. Activities of the triazole D0870 in vitro and against murine blastomycosis. Antimicrob Agents Chemother. 1993 May;37(5):1177–1179. doi: 10.1128/aac.37.5.1177. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Clemons K. V., Stevens D. A. Comparative efficacies of amphotericin B lipid complex and amphotericin B deoxycholate suspension against murine blastomycosis. Antimicrob Agents Chemother. 1991 Oct;35(10):2144–2146. doi: 10.1128/aac.35.10.2144. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ganer A., Arathoon E., Stevens D. A. Initial experience in therapy for progressive mycoses with itraconazole, the first clinically studied triazole. Rev Infect Dis. 1987 Jan-Feb;9 (Suppl 1):S77–S86. doi: 10.1093/clinids/9.supplement_1.s77. [DOI] [PubMed] [Google Scholar]
- Hector R. F., Schaller K. Positive interaction of nikkomycins and azoles against Candida albicans in vitro and in vivo. Antimicrob Agents Chemother. 1992 Jun;36(6):1284–1289. doi: 10.1128/aac.36.6.1284. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hector R. F., Zimmer B. L., Pappagianis D. Evaluation of nikkomycins X and Z in murine models of coccidioidomycosis, histoplasmosis, and blastomycosis. Antimicrob Agents Chemother. 1990 Apr;34(4):587–593. doi: 10.1128/aac.34.4.587. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hostetler J. S., Hanson L. H., Stevens D. A. Effect of hydroxypropyl-beta-cyclodextrin on efficacy of oral itraconazole in disseminated murine cryptococcosis. J Antimicrob Chemother. 1993 Sep;32(3):459–463. doi: 10.1093/jac/32.3.459. [DOI] [PubMed] [Google Scholar]