Comparison of nikkomycin Z with amphotericin B and itraconazole for treatment of histoplasmosis in a murine model.

Abstract

Nikkomycin Z was tested both in vitro and in vivo for efficacy against Histoplasma capsulatum. Twenty clinical isolates were tested for susceptibility to nikkomycin Z in comparison to amphotericin B and itraconazole. The median MIC was 8 microg/ml with a range of 4 to 64 microg/ml for nikkomycin Z, 0.56 microg/ml with a range of 0.5 to 1.0 microg/ml for amphotericin B, and < or =0.019 microg/ml for itraconazole. Primary studies were carried out by using a clinical isolate of H. capsulatum for which the MIC of nikkomycin Z was greater than or equal to 64 microg/ml. In survival experiments, mice treated with amphotericin B at 2.0 mg/kg/dose every other day (QOD) itraconazole at 75 mg/kg/dose twice daily (BID), and nikkomycin Z at 100 mg/kg/dose BID survived to day 14, while 70% of mice receiving nikkomycin Z at 20 mg/kg/dose BID and none of the mice receiving nikkomycin Z at 5 mg/kg/dose BID survived to day 14. All vehicle control mice died by day 12. Fungal burden was assessed on survivors. Mice treated with nikkomycin Z at 20 and 100 mg/kg/dose BID had significantly higher CFUs per gram of organ weight in quantitative cultures and higher levels of Histoplasma antigen in lung and spleen homogenates than mice treated with amphotericin B at 2.0 mg/kg/dose QOD or itraconazole at 75 mg/kg/dose BID. Studies also were carried out with a clinical isolate for which the MIC of nikkomycin Z was 4 microg/ml. All mice treated with amphotericin B at 2.0 mg/kg/dose QOD; itraconazole at 75 mg/kg/dose BID; and nikkomycin Z at 100, 20, and 5 mg/kg/dose BID survived until the end of the study at day 17 postinfection, while 30% of the untreated vehicle control mice survived. Fungal burden assessed on survivors showed similar levels of Histoplasma antigen in lung and spleen homogenates of mice treated with amphotericin B at 2.0 mg/kg/dose QOD; itraconazole at 75 mg/kg/dose BID; and nikkomycin Z at 100, 20, and 5 mg/kg/dose BID. The three surviving vehicle control mice had significantly higher antigen levels in lung and spleen than other groups (P<0.05). The efficacy of nikkomycin Z at preventing mortality and reducing fungal burden correlates with in vitro susceptibility.

• Authors: J Goldberg, P Connolly, C Schnizlein-Bick, M Durkin, S Kohler, M Smedema, E Brizendine, R Hector, J Wheat
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 44 Issue 6 Pg. 1624-9 (Jun 2000) ISSN: 0066-4804 [Print] United States
• PMID: 10817719 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Aminoglycosides
• Anti-Bacterial Agents
• Antifungal Agents
• Itraconazole
• Amphotericin B
• nikkomycin

Topics

• Aminoglycosides
• Amphotericin B (pharmacology, therapeutic use)
• Animals
• Anti-Bacterial Agents (pharmacology, therapeutic use)
• Antifungal Agents (pharmacology, therapeutic use)
• Cells, Cultured
• Disease Models, Animal
• Histoplasmosis (drug therapy)
• Itraconazole (pharmacology, therapeutic use)
• Mice