title: 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.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: J
authors.initials: J
authors.lastname: Goldberg
authors.forename: P
authors.initials: P
authors.lastname: Connolly
authors.forename: C
authors.initials: C
authors.lastname: Schnizlein-Bick
authors.forename: M
authors.initials: M
authors.lastname: Durkin
authors.forename: S
authors.initials: S
authors.lastname: Kohler
authors.forename: M
authors.initials: M
authors.lastname: Smedema
authors.forename: E
authors.initials: E
authors.lastname: Brizendine
authors.forename: R
authors.initials: R
authors.lastname: Hector
authors.forename: J
authors.initials: J
authors.lastname: Wheat
mesh_terms: D000617:Aminoglycosides; D000666:Amphotericin B / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006660:Histoplasmosis / Q000188:drug therapy*; D017964:Itraconazole / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D017964:Itraconazole; D000666:Amphotericin B; C011952:nikkomycin