Dose range evaluation of liposomal nystatin and comparisons with amphotericin B and amphotericin B lipid complex in temporarily neutropenic mice infected with an isolate of Aspergillus fumigatus with reduced susceptibility to amphotericin B.
Using an isolate of Aspergillus fumigatus that is less susceptible in vivo to amphotericin B than most other isolates, we compared different doses of liposomal nystatin (L-nystatin), liposomal amphotericin B (L-amphotericin), and amphotericin B lipid complex (ABLC) with amphotericin B deoxycholate. Four experiments with intravenously infected neutropenic mice were conducted. A dose of L-nystatin at 10 mg/kg of body weight was toxic (the mice had fits or respiratory arrest). The optimal dosage of L-nystatin was 5 mg/kg daily on days 1, 2, 4, and 7 (90% survival). This was superior to L-amphotericin (5 mg/kg [P = 0.24] and 1 mg/kg [P < 0.0001]), ABLC (5 mg/kg [P = 0.014] and 1 mg/kg [P < 0.0001]), and amphotericin B deoxycholate (5 mg/kg [P = 0.008]). In terms of liver and kidney cultures, L-nystatin (5 mg/kg) was superior to all other regimens (P = 0.0032 and <0.0001, respectively). Higher doses of L-amphotericin (25 and 50 mg/kg) in one earlier experiment were more effective (100% survival) than 1 mg of L-amphotericin per kg and amphotericin deoxycholate (5 mg/kg) in terms of mortality and both liver and kidney culture results and to L-amphotericin (5 mg/kg) in terms of liver and kidney culture results only. ABLC (25 mg/kg) given daily for 7 days was superior to ABLC (50 mg/kg [P = 0.03]) but not to ABLC at 5 mg/kg or amphotericin B deoxycholate in terms of mortality, although it was in terms of liver and kidney culture results. No dose-response for amphotericin B (5 and 1 mg/kg) was demonstrable. In conclusion, in this stringent model, high doses of L-amphotericin and ABLC could overcome reduced susceptibility to amphotericin B deoxycholate, but all were inferior to 5- to 10-fold lower doses of L-nystatin.
Denning
D W
DW
Hope Hospital, School of Medicine, University of Manchester, Salford M6 8HD, Manchester M8 6RB, United Kingdom.
Warn
P
P
D000666:Amphotericin B / Q000008:administration & dosage* / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology; D001232:Aspergillus fumigatus; D015169:Colony Count, Microbial; D003520:Cyclophosphamide; D003840:Deoxycholic Acid / Q000008:administration & dosage* / Q000627:therapeutic use*; D004337:Drug Carriers; D004338:Drug Combinations; D004352:Drug Resistance, Microbial; D007166:Immunosuppressive Agents; D008081:Liposomes; D051379:Mice; D009503:Neutropenia / Q000139:chemically induced / Q000188:drug therapy* / Q000382:microbiology; D009761:Nystatin / Q000008:administration & dosage* / Q000627:therapeutic use*
D000935:Antifungal Agents; D004337:Drug Carriers; D004338:Drug Combinations; D007166:Immunosuppressive Agents; D008081:Liposomes; D003840:Deoxycholic Acid; D009761:Nystatin; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination; D003520:Cyclophosphamide