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

Abstract

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.

FIG. 1

Study of activity of L-nystatin at cumulative doses ranging from 10 to 35 mg/kg compared with those of amphotericin B and empty liposomes (control). Plots are of cumulative mortality against time after AF65 infection and treatment with L-nystatin. □, L-nystatin at 5 mg/kg on days 1 to 7; ●, L-nystatin at 5 mg/kg on days 1, 2, 4, and 7; ○, L-nystatin at 2.5 mg/kg on days 1 to 7; ▴, L-nystatin at 2.5 mg/kg twice daily on days 1, 2, 4, and 7; ◊, L-nystatin at 2.5 mg/kg on days 1, 2, 4, and 7; ■, amphotericin B at 5 mg/kg days on 1, 2, 4, and 7; ×, no active treatment.

FIG. 2

Study of activity of L-amphotericin at doses ranging from 1 to 50 mg/kg given four times to mice infected with strain AF65 compared with those of amphotericin B and dextrose (control). Plots are of cumulative mortality against time after AF65 infection and treatment with L-amphotericin. □, L-amphotericin at 50 mg/kg on days 1, 2, 4, and 7; ▵, L-amphotericin at 25 mg/kg on days 1, 2, 4, and 7; ⧫, L-amphotericin at 5 mg/kg on days 1, 2, 4, and 7; ◊, L-amphotericin at 1 mg/kg on days 1, 2, 4, and 7; ■, amphotericin B at 5 mg/kg on days 1, 2, 4, and 7; ×, no active treatment.

FIG. 3

Study of activity of ABLC at doses ranging from 1 to 50 mg/kg given seven times to mice infected with AF65 compared with those of amphotericin B and dextrose (control). Plots are of cumulative mortality against time after AF65 infection and treatment with ABLC. □, ABLC at 50 mg/kg on days 1 to 7; ▵, ABLC at 25 mg/kg on days 1 to 7; ●, ABLC at 5 mg/kg on days 1 to 7; ○, ABLC at 1 mg/kg on days 1 to 7; ■, amphotericin B at 5 mg/kg on days 1, 2, 4, and 7; ×, no active treatment.

FIG. 4

Comparison of treatment with two doses (1 and 5 mg/kg) of L-nystatin, L-amphotericin, ABLC, and amphotericin B with control treatments in a model of invasive aspergillosis caused by AF65 in temporarily neutropenic mice. For all groups except L-nystatin at 1 mg/kg and amphotericin B at 1 mg/kg, the data are from two experiments. Plots are of cumulative mortality against time after AF65 infection and various treatments. ▴, L-nystatin at 2.5 mg/kg twice daily on days 1, 2, 4, and 7; ▵, L-nystatin at 0.5 mg/kg twice daily on days 1, 2, 4, and 7; ⧫, L-amphotericin at 5 mg/kg on days 1, 2, 4, and 7; ◊, L-amphotericin at 1 mg/kg on days 1, 2, 4, and 7; ●, ABLC at 5 mg/kg on days 1 to 7; ○, ABLC at 1 mg/kg on days 1 to 7; ■, amphotericin B at 5 mg/kg on days 1, 2, 4, and 7; □, amphotericin B at 1 mg/kg on days 1, 2, 4, and 7; ×, no active treatment.