Efficacy of intravenous liposomal amphotericin B (AmBisome) against coccidioidal meningitis in rabbits

Abstract

The efficacy of intravenously administered liposomal amphotericin B (AmBisome [AmBi]) for the treatment of experimental coccidioidal meningitis was compared with those of oral fluconazole (FLC) and intravenously administered conventional amphotericin B (AMB). Male New Zealand White rabbits were infected by intracisternal inoculation of arthroconidia of Coccidioides immitis. Starting 5 days postinfection, animals received one of the following: 5% dextrose water diluent; AMB given at 1 mg/kg of body weight; AmBi given at 7.5, 15, or 22.5 mg/kg intravenously three times per week for 3 weeks; or oral FLC given at 80 mg/kg for 19 days. One week after the cessation of therapy, all survivors were euthanatized, the numbers of CFU remaining in the spinal cord and brain were determined, and histological analyses were performed. All AmBi-, FLC-, or AMB-treated animals survived and had prolonged lengths of survival compared with those for the controls (P < 0.0001). Treated groups had significantly lower numbers of white blood cells and significantly lower protein concentrations in the cerebrospinal fluid compared with those for the controls (P < 0.01 to 0.0005) and had fewer clinical signs of infection (e.g., weight loss, elevated temperature, and neurological abnormalities including motor abnormalities). The mean histological scores for AmBi-treated rabbits were lower than those for FLC-treated and control rabbits (P < 0.016 and 0.0005, respectively); the scores for AMB-treated animals were lower than those for the controls (P < 0.0005) but were similar to those for FLC-treated rabbits. All regimens reduced the numbers of CFU in the brain and spinal cord compared with those for the controls (P < or =0.0005). AmBi-treated animals had 3- to 11-fold lower numbers of CFU than FLC-treated rabbits and 6- to 35-fold lower numbers of CFU than AmB-treated rabbits. Three of eight animals given 15 mg of AmBi per kg had no detectable infection in either tissue, whereas other doses of AmBi or FLC cleared either the brain or the spinal cord of infection in fewer rabbits. In addition, clearance of the infection from both tissues was achieved in none of the rabbits, and neither tissue was cleared of infection in AMB-treated animals. Overall, these data indicate that intravenously administered AmBi is superior to oral FLC or intravenous AMB and that FLC is better than AMB against experimental coccidioidal meningitis. These data indicate that AmBi may offer an improvement in the treatment of coccidioidal meningitis. Additional studies are warranted.

FIG. 1.

Cumulative mortality of rabbits infected intracisternally with C. immitis and given one of the indicated treatments. A χ² test for homogeneity was done on the survival in the D5W treatment arms (Table 1), in which the total number of animals surviving in blocks 1, 2, and 3 were compared (e.g., two of eight, two of eight, and five of eight animals, respectively) and showed that P was equal to 0.2019 (χ² = 3.2; two degrees of freedom). Thus, the survival results for the D5W treatments were pooled across the blocks. The statistical analyses of survival times by a log rank test showed that treatment with FLC (FCZ), AMB, and all doses of AmBi significantly prolonged survival compared with that with D5W treatment (P = 0.0001).

FIG. 2.

Mean body weights of rabbits in each treatment arm (n = 8 to 24, depending on the group) monitored during the course of infection. FCZ represents FLC.

FIG. 3.

Mean mobility scores for rabbits in each treatment arm (n = 8 to 24, depending on the group) during the course of infection. Mobility decreases as the scores increase. FCZ represents FLC

FIG. 4.

Mean concentrations of AMB in serum at various times after the administration of dose 5 of AmBi or AMB.