Comparison of itraconazole and fluconazole treatments in a murine model of coccidioidal meningitis

Abstract

Coccidioidal meningitis (CM) is a devastating disease that requires long-term therapy and for which there is little hope of a cure. A model was used to compare the efficacies of itraconazole and fluconazole. CD-1 mice were infected intrathecally with 30 to 36 viable arthroconidia of Coccidioides. Oral therapy with cyclodextrin (control) or itraconazole or fluconazole at 10, 25, or 50 mg/kg of body weight twice daily (BID) was given for 12 days, from day 3 of infection. Treatment with both antifungals at all doses prolonged survival compared with that of the control treatment (P < 0.01 to 0.0001). At 50 mg/kg, itraconazole and fluconazole were equivalent, whereas itraconazole at 10 or 25 mg/kg prolonged survival compared to that achieved with fluconazole at these dosages (P < 0.05 and 0.01, respectively). Early histologic analysis (10 days of treatment) with 50 mg/kg BID itraconazole or fluconazole showed suppression of CM in all five animals per group; in quantitative cultures, three of three animals from each group had no detectable infection in the brain, spinal cord, or a site of secondary infection, the lungs. In contrast, four of seven controls showed mild to severe meningitis, with arteritis detected in three animals. In a short-term organ clearance study, 5 days of treatment with 10 or 50 mg/kg BID itraconazole or fluconazole reduced the tissue burdens in the brain and spinal cord compared to the tissue burdens in the controls (P < 0.02 to 0.0003). Fluconazole at 10 mg/kg did not reduce the fungal burden in secondary sites, the lungs and kidneys, whereas this itraconazole dose was more effective in clearing the fungi from both organs (P < 0.05 and P < 0.001, respectively). At 50 mg/kg, itraconazole and fluconazole were equivalent in clearing the fungi from the brain and kidney, but itraconazole was superior to fluconazole in clearing the fungi from the spinal cord and lungs (P < 0.05). Thus, both itraconazole and fluconazole were effective at controlling CM, but neither eliminated Coccidioides from tissues. Overall, itraconazole was more efficacious on an mg/kg basis; at high doses they were similarly effective.

FIG. 1.

Cumulative mortality of CD-1 mice infected intrathecally with 30 viable arthroconidia of C. immitis and given cyclodextrin (control), itraconazole, or fluconazole at the indicated doses. Therapies (Rx) were given BID by gavages on days 3 to 14 of infection. Five mice in each treatment group were randomly selected and euthanized on day 16 of infection for the quantitation of tissue burdens. n, numbers of mice per group; P < 0.001 (either treatment) versus the results for the control (log rank test).

FIG. 2.

Cumulative mortality of CD-1 mice infected intrathecally with 36 viable arthroconidia of C. immitis and given cyclodextrin (control), itraconazole, or fluconazole at the indicated dosages. Therapies were given BID by gavages on days 3 to 14 of infection.

FIG. 3.

Scattergram plot of individual CFU burdens on day 28 postinfection in the brains, spinal cords, and lungs of mice with CM. Itraconazole, fluconazole, and cyclodextrin were given BID through days 3 to 14 of infection. For the analysis of the fungal burdens in the surviving animals, a value of 8 log₁₀ CFU/g was given to missing datum points (due to the death of the animal) (21, 27). Horizontal lines, median log₁₀ of numbers of CFU/g tissue; *, P < 0.001 versus the results for the control; †, P < 0.05 for the results for ICZ versus the results for FCZ at 25 mg/kg; ‡, P < 0.005 for the results for ICZ versus the results for FCZ at 25 mg/kg.

FIG. 4.

Scattergram plot of individual CFU burdens on day 8 postinfection in the brains, spinal cords, lungs, and kidneys of mice that were treated with cyclodextrin (control), itraconazole, or fluconazole at the indicated dosages. Therapies were given BID on days 3 to 7 of infection. Horizontal lines, median numbers of CFU/organ for 9 or 10 mice.