Efficacy of antifungal therapy in a nonneutropenic murine model of zygomycosis

Abstract

Three isolates of zygomycetes belonging to three different genera (Rhizopus microsporus, Absidia corymbifera, and Apophysomyces elegans) were used to produce a disseminated infection in nonimmunocompromised mice. The therapeutic efficacy of amphotericin B, given intraperitoneally at doses ranging from 0.5 to 4.5 mg/kg of body weight/day, oral itraconazole at 100 mg/kg/day, and oral terbinafine at 150 mg/kg/day was evaluated in this model. The markers of antifungal efficacy were the median survival time, the mortality rate, and the percentage of infected organs. Organ culture was performed along with microscopic direct examinations of tissues to assess the presence of an active infection. An acute and lethal infection was obtained in untreated mice challenged with each of the three strains. The data obtained for direct examinations and qualitative cultures indicate that, due to the nonseptate nature of the hyphae, each technique gives different information and should be used together with the others. Against all three strains, amphotericin B yielded a 90 to 100% survival rate. Itraconazole was inactive against R. microsporus but significantly reduced mortality in mice infected with A. corymbifera or A. elegans. Terbinafine had no beneficial effects against R. microsporus and A. corymbifera despite documented absorption of the drug. Overall, only limited correlations were observed between MICs determined in vitro and in vivo efficacy of the drugs. The efficacy of itraconazole in these models of zygomycosis suggests that this drug, as well as the new azole compounds presently under development, warrants close evaluation.

FIG. 1.

Cumulative mortality for mice infected with strain R. microsporus AZN 1185 (A), A. corymbifera AZN 4095 (B), and A. elegans AZN 1829 (C) in treated and control groups. Each experiment was done once with 10 mice in each treated group and 20 mice in the control group. Mice were treated for 10 days starting 2 h after inoculation. ▴, itraconazole at 100 mg/kg of body weight/day given by gavage; ▪, amphotericin B at 4.5 mg/kg/day given intraperitoneally; ▾, terbinafine at 150 mg/kg/day given by gavage; ⧫, 5% glucose control.

FIG. 1.

Cumulative mortality for mice infected with strain R. microsporus AZN 1185 (A), A. corymbifera AZN 4095 (B), and A. elegans AZN 1829 (C) in treated and control groups. Each experiment was done once with 10 mice in each treated group and 20 mice in the control group. Mice were treated for 10 days starting 2 h after inoculation. ▴, itraconazole at 100 mg/kg of body weight/day given by gavage; ▪, amphotericin B at 4.5 mg/kg/day given intraperitoneally; ▾, terbinafine at 150 mg/kg/day given by gavage; ⧫, 5% glucose control.