Combination treatment of liposomal amphotericin B and isavuconazole is synergistic in treating experimental mucormycosis

Abstract

Objectives: Liposomal amphotericin B (L-AMB) and isavuconazonium sulphate are commonly used antifungal drugs to treat mucormycosis. However, the efficacy of combination therapy of L-AMB/isavuconazonium sulphate versus monotherapy is unknown. We used an immunosuppressed mouse model of pulmonary mucormycosis to compare the efficacy of L-AMB/isavuconazonium sulphate versus either drug alone.

Methods: Neutropenic mice were intratracheally infected with either Rhizopus delemar or Mucor circinelloides. Treatment with L-AMB, isavuconazonium sulphate, or a combination of both started 8 h post-infection and continued through to Day +4. Placebo mice received vehicle control. Survival to Day +21 and tissue fungal burden (by conidial equivalent using quantitative PCR) on Day +4, served as primary and secondary endpoints, respectively.

Results: For mice infected with R. delemar, L-AMB and isavuconazonium sulphate equally prolonged median survival time and enhanced survival versus placebo (an overall survival of 50% for either drug alone, versus 5% for placebo). Importantly, combination treatment resulted in an overall survival of 80%. Both antifungal drugs reduced tissue fungal burden of lungs and brain by ∼1.0-2.0 log versus placebo-treated mice. Treatment with combination therapy resulted in 2.0-3.5 log reduction in fungal burden of either organ versus placebo and 1.0 log reduction versus either drug alone. Similar treatment outcomes were obtained using mice infected with M. circinelloides.

Conclusions: The L-AMB/isavuconazonium sulphate combination demonstrated greater activity versus monotherapy in immunosuppressed mice infected with either of the two most common causes of mucormycosis. These studies warrant further investigation of L-AMB/isavuconazonium sulphate combination therapy as an optimal therapy of human mucormycosis.

Figure 1.

Combination therapy of L-AMB and isavuconazonium sulphate (ISAV) synergistically protects mice from R. delemar infection. (a) Mice survival (n = 20/group from two independent experiments with similar results) were infected intratracheally (average inhaled inoculum of 2.9 × 10³ spores). *P < 0.002 versus placebo, **P < 0.0001 versus placebo and P < 0.05 versus either drug alone. (b) Tissue fungal burden of lungs or brain (expressed as CE/g tissue) of mice (n = 10) euthanized on Day +4 post-infection. P values are shown on each graph and conducted by Wilcoxon rank sum test.

Figure 2.

Combination therapy of L-AMB and isavuconazonium sulphate (ISAV) synergistically protects mice from M. circinelloides infection. (a) Mice survival (n = 20/group from two independent experiments with similar results) were infected intratracheally (average inhaled inoculum of 4.6 × 10⁴ spores). *P < 0.05 versus placebo, **P < 0.0001 versus placebo and P < 0.05 versus either drug alone. (b) Tissue fungal burden of lungs or brain (expressed as CE/g tissue) of mice (n = 10) euthanized on Day +4 post-infection. P values are shown on each graph and conducted by Wilcoxon rank sum test.