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.

• Authors: Teclegiorgis Gebremariam, Yiyou Gu, Shakti Singh, Therese M Kitt, Ashraf S Ibrahim
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 76 Issue 10 Pg. 2636-2639 (09 15 2021) ISSN: 1460-2091 [Electronic] England
• PMID: 34263306 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

Chemical References

• Antifungal Agents
• Nitriles
• Pyridines
• Triazoles
• liposomal amphotericin B
• isavuconazole
• Amphotericin B

Topics

• Amphotericin B
• Animals
• Antifungal Agents (therapeutic use)
• Mice
• Mucor
• Mucormycosis (drug therapy)
• Nitriles
• Pyridines
• Rhizopus
• Triazoles