The Long-Acting Echinocandin, Rezafungin, Prevents Pneumocystis Pneumonia and Eliminates Pneumocystis from the Lungs in Prophylaxis and Murine Treatment Models

Rezafungin is a novel echinocandin in Phase 3 development for prevention of invasive fungal disease caused by <i>Candida</i> spp., <i>Aspergillus</i> spp. and <i>Pneumocystis jirovecii</i> in blood and marrow transplantation patients. For such patients, standard antifungal prophylaxis currently comprises an azole for <i>Candida</i> and <i>Aspergillus</i> plus trimethoprim-sulfamethoxazole (TMP-SMX) for Pneumocystis pneumonia (PCP) despite drug-drug-interactions and intolerability that may limit their use, thus, alternatives are desirable. Rezafungin demonstrates a favorable safety profile and pharmacokinetic properties that allow for once-weekly dosing in addition, to antifungal activity against these predominant pathogens. Herein, the in vivo effects of rezafungin against <i>Pneumocystis murina</i> pneumonia were evaluated in immunosuppressed mouse models of prophylaxis and treatment using microscopy and qPCR assessments. In the prophylaxis model, immunosuppressed mice inoculated with <i>P. murina</i> were administered TMP-SMX (50/250 mg/kg 1×/week or 3×/week), caspofungin (5 mg/kg 3×/week), rezafungin (20 mg/kg, 1×/week or 3×/week; 5 mg/kg, 3×/week) intraperitoneally for 2, 4, 6 and 8 weeks, then immunosuppressed for an additional 6 weeks. Rezafungin administered for 4 weeks prevented <i>P. murina</i> from developing infection after rezafungin was discontinued. In the treatment model, immunosuppressed mice with <i>P. murina</i> pneumonia were treated with rezafungin 20 mg/kg 3×/week intraperitoneally for 2, 4, 6 and 8 weeks. Treatment with rezafungin for 8 weeks resulted in elimination of <i>P. murina</i>. Collectively, these studies showed that rezafungin could both prevent infection and eliminate <i>P. murina</i> from the lungs of mice. These findings support the obligate role of sexual reproduction for survival and growth of <i>Pneumocystis</i> spp. and warrant further investigation for treatment of <i>P. jirovecii</i> pneumonia in humans.