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

Melanie T Cushion,Alan Ashbaugh

doi:10.3390/jof7090747

Abstract

Rezafungin is a novel echinocandin in Phase 3 development for prevention of invasive fungal disease caused by Candida spp., Aspergillus spp. and Pneumocystis jirovecii in blood and marrow transplantation patients. For such patients, standard antifungal prophylaxis currently comprises an azole for Candida and Aspergillus 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 Pneumocystis murina pneumonia were evaluated in immunosuppressed mouse models of prophylaxis and treatment using microscopy and qPCR assessments. In the prophylaxis model, immunosuppressed mice inoculated with P. murina 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 P. murina from developing infection after rezafungin was discontinued. In the treatment model, immunosuppressed mice with P. murina 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 P. murina. Collectively, these studies showed that rezafungin could both prevent infection and eliminate P. murina from the lungs of mice. These findings support the obligate role of sexual reproduction for survival and growth of Pneumocystis spp. and warrant further investigation for treatment of P. jirovecii pneumonia in humans.

Highlights

Pneumocystis jirovecii is an important fungal pathogen in immunocompromised patients [1,2,3,4,5]
In previous studies with rezafungin in immunosuppressed mouse models of prophylaxis and treatment, we reported the inhibition of growth of all life cycle stages of P. murina [22,23]
Echinocandins inhibit the synthesis of BG, an essential component of the fungal cell wall [23] found in the asci form of Pneumocystis spp

Summary

Introduction

Pneumocystis jirovecii is an important fungal pathogen in immunocompromised patients [1,2,3,4,5]. Owing to the change of nomenclature, the pneumonia can be referred to as PCP or PJP (Pneumocystis jirovecii pneumonia) in humans. Patients who are most vulnerable to developing PCP are severely immunocompromised following allogeneic hematopoietic stem cell transplantation or solid organ transplantation, those with hematological malignancies undergoing immunosuppressive chemotherapy, as well as patients with rheumatologic disorders and those with HIV infection (CD4 count < 200 cells/μL) [2,3,4,10]. Among patients hospitalized for PCP, the most prevalent host factors were malignancies (46%; 61% of the malignancies were hematologic) and HIV infection (18%) [11]

Objectives

Methods

Results

Conclusion