Review of the Novel Echinocandin Antifungal Rezafungin: Animal Studies and Clinical Data

Zhao, Yanan; Perlin, David S.

doi:10.3390/jof6040192

Cited by 32 publications

(25 citation statements)

References 30 publications

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“…In previous studies with rezafungin in immunosuppressed mouse models of prophylaxis and treatment, we reported the inhibition of growth (but not clearance) of all life cycle stages of P. murina [ 22 , 23 ]. Thus, the objectives of the present study were 2-fold: to identify the precise dose and duration of rezafungin (1) that completely prevented infection in the prophylactic mouse model and (2) that eliminated established infection in the treatment mouse model of PCP.…”

Section: Introductionmentioning

confidence: 99%

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

Cushion

Ashbaugh

2021

JoF

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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.

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Section: Introductionmentioning

confidence: 99%

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

Cushion

Ashbaugh

2021

JoF

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“…Structural modification may also help improve the solubility and stability of such drugs in addition to expanding their antibacterial spectra [ 20 ]. Moreover (as can be seen from Table 1 ), the antifungal targets of many antifungal peptides from different sources overlap.…”

Section: Microorganisms Producing Antifungal Peptidesmentioning

confidence: 99%

Activity and Mechanism of Action of Antifungal Peptides from Microorganisms: A Review

et al. 2021

Molecules

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Harmful fungi in nature not only cause diseases in plants, but also fungal infection and poisoning when people and animals eat food derived from crops contaminated with them. Unfortunately, such fungi are becoming increasingly more resistant to traditional synthetic antifungal drugs, which can make prevention and control work increasingly more difficult to achieve. This means they are potentially very harmful to human health and lifestyle. Antifungal peptides are natural substances produced by organisms to defend themselves against harmful fungi. As a result, they have become an important research object to help deal with harmful fungi and overcome their drug resistance. Moreover, they are expected to be developed into new therapeutic drugs against drug-resistant fungi in clinical application. This review focuses on antifungal peptides that have been isolated from bacteria, fungi, and other microorganisms to date. Their antifungal activity and factors affecting it are outlined in terms of their antibacterial spectra and effects. The toxic effects of the antifungal peptides and their common solutions are mentioned. The mechanisms of action of the antifungal peptides are described according to their action pathways. The work provides a useful reference for further clinical research and the development of safe antifungal drugs that have high efficiencies and broad application spectra.

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“…Based on these data, two clinical trials are ongoing to determine the efficacy of caspofungin in non-HIV patients with PCP (NCT02603575, NCT03978559). Another echinocandin, rezafungin [ 91 ], has shown prophylactic efficacy against Pneumocystis in an immunosuppressed mouse model by a reduction in nuclei and asci counts [ 92 ]. In addition, rezafungin was shown to limit Pneumocystis reactivation following cessation of therapy in the same mouse model [ 93 ].…”

Section: Drug Treatmentsmentioning

confidence: 99%

Pneumocystis Pneumonia: Immunity, Vaccines, and Treatments

2021

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For individuals who are immunocompromised, the opportunistic fungal pathogen Pneumocystis jirovecii is capable of causing life-threatening pneumonia as the causative agent of Pneumocystis pneumonia (PCP). PCP remains an acquired immunodeficiency disease (AIDS)-defining illness in the era of antiretroviral therapy. In addition, a rise in non-human immunodeficiency virus (HIV)-associated PCP has been observed due to increased usage of immunosuppressive and immunomodulating therapies. With the persistence of HIV-related PCP cases and associated morbidity and mortality, as well as difficult to diagnose non-HIV-related PCP cases, an improvement over current treatment and prevention standards is warranted. Current therapeutic strategies have primarily focused on the administration of trimethoprim-sulfamethoxazole, which is effective at disease prevention. However, current treatments are inadequate for treatment of PCP and prevention of PCP-related death, as evidenced by consistently high mortality rates for those hospitalized with PCP. There are no vaccines in clinical trials for the prevention of PCP, and significant obstacles exist that have slowed development, including host range specificity, and the inability to culture Pneumocystis spp. in vitro. In this review, we overview the immune response to Pneumocystis spp., and discuss current progress on novel vaccines and therapies currently in the preclinical and clinical pipeline.

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Review of the Novel Echinocandin Antifungal Rezafungin: Animal Studies and Clinical Data

Cited by 32 publications

References 30 publications

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

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

Activity and Mechanism of Action of Antifungal Peptides from Microorganisms: A Review

Pneumocystis Pneumonia: Immunity, Vaccines, and Treatments

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