Introduction
Candidemia and invasive candidiasis continue to pose high morbidity and mortality risks, especially in healthcare settings. With rising fluconazole resistance and limitations of current echinocandin treatments such as prolonged IV therapy and hospitalization—there’s a growing need for alternatives. Rezafungin, a novel echinocandin recently FDA-approved, offers a promising solution. Its once-weekly dosing due to a long half-life allows for shorter hospital stays and reduces the need for extended IV access, making it a convenient and effective option for managing invasive candidiasis and potentially for prophylaxis in high-risk patients.
Rezafungin, a modified derivative of anidulafungin, retains the antifungal action of traditional echinocandins but with improved pharmacokinetics. It has a long half-life (~133 hours), minimal drug-drug interactions, and requires no renal or hepatic dose adjustments. Early clinical trials show it to be safe and effective, with a broad spectrum against Candida species, including azole-resistant strains and Candida auris. With its favorable profile and ease of administration, rezafungin is emerging as a valuable addition in the fight against invasive fungal infections, though continued studies are needed to establish its long-term impact and role in antifungal guidelines.
CLINICAL DATA
Phase II (STRIVE) Trial Summary: STRIVE was a Phase II double-blind RCT comparing rezafungin (RZF) to caspofungin (CAS) in patients with candidemia or invasive candidiasis (IC). Three treatment groups were tested, and the primary endpoints were symptom resolution and fungal eradication. RZF 400/200 showed the highest cure rate (76.1%) and lowest mortality (4.4%). RZF cleared blood cultures faster and had a similar side effect profile to CAS. Differences between RZF doses were attributed to indeterminate cases, not efficacy.
Phase III (ReSTORE) Trial Summary: ReSTORE was a Phase III RCT comparing RZF 400/200 to CAS, with similar exclusion criteria as STRIVE but including neutropenic patients. It confirmed RZF’s non-inferiority with comparable cure rates (59% vs 61%) and mortality (24% vs 21%). Safety profiles were similar, and early response differences noted at day 5 in RZF were not significant by day 14. Candida species outcomes were also similar.
Clinical Utility of RZF: RZF’s long half-life and weekly dosing offer clinical benefits like reduced hospital stays and avoiding IV outpatient therapy. It may be especially useful in complex cases (e.g., endocarditis, osteomyelitis) where long therapy and catheter use pose risks. Case studies support RZF’s effectiveness in tough-to-treat cases like C. glabrata endocarditis.
Resistance Prevention and PK/PD Insights: Studies show RZF’s efficacy relates to its AUC:MIC ratio. Mouse models favored front-loaded dosing for better fungal killing. RZF’s longer tissue presence and higher penetration above mutant prevention concentration (MPC) may offer resistance advantages over other echinocandins.
Efficacy Against Resistant Strains: Despite some reduced in vitro susceptibility due to FKS mutations in C. glabrata, RZF maintained clinical efficacy. This suggests RZF may overcome echinocandin resistance due to its unique pharmacokinetics.
Candida auris and RZF: C. auris is a rising global threat with high mortality and resistance to multiple antifungal classes. Echinocandins, including RZF, are the first-line agents, though resistance is emerging. RZF’s efficacy against resistant isolates and its PK profile make it a promising option for managing C. auris infections.
Conclusion:
Rezafungin offers significant potential in addressing antifungal resistance due to its unique pharmacology and extended half-life. Its once-weekly dosing matches the efficacy of daily echinocandins while offering better convenience and resource optimization. With strong tolerability and promising early data, rezafungin may improve outcomes and resistance prevention, especially in high-risk patients. Ongoing trials like ReSPECT may further define its role in antifungal prophylaxis.
Source: Forrister NM, McCarty TP, Pappas PG. 2025. New Perspectives on Antimicrobial Agents: Rezafungin. Antimicrob Agents Chemother 69:e00646-23. https://doi.org/10.1128/aac.00646-23
