What is the role of isavuconazole (Cresemba) in the treatment of mucormycosis (zygomycosis)?

Updated: Jul 06, 2021
  • Author: Avnish Sandhu, DO; Chief Editor: Pranatharthi Haran Chandrasekar, MBBS, MD  more...
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Answer

Isavuconazole (Cresemba) is a novel triazole antifungal agent that was approved for the treatment of mucormycosis in March 2015. The prodrug isavuconazonium sulfate is rapidly metabolized by serum butylcholinesterase to the active form, isavuconazole (ISZ). [75]

The efficacy of isavuconazole in the treatment of invasive mucormycosis has not been evaluated in randomized controlled trials because of the rarity of this disease. The approval of this medication was based on a noncomparative, single-arm, open-label, matched, case-control trial (VITAL). Of 149 patients enrolled, 37 had proven (86%) or probable (14%) mucormycosis. Twenty-one patients received primary treatment with ISZ, whereas 11 patients received isavuconazole salvage therapy; 5 were intolerant to other antifungals. Controls treated with amphotericin (67% liposomal, 12% lipid complex, 21% deoxycholate) were matched from the Fungiscope Registry. Isavuconazole- and amphotericin-treated patients had similar day-42 weighted all-cause mortality at 33% and 41%, respectively. Patients received isavuconazole for a median of 84 days versus 18 for amphotericin, suggesting more favorable tolerability. [86]  ECMM recommends isavuconazole with moderate strength as first-line treatment. [39] Isavuconazole brain penetration is low in necrotic center, however it is adequate in inflammatory brain tissue, comparable to plasma concentration. [87] Isavuconazole was efficacious in Mucorales CNS infection in a retrospective study. [88]

Isavuconazole offers several advantages over other triazoles (ie, posaconazole, voriconazole), apart from its wider spectrum of antifungal activity. The drug has excellent oral bioavailability not reliant on food intake or gastric pH and is also available in an intravenous formulation, which does not contain the nephrotoxic solubilizing agent cyclodextrin. Switching between oral and IV forms does not require dose adjustment. ISZ displays linear and predictable pharmacokinetics with minimal CYP3A4 interactions, reducing or eliminating the need for therapeutic drug monitoring. Unlike voriconazole, ISZ does not cause phototoxicity, increased risk of squamous cell carcinoma, or visual disturbance. The clinical significance of ISZ-related QTc shortening is unknown, but it is reasonable to avoid this medication in patients with familial short QT syndrome and to avoid co-administrating with sodium channel–blocking antiepileptics. [89]

Given the highly variable, species-dependent susceptibility pattern of the Mucorales to isavuconazole, clinical susceptibility testing may be indicated in some situations. [90]


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