isavuconazole and Candidemia

Isavuconazole, the active moiety of its prodrug isavuconazonium, is a new extended-spectrum triazole whose activity against yeasts, molds, including Aspergillus and mucorales, and dimorphic fungi has been shown in vitro and in preclinical models. The most relevant pharmacokinetics features are water-solubility of the prodrug, rapid cleavage of the prodrug into active moiety and cleavage product by plasmatic esterases, high oral bioavailability of isavuconazole with an extensive penetration into most tissues and a good safety profile even in case of renal impairment. The results of two main clinical studies have led to an approval by FDA and EMA in the treatment of invasive aspergillosis and invasive mucormycosis. Isavuconazole is non-inferior to voriconazole in terms of response and survival in invasive aspergillosis and has shown improved safety and tolerability. Importantly, less hepatobiliary, skin and eye disorders have been reported in isavuconazole-treated patients. Isavuconazole has therefore been granted a grade A-I recommendation by the European Conference on Infections in Leukemia (ECIL) for the treatment of invasive aspergillosis. Efficacy has also been demonstrated in mucormycosis in an open-label study. Survival was similar to the survival of matched patients from the international Fungiscope registry and treated with an amphotericin B formulation. Isavuconazole failed to show non-inferiority to caspofungin in a large double-blind candidemia trial. The aim of this review is to give the reader an overview of the data available so far to support inclusion of isavuconazole in the anti-mold therapeutic arsenal.

Topics: Animals; Antifungal Agents; Aspergillosis; Azoles; Candidemia; Clinical Trials as Topic; Double-Blind Method; Drug Evaluation, Preclinical; Esterases; Humans; Invasive Fungal Infections; Mice; Mucormycosis; Nitriles; Pyridines; Triazoles

To review the pharmacology, chemistry, in vitro susceptibility, pharmacokinetics, clinical efficacy, safety, tolerability, dosage, and administration of isavuconazole, a triazole antifungal agent.. Studies and reviews were identified through an English language MEDLINE search (1978 to March 2015) and from http://www.clinicaltrials.gov, Food and Drug Administration (FDA) briefing documents, program abstracts from international symposia, and the manufacturer's Web site.. All published and unpublished trials, abstracts, in vitro and preclinical studies, and FDA briefing documents were reviewed.. Isavuconazole has activity against a number of clinically important yeasts and molds, including Candida spp, Aspergillus spp, Cryptococcus neoformans, and Trichosporon spp and variable activity against the Mucorales. Isavuconazole, available for both oral and intravenous administration, is characterized by slow elimination allowing once-daily dosing, extensive tissue distribution, and high (>99%) protein binding. The most commonly reported adverse events, which are mild and limited in nature, include nausea, diarrhea, and elevated liver function tests. Its drug interaction potential appears to be similar to other azole antifungals but less than those observed with voriconazole. Comparative trials are under way or have been recently completed for the treatment of candidemia, invasive candidiasis and aspergillosis, and rare mold infections.. Isavuconazole has a broad spectrum of activity and favorable pharmacokinetic properties, providing an advantage over other currently available broad-spectrum azole antifungals and a clinically useful alternative to voriconazole for the treatment of invasive aspergillosis. It may also prove useful for the treatment of candidemia and invasive mold infections; however, these indications await the results of clinical trials.

Topics: Animals; Antifungal Agents; Aspergillosis; Candidemia; Candidiasis; Candidiasis, Invasive; Clinical Trials as Topic; Drug Resistance, Fungal; Humans; Nitriles; Pyridines; Triazoles; Voriconazole

Coinciding with the continually increasing population of immunocompromised patients worldwide, the incidence of invasive fungal infections has grown over the past 4 decades. Unfortunately, infections caused by both yeasts such as Candida and molds such as Aspergillus or Mucorales remain associated with unacceptably high morbidity and mortality. In addition, the available antifungals with proven efficacy in the treatment of these infections remain severely limited. Although previously available second-generation triazole antifungals have significantly expanded the spectrum of the triazole antifungal class, these agents are laden with shortcomings in their safety profiles as well as formulation and pharmacokinetic challenges. Isavuconazole, administered as the prodrug isavuconazonium, is the latest second-generation triazole antifungal to receive U.S. Food and Drug Administration approval. Approved for the treatment of both invasive aspergillosis and invasive mucormycosis, and currently under investigation for the treatment of candidemia and invasive candidiasis, isavuconazole may have therapeutic advantages over its predecessors. With clinically relevant antifungal potency against a broad range of yeasts, dimorphic fungi, and molds, isavuconazole has a spectrum of activity reminiscent of the polyene amphotericin B. Moreover, clinical experience thus far has revealed isavuconazole to be associated with fewer toxicities than voriconazole, even when administered without therapeutic drug monitoring. These characteristics, in an agent available in both a highly bioavailable oral and a β-cyclodextrin-free intravenous formulation, will likely make isavuconazole a welcome addition to the triazole class of antifungals.

Topics: Antifungal Agents; Aspergillosis; Candidemia; Candidiasis, Invasive; Humans; Mucormycosis; Nitriles; Pyridines; Triazoles

Isavuconazole was compared to caspofungin followed by oral voriconazole in a Phase 3, randomized, double-blind, multinational clinical trial for the primary treatment of patients with candidemia or invasive candidiasis.. Adult patients were randomized 1:1 to isavuconazole (200 mg intravenous [IV] three-times-daily [TID] for 2 days, followed by 200 mg IV once-daily [OD]) or caspofungin (70 mg IV OD on day 1, followed by 50 mg IV OD [70 mg in patients > 80 kg]) for a maximum of 56 days. After day 10, patients could switch to oral isavuconazole (isavuconazole arm) or voriconazole (caspofungin arm). Primary efficacy endpoint was successful overall response at the end of IV therapy (EOIVT) in patients with proven infections who received ≥1 dose of study drug (modified-intent-to-treat [mITT] population). The pre-specified noninferiority margin was 15%. Secondary outcomes in the mITT population were successful overall response at 2 weeks after the end of treatment, all-cause mortality at days 14 and 56, and safety.. Of 450 patients randomized, 400 comprised the mITT population. Baseline characteristics were balanced between groups. Successful overall response at EOIVT was observed in 60.3% of patients in the isavuconazole arm and 71.1% in the caspofungin arm (adjusted difference -10.8, 95% confidence interval -19.9--1.8). The secondary endpoints, all-cause mortality, and safety were similar between arms. Median time to clearance of the bloodstream was comparable between groups.. This study did not demonstrate non-inferiority of isavuconazole to caspofungin for primary treatment of invasive candidiasis. Secondary endpoints were similar between both groups.. NCT00413218.

Topics: Adult; Aged; Candida; Candidemia; Candidiasis, Invasive; Caspofungin; Female; Humans; Male; Middle Aged; Nitriles; Pyridines; Treatment Outcome; Triazoles

Topics: Candida; Candidemia; Candidiasis, Invasive; Caspofungin; Humans; Nitriles; Pyridines; Triazoles

We retrospectively assessed breakthrough invasive fungal infections (b-IFIs) in 100 consecutive patients with leukemia receiving single-agent isavuconazole; 13 had documented b-IFIs (candidiasis in 6, mucormycosis in 4). All b-IFIs were observed in patients with prolonged neutropenia and active leukemia.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Candidemia; Electronic Health Records; Female; Humans; Invasive Fungal Infections; Leukemia; Male; Middle Aged; Nitriles; Pyridines; Retrospective Studies; Triazoles; Young Adult

Isavuconazole is a triazole previously shown to have potent in vitro activity against Aspergillus spp., Mucorales and Candida spp. Unlike other azoles, it is unclear whether isavuconazole induces a trailing effect. We studied isavuconazole MICs for a large collection of Candida isolates from blood samples and determined the extent of the trailing effect when using the European Committee on Antimicrobial Susceptibility Testing (EUCAST) E.Def 7.3.1 method.. A total of 762 molecularly identified Candida isolates from blood samples of 743 patients admitted to hospital (January 2007 to September 2017) were evaluated and further tested for in vitro susceptibility to isavuconazole following the EUCAST E.Def 7.3.1 test method.. C. albicans showed the highest susceptibility, followed by C. parapsilosis and C. tropicalis (geometric mean MIC 0.0029 vs. 0.0049/0.0052, respectively; p <0.001). In contrast, C. glabrata and C. krusei had significantly higher MIC values (geometric mean MIC 0.171 vs. 0.117, respectively). Isavuconazole MIC distributions were not truncated at the lowest concentration tested except for C. albicans. Overall, the mean percentage of trailing was 13.6%, but differences among species were observed: C. glabrata, C. albicans and C. tropicalis exhibited higher trailing compared to C. parapsilosis and non-Candida yeasts (p <0.001). The percentage of non-wild-type C. albicans (considering the heavy trailer isolates as wild type), C. parapsilosis and C. glabrata isolates were 1.1% (4/357), 1.5% (3/201) and 1.1% (1/86), respectively.. Isavuconazole showed high in vitro activity against Candida spp., particularly against C. albicans. A trailing effect is commonly observed with isavuconazole, particularly with C. glabrata.

Topics: Antifungal Agents; Candida; Candida albicans; Candida glabrata; Candidemia; Drug Resistance, Fungal; Humans; Microbial Sensitivity Tests; Nitriles; Pyridines; Triazoles