Systematic Review and Meta-Analysis of the Tolerability and Hepatotoxicity of Antifungals in Empirical and Definitive Therapy for Invasive Fungal Infection

Abstract

To evaluate the tolerability and liver safety profiles of the systemic antifungal agents commonly used for the treatment of invasive fungal infection, we conducted a systematic review and meta-analysis of randomized controlled trials published before 31 August 2009. Two reviewers independently applied selection criteria, performed quality assessment, and extracted data. We used the beta-binomial model to account for variation across studies and the maximum likelihood method to estimate the pooled risks. We identified 39 studies with more than 8,000 enrolled patients for planned comparisons. The incidence rates of treatment discontinuation due to adverse reactions and liver injury associated with antifungal therapy ranged widely. The pooled risks of treatment discontinuation due to adverse reactions were above 10% for amphotericin B formulations and itraconazole, whereas they were 2.5% to 3.8% for fluconazole, caspofungin, and micafungin. We found that 1.5% of the patients stopped itraconazole treatment due to hepatotoxicity. Furthermore, 19.7% of voriconazole users and 17.4% of itraconazole users had elevated serum liver enzyme levels, although they did not require treatment discontinuation, whereas 2.0% or 9.3% of fluconazole and echinocandin users had elevated serum liver enzyme levels but did not require treatment discontinuation. The results were similar when we stratified the data by empirical or definitive antifungal therapy. Possible explanations for antifungal agent-related hepatotoxicity were confounded by antifungal prescription to patients with a high risk of liver injury, the increased chance of detection of hepatotoxicity due to prolonged treatment, or the pharmacological entity.Invasive fungal infection is a leading cause of morbidity and mortality among immunocompromised and debilitated patients, including those with hematological malignancy, solid organ or bone marrow transplantation, and neutropenia and those receiving systemic corticosteroid therapy. Candida species and Aspergillus species are the two predominant causative fungi, with the case fatality rates being 30% and 50% among those infected with members of these two fungal genera, respectively (19,53). Over the past few decades, amphotericin B has been the mainstay treatment of candidiasis and aspergillosis, whereas fluconazole has been extensively used among patients with Candida albicans infection. After randomized controlled trials showed that extended-spectrum azoles (itraconazole, voriconazole, posaconazole) and echinocandins (anidulafungin, caspofungin, micafungin) had efficacies similar to those of amphotericin B and fluconazole, these newer antifungal agents have been used more frequently for the treatment of patients with probable or proven invasive fungal infection (18,32,56,59,81). Current practice guidelines recommend amphotericin B formulations, fluconazole, and echinocandins as first-line therapy for patients with candidemia; and amphotericin B formulations or voriconazole are the drugs of choice for the primary therapy of i...

Caspofungin versus fluconazole as prophylaxis of invasive fungal infection in high‐risk liver transplantation recipients: A propensity score analysis

“…Other studies performed in patients with liver disease confirm the hepatic safety of caspofungin. (10,16,(31)(32)(33) The present study is subject to a number of limitations. First, it is not a clinical trial, and selection of prophylaxis regimens could be conditioned by various circumstances in a specific case or center.…”

“…(8) The benefit of voriconazole or itraconazole, both of which are active against Aspergillus spp., is limited because of potential liver toxicity. (10) Prophylaxis with a lipid preparation of amphotericin B (AmB) significantly reduced the frequency of IFI in HR-LTRs. (11,12) However, prophylaxis with a lipid formulation of AmB may be limited by infusion-related toxicity and nephrotoxicity, particularly in patients with renal failure, a major risk factor for the development of IFI in LTRs.…”

Early invasive fungal infections and colonization in patients with cirrhosis admitted to the intensive care unit

“…The finding that non-colonized patients had higher mortality than colonized patients most likely reflects that survivors have longer ICU stay and hence higher risk of colonization. The first-line antifungal regimen was fluconazole, which is associated with lower risk of hepatotoxicity compared with other antifungals such as voriconazole and itraconazole [18].…”

Evaluation of VT-1161 for Treatment of Coccidioidomycosis in Murine Infection Models

“…Additionally, VT-1161 was rationally designed to selectively inhibit fungal CYP51 versus human CYPs (13,14), thus potentially reducing toxicity and drug-drug interactions. Azole antifungals, which target the same fungal CYP51 enzyme, are less selective and suffer from a range of toxicities directly related to the binding of human CYPs, including hepatotoxicity, drug-drug interactions due to induction or binding of liver microsome CYPs and other enzymes, limitations of metabolism, and some toxicities unique to the individual drugs (7,12,(24)(25)(26). The VT-1161 preclinical and clinical safety profiles to date show few if any of these concerns and are consistent with a reduction in binding to mammalian CYPs (14).…”