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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.

Background: The beta-binomial model is one of the methods that can be used to validly combine event rates from overdispersed binomial data. Our objective is to provide a full description of this method and to update and broaden its applications in clinical and public health research., Methods: We describe the statistical theories behind the beta-binomial model and the associated estimation methods. We supply information about statistical software that can provide beta-binomial estimations. Using a published example, we illustrate the application of the beta-binomial model when pooling overdispersed binomial data., Results: In an example regarding the safety of oral antifungal treatments, we had 41 treatment arms with event rates varying from 0% to 13.89%. Using the beta-binomial model, we obtained a summary event rate of 3.44% with a standard error of 0.59%. The parameters of the beta-binomial model took the values of 1.24 for alpha and 34.73 for beta., Conclusion: The beta-binomial model can provide a robust estimate for the summary event rate by pooling overdispersed binomial data from different studies. The explanation of the method and the demonstration of its applications should help researchers incorporate the beta-binomial method as they aggregate probabilities of events from heterogeneous studies.

Purpose: We estimated the absolute risks of treatment termination and incidence of adverse liver outcomes among all commonly used oral antifungal treatments for superficial dermatophytosis and onychomycosis., Methods: MEDLINE, EMBASE, and Cochrane Library were searched to identify randomized and nonrandomized controlled trials, case series, and cohort studies published before December 31, 2005. Two reviewers independently applied selection criteria, performed quality assessment, and extracted data. Treatment arms with the same regimen in terms of drug, type (continuous or intermittent), and dosage were combined to estimate the risk of an outcome of interest., Results: We identified 122 studies with approximately 20,000 enrolled patients for planned comparison. The pooled risks (95% confidence intervals) of treatment discontinuation resulting from adverse reactions for continuous therapy were 3.44% (95% confidence interval [CI], 2.28%-4.61%) for terbinafine 250 mg/day; 1.96% (95% CI, 0.35%-3.57%) for itraconazole 100 mg/day; 4.21% (95% CI, 2.33%-6.09%) for itraconazole 200 mg/day; and 1.51% (95% CI, 0%-4.01%) for fluconazole 50 mg/day. For intermittent therapy, the pooled risks were as follows: pulse terbinafine: 2.09% (95% CI, 0%-4.42%); pulse itraconazole: 2.58% (95% CI, 1.15%-4.01%); intermittent fluconazole 150 mg/week: 1.98% (95% CI, 0.05%-3.92%); and intermittent fluconazole 300 to 450 mg/week: 5.76% (95% CI, 2.42%-9.10%). The risk of liver injury requiring termination of treatment ranged from 0.11% (continuous itraconazole 100 mg/day) to 1.22% (continuous fluconazole 50 mg/day). The risk of having asymptomatic elevation of serum transaminase but not requiring treatment discontinuation was less than 2.0% for all treatment regimens evaluated., Conclusion: Oral antifungal therapy against superficial dermatophytosis and onychomycosis, including intermittent and continuous terbinafine, itraconazole, and fluconazole, was associated with a low incidence of adverse events in an immunocompetent population.

In this meta-analysis, the authors evaluated the hepatotoxicity of antifungal agents in the treatment of invasive fungal infections, and examined whether hepatotoxicity was the cause of treatment discontinuation and study withdrawal. The risk of hepatotoxicity was higher in patients with aspergillosis compared with those with candidiasis. Voriconazole, itraconazole, and amphotericin B formulations were the antifungal agents associated with the highest risks of hepatotoxicity. [ABSTRACT FROM AUTHOR]