The use of antifungal interventions in critically ill patients prior to invasive fungal infection (IFI) being microbiologically confirmed as well as the preferred drug are still controversial. A systematic literature search was performed to identify randomized controlled trials (RCTs) that have compared untargeted antifungal treatments applied to non-neutropenic critically ill patients. The primary outcomes were all-cause mortality and proven IFI rates. A random-effects model was used with trial sequential analyses (TSA), a network meta-analysis (NMA) was conducted to obtain indirect evidence, and a cost-effectiveness analysis using a decision-analytic model was completed from the patient perspective over a lifetime horizon. In total, 19 RCTs involving 2556 patients (7 interventions) were included. Untargeted antifungal treatment did not significantly decrease all-cause mortality (odds ratio [OR]=0.89, 95% confidence interval [CI]=0.70--1.14), but it did reduce the incidence of proven IFI (OR=0.45, 95%CI=0.29--0.71) relative to placebo/no intervention. The TSA showed that there was sufficient evidence supporting these findings. In the NMA, the only significant difference found for both primary outcomes was between fluconazole and placebo/no intervention in preventing proven IFI (OR=0.35, 95%CI=0.19--0.65). The incremental cost-effectiveness ratios per life-years saved for fluconazole, caspofungin, and micafungin relative to placebo/no intervention were US$ 889, US$ 9994 and US$ 10351, respectively. Untargeted antifungal treatment significantly reduced proven IFI rates in non-neutropenic critically ill patients but with no mortality benefits relative to placebo/no intervention. Fluconazole remains an only effective for IFI prevention and well-tolerated antifungals that is significantly cheaper than echinocandins.
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