Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients

Playford EG, Webster AC, Sorrell TC, Craig JC

Published Online:

January 21, 2009

Critically ill patients are at risk of invasive fungal infections, such as those affecting the bloodstream and other organs. Once established, such infections are difficult to treat and result in a high mortality. Results from 12 randomized trials demonstrate that the administration of antifungal drugs to critically ill patients reduces the incidence of invasive fungal infections by about one half and reduces mortality by about one quarter. Although no increase in adverse effects or resistance amongst fungi was reported by these studies, such effects are not excluded. However, concerns that the widespread use of antifungal drugs may promote resistance amongst fungi justify their selective use in patients at greatest risk of fungal infections.

Abstract (click to read)

Background:

Invasive fungal infections, important causes of morbidity and mortality in critically ill patients, may be preventable with the prophylactic administration of antifungal agents.

Objectives:

This study aims to systematically identify and summarize the effects of antifungal prophylaxis in non-neutropenic critically ill adult patients on all-cause mortality and the incidence of invasive fungal infections.

Search strategy:

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 3, 2005), MEDLINE (1966 to 2 September 2005), and EMBASE (1980 to week 36, 2005). We also handsearched reference lists, abstracts of conference proceedings and scientific meetings (1998 to 2004), and contacted authors of included studies and pharmaceutical manufacturers.

Selection criteria:

We included randomized controlled trials in all languages comparing the prophylactic use of any antifungal agent or regimen with placebo, no antifungal, or another antifungal agent or regimen in non-neutropenic critically ill adult patients.

Data collection and analysis:

Two authors independently applied selection criteria, performed quality assessment, and extracted data using an intention-to-treat approach. We resolved differences by discussion. We synthesized data using the random effects model and expressed results as relative risk with 95% confidence intervals.

Main results:

We included 12 unique trials (eight comparing fluconazole and four ketoconazole with no antifungal or a nonabsorbable agent) involving 1606 randomized patients. For both outcomes of total mortality and invasive fungal infections, almost all trials of fluconazole and ketoconazole separately showed a non-significant risk reduction with prophylaxis. When combined, fluconazole/ketoconazole reduced total mortality by about 25% (relative risk 0.76, 95% confidence interval 0.59 to 0.97) and invasive fungal infections by about 50% (relative risk 0.46, 95% confidence interval 0.31 to 0.68). We identified no significant increase in the incidence of infection or colonization with the azole-resistant fungal pathogens Candida glabrata or C. krusei, although the confidence intervals of the summary effect measures were wide. Adverse effects were not more common amongst patients receiving prophylaxis. Results across all trials were homogeneous despite considerable heterogeneity in clinical and methodological characteristics.

Authors' conclusions:

Prophylaxis with fluconazole or ketoconazole in critically ill patients reduces invasive fungal infections by one half and total mortality by one quarter. Although no significant increase in azole-resistant Candida species associated with prophylaxis was demonstrated, trials were not powered to exclude such an effect. In patients at increased risk of invasive fungal infections, antifungal prophylaxis with fluconazole should be considered.

This record should be cited as:

Playford EG, Webster AC, Sorrell TC, Craig JC. Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD004920. DOI: 10.1002/14651858.CD004920.pub2

Assessed as up to date:

November 8, 2005

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Primary Review Group:

Anaesthesia Group

Health topics:

Anaesthesia & pain control > Post-anaesthetic unit/intensive care unit > Sepsis & critical care

Infectious disease > Sepsis & critical care

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Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients

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