title: Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients.
abstract: BACKGROUND
  Invasive fungal infections, important causes of morbidity and mortality in critically ill patients, may be preventable with the prophylactic administration of antifungal agents.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  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.
authors.affiliation: Princess Alexandra Hospital, Infection Management Services, Ipswich Road, Woolloongabba, Queensland, Australia, 4102. geoffrey_playford@health.qld.gov.au
authors.forename: E G
authors.initials: EG
authors.lastname: Playford
authors.forename: A C
authors.initials: AC
authors.lastname: Webster
authors.forename: T C
authors.initials: TC
authors.lastname: Sorrell
authors.forename: J C
authors.initials: JC
authors.lastname: Craig
mesh_terms: D000328:Adult; D000666:Amphotericin B / Q000627:therapeutic use; D000935:Antifungal Agents / Q000627:therapeutic use*; D016638:Critical Illness / Q000401:mortality; D015725:Fluconazole / Q000627:therapeutic use; D006801:Humans; D016867:Immunocompromised Host; D009181:Mycoses / Q000401:mortality / Q000517:prevention & control*; D016032:Randomized Controlled Trials as Topic
chemical_list: D000935:Antifungal Agents; D000666:Amphotericin B; D015725:Fluconazole