Schuster 2008.

Methods	Multicentre, randomized, parallel‐group study Duration of the study: 1995 to 2000 Patients excluded/patients randomized: 21/270 (8%) Sample size calculation/method described: Yes/Yes
Participants	Patients randomized: 270 Age (mean): 53 years (treatment group), 51 years (placebo group) Sex: 192 men, 57 women Inclusion criteria: age 18 years or older, ICU stay of at least 96 consecutive hours, APACHE II score within 24 hours of randomization of 16 or more, four days of fever (defined as temperature > 38.3 °C on three separate occasions at least 12 hours apart within 72 hours before study entry, with at least one temperature spike within 12 hours of study entry), broad‐spectrum antibiotics (both gram‐positive and gram‐negative coverage) for at least 4 of the preceding six days, and the presence of a central venous catheter for at least 24 hours before study entry Exclusion criteria: serum aspartate aminotransferase, alanine aminotransferase, or total bilirubin levels greater than 5 times the upper limit of normal; neutropenia (absolute neutrophil count < 1.0 x 109 cells/L); AIDS or HIV with CD4 count less than 0.5 x 109 cells/L; immunosuppressive treatment for organ or bone marrow transplantation; and ICU admission due to burn injury. Further exclusion criteria were receipt of terfenadine, cisapride, or any investigational drug within 14 days before study enrolment; evidence of an invasive fungal infection within seven days before study entry; life expectancy of 48 hours or less; or previous enrolment in the study Percentage post‐surgical: 52% Percentage colonized with Candida at baseline: 21%
Interventions	1. Fluconazole 800 mg/day IV (n = 133) 2. Placebo (n = 137) Duration of the intervention: 14 days
Outcomes	Mortality Proven IFI Proven IFI azole‐resistant Candida species Fungal colonization Adverse events requiring cessation Follow‐up duration: 30 days after the study drug was discontinued
Type of antifungal treatment	Empiric
Funding sources	Quote: "Grant Support: By Pfizer, New York, New York. Our study was initiated and designed by investigators. Pfizer (New York, New York) sponsored and monitored the trial, assisted in protocol development and creation of the case report form, provided the study drug, and maintained the database. The sponsor assisted in analysis but not in interpretation of the data. The sponsor was not involved in the decision to publish the results"
Declaration of interest among the primary researchers	Quote: "Employment: H. Panzer (Pfizer), P. Biswas (Pfizer). Consultancies: J.E. Edwards (Merck & Co. Pfizer, Cerexa, Eisai, Enzon), J.D. Sobel (Merck & Co., Pfizer, Ther‐ Rx/KV Pharmaceutical), S. Hadley (Pfizer, Schering‐Plough). Honoraria: J.D. Sobel (Merck & Co., Pfizer, Astellas). Stock ownership or options (other than mutual funds): H. Panzer (Pfizer). Grants received: M.G. Schuster (Pfizer), J.E. Edwards (Merck & Co., Pfizer, Astellas), J.D. Sobel (Merck, Pfizer), S. Hadley (Pfizer, Astellas). Grants pending: J.E. Edwards (Pfizer). Other: R.O. Darouiche (Pfizer Speakers’ Bureau)"
Notes	Country: USA Setting: 26 centres, ICU
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Randomization was stratified by site and generated centrally by computer”
Allocation concealment (selection bias)	Low risk	Quote: “Study drugs were assigned through a telephone call from the pharmacist to a central interactive voice‐response system”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “Participants and all members of the study and health care team, except the investigational pharmacist, were blinded to study drug assignment”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “Participants and all members of the study and health care team, except the investigational pharmacist, were blinded to study drug assignment”
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: missing outcome data balanced in numbers across groups, with similar reasons for missing data across groups
Selective reporting (reporting bias)	Low risk	Comment: the study protocol was not available but it was clear that the published report included all expected outcomes
Other bias	Low risk	The study appears to have been free of other sources of bias