title: Association of fluconazole area under the concentration-time curve/MIC and dose/MIC ratios with mortality in nonneutropenic patients with candidemia.
abstract: The present study tested in vitro susceptibility of Candida bloodstream isolates to fluconazole to determine if the ratio of the fluconazole area under the concentration-time curve (AUC) or weight-normalized daily dose (dose(wn)) to MIC correlated with mortality. Fluconazole susceptibility and outcome data were determined for 77 patients with a positive Candida blood culture between 2002 and 2005. The most commonly isolated Candida species were C. albicans (64%), C. glabrata (14%), C. parapsilosis (8%), C. tropicalis (6%), and C. lusitaniae (4%). Only two isolates were classified as fluconazole resistant by the CLSI M27-A2 method. Fluconazole MICs were highest against C. glabrata relative to other Candida species. Overall the crude mortality assessed at hospital discharge was 19.4% (n = 15). Mortality rates by species were as follows: C. albicans, 16.3%; C. glabrata, 36.4%; C. parapsilosis, 0%; C. tropicalis, 0%; C. lusitaniae, 33.3%. A mortality rate of 50% was noted among patients infected with nonsusceptible isolates (MIC > or = 16 microg/ml) compared to 18% for patients infected with susceptible (MIC < or = 8 microg/ml) isolates (P = 0.17). The fluconazole dose(wn)/MIC (24-h) values were significantly higher for the 62 survivors (13.3 +/- 10.5 [mean +/- standard deviation]) compared to the 15 nonsurvivors (7.0 +/- 8.0) (P = 0.03). The fluconazole AUC/MIC (24 h) values also trended higher for survivors (775 +/- 739) compared to nonsurvivors (589 +/- 715) (P = 0.09). These data support the dose-dependent properties of fluconazole. Underdosing fluconazole against less-susceptible Candida isolates has the potential to increase the risk of mortality associated with candidemia.
authors.affiliation: University of New Mexico, Albuquerque, New Mexico, USA.
authors.forename: Manjunath P
authors.initials: MP
authors.lastname: Pai
authors.forename: Robin S
authors.initials: RS
authors.lastname: Turpin
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Garey
mesh_terms: D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D002175:Candida / Q000145:classification / Q000187:drug effects* / Q000254:growth & development; D002177:Candidiasis / Q000097:blood / Q000382:microbiology; D005260:Female; D015725:Fluconazole / Q000493:pharmacokinetics / Q000494:pharmacology*; D016469:Fungemia / Q000382:microbiology; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D013997:Time Factors
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole