To our knowledge, the present study is the first to evaluate independent risk factors for fluconazole-resistant C glabrata BSIs. We found that previous fluconazole use and linezolid use were independent risk factors for fluconazole-resistant C glabrata BSIs. Previous cefepime use and metronidazole use were independent risk factors for fluconazole-susceptible C glabrata BSIs.
Previous fluconazole use could promote either de novo resistance by 1 or more mechanisms including upregulating efflux pumps or resistance by changing a patient's endogenous flora, enabling colonization and infection with fluconazole-resistant C glabrata
Our results are similar to those of 2 previous studies in patients with cancer that identified previous fluconazole use as a risk factor for invasive C glabrata
infections (OR, 5–11).11,12
However, subsequent studies that broadened the study population to include the general inpatient population did not find this association. Several ecologic studies did not enable identification of significant increases in C glabrata
BSIs despite significant increases in fluconazole use.13,14
A case-case-control study by Lin et al15
found that previous fluconazole use was not a risk factor for C glabrata
and Candida krusei
BSIs at bivariate or multivariate analyses. Malani et al24
reported no difference in fluconazole-resistance rates between patients with and without previous fluconazole exposure. Limitations of the study by Malani et al, however, include that multivariate analysis was not performed and that the study may not have been powered to detect this difference.
The difference between the present study and previous studies in general inpatient populations may be related to case group selection. Although previous studies focused on C glabrata because of its association with fluconazole resistance, susceptibility testing was typically absent. Both patients with fluconazole-resistant and fluconazole-susceptible isolates were included in the case group. This may have decreased the ability to detect risk factors for fluconazole-resistant C glabrata, particularly given the results of this study, which found that previous fluconazole use was significantly associated with fluconazole-resistant C glabrata BSIs but not with fluconazole-susceptible C glabrata BSIs. High rates of fluconazole use in patients with cancer, however, may have resulted in higher rates of resistance in this population, enabling the investigators to find a strong association.
Linezolid use was also identified as an independent risk factor for fluconazole-resistant C glabrata
BSIs. Linezolid has broad gram-positive coverage that could alter skin and possibly gastrointestinal flora such as Enterococcus
species, enabling colonization and subsequent infection with fluconazole-resistant C glabrata
. Lin et al15
found vancomycin, another antibiotic with broad gram-positive coverage, to be an independent risk factor for C glabrata
and C krusei
Cefepime use and metronidazole use were found to be independent risk factors for fluconazole-susceptible C glabrata
BSIs. Lin et al15
identified piperacillin-tazobactam, an antimicrobial agent with both gram-negative and anaerobic coverage, as a significant risk factor for C glabrata
and C krusei
BSIs. Animal models have suggested that C glabrata
may have fewer virulence factors.25,26
If C glabrata
is less pathogenic than C albicans
, C glabrata
may require selection pressure from antecedent antibiotic use for colonization and infection. Previous studies have also suggested that Candida
infections can occur via horizontal transfer, and this mode of transmission may be particularly important in C glabrata
infections, the incidence of which increases with age.27,28
There are several potential limitations of the present study. Misclassification of risk factors is possible because data were not collected prospectively (ie, the database may be missing comorbid conditions not identified via International Classification of Diseases, Ninth Revision, coding and medications prescribed outside of the University of Pennsylvania Health System). However, the percentage of missing data is unlikely to be dissimilar between groups, and this nondifferential misclassification would bias results toward null. In addition, the study was conducted in 3 hospitals in the same city. Geographic and hospital-associated differences in the susceptibility patterns of C glabrata
have been previously demonstrated.2,29
To our knowledge, the present study is the first to evaluate independent risk factors for fluconazole-resistant C glabrata BSIs and to identify previous fluconazole use as a significant risk factor for resistance in the general inpatient population. Future studies will be needed to identify the effect of decreasing fluconazole use on the rates of fluconazole-resistant C glabrata BSIs.