title: Fungaemia caused by Candida glabrata with reduced susceptibility to fluconazole due to altered gene expression: risk factors, antifungal treatment and outcome.
abstract: BACKGROUND
  The role of Candida glabrata in fungaemia is attributed in part to its reduced susceptibility to azoles, usually due to altered expression of genes encoding drug efflux pumps. The aims of this study were to identify risk factors for fungaemia due to C. glabrata isolates with decreased susceptibility to fluconazole and to analyse the response to antifungal treatment and the clinical outcome of C. glabrata infections in hospitalized patients.
  
  
  METHODS
  A retrospective case-case-control study was conducted at a university hospital from 2000 to 2006. Three patient groups were studied: 14 patients infected by a fluconazole-less-susceptible isolate [susceptible-dose-dependent (SDD) or resistant]; 21 patients infected by a fluconazole-susceptible (FS) isolate; and 70 uninfected controls. We measured expression of the drug efflux pump-encoding CgCDR1 and CgCDR2 genes in isolates of the two infected groups using quantitative real-time PCR.
  
  
  RESULTS
  Multivariable analysis found that patients with prior fluconazole use [odds ratio (OR) 12.24, 95% confidence intervals (CIs) 1.77-84.39, P = 0.01], diabetes (OR 10.47, 95% CI 1.96-55.96, P = 0.006) and a central venous catheter (CVC) (OR 8.48, 95% CI 1.82-39.36, P = 0.006) were more likely to develop fungaemia due to a less-susceptible isolate. Previous surgery (OR 7.73, 95% CI 2.18-27.41, P = 0.002) was an independent risk factor for fungaemia due to a susceptible isolate, in addition to the presence of a CVC (OR 5.48, 95% CI 1.69-17.72, P = 0.004). The crude 30 day mortality rate was high for both case groups. Seven patients received inadequate antifungal treatment, including five infected by a fluconazole-resistant isolate but empirically treated with fluconazole; six of these seven patients died. Expression of the CgCDR genes was up-regulated in all fluconazole-resistant and, to a lesser extent, SDD isolates, but not in the FS isolates.
  
  
  CONCLUSIONS
  Our data suggest that when candidaemia is suspected or detected, a more broad-spectrum antifungal drug (i.e. echinocandins or amphotericin B) should be considered as initial treatment for patients with prior azole exposure.
authors.affiliation: Institute of Infectious Diseases, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Tumbarello
authors.forename: Maurizio
authors.initials: M
authors.lastname: Sanguinetti
authors.forename: Enrico Maria
authors.initials: EM
authors.lastname: Trecarichi
authors.forename: Marilena
authors.initials: M
authors.lastname: La Sorda
authors.forename: Marianna
authors.initials: M
authors.lastname: Rossi
authors.forename: Elena
authors.initials: E
authors.lastname: de Carolis
authors.forename: Katleen
authors.initials: K
authors.lastname: de Gaetano Donati
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fadda
authors.forename: Roberto
authors.initials: R
authors.lastname: Cauda
authors.forename: Brunella
authors.initials: B
authors.lastname: Posteraro
mesh_terms: D000368:Aged; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D041221:Candida glabrata / Q000187:drug effects* / Q000302:isolation & purification; D002177:Candidiasis / Q000188:drug therapy* / Q000453:epidemiology / Q000382:microbiology* / Q000401:mortality; D016022:Case-Control Studies; D025141:Drug Resistance, Fungal; D005260:Female; D015725:Fluconazole / Q000494:pharmacology / Q000627:therapeutic use*; D005656:Fungal Proteins / Q000096:biosynthesis; D016469:Fungemia / Q000188:drug therapy* / Q000453:epidemiology / Q000382:microbiology* / Q000401:mortality; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000096:biosynthesis; D008875:Middle Aged; D015999:Multivariate Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; D015725:Fluconazole