Fungaemia caused by Candida glabrata with reduced susceptibility to fluconazole due to altered gene expression: Risk factors, antifungal treatment and outcome

Tumbarello, Mario; Sanguinetti, Maurizio; Trecarichi, Enrico Maria; La Sorda, Marilena; Rossi, Marianna; de Carolis, Elena; de Gaetano Donati, Katleen; Fadda, Giovanni; Cauda, Roberto; Posteraro, Brunella

doi:10.1093/jac/dkn381

Cited by 53Antifungal resistance and susceptibilityFungal Infections and StudiesFungal and yeast genetics research

Fungaemia caused by Candida glabrata with reduced susceptibility to fluconazole due to altered gene expression: Risk factors, antifungal treatment and outcome

Tumbarello, Mario, Sanguinetti, Maurizio, Trecarichi, Enrico Maria, La Sorda, Marilena, Rossi, Marianna, de Carolis, Elena, de Gaetano Donati, Katleen, Fadda, Giovanni +2 more·2008·Journal of Antimicrobial Chemotherapy

DOI 10.1093/jac/dkn381

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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.

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Alterations in PDR1 have been described as the main mechanism for enhancement of azole resistance in C. glabrata, with efflux pumps often induced during azole therapy.
“Alterations in this transcription factor have been described as the main mechanism for the enhancement of azole resistance in C. glabrata, with efflux pumps often induced during azole therapy [99].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [99]

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Authors: Tumbarello, M., Sanguinetti, M., Trecarichi, E. M., La Sorda, M., Rossi, M., de Carolis, E., de Gaetano Donati, K., Fadda, G., Cauda, R., & Posteraro, B.
Affiliations: Università Cattolica del Sacro Cuore (IT)
Corresponding author: Posteraro, Brunella
ORCID: Tumbarello, Mario
Sanguinetti, Maurizio
Trecarichi, Enrico Maria
Cauda, Roberto
Posteraro, Brunella
Venue: Journal of Antimicrobial Chemotherapy
Publisher: Oxford University Press (OUP)
Published: 2008-09-08
Volume: 62
Issue: 6
Pages: 1379-1385
ISSN: 0305-7453 (ISSN-L)
1460-2091
DOI: 10.1093/jac/dkn381
OpenAlex: W2117131280
Cited by: 53
References: 46
Citations by year: 2026: 1 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 4 · 2017: 3 · 2015: 5 · 2014: 4 · 2013: 4 · 2012: 9
FWCI: 2.77
Type: journal article
Language: en
Open access: closed
Locations: Journal of Antimicrobial Chemotherapy (publishedVersion)
PubMed (publishedVersion)
HighWire Press Open Archive (submittedVersion)
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords: Candida glabrata, fungemia, fluconazole resistance, drug efflux pumps, gene expression, risk factors, central venous catheters, diabetes mellitus, previous surgery, antifungal therapy, mortality, hospitalized patients, invasive candidiasis, antifungal susceptibility
MeSH terms: Aged, Antifungal Agents, Candidiasis, Female, Fungal Proteins, Humans, Male, Middle Aged, Risk Factors, Fluconazole, Multivariate Analysis, Case-Control Studies, Fungemia, Treatment Outcome, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Drug Resistance, Fungal, Membrane Transport Proteins, Candida glabrata

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Fungaemia caused by Candida glabrata with reduced susceptibility to fluconazole due to altered gene expression: Risk factors, antifungal treatment and outcome

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