Increasing Echinocandin Resistance in Candida glabrata: Clinical Failure Correlates With Presence of FKS Mutations and Elevated Minimum Inhibitory Concentrations

• Published in: Clinical infectious diseases Vol. 56; no. 12; pp. 1724 - 1732
• Main Authors: Alexander, Barbara D., Johnson, Melissa D., Pfeiffer, Christopher D., Jiménez-Ortigos, Cristina, Catania, Jelena, Booker, Rachel, Castanheira, Mariana, Messer, Shawn A., Perlin, David S., Pfaller, Michael A.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.06.2013
• Series: Editor's choice
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; and Commentaries; Antifungal Agents - pharmacology; Antifungal Agents - therapeutic use; Antifungals; ARTICLES AND COMMENTARIES; Azoles; Biological and medical sciences; Blood; Candida glabrata; Candida glabrata - drug effects; Candida glabrata - genetics; Candidiasis - drug therapy; Candidiasis - microbiology; Child; Child, Preschool; Drug resistance; Drug Resistance, Fungal; Drug therapy; Echinocandins - pharmacology; Echinocandins - therapeutic use; Female; Fungal infections; Fungal Proteins - genetics; Genes; Genetic mutation; Glucosyltransferases - genetics; Health outcomes; Humans; Infant; Infant, Newborn; Infections; Infectious diseases; Male; Medical sciences; Membrane Proteins - genetics; Microbial Sensitivity Tests; Middle Aged; Mortality; Mutation; Mutation - genetics; Pesticides; Polyenes; Retrospective Studies; Treatment Outcome; United States > US; Fungi; Infection; Resistance; Minimum inhibitory concentration; Candida glabrata; Fungi Imperfecti; Mutation; Failure; susceptibility; micafungin; resistance; echinocandin
• ISSN: 1058-4838; 1537-6591
• DOI: 10.1093/cid/cit136

Background. Fluconazole (FLC) resistance is common in C. glabrata and echinocandins are often used as first-line therapy. Resistance to echinocandin therapy has been associated with FKS1 and FKS2 gene alterations. Methods. We reviewed records of all patients with C. glabrata bloodstream infection at Duke Hospital over the past decade (2001–2010) and correlated treatment outcome with minimum inhibitory concentration (MIC) results and the presence of FKS gene mutations. For each isolate, MICs to FLC and echinocandins (anidulafungin, caspofungin, and micafungin) and FKS1 and FKS2 gene sequences were determined. Results. Two hundred ninety-three episodes (313 isolates) of C. glabrata bloodstream infection were analyzed. Resistance to echinocandins increased from 4.9% to 12.3% and to FLC from 18% to 30% between 2001 and 2010, respectively. Among the 78 FLC resistant isolates, 14.1% were resistant to 1 or more echinocandin. Twenty-five (7.9%) isolates harbored a FKS mutation. The predictor of a FKS mutant strain was prior echinocandin therapy (stepwise multivariable analysis, odds ratio, 19.647 [95% confidence interval, 7.19–58.1]). Eighty percent (8/10) of patients infected with FKS mutants demonstrating intermediate or resistant MICs to an echinocandin and treated with an echinocandin failed to respond or responded initially but experienced a recurrence. Conclusions. Echinocandin resistance is increasing, including among FLC-resistant isolates. The new Clinical and Laboratory Standards Institute clinical breakpoints differentiate wild-type from C. glabrata strains bearing clinically significant FKS1/FKS2 mutations. These observations underscore the importance of knowing the local epidemiology and resistance patterns for Candida within institutions and susceptibility testing of echinocandins for C. glabrata to guide therapeutic decision making.