Impact of fluconazole susceptibility on the outcome of patients with candidaemia: data from a population-based surveillance

CANDIPOP Project: B. Padilla, P. Muñoz, J. Guinea, J. R. Paño Pardo, J. García-Rodríguez, C. G. Cerrada, J. Fortún, P. Martín, E. Gómez, P. Ryan, C. Campelo, I. de los Santos, Gil, V. Buendía, B. P. Gorricho, M. Alonso, F. S. Sanz, J. M. Aguado, P. Merino, F. González Romo, M. Gorgolas, I. Gadea, J. E. Losa, A. Delgado-Iribarren, A. Ramos, Y. Romero, I. S. Romero, O. Zaragoza, M. Cuenca-Estrella, J. Rodríguez-Baño, A. I. Suarez, A. Loza, A. I. Aller García, E. Martín-Mazuelos, M. R. Pérez de Pipaón, J. Garnacho, C. Ortiz, M. Chávez, F. L. Maroto, M. Salavert, J. Pemán, J. Blanquer, D. Navarro, J. J. Camarena, R. Zaragoza, V. Abril, C. Gimeno, S. Hernández, G. Ezpeleta, E. Bereciartua, J. L. Hernández Almaraz, M. Montejo, R. A. Rivas, R. Ayarza, A. M. Planes, I. R. Camps, B. Almirante, J. Mensa, M. Almela, M. Gurgui, F. Sánchez-Reus, J. Martínez-Montauti, M. Sierra, J. P. Horcajada, L.Sorli, J. Gómez, A. Gené, M. Urrea, A. Mularoni, M.Valerio, A. Díaz-Martín, F. Puchades.
[Objectives] The clinical correlation of fluconazole antifungal susceptibility testing (AST) for Candida isolates and its integration with pharmacokinetics/pharmacodynamics (PK/PD) parameters is unclear. We analysed the impact of fluconazole minimum inhibitory concentration (MIC) values, 24-hour area under the concentration–time curve (AUC24) and AUC24/MIC ratio on the outcome of candidemic patients.
[Methods] We included 257 episodes of candidaemia treated with fluconazole monotherapy for ≥72 hours from a population-based surveillance conducted in 29 hospitals (CANDIPOP Project). AST was centrally performed by European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) microdilution methods. Primary outcome was clinical failure (30-day mortality and/or persistent candidaemia for ≥72 hours from initiation of therapy). Secondary outcomes included early (3–7 days) and late (3–30 days) mortality.
[Results] Rates of clinical failure, early and late mortality among evaluable episodes were 32.3% (80/248), 3.1% (8/257) and 23.4% (59/248). There was no relationship between fluconazole MIC values or PK/PD parameters and clinical failure. Although MIC values ≥2 mg/L by EUCAST (positive predictive value 32.1%, negative predictive value 68.7%) and ≥0.5 mg/L by CLSI (positive predictive value 34.8%, negative predictive value 74.4%) appeared to be optimal for predicting clinical failure, no significant associations remained after multivariate adjustment (odds ratio 1.67; 95% confidence interval 0.48–5.79; p 0.423). Lack of association was consistent for alternative thresholds (including proposed clinical breakpoints). The only association found for secondary outcomes was between an AUC24/MIC ratio >400 h by CLSI and early mortality (odds ratio 0.18; 95% confidence interval 0.04–0.98; p 0.026).
[Conclusions] High fluconazole MIC values did not negatively impact outcome of patients with candidaemia treated with fluconazole. No effect of PK/PD targets on the risk of clinical failure was found.
Supported in part by nonrestrictive research grants from Gilead, MSD, Astellas and Pfizer. This study was cofunded by Fundación SEIMC-GESIDA; the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III (cofinanced by the European Development Regional Fund (ERDF) ‘A Way to Achieve Europe’); and the Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015). MFR holds a ‘Juan Rodés’ clinical research contract (JR14/00036) and JG a ‘Miguel Servet’ contract (CPII15/00006), both from the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III. MFR has received honoraria for talks on behalf of Pfizer and Gilead Sciences. JG has received grant support from Astellas Pharma, MICOLAB, the Mutua Madrileña Foundation and the Spanish Health Research Fund (FIS). He has been paid for talks on behalf of Gilead Sciences, Merck Sharp & Dohme, Pfizer, Astellas Pharma, Hickma Pharmaceutica and United Medical. BA has received grant support from Gilead Sciences, Pfizer and the Instituto de Salud Carlos III. He has received honoraria for talks on behalf of Gilead Sciences, Merck Sharp & Dohme, Pfizer, Astellas Pharma and Novartis. BP has received honoraria for talks on behalf of Gilead Sciences, Merck Sharp & Dohme, Pfizer, Astellas Pharma and Novartis. MCE has received grant support from Astellas Pharma, bioMérieux, Gilead Sciences, Merck Sharp & Dohme, Pfizer, Schering Plough, Soria Melguizo SA, Ferrer International, the Europea Union, the ALBAN program, the Spanish Agency for International Cooperation, the Spanish Ministry of Culture and Education, the Spanish Health Research Fund, the Instituto de Salud Carlos III (Spanish Ministry of Economy and Competitiveness), the Ramon Areces Foundation and the Mutua Madrileña Foundation.