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Fluconazole non-susceptible breakthrough candidemia after prolonged low-dose prophylaxis: a prospective FUNGINOS study

Christina Orasch, Dominik Mertz, Jorge Garbino, Christian Van Delden, Stephane Emonet, Jacques Schrenzel, Stefan Zimmerli, Lauro Damonti, Konrad Mühlethaler, Alexander Imhof, Christian Ruef, Jan Fehr, Reinhard Zbinden, Katia Boggian, Thomas Bruderer, Ursula Flückiger, Anna Conen, Nina Khanna, Reno Frei, Thomas Bregenzer, Frédéric Lamoth, Véronique Erard, Pierre-Yves Bochud, Thierry Calandra, Jacques Bille, Oscar Marchetti & Fungal Infection Network Of Switzerland (FUNGINOS)

abstract

OBJECTIVES
Breakthrough candidemia (BTC) on fluconazole was associated with non-susceptible Candida spp. and increased mortality. This nationwide FUNGINOS study analyzed clinical and mycological BTC characteristics.

METHODS
3-year prospective study in 567 consecutive candidemias. Species identification and susceptibility testing (CLSI) in reference laboratory. Data analysis according to STROBE criteria.

RESULTS
43/576 (8%) BTC were studied: 37/43 (86%) on fluconazole (28 prophylaxis, median 200mg/day). 21% BTC vs. 23% non-BTC presented severe sepsis/septic shock. Overall mortality was 34% vs. 32%. BTC was associated with gastrointestinal mucositis (multivariate OR 5.25, 95%CI 2.23-12.40, p<0.001) and graft-versus-host-disease (6.25, 1.00-38.87, p=0.05), immunosuppression (2.42, 1.03-5.68, p=0.043), parenteral nutrition (2.87, 1.44-5.71, p=0.003). Non-albicans Candida were isolated in 58% BTC vs. 35% non-BTC (p=0.005). 63% of 16 BTC occurring after 10-day fluconazole were non-susceptible (Candida glabrata, Candida krusei, Candida norvegensis) vs. 19% of 21 BTC (C. glabrata) following shorter exposure (7.10, 1.60-31.30, p=0.007). Median fluconazole MIC was 4mg/l vs. 0.25mg/l (p<0.001). Ten-day fluconazole exposure predicted non-susceptible BTC with 73% accuracy.

CONCLUSIONS
Outcome of BTC and non-BTC was similar. Fluconazole non-susceptible BTC occurred in three out of four cases after prolonged low-dose prophylaxis. This implies reassessment of prophylaxis duration and rapid de-escalation of empirical therapy in BTC after short fluconazole exposure.
   
citation Orasch C, Mertz D, Garbino J, Van Delden C, Emonet S, Schrenzel J, Zimmerli S, Damonti L, Mühlethaler K, Imhof A, Ruef C, Fehr J, Zbinden R, Boggian K, Bruderer T, Flückiger U, Conen A, Khanna N, Frei R, Bregenzer T, Lamoth F, Erard V, Bochud P Y, Calandra T, Bille J, Marchetti O, Fungal Infection Network Of Switzerland (FUNGINOS) . Fluconazole non-susceptible breakthrough candidemia after prolonged low-dose prophylaxis: a prospective FUNGINOS study. J Infect 2018;.
   
type journal paper/review (English)
date of publishing 26-01-2018
journal title J Infect
ISSN electronic 1532-2742
PubMed 29378240
DOI 10.1016/j.jinf.2017.12.018