Fluconazole non-susceptible breakthrough candidemia after prolonged low-dose prophylaxis: a prospective FUNGINOS study.
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
A 3-year prospective study was conducted in 567 consecutive candidemias. Species identification and antifungal susceptibility testing (CLSI) were performed in the FUNGINOS reference laboratory. Data were analyzed according to STROBE criteria.


RESULTS
43/576 (8%) BTC occurred: 37/43 (86%) on fluconazole (28 prophylaxis, median 200 mg/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), and 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 4 mg/l vs. 0.25 mg/l (p < 0.001). Ten-day fluconazole exposure predicted non-susceptible BTC with 73% accuracy.


CONCLUSIONS
Outcomes of BTC and non-BTC were 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.
['Orasch|Christina|C|', 'Mertz|Dominik|D|', 'Garbino|Jorge|J|', 'van Delden|Christian|C|', 'Emonet|Stephane|S|', 'Schrenzel|Jacques|J|', 'Zimmerli|Stefan|S|', 'Damonti|Lauro|L|', 'Mühlethaler|Konrad|K|', 'Imhof|Alexander|A|', 'Ruef|Christian|C|', 'Fehr|Jan|J|', 'Zbinden|Reinhard|R|', 'Boggian|Katia|K|', 'Bruderer|Thomas|T|', 'Flückiger|Ursula|U|', 'Conen|Anna|A|', 'Khanna|Nina|N|', 'Frei|Reno|R|', 'Bregenzer|Thomas|T|', 'Lamoth|Frédéric|F|', 'Erard|Véronique|V|', 'Bochud|Pierre-Yves|PY|', 'Calandra|Thierry|T|', 'Bille|Jacques|J|', 'Marchetti|Oscar|O|', '|||']
D000293:Adolescent D000328:Adult D000368:Aged D000369:Aged, 80 and over D000935:Antifungal Agents D002175:Candida D058387:Candidemia D002648:Child D002675:Child, Preschool D025141:Drug Resistance, Fungal D062665:Epidemiological Monitoring D005260:Female D015725:Fluconazole D006801:Humans D007223:Infant D007231:Infant, Newborn D008297:Male D008826:Microbial Sensitivity Tests D008875:Middle Aged D011446:Prospective Studies D055815:Young Adult
Fluconazole Breakthrough Candidemia FUNGINOS Candida Species Susceptibility