Fluconazole non-susceptible breakthrough candidemia after prolonged low-dose prophylaxis: a prospective FUNGINOS study
Open accessAbstract
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.
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In most large series, overall mortality at 30 days is similar for breakthrough Candida infections compared to de novo Candida infections (~30%).
“In most large series, overall mortality at 30 days is similar for BT Candida infections compared to de novo Candida infections (~30%).99,100”
From Epidemiology of Invasive Candidiasis (2024) · cites this paper as [100]
The Results report similar overall mortality in this prospective series: 34% for breakthrough candidemia versus 32% for non-breakthrough candidemia (p = 0.73). Our copy does not establish that these were 30-day mortality rates or that the same pattern holds in most large series. (LLM, conf=0.85)
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- Authors
- 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., Bregenzer, T., Conen, A., Flückiger, U., Khanna, N., Orasch, C., Heininger, U., Franciolli, M., Damonti, L., Zimmerli, S., Rothen, M., Zellweger, C., Rothen, M., Tarr, P., Fleisch, F., Chuard, C., Erard, V., Emonet, S., Garbino, J., van Delden, C., Genne, D., Bochud, P.-Y., Calandra, T., Damonti, L., Erard, V., Lamoth, F., Marchetti, O., Orasch, C., Chave, J.-P., Graber, P., Monotti, R., Bernasconi, E., Rossi, M., Krause, M., Piso, R.-J., Bally, F., Troillet, N., Boggian, K., Eich, G., Gubler, J., Fehr, J., Imhof, A., Ruef, C., Eich, G., Gubler, J., Berger, C., Fankhauser, H., Heinzer, I., Frei, R., Hertel, R., Dolina, M., Petrini, O., Dubuis, O., Mühlethaler, K., Graf, S., Risch, M., Ritzler, E., Fracheboud, D., Rohner, P., Schrenzel, J., Lienhardt, R., Bille, J., Lamoth, F., Andreutti-Zaugg, C., Gallusser, A., Graf, S., Pfyffer, G., Herzog, K., Schibli, U., Tissière, L., Bruderer, T., Schultze, D., & Zbinden, R.
- Affiliations
- McMaster University (CA)
- University Children’s Hospital Basel (CH)
- Ente Ospedaliero Cantonale (CH)
- Spitalzentrum Centre hospitalier Biel- Bienne (CH)
- Kantonsspital Baselland Standort Bruderholz (CH)
- Kantonsspital Graubünden (CH)
- University of Zurich (CH)
- Hirslanden Clinique Cecil (CH)
- Kantonsspital Baselland (CH)
- Ospedale Regionale di Locarno (CH)
- Luzerner Kantonsspital (CH)
- Kantonsspital Münsterlingen (CH)
- Hôpital du Valais (CH)
- University Children's Hospital Zurich (CH)
- Kantonsspital Aarau (CH)
- Laboratoire de Microbiologie, Adaptation et Pathogénie (FR)
- HFR Freiburg Kantonsspital (CH)
- University Hospital of Geneva (CH)
- Clinique de La Source (CH)
- University Hospital of Basel (CH)
- Kantonsspital St. Gallen (CH)
- Venue
- Journal of Infection
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 76
- Issue
- 5
- Pages
- 489-495
- ISSN
- 0163-4453 (ISSN-L)
- OpenAlex
- W2786692887
- Semantic Scholar
- 54fedd1d72915a2c5205ab24b6ff355594043d6a
- Cited by
- 19
- References
- 41
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 5 · 2022: 3 · 2021: 3 · 2019: 2 · 2018: 2
- FWCI
- 1.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Infection (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- Bern Open Repository and Information System (University of Bern) (submittedVersion, cc-by-nc-nd)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Open Access CRIS of the University of Bern
- Funders
- Essex Schering-Plough
- Gilead
- Merck
- Merck Sharp and Dohme
- Novartis
- Pfizer
- Leenaards Foundation
- Foundation for the Advancement in Medical Microbiology and Infectious Diseases
- Hamilton Health Sciences Foundation
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Oncology › Neutropenia and Cancer Infections
- Health Sciences › Medicine › Ophthalmology › Ocular Infections and Treatments
- Keywords
- antifungal prophylaxis, Candida glabrata, Candida krusei, Candida norvegensis, non-albicans Candida, fluconazole resistance, sepsis, graft-versus-host disease, gastrointestinal mucositis, parenteral nutrition
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Antifungal Agents, Candida, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Microbial Sensitivity Tests, Middle Aged, Prospective Studies, Fluconazole, Drug Resistance, Fungal, Young Adult, Candidemia, Epidemiological Monitoring
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