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Breakthrough Bloodstream Infections Caused by Echinocandin-Resistant Candida tropicalis: An Emerging Threat to Immunocompromised Patients with Hematological Malignancies

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Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY 10065, USA
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Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY 10065, USA
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Public Health Research Institute, New Jersey Medical School/ Rutgers Biomedical and Health Sciences, Newark, NJ 07103, USA
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Department of Pathophysiology, Laikon General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55901, USA
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Transplantation-Oncology Infectious Diseases Program, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY 10065, USA
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Division of Hematology/Oncology, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY 10065, USA
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Departments of Pediatrics, and Microbiology & Immunology, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY 10065, USA
*
Author to whom correspondence should be addressed.
Current address: Director, Clinical Microbiology Laboratory, University of Connecticut Health Sciences Center, Storrs, CT 06269-1101, USA.
J. Fungi 2020, 6(1), 20; https://doi.org/10.3390/jof6010020
Received: 14 December 2019 / Revised: 27 January 2020 / Accepted: 27 January 2020 / Published: 31 January 2020
Background. Candida tropicalis is a virulent fungal pathogen for which echinocandins are the primary therapy. Emergence of resistance to echinocandins of C. tropicalis carries potentially ominous therapeutic implications. Methods. We describe herein two patients with breakthrough C. tropicalis fungemia during echinocandin therapy, characterize their molecular mechanism of resistance, and systematically review 13 previously reported cases of echinocandin-resistant C. tropicalis bloodstream infections (BSIs) and other diseases. Results. Among these 15 patients with echinocandin-resistant C. tropicalis infections, the median age was 61 years (ages 28–84 years) and 13 (86%) were immunocompromised. Thirteen (86%) of all patients had a history of pervious or concurrent exposure to echinocandins. Isolates of C. tropicalis from 11 cases, including the two index cases, underwent DNA sequencing of the FKS1 gene for mutations known to confer echinocandin resistance. The amino acid substitution Ser654Pro was shown in four cases, while other FKS1 mutations encoded Ser80S/Pro, Phe641Leu, Phe641Ser, Ser80S/Pro substitutions. These mutational events were not associated with collateral increases in minimum inhibitory concentrations to antifungal triazoles and amphotericin B. Overall mortality in patients with echinocandin-resistant C. tropicalis infections was 40%. Among those six patients who died, two received monotherapy with voriconazole, one was treated with fluconazole, one remained on caspofungin, and two were switched to liposomal amphotericin B. Nine patients (60%) survived after being treated with an antifungal agent other than an echinocandin. Conclusions. Emergence of resistance to echinocandins by C. tropicalis, occurs during antifungal therapy, is associated with high mortality, is mediated by a diverse range of FKS1 mutations, retains in vitro susceptibility to triazoles and amphotericin B, and constitutes an emerging threat to patients with hematological malignancies.
Keywords: Candida tropicalis; candidemia; echinocandin resistance; FKS1 gene Candida tropicalis; candidemia; echinocandin resistance; FKS1 gene
MDPI and ACS Style

Sfeir, M.M.; Jiménez-Ortigosa, C.; Gamaletsou, M.N.; Schuetz, A.N.; Soave, R.; Besien, K.V.; Small, C.B.; Perlin, D.S.; Walsh, T.J. Breakthrough Bloodstream Infections Caused by Echinocandin-Resistant Candida tropicalis: An Emerging Threat to Immunocompromised Patients with Hematological Malignancies. J. Fungi 2020, 6, 20.

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