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

Maroun M Sfeir,Rosemary Soave,Koen Van Besien,Cristina Jiménez-Ortigosa,Audrey N Schuetz,David S Perlin,Maria N Gamaletsou,Thomas J Walsh,Catherine B Small

doi:10.3390/jof6010020

Abstract

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.

Highlights

Invasive candidiasis represents an important cause of morbidity and mortality among immunocompromised individuals, especially those with malignancies [1]
This report describes the emergence of resistance of C. tropicalis to echinocandins in immunocompromised patients either during treatment or prophylaxis with an echinocandin
Candida tropicalis is a highly virulent pathogen in neutropenic hosts, where it causes increased mortality corresponding to greater degrees of tissue invasion in experimental models and immunocompromised patients with hematological malignancies [6,7,22]

Summary

Introduction

Invasive candidiasis represents an important cause of morbidity and mortality among immunocompromised individuals, especially those with malignancies [1]. Echinocandins are the first-line empirical therapy of candidemia in immunocompetent and immunocompromised patients [2]. Antifungal surveillance programs demonstrate a high rate of susceptibility of Candida species to echinocandins in general, and Candida tropicalis [3]. Candida tropicalis represents the third or fourth most commonly isolated non-Candida albicans. Candida species in the clinical practice [4]. Studies demonstrated that C. tropicalis was highly virulent in immunocompromised animal models and in patients with hematological malignancies [6,7]. 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. Among these 15 patients with echinocandin-resistant C. tropicalis infections, the median age was 61 years (ages 28–84 years) and

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