Breakthrough candidaemia caused by phenotypically susceptible Candida spp. in patients with haematological malignancies does not correlate with established interpretive breakpoints

Maria N. Gamaletsou, George L. Daikos, Thomas J. Walsh, David S. Perlin, Cristina J imenez Ortigosa, Anna Psaroulaki, Maria Pagoni, Athina Argyropoulou, Martha Nepka, Efstathia Perivolioti, Maria Kotsopoulou, Stavroula Perloretzou, Markos Marangos, Diamantis Kofteridis, Maria Grammatikou, Dimitrios Goukos, George Petrikkos, Nikolaos V. Sipsas

Research output: Contribution to journalArticlepeer-review

Abstract

In a study of 27,864 patients with haematological malignancies, 40 patients with candidaemia were identified, among whom 21 developed candidaemia while receiving systemic antifungal therapy [breakthrough candidaemia (BTC)]. Demographic, clinical, microbiological and molecular features of these episodes were analysed. Compared with 19 patients with de novo candidaemia, patients with BTC were more likely to have neutropenia (81% vs. 63%), longer median duration of neutropenia (27 days vs. 15 days), hypogammaglobulinaemia (62% vs. 37%) and central venous catheters (CVCs) (86% vs. 68%). The median duration of prior antifungal exposure was 46 days (range 3-108 days). Among the 18 available Candida spp. isolates, 15 (83%) were phenotypically susceptible to the antifungal agent that the patient was receiving. Emergence of resistance was the mechanism leading to BTC in three cases of patients receiving echinocandins. Other possible mechanisms of BTC were (i) elevated (≥2) minimum lethal concentration/minimum inhibitory concentration (MLC/MIC) ratio (reduced ability for a fungicidal agent to kill a fungal pathogen) in all patients receiving amphotericin B and (ii) elevated MLC/MIC ratios in all Candida parapsilosis isolates with MICs≤1 μg/mL to echinocandins. DNA sequencing of the hotspot 1 region of the fks1 and fks2 genes in seven different isolates of C. parapsilosis group demonstrated P660A in Fks1 but no polymorphisms in fks2. In conclusion, mechanisms for BTC in the setting of prolonged neutropenia may be host-based (hypogammaglobulinaemia and CVC) and pathogen-based. CLSI interpretive breakpoints do not reliably predict BTC in patients with haematological malignancies and warrant further investigation.

Original languageEnglish (US)
Pages (from-to)248-255
Number of pages8
JournalInternational Journal of Antimicrobial Agents
Volume44
Issue number3
DOIs
StatePublished - Sep 1 2014
Externally publishedYes

Keywords

  • Antifungals
  • Breakthrough candidaemia
  • Haematological malignancy
  • Resistance

ASJC Scopus subject areas

  • Medicine(all)

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