title: Breakthrough candidaemia caused by phenotypically susceptible Candida spp. in patients with haematological malignancies does not correlate with established interpretive breakpoints.
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.
authors.affiliation: Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Maria N
authors.initials: MN
authors.lastname: Gamaletsou
authors.affiliation: Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: George L
authors.initials: GL
authors.lastname: Daikos
authors.affiliation: Transplantation Oncology Infectious Diseases Program, Division of Infectious Diseases, Weill Cornell University Medical Center, New York, NY, USA; Department of Pediatrics, Weill Cornell University Medical Center, New York, NY, USA; Department of Microbiology & Immunology, Weill Cornell University Medical Center, New York, NY, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
authors.affiliation: Public Health Research Institute, New Jersey Medical School-UMDNJ, Newark, NJ, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Perlin
authors.affiliation: Public Health Research Institute, New Jersey Medical School-UMDNJ, Newark, NJ, USA.
authors.forename: Cristina Jimenez
authors.initials: CJ
authors.lastname: Ortigosa
authors.affiliation: Laboratory of Clinical Bacteriology, Parasitology, Zoonoses and Geographical Medicine, Medical School, University of Crete, Heraklion, Crete, Greece.
authors.forename: Anna
authors.initials: A
authors.lastname: Psaroulaki
authors.affiliation: Evangelismos Hospital, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Pagoni
authors.affiliation: Evangelismos Hospital, Athens, Greece.
authors.forename: Athina
authors.initials: A
authors.lastname: Argyropoulou
authors.affiliation: Evangelismos Hospital, Athens, Greece.
authors.forename: Martha
authors.initials: M
authors.lastname: Nepka
authors.affiliation: Evangelismos Hospital, Athens, Greece.
authors.forename: Efstathia
authors.initials: E
authors.lastname: Perivolioti
authors.affiliation: Metaxa Hospital, Piraeus, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Kotsopoulou
authors.affiliation: Metaxa Hospital, Piraeus, Greece.
authors.forename: Stavroula
authors.initials: S
authors.lastname: Perloretzou
authors.affiliation: Medical School, University of Patras, Patras, Greece.
authors.forename: Markos
authors.initials: M
authors.lastname: Marangos
authors.affiliation: Medical School, University of Crete, Heraklion, Crete, Greece.
authors.forename: Diamantis
authors.initials: D
authors.lastname: Kofteridis
authors.affiliation: Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Grammatikou
authors.affiliation: Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Goukos
authors.affiliation: Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Petrikkos
authors.affiliation: Medical School, National and Kapodistrian University of Athens, Athens, Greece. Electronic address: nsipsas@med.uoa.gr.
authors.forename: Nikolaos V
authors.initials: NV
authors.lastname: Sipsas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002175:Candida / Q000187:drug effects* / Q000302:isolation & purification*; D058387:Candidemia / Q000382:microbiology*; D025141:Drug Resistance, Fungal; D005260:Female; D005656:Fungal Proteins / Q000235:genetics; D019337:Hematologic Neoplasms / Q000150:complications*; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins
keywords: Antifungals; Breakthrough candidaemia; Haematological malignancy; Resistance