Amir Arastehfar1, Farnaz Daneshnia2, Süleyha Hilmioglu-Polat3, Macit Ilkit4, Melike Yasar3, Furkan Polat3, Dilek Yeşim Metin3, Ülküm Zafer Dokumcu5, Weihua Pan6, Ferry Hagen2,7, Teun Boekhout2,5,8, David S Perlin1, Cornelia Lass-Flörl9. 1. Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA. 2. Westerdijk Fungal Biodiversity Institute, Utrecht, The Netherlands. 3. Division of Mycology, University of Ege, Izmir, Turkey. 4. Divison of Mycology, University of Çukurova, Adana, Turkey. 5. Department of Paediatric Surgery, Faculty of Medicine, University of Ege, Izmir, Turkey. 6. Shanghai Key Laboratory Molecular Medical Mycology, Shanghai, China. 7. University Medical Center Utrecht, Utrecht, The Netherlands. 8. Institute of Biodiversity and Ecosystems Dynamics (IBED), University of Amsterdam, Amsterdam, The Netherlands. 9. Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
Abstract
BACKGROUND: Echinocandin resistance rarely occurs in clinical Candida parapsilosis isolates and the underlying mechanism is unknown. OBJECTIVES: To determine the prevalence of echinocandin resistance and the underlying mechanism for a large collection of C. parapsilosis blood isolates and to determine whether the echinocandin-resistant isolates were clonally related. METHODS: C. parapsilosis blood isolates (n = 213) were subjected to antifungal susceptibility testing (CLSI M27), for micafungin, anidulafungin, amphotericin B and, if appropriate, caspofungin. Hotspot (HS) 1 and HS2 of FKS1 were sequenced for all isolates (n = 213) and microsatellite typing was performed for echinocandin-resistant isolates. RESULTS: All isolates were susceptible to amphotericin B and two isolates were intermediate to anidulafungin (MIC = 4 mg/L), while micafungin resistance was noted in four isolates (MIC >8 mg/L); three of which were also fluconazole resistant and therefore were MDR. Interestingly, micafungin-resistant isolates, but not those intermediate to anidulafungin, carried novel mutation R658G in HS1 of Fks1p; three of which also harboured Y132F+K143R in Erg11. The first isolate (MICR1) was recovered in November 2017 from a patient admitted to paediatric gastroenterology who showed therapeutic failure under caspofungin treatment. MICR2-MICR4 were collected during 2018-19 and were recovered from three echinocandin-naive paediatric-surgery patients; the isolates shared the same genotype. CONCLUSIONS: Herein, for the first time (to the best of our knowledge), we identified micafungin-resistant C. parapsilosis blood isolates harbouring a novel mutation in HS1 of FKS1, which was likely attributable to in vitro micafungin resistance and in vivo caspofungin therapeutic failure. The acquisition of micafungin-resistant C. parapsilosis isolates in echinocandin-naive patients likely implicates clonal expansion, as supported by the close genetic relatedness of MICR2-MICR4.
BACKGROUND: Echinocandin resistance rarely occurs in clinical Candida parapsilosis isolates and the underlying mechanism is unknown. OBJECTIVES: To determine the prevalence of echinocandin resistance and the underlying mechanism for a large collection of C. parapsilosis blood isolates and to determine whether the echinocandin-resistant isolates were clonally related. METHODS: C. parapsilosis blood isolates (n = 213) were subjected to antifungal susceptibility testing (CLSI M27), for micafungin, anidulafungin, amphotericin B and, if appropriate, caspofungin. Hotspot (HS) 1 and HS2 of FKS1 were sequenced for all isolates (n = 213) and microsatellite typing was performed for echinocandin-resistant isolates. RESULTS: All isolates were susceptible to amphotericin B and two isolates were intermediate to anidulafungin (MIC = 4 mg/L), while micafungin resistance was noted in four isolates (MIC >8 mg/L); three of which were also fluconazole resistant and therefore were MDR. Interestingly, micafungin-resistant isolates, but not those intermediate to anidulafungin, carried novel mutation R658G in HS1 of Fks1p; three of which also harboured Y132F+K143R in Erg11. The first isolate (MICR1) was recovered in November 2017 from a patient admitted to paediatric gastroenterology who showed therapeutic failure under caspofungin treatment. MICR2-MICR4 were collected during 2018-19 and were recovered from three echinocandin-naive paediatric-surgery patients; the isolates shared the same genotype. CONCLUSIONS: Herein, for the first time (to the best of our knowledge), we identified micafungin-resistant C. parapsilosis blood isolates harbouring a novel mutation in HS1 of FKS1, which was likely attributable to in vitro micafungin resistance and in vivo caspofungin therapeutic failure. The acquisition of micafungin-resistant C. parapsilosis isolates in echinocandin-naive patients likely implicates clonal expansion, as supported by the close genetic relatedness of MICR2-MICR4.
Authors: Martin Hoenigl; Rosanne Sprute; Amir Arastehfar; John R Perfect; Cornelia Lass-Flörl; Romuald Bellmann; Juergen Prattes; George R Thompson; Nathan P Wiederhold; Mohanad M Al Obaidi; Birgit Willinger; Maiken C Arendrup; Philipp Koehler; Matteo Oliverio; Matthias Egger; Ilan S Schwartz; Oliver A Cornely; Peter G Pappas; Robert Krause Journal: Expert Opin Investig Drugs Date: 2022-06-15 Impact factor: 6.498
Authors: Amir Arastehfar; Toni Gabaldón; Rocio Garcia-Rubio; Jeffrey D Jenks; Martin Hoenigl; Helmut J F Salzer; Macit Ilkit; Cornelia Lass-Flörl; David S Perlin Journal: Antibiotics (Basel) Date: 2020-12-08
Authors: Martin Hoenigl; Rosanne Sprute; Matthias Egger; Amir Arastehfar; Oliver A Cornely; Robert Krause; Cornelia Lass-Flörl; Juergen Prattes; Andrej Spec; George R Thompson; Nathan Wiederhold; Jeffrey D Jenks Journal: Drugs Date: 2021-10-09 Impact factor: 9.546
Authors: Amir Arastehfar; Nevzat Ünal; Tuğrul Hoşbul; Muhammed Alper Özarslan; Ayşe Sultan Karakoyun; Furkan Polat; Diego Fuentes; Ramazan Gümral; Tuba Turunç; Farnaz Daneshnia; David S Perlin; Cornelia Lass-Flörl; Toni Gabaldón; Macit Ilkit; M Hong Nguyen Journal: Open Forum Infect Dis Date: 2022-02-13 Impact factor: 3.835
Authors: Farnaz Daneshnia; João N de Almeida Júnior; Amir Arastehfar; Lisa Lombardi; Erika Shor; Lis Moreno; Ana Verena Mendes; Maria Goreth Barberino; Danilo Thomaz Yamamoto; Geraldine Butler; David S Perlin; Arnaldo Lopes Colombo Journal: Emerg Microbes Infect Date: 2022-12 Impact factor: 19.568
Authors: Danilo Y Thomaz; João N de Almeida; Odeli N E Sejas; Gilda M B Del Negro; Gabrielle O M H Carvalho; Viviane M F Gimenes; Maria Emilia B de Souza; Amir Arastehfar; Carlos H Camargo; Adriana L Motta; Flávia Rossi; David S Perlin; Maristela P Freire; Edson Abdala; Gil Benard Journal: J Fungi (Basel) Date: 2021-03-30