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Clinical Epidemiology of Pulmonary Aspergillosis in Hospitalized Patients and Contribution of Cyp51a, Yap1, and Cdr1b Mutations to Voriconazole Resistance in Etiologic Aspergillus Species Publisher Pubmed



Salehi Z1 ; Sharifynia S2 ; Jamzivar F1 ; Shamsghahfarokhi M3 ; Poorabdollah M4 ; Abtahian Z2 ; Nasiri N5 ; Marjani M2 ; Moniri A2 ; Salehi M6 ; Tabarsi P2 ; Razzaghiabyaneh M1
Authors
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Authors Affiliations
  1. 1. Department of Mycology, Pasteur Institute of Iran, Tehran, 1316943551, Iran
  2. 2. Clinical Tuberculosis and Epidemiology Research Center, NRITLD, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  3. 3. Department of Mycology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
  4. 4. Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
  5. 5. HIV/STI Surveillance Research Center, and WHO Collaborating Center for HIV Surveillance, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman, Iran
  6. 6. Research Center for Antibiotic Stewardship & Antimicrobial Resistance, Department of Infectious Diseases, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran

Source: European Journal of Clinical Microbiology and Infectious Diseases Published:2023


Abstract

Pulmonary aspergillosis is a life-threatening fungal infection with worldwide distribution. In the present study, clinical epidemiology of pulmonary aspergillosis and antifungal susceptibility of etiologic Aspergillus species were evaluated in one-hundred fifty patients with special focus on the frequency of voriconazole resistance. All the cases were confirmed by the clinical pictures, laboratory findings, and isolation of etiologic Aspergillus species which belonged to two major species, i.e., A. flavus and A. fumigatus. Seventeen isolates displayed voriconazole MIC greater than or equal to the epidemiological cutoff value. Expression of cyp51A, Cdr1B, and Yap1 genes was analyzed in voriconazole-intermediate/resistant isolates. In A. flavus, Cyp51A protein sequencing showed the substitutions T335A and D282E. In the Yap1 gene, A78C replacement led to Q26H amino acid substitution that was not reported previously in A. flavus resistant to voriconazole. No mutations associated with voriconazole resistance were found in the three genes of A. fumigatus. The expression of Yap1 was higher than that of two other genes in both A. flavus and A. fumigatus. Overall, voriconazole-resistant strains of both A. fumigatus and A. flavus demonstrated overexpression of Cdr1B, Cyp51A, and Yap1 genes compared to voriconazole-susceptible strains. Although there are still ambiguous points about the mechanisms of azole resistance, our results showed that mutations were not present in majority of resistant and intermediate isolates, while all of these isolates showed overexpression in all three genes studied. As a conclusion, it seems that the main reason of the emergence of mutation in voriconazole-resistant isolates of A. flavus and A. fumigatus is previous or prolonged exposure to azoles. © 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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