First Determination of Azol Resistance in Aspergillus fumigatus Strains Carrying the TR34/L98H Mutations in Turkey

G. E. Ozmerdiven, S. Ak, B. Ener, H. Agca, B. Dalyan Cilo, B. Tunca, H. Akalin; Uludag Univ. Faculty of Med., Bursa, Turkey


Background: Aspergillus fumigatus is the most important etiological agent of invasive aspergillosis in immunocompromised patients. Azoles are the drugs of choice for treatment of invasive infections. Recently, an increasing number of azole-resistant A. fumigatus isolates have been described in different countries. The most commonly reported mechanism conferring azole resistance is an alteration at codon 98 (L98H), in combination with a tandem repeat (34bp) in the promoter region of cyp51A gene. We investigated the prevalence and spread of azole resistance using our culture collection that contained A. fumigatus isolates collected between 1999 and 2012 from clinical specimens. Methods: Seven hundred and fifty three A. fumigatus isolates, collected from 413 patients were investigated. First, all isolates were screened for resistance to itraconazole (ITZ) by subculturing on Sabouraud’s dextrose agar that contained 4 mg/liter ITZ. For isolates that grew on ITZ containing agar (ITZ resistant isolates), the in vitro activities of amphotericin B (AMB), itraconazole, voriconazole (VOR), and caspofungin (CAS) were determined by using the Clinical and Laboratory Standards Institute (CLSI) M38-A reference method. After PCR amplification, the full sequence of the cyp51A gene and its promoter region was determined for all in vitro azol resistance isolates Results: ITZ resistance was found in 10.1% (76/753) of A. fumigatus isolates. From the year 2000 onwards, patients were observed annually with an itraconazole-resistant isolate, with a maximum prevalence (24.2%) in 2007. According to in vitro susceptibility tests, AMB and CAS (MIC ranges / AMB: 0,5-2 µg/ml and CAS≤0,03-0,5 µg/ml) exhibited a good activity against all of them where as ITZ and VOR was resistant (MIC ranges / ITZ: >16 µg/ml and VOR: 2-8 µg/ml ). Sequence analysis of the promoter region and CYP51A gene indicated the presence of TR34/L98H in 86.8% (66 isolates) of isolates. Conclusions: The analysis of the resistance mechanism for the first time from Turkey revealed common TR34/L98H mutation in the cyp51A gene, which indicates an environmental origin of the strains.


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54th Interscience Conference of Antimicrobial Agents and Chemotherapy
    • ICAAC 54th (2014)