Abstract
BackgroundResistance to triazoles was recently reported in Aspergillus fumigatus isolates cultured from patients with invasive aspergillosis. The prevalence of azole resistance in A. fumigatus is unknown. We investigated the prevalence and spread of azole resistance using our culture collection that contained A. fumigatus isolates collected between 1994 and 2007.Methods and FindingsWe investigated the prevalence of itraconazole (ITZ) resistance in 1,912 clinical A. fumigatus isolates collected from 1,219 patients in our University Medical Centre over a 14-y period. The spread of resistance was investigated by analyzing 147 A. fumigatus isolates from 101 patients, from 28 other medical centres in The Netherlands and 317 isolates from six other countries. The isolates were characterized using phenotypic and molecular methods. The electronic patient files were used to determine the underlying conditions of the patients and the presence of invasive aspergillosis. ITZ-resistant isolates were found in 32 of 1,219 patients. All cases were observed after 1999 with an annual prevalence of 1.7% to 6%. The ITZ-resistant isolates also showed elevated minimum inhibitory concentrations of voriconazole, ravuconazole, and posaconazole. A substitution of leucine 98 for histidine in the cyp51A gene, together with two copies of a 34-bp sequence in tandem in the gene promoter (TR/L98H), was found to be the dominant resistance mechanism. Microsatellite analysis indicated that the ITZ-resistant isolates were genetically distinct but clustered. The ITZ-sensitive isolates were not more likely to be responsible for invasive aspergillosis than the ITZ-resistant isolates. ITZ resistance was found in isolates from 13 patients (12.8%) from nine other medical centres in The Netherlands, of which 69% harboured the TR/L98H substitution, and in six isolates originating from four other countries.ConclusionsAzole resistance has emerged in A. fumigatus and might be more prevalent than currently acknowledged. The presence of a dominant resistance mechanism in clinical isolates suggests that isolates with this mechanism are spreading in our environment.
Highlights
The saprophytic mould Aspergillus is known to cause a spectrum of diseases in humans including allergic syndromes, noninvasive infections, as well as invasive aspergillosis
We investigated the prevalence of itraconazole (ITZ) resistance in 1,912 clinical A. fumigatus isolates collected from 1,219 patients in our University Medical Centre over a 14-y period
Azole resistance has emerged in A. fumigatus and might be more prevalent than currently acknowledged
Summary
The saprophytic mould Aspergillus is known to cause a spectrum of diseases in humans including allergic syndromes, noninvasive infections, as well as invasive aspergillosis. Voriconazole was superior to amphotericin B for the treatment of invasive aspergillosis and has become the primary choice to treat this condition [2]. Another triazole, posaconazole, was reported to be highly effective in preventing invasive aspergillosis in neutropaenic patients with acute myeloid leukaemia and myelodysplastic syndrome and in patients with graft-versushost-disease [3,4]. Patients with MTR aspergillosis presented with primary invasive aspergillosis or with breakthrough infection while receiving itraconazole (ITZ) or voriconazole. Resistance to triazoles was recently reported in Aspergillus fumigatus isolates cultured from patients with invasive aspergillosis. Voriconazole is the first-line therapy for aspergillosis but itraconazole and posaconazole are sometimes used and ravuconazole is in clinical development
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