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dc.contributor.authorSnelders, Eveline
dc.contributor.authorvan der Lee, Henrich A L
dc.contributor.authorKuijpers, Judith
dc.contributor.authorRijs, Anthonius J M M
dc.contributor.authorVarga, János
dc.contributor.authorSamson, Robert A
dc.contributor.authorMellado, Emilia 
dc.contributor.authorDonders, A Rogier T
dc.contributor.authorMelchers, Willem J G
dc.contributor.authorVerweij, Paul E
dc.identifier.citationPLoS Med. 2008 Nov 11;5(11):e219.es_ES
dc.description.abstractBACKGROUND: Resistance 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 FINDINGS: 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. 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. CONCLUSIONS: Azole 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.es_ES
dc.description.sponsorshipThis work was funded in part by The Netherlands Organisation for Health Research and Development (ZonMw; grant: 50-50800-98–030). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.es_ES
dc.publisherPublic Library of Science (PLOS) es_ES
dc.subject.meshAntifungal Agents es_ES
dc.subject.meshAspergillosis es_ES
dc.subject.meshAspergillus fumigatus es_ES
dc.subject.meshAzoles es_ES
dc.subject.meshDrug Resistance, Multiple, Fungal es_ES
dc.subject.meshHumans es_ES
dc.subject.meshItraconazole es_ES
dc.subject.meshPyrimidines es_ES
dc.subject.meshTriazoles es_ES
dc.subject.meshVoriconazole es_ES
dc.titleEmergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanismes_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.contributor.funderNetherlands Organisation for Health Research and Development 
dc.identifier.journalPLoS medicinees_ES
dc.repisalud.centroISCIII::Centro Nacional de Microbiologíaes_ES
dc.rights.accessRightsopen accesses_ES

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