Mutations in Aspergillus fumigatus resulting in reduced susceptibility to posaconazole appear to be restricted to a single amino acid in the cytochrome P450 14alpha-demethylase
| Autor: | Paul M. McNicholas, Cara Mendrick, Scott S. Walker, Roberta S. Hare, David Loebenberg, Beth DiDomenico, Xin Li, Paul A. Mann, Shui-Qing Wei, Raulo Parmegiani |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Posaconazole
Antifungal Agents Itraconazole Microbial Sensitivity Tests Aspergillosis Aspergillus fumigatus Microbiology chemistry.chemical_compound Sterol 14-Demethylase Cytochrome P-450 Enzyme System Mechanisms of Resistance Amphotericin B medicine Point Mutation Pharmacology (medical) skin and connective tissue diseases Pharmacology Voriconazole biology Triazoles biology.organism_classification medicine.disease Infectious Diseases chemistry Caspofungin Oxidoreductases Fluconazole medicine.drug |
| Zdroj: | Antimicrobial agents and chemotherapy. 47(2) |
| ISSN: | 0066-4804 |
| Popis: | The last decade has seen a dramatic increase in serious fungal infections. Those primarily at risk are immunocompromised individuals. Up to 80% of human immunodeficiency virus-infected patients are thought to develop a fungal infection at some point in the course of their illness (21). Aspergillus fumigatus, originally viewed as a weak pathogen, is now a major cause of death at cancer centers, with the mortality rate for leukemia patients approaching 90% even with antifungal therapy (12). Neither the current standards, amphotericin B (AMB) and itraconazole (ITZ), nor new therapies, caspofungin (CAS) and voriconazole (VOR), have satisfactorily met the therapeutic needs of patients with aspergillosis. Clinical failures with AMB are common, but correlating such failures with resistance is often difficult (19). Mechanism-based toxicity has limited the usefulness of AMB (12); newer less-toxic formulations are now available but are expensive. Isolates resistant to ITZ have been obtained from both in vivo (5, 7, 8) and in vitro sources (14, 15). VOR-resistant isolates have been generated in the laboratory (16; E. K. Manavathu, I. Baskaran, G. J. Alangaden, and P. H. Chandrasekar, Abstr. 41st Intersci. Conf. Antimicrob. Agents Chemother., abstr. J-817, 2001), but there have been no reports of in vivo resistance. Finally, there are insufficient data available on CAS to assess development of resistance. Posaconazole (POS; SCH56592), a novel triazole currently in phase 3 clinical trials, is active against a broad spectrum of fungal pathogens including Aspergillus and Candida spp. (4, 10, 15). In vitro and in vivo testing has demonstrated that the drug is more effective than either ITZ or AMB against Aspergillus spp. (15, 25, 29) and that it is more effective than fluconazole (FLZ) against Candida spp. (4). In this study we characterized isolates of A. fumigatus, both clinical and in vitro laboratory-selected mutants, which exhibit a reduced susceptibility to POS. We demonstrate that resistance is caused by mutations in the cyp51A gene, which encodes the target protein for POS. (Part of this work was presented at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, Calif., September 2002.) |
| Databáze: | OpenAIRE |
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