The DOI matches its Crossref record; 29 of the 29 references it cites were found in a registry or an index.
Itraconazole resistance in Aspergillus fumigatus
Open accessAbstract
Invasive aspergillosis is an increasingly frequent opportunistic infection in immunocompromised patients. Only two agents, amphotericin B and itraconazole, are licensed for therapy. Itraconazole acts through inhibition of a P-450 enzyme undertaking sterol 14alpha demethylation. In vitro resistance in Aspergillus fumigatus to itraconazole correlated with in vivo outcome has not been previously described. For three isolates (AF72, AF90, and AF91) of A. fumigatus from two patients with invasive aspergillosis itraconazole MICs were elevated. A neutropenic murine model was used to establish the validity of the MICs. The isolates were typed by random amplification of polymorphic DNA. Analysis of sterols, inhibition of cell-free sterol biosynthesis from [14C] mevalonate, quantitation of P-450 content, and [3H]itraconazole concentration in mycelial pellets were used to determine the mechanisms of resistance. The MICs for the three resistant isolates were >16 microg/ml. In vitro resistance was confirmed in vivo for all three isolates. Molecular typing showed the isolates from the two patients to be genetically distinct. Compared to the susceptible isolate from patient 1, AF72 had a reduced ergosterol content, greater quantities of sterol intermediates, a similar susceptibility to itraconazole in cell-free ergosterol biosynthesis, and a reduced intracellular [3H]itraconazole concentration. In contrast, AF91 and AF92 had slightly higher ergosterol and lower intermediate sterol concentrations, fivefold increased resistance in cell-free systems to the effect of itraconazole on sterol 14alpha demethylation, and intracellular [3H] itraconazole concentrations found in susceptible isolates. Resistance to itraconazole in A. fumigatus is detectable in vitro and is present in wild-type isolates, and at least two mechanisms of resistance are responsible.
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Cites
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Self-citationPrasad, R., De Wergifosse, P., Goffeau, A., & Balzi, E. (1995) · Current Genetics · doi:10.1007/bf00352101 · Cited by 486
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Self-citationMolecular mechanisms of drug resistance in fungi
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Self-citationCharacterization of an azole-resistant Candida glabrata isolate
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Cited by
Aspergillus fumigatus and Aspergillosis
Latgé, J.-P. (1999) · Clinical Microbiology Reviews · doi:10.1128/cmr.12.2.310 · Cited by 2,307
Ullmann, A. J., Aguado, J. M., Arikan-Akdagli, S., Denning, D. W., Groll, A. H., Lagrou, K., Lass-Flörl, C., Lewis, R. E., Munoz, P., Verweij, P. E., et al. (2018) · Clinical Microbiology and Infection · doi:10.1016/j.cmi.2018.01.002 · Cited by 1,556
Self-citationClinical, Cellular, and Molecular Factors That Contribute to Antifungal Drug Resistance
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Current and emerging azole antifungal agents
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Aspergillus flavus: human pathogen, allergen and mycotoxin producer
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Metadata
- Authors
- Denning, D. W., Venkateswarlu, K., Oakley, K. L., Anderson, M. J., Manning, N. J., Stevens, D. A., Warnock, D. W., & Kelly, S. L.
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 1997-06
- Volume
- 41
- Issue
- 6
- Pages
- 1364-1368
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- OpenAlex
- W2156024232
- Cited by
- 508
- References
- 29
- FWCI
- 16.37
- Type
- journal article
- Language
- en
- Open access
- green
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