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. 1997 Apr;41(4):748–751. doi: 10.1128/aac.41.4.748

Fluconazole tolerance in clinical isolates of Cryptococcus neoformans.

K Venkateswarlu 1, M Taylor 1, N J Manning 1, M G Rinaldi 1, S L Kelly 1
PMCID: PMC163787  PMID: 9087482

Abstract

Eleven isolates of Cryptococcus neoformans were investigated to determine the biochemical basis of their tolerance to fluconazole. The MICs of fluconazole for three isolates with low-level resistance were 3- to 6-fold higher than those for sensitive isolates, while the MICs for four isolates with high-level resistance were 100- to 200-fold higher than those for sensitive isolates. The level of ergosterol present in the isolates varied, and those which had relatively low levels of ergosterol were resistant to amphotericin B. Changes in the affinity of the target enzyme (sterol 14alpha-demethylase) and decreases in the cellular content of fluconazole seemed to be responsible for the resistance in isolates with low-level and high-level resistance, respectively.

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Selected References

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  1. Banerjee S. N., Emori T. G., Culver D. H., Gaynes R. P., Jarvis W. R., Horan T., Edwards J. R., Tolson J., Henderson T., Martone W. J. Secular trends in nosocomial primary bloodstream infections in the United States, 1980-1989. National Nosocomial Infections Surveillance System. Am J Med. 1991 Sep 16;91(3B):86S–89S. doi: 10.1016/0002-9343(91)90349-3. [DOI] [PubMed] [Google Scholar]
  2. Beck-Sagué C., Jarvis W. R. Secular trends in the epidemiology of nosocomial fungal infections in the United States, 1980-1990. National Nosocomial Infections Surveillance System. J Infect Dis. 1993 May;167(5):1247–1251. doi: 10.1093/infdis/167.5.1247. [DOI] [PubMed] [Google Scholar]
  3. Bodey G., Bueltmann B., Duguid W., Gibbs D., Hanak H., Hotchi M., Mall G., Martino P., Meunier F., Milliken S. Fungal infections in cancer patients: an international autopsy survey. Eur J Clin Microbiol Infect Dis. 1992 Feb;11(2):99–109. doi: 10.1007/BF01967060. [DOI] [PubMed] [Google Scholar]
  4. Gallis H. A., Drew R. H., Pickard W. W. Amphotericin B: 30 years of clinical experience. Rev Infect Dis. 1990 Mar-Apr;12(2):308–329. doi: 10.1093/clinids/12.2.308. [DOI] [PubMed] [Google Scholar]
  5. Joseph-Horne T., Hollomon D., Loeffler R. S., Kelly S. L. Altered P450 activity associated with direct selection for fungal azole resistance. FEBS Lett. 1995 Oct 30;374(2):174–178. doi: 10.1016/0014-5793(95)01102-k. [DOI] [PubMed] [Google Scholar]
  6. Joseph-Horne T., Hollomon D., Loeffler R. S., Kelly S. L. Cross-resistance to polyene and azole drugs in Cryptococcus neoformans. Antimicrob Agents Chemother. 1995 Jul;39(7):1526–1529. doi: 10.1128/aac.39.7.1526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Joseph-Horne T., Hollomon D., Manning N., Kelly S. L. Investigation of the Sterol Composition and Azole Resistance in Field Isolates of Septoria tritici. Appl Environ Microbiol. 1996 Jan;62(1):184–190. doi: 10.1128/aem.62.1.184-190.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kelly S. L., Arnoldi A., Kelly D. E. Molecular genetic analysis of azole antifungal mode of action. Biochem Soc Trans. 1993 Nov;21(4):1034–1038. doi: 10.1042/bst0211034. [DOI] [PubMed] [Google Scholar]
  9. Kelly S. L., Lamb D. C., Corran A. J., Baldwin B. C., Kelly D. E. Mode of action and resistance to azole antifungals associated with the formation of 14 alpha-methylergosta-8,24(28)-dien-3 beta,6 alpha-diol. Biochem Biophys Res Commun. 1995 Feb 27;207(3):910–915. doi: 10.1006/bbrc.1995.1272. [DOI] [PubMed] [Google Scholar]
  10. Kelly S. L., Lamb D. C., Taylor M., Corran A. J., Baldwin B. C., Powderly W. G. Resistance to amphotericin B associated with defective sterol delta 8-->7 isomerase in a Cryptococcus neoformans strain from an AIDS patient. FEMS Microbiol Lett. 1994 Sep 15;122(1-2):39–42. doi: 10.1111/j.1574-6968.1994.tb07140.x. [DOI] [PubMed] [Google Scholar]
  11. Lamb D. C., Corran A., Baldwin B. C., Kwon-Chung J., Kelly S. L. Resistant P45051A1 activity in azole antifungal tolerant Cryptococcus neoformans from AIDS patients. FEBS Lett. 1995 Jul 17;368(2):326–330. doi: 10.1016/0014-5793(95)00684-2. [DOI] [PubMed] [Google Scholar]
  12. Parkinson T., Falconer D. J., Hitchcock C. A. Fluconazole resistance due to energy-dependent drug efflux in Candida glabrata. Antimicrob Agents Chemother. 1995 Aug;39(8):1696–1699. doi: 10.1128/aac.39.8.1696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Sanglard D., Kuchler K., Ischer F., Pagani J. L., Monod M., Bille J. Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters. Antimicrob Agents Chemother. 1995 Nov;39(11):2378–2386. doi: 10.1128/aac.39.11.2378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Vanden Bossche H., Marichal P., Gorrens J., Coene M. C. Biochemical basis for the activity and selectivity of oral antifungal drugs. Br J Clin Pract Suppl. 1990 Sep;71:41–46. [PubMed] [Google Scholar]
  15. Vanden Bossche H., Marichal P., Gorrens J., Coene M. C., Willemsens G., Bellens D., Roels I., Moereels H., Janssen P. A. Biochemical approaches to selective antifungal activity. Focus on azole antifungals. Mycoses. 1989;32 (Suppl 1):35–52. doi: 10.1111/j.1439-0507.1989.tb02293.x. [DOI] [PubMed] [Google Scholar]
  16. Vanden Bossche H., Marichal P., Le Jeune L., Coene M. C., Gorrens J., Cools W. Effects of itraconazole on cytochrome P-450-dependent sterol 14 alpha-demethylation and reduction of 3-ketosteroids in Cryptococcus neoformans. Antimicrob Agents Chemother. 1993 Oct;37(10):2101–2105. doi: 10.1128/aac.37.10.2101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Venkateswarlu K., Denning D. W., Manning N. J., Kelly S. L. Resistance to fluconazole in Candida albicans from AIDS patients correlated with reduced intracellular accumulation of drug. FEMS Microbiol Lett. 1995 Sep 15;131(3):337–341. doi: 10.1111/j.1574-6968.1995.tb07797.x. [DOI] [PubMed] [Google Scholar]
  18. Wang Y., Casadevall A. Growth of Cryptococcus neoformans in presence of L-dopa decreases its susceptibility to amphotericin B. Antimicrob Agents Chemother. 1994 Nov;38(11):2648–2650. doi: 10.1128/aac.38.11.2648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Watson P. F., Rose M. E., Ellis S. W., England H., Kelly S. L. Defective sterol C5-6 desaturation and azole resistance: a new hypothesis for the mode of action of azole antifungals. Biochem Biophys Res Commun. 1989 Nov 15;164(3):1170–1175. doi: 10.1016/0006-291x(89)91792-0. [DOI] [PubMed] [Google Scholar]
  20. Woods R. A. Nystatin-resistant mutants of yeast: alterations in sterol content. J Bacteriol. 1971 Oct;108(1):69–73. doi: 10.1128/jb.108.1.69-73.1971. [DOI] [PMC free article] [PubMed] [Google Scholar]

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