1887

Abstract

Triazole antifungal agents are the mainstay of aspergillosis treatment. As highlighted in numerous studies, the global increase in the prevalence of triazole resistance could hamper the management of aspergillosis. In the present three-year study, 513 samples (213 clinical and 300 environmental samples) from 10 provinces of Iran were processed and screened in terms of azole resistance (4 and 1 mg l of itraconazole and voriconazole, respectively), using selective plates. Overall, 150 isolates (71 clinical and 79 environmental isolates) were detected. The isolates were confirmed by partial sequencing of the β-tubulin gene. Afterwards, antifungal susceptibility tests against triazole agents were performed, based on the Clinical and Laboratory Standards Institute (CLSI) M38-A2 document. The gene was sequenced in order to detect mutations. The MIC of itraconazole against 10 (6.6 %) strains, including clinical (=3, 4.2 %) and environmental (=7, 8.8 %) strains, was higher than the breakpoint and epidemiological cut-off value. Based on the findings, the prevalence of azole-resistant in Iran has increased remarkablyfrom 3.3 % to 6.6 % in comparison with earlier epidemiological research. Among resistant isolates, TR/L98H mutations in the gene were the most prevalent (=8, 80 %), whereas other point mutations (F46Y, G54W, Y121F, G138C, M172V, F219C, M220I, D255E, T289F, G432C and G448S mutations) were not detected. Although the number of patients affected by azole-resistant isolates was limited, strict supervision of clinical azole-resistant isolates and persistent environmental screening of azole resistance are vital to the development of approaches for the management of azole resistance in human pathogenic fungi.

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2016-06-01
2020-04-04
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References

  1. Ahmad S., Khan Z., Hagen F., Meis J. F.. 2014; Simple, low-cost molecular assays for TR34/L98H mutations in the cyp51a gene for rapid detection of triazole-resistant Aspergillus fumigatus isolates. J Clin Microbiol52:2223–2227 [CrossRef][PubMed]
    [Google Scholar]
  2. Albarrag A. M., Anderson M. J., Howard S. J., Robson G. D., Warn P. A., Sanglard D., Denning D. W.. 2011; Interrogation of related clinical pan-azole-resistant Aspergillus fumigatus strains: G138c, Y431C, and G434C single nucleotide polymorphisms in cyp51a, upregulation of cyp51a, and integration and activation of transposon atf1 in the cyp51a promoter. Antimicrob Agents Chemother 55:5113–5121 [CrossRef]
    [Google Scholar]
  3. Arendrup M. C., Mavridou E., Mortensen K. L., Snelders E., Frimodt-Møller N., Khan H., Melchers W., Verweij P. E.. 2010; Development of azole resistance in Aspergillus fumigatus during azole therapy associated with change in virulence. PLoS One5:e10080 [CrossRef][PubMed]
    [Google Scholar]
  4. Astvad K. M., Jensen R. H., Hassan T. M., Mathiasen E. G., Thomsen G. M., Pedersen U. G., Christensen M., Hilberg O., Arendrup M. C.. 2014; First detection of TR46/Y121F/T289A and TR34/L98H alterations in Aspergillus fumigatus isolates from azole-naive patients in denmark despite negative findings in the environment. Antimicrob Agents Chemother58:5096–5101 [CrossRef][PubMed]
    [Google Scholar]
  5. Badali H., Vaezi A., Haghani I., Yazdanparast S. A., Hedayati M. T., Mousavi B., Ansari S., Hagen F., Meis J. F., Chowdhary A.. 2013; Environmental study of azole-resistant Aspergillus fumigatus with TR34/L98H mutations in the cyp51a gene in iran. Mycoses56:659–663 [CrossRef][PubMed]
    [Google Scholar]
  6. Bader O., Weig M., Reichard U., Lugert R., Kuhns M., Christner M., Held J., Peter S., Schumacher U., other authors. 2013; cyp51A-based mechanisms of Aspergillus fumigatus azole drug resistance present in clinical samples from Germany. Antimicrob Agents Chemother57:3513–3517 [CrossRef][PubMed]
    [Google Scholar]
  7. Baselt R. C., Wright J. A., Burgel P. -R., Baixench M. -T., Amsellem M., Audureau E., Chapron J., Kanaan R., Honore I., other authors. 1975; Propoxyphene and norpropoxyphene tissue concentrations in fatalities associated with propoxyphene hydrochloride and propoxyphene napsylate. Arch Toxicol34:869–874[CrossRef]
    [Google Scholar]
  8. Bowyer P., Denning D. W.. 2014; Environmental fungicides and triazole resistance in aspergillus. Pest Manag Sci70:173–178 [CrossRef][PubMed]
    [Google Scholar]
  9. Bowyer P., Mosquera J., Anderson M., Birch M., Bromley M., Denning D. W.. 2012; Identification of novel genes conferring altered azole susceptibility in Aspergillus fumigatus . FEMS Microbiol Lett332:10–19 [CrossRef][PubMed]
    [Google Scholar]
  10. Bueid A., Howard S. J., Moore C. B., Richardson M. D., Harrison E., Bowyer P., Denning D. W.. 2010; Azole antifungal resistance in Aspergillus fumigatus: 2008 and 2009. J Antimicrob Chemother65:2116–2118 [CrossRef][PubMed]
    [Google Scholar]
  11. Camps S. M., Dutilh B. E., Arendrup M. C., Rijs A. J., Snelders E., Huynen M. A., Verweij P. E., Melchers W. J.. 2012; Discovery of a hape mutation that causes azole resistance in Aspergillus fumigatus through whole genome sequencing and sexual crossing. PLoS One7:e50034 [CrossRef][PubMed]
    [Google Scholar]
  12. Cannon R. D., Lamping E., Holmes A. R., Niimi K., Baret P. V., Keniya M. V., Tanabe K., Niimi M., Goffeau A., Monk B. C.. 2009; Efflux-mediated antifungal drug resistance. Clin Microbiol Rev22:291–321 [CrossRef][PubMed]
    [Google Scholar]
  13. Chen J., Li H., Li R., Bu D., Wan Z.. 2005; Mutations in the cyp51a gene and susceptibility to itraconazole in Aspergillus fumigatus serially isolated from a patient with lung aspergilloma. J Antimicrob Chemother55:31–37 [CrossRef][PubMed]
    [Google Scholar]
  14. Chowdhary A., Kathuria S., Randhawa H. S., Gaur S. N., Klaassen C. H., Meis J. F.. 2012; Isolation of multiple-triazole-resistant Aspergillus fumigatus strains carrying the TR/L98H mutations in the cyp51A gene in India. J Antimicrob Chemother67:362–366 [CrossRef]
    [Google Scholar]
  15. Chowdhary A., Kathuria S., Xu J., Sharma C., Sundar G., Singh P. K., Gaur S. N., Hagen F., Klaassen C. H., Meis J. F.. 2012; Clonal expansion and emergence of environmental multiple-triazole-resistant Aspergillus fumigatus strains carrying the TR34/L98H mutations in the cyp51a gene in india. PLoS One7:e52871 [CrossRef]
    [Google Scholar]
  16. Chowdhary A., Sharma C., Kathuria S., Hagen F., Meis J. F.. 2014; Azole-resistant Aspergillus fumigatus with the environmental TR46/Y121F/T289A mutation in India. J Antimicrob Chemother69:555–557 [CrossRef][PubMed]
    [Google Scholar]
  17. Chowdhary A., Sharma C., van den Boom M., Yntema J. B., Hagen F., Verweij P. E., Meis J. F.. 2014; Multi-azole-resistant Aspergillus fumigatus in the environment in tanzania. J Antimicrob Chemother69:2979–2983 [CrossRef][PubMed]
    [Google Scholar]
  18. Chryssanthou E.. 1997; In vitro susceptibility of respiratory isolates of aspergillus species to itraconazole and amphotericin B. acquired resistance to itraconazole. Scand J Infect Dis29:509–512 [CrossRef][PubMed]
    [Google Scholar]
  19. Daniel W. W.. 1987; Biostatistics: A Foundation for Analysis in the Health Sciences New York: Wiley;
    [Google Scholar]
  20. Denning D. W., Venkateswarlu K., Oakley K. L., Anderson M., Manning N., Stevens D. A., Warnock D. W., Kelly S. L.. 1997; Itraconazole resistance in Aspergillus fumigatus . Antimicrobial Gents Chemother41:1364–1368
    [Google Scholar]
  21. Espinel-Ingroff A., Diekema D. J., Fothergill A., Johnson E., Pelaez T., Pfaller M. A., Rinaldi M. G., Canton E., Turnidge J.. 2010; Wild-type MIC distributions and epidemiological cutoff values for the triazoles and six aspergillus spp. for the CLSI broth microdilution method (M38-A2 document). J Clin Microbiol48:3251–3257 [CrossRef][PubMed]
    [Google Scholar]
  22. Fischer J., van Koningsbruggen-Rietschel S., Rietschel E., Vehreschild M., Wisplinghoff H., Kronke M., Hamprecht A.. 2014; Prevalence and molecular characterization of azole resistance in aspergillus spp. isolates from german cystic fibrosis patients. J Antimicrobial Chemother69:1533–1536 [CrossRef]
    [Google Scholar]
  23. Gulshan K., Moye-Rowley W. S.. 2007; Multidrug resistance in fungi. Eukaryot Cell6:1933–1942 [CrossRef][PubMed]
    [Google Scholar]
  24. Howard S. J., Cerar D., Anderson M. J., Albarrag A., Fisher M. C., Pasqualotto A. C., Laverdiere M., Arendrup M. C., Perlin D. S., Denning D. W.. 2009; Frequency and evolution of Azole resistance in Aspergillus fumigatus associated with treatment failure. Emer Infect Dis15:1068–1076 [CrossRef]
    [Google Scholar]
  25. Khodavaisy S., Badali H., Hashemi S. J., Aala F., Nazeri M., Nouripour-Sisakht S., Sorkherizi M. S., Amirizad K., Aslani N., Rezaie S.. 2016a; In vitro activities of five antifungal agents against 199 clinical and environmental isolates of Aspergillus flavus, an opportunistic fungal pathogen. J Mycol Med pii: S1156-5233(16)00006-8
    [Google Scholar]
  26. Khodavaisy S., Badali H., Rezaie S., Nabili M., Moghadam K. G., Afhami S., Hagen F., Aala F., Hashemi S. -J., Meis J. F.. 2016b; Genotyping of clinical and environmental aspergillus flavus isolates from iran using microsatellites. Mycoses59:220–225 [CrossRef]
    [Google Scholar]
  27. Kleinkauf N.. 2013; Risk assessment on the impact of environmental usage of triazoles on the development and spread of resistance to medical triazoles in Aspergillus species . ECDC
    [Google Scholar]
  28. Lavergne R. -A., Morio F., Favennec L., Dominique S., Meis J. F., Gargala G., Verweij P. E., Le Pape P.. 2015; First description of azole-resistant Aspergillus fumigatus due to TR 46 /Y121F/T289A mutation in France. Antimicrob Agents Chemother59:4331–4335 [CrossRef]
    [Google Scholar]
  29. Lestrade P. P., Meis J. F., Arends J. P., van der Beek M. T., de Brauwer E., van Dijk K., de Greeff S. C., Haas P. J., Hodiamont C. J., other authors. 2016; Diagnosis and management of aspergillosis in the Netherlands: a national survey. Mycoses59:101–107 [CrossRef][PubMed]
    [Google Scholar]
  30. Lockhart S. R., Frade J. P., Etienne K. A., Pfaller M. A., Diekema D. J., Balajee S. A.. 2011; Azole resistance in Aspergillus fumigatus isolates from the ARTEMIS global surveillance study is primarily due to the TR/L98H mutation in the cyp51a gene. Antimicrob Agents Chemother55:4465–4468 [CrossRef][PubMed]
    [Google Scholar]
  31. Manavathu E. K., Vazquez J. A., Chandrasekar P. H.. 1999; Reduced susceptibility in laboratory-selected mutants of Aspergillus fumigatus to itraconazole due to decreased intracellular accumulation of the antifungal agent. Int J Antimicrob Agents12:213–219 [CrossRef][PubMed]
    [Google Scholar]
  32. Mellado E., Diaz-Guerra T. M., Cuenca-Estrella M., Rodriguez-Tudela J. L.. 2001; Identification of two different 14-alpha sterol demethylase-related genes (cyp51a and cyp51b) in Aspergillus fumigatus and other aspergillus species. J Clin Microbiol39:2431–2438 [CrossRef][PubMed]
    [Google Scholar]
  33. Mortensen K. L., Mellado E., Lass-Florl C., Rodriguez-Tudela J. L., Johansen H. K., Arendrup M. C.. 2010; Environmental study of azole-resistant aspergillus fumigatus and other Aspergilli in austria, denmark, and spain. Antimicrob Agents Chemother 54:4545–4549 [CrossRef]
    [Google Scholar]
  34. Pham C. D., Reiss E., Hagen F., Meis J. F., Lockhart S. R.. 2014; Passive surveillance for Azole-resistant Aspergillus fumigatus, United States, 2011–2013. Emerg Infect Dis20:1498–1503 [CrossRef]
    [Google Scholar]
  35. Rodriguez-Tudela J. L., Alcazar-Fuoli L., Mellado E., Alastruey-Izquierdo A., Monzon A., Cuenca-Estrella M.. 2008; Epidemiological cutoffs and cross-resistance to azole drugs in Aspergillus fumigatus . Antimicrob Agents Chemother52:2468–2472 [CrossRef][PubMed]
    [Google Scholar]
  36. Seyedmousavi S., Hashemi S. J., Zibafar E., Zoll J., Hedayati M. T., Mouton J. W., Melchers W. J. G., Verweij P. E.. 2013; Azole-resistant Aspergillus fumigatus, Iran. Emerg Infect Dis19:832–834 [CrossRef]
    [Google Scholar]
  37. Slaven J. W., Anderson M. J., Sanglard D., Dixon G. K., Bille J., Roberts I. S., Denning D. W.. 2002; Increased expression of a novel Aspergillus fumigatus ABC transporter gene, atrf, in the presence of itraconazole in an itraconazole resistant clinical isolate. Fungal Genet Biol36:199–206 [CrossRef][PubMed]
    [Google Scholar]
  38. Snelders E., Rijs A. J., Kema G. H., Melchers W. J., Verweij P. E.. 2009; Possible environmental origin of resistance of Aspergillus fumigatus to medical triazoles. App Environ Microbiol75:4053–4057 [CrossRef]
    [Google Scholar]
  39. Snelders E., van der Lee H. A., Kuijpers J., Rijs A. J., Varga J., Samson R. A., Mellado E., Donders A. R., Melchers W. J., Verweij P. E.. 2008; Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLoS Med5:e219 [CrossRef][PubMed]
    [Google Scholar]
  40. Tamura K., Peterson D., Peterson N., Stecher G., Nei M., Kumar S.. 2011; MEGA5: Molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol28:2731–2739 [CrossRef][PubMed]
    [Google Scholar]
  41. van der Linden J. W., Arendrup M. C., Warris A., Lagrou K., Pelloux H., Hauser P. M., Chryssanthou E., Mellado E., Kidd S. E., Tortorano A.. 2015; Prospective multicenter international surveillance of azole resistance in Aspergillus fumigatus . Emerg Infect Dis21:1041–1044 [CrossRef][PubMed]
    [Google Scholar]
  42. van der Linden J. W., Camps S. M., Kampinga G. A., Arends J. P., Debets-Ossenkopp Y. J., Haas P. J., Rijnders B. J., Kuijper E. J., van Tiel F. H., Varga J.. 2013; Aspergillosis due to voriconazole highly resistant Aspergillus fumigatus and recovery of genetically related resistant isolates from domiciles. Clin Infect Dis57:513–520 [CrossRef][PubMed]
    [Google Scholar]
  43. van der Linden J. W., Snelders E., Kampinga G. A., Rijnders B. J., Mattsson E., Debets-Ossenkopp Y. J., Kuijper E. J., Van Tiel F. H., Melchers W. J., Verweij P. E.. 2011; Clinical implications of azole resistance in Aspergillus fumigatus, The Netherlands, 2007-2009. Emerg Infect Dis17:1846–1854 [CrossRef][PubMed]
    [Google Scholar]
  44. van Ingen J., van der Lee H. A., Rijs T. A., Zoll J., Leenstra T., Melchers W. J., Verweij P. E.. 2014; Azole, polyene and echinocandin MIC distributions for wild-type, TR34/L98H and TR46/Y121F/T289A Aspergillus fumigatus isolates in the netherlands. J Antimicrobiol Chemother70:171–181
    [Google Scholar]
  45. Vermeulen E., Maertens J., De Bel A., Nulens E., Boelens J., Surmont I., Mertens A., Boel A., Lagrou K.. 2015; Nationwide surveillance of azole resistance in aspergillus diseases. Antimicrob Agents Chemother (Bethesda)59:4569–4576 [CrossRef]
    [Google Scholar]
  46. Vermeulen E., Maertens J., Schoemans H., Lagrou K.. 2012; Azole-resistant Aspergillus fumigatus due to TR46/Y121F/T289A mutation emerging in Belgium, July 2012. Euro Surveill17:20326[PubMed]
    [Google Scholar]
  47. Verweij P. E., Howard S. J., Melchers W. J., Denning D. W.. 2009a; Azole-resistance in aspergillus: Proposed nomenclature and breakpoints. Drug Resist Updat12:141–147 [CrossRef][PubMed]
    [Google Scholar]
  48. Verweij P. E., Mellado E., Melchers W. J.. 2007; Multiple-triazole-resistant aspergillosis. N Engl J Med356:1481–1483 [CrossRef][PubMed]
    [Google Scholar]
  49. Verweij P. E., Snelders E., Kema G. H., Mellado E., Melchers W. J.. 2009b; Azole resistance in Aspergillus fumigatus: A side-effect of environmental fungicide use?. Lancet Infect Dis9:789–795 [CrossRef][PubMed]
    [Google Scholar]
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