{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T01:45:57Z","timestamp":1794015957058,"version":"4.8.0"},"reference-count":30,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2003,1,1]],"date-time":"2003-01-01T00:00:00Z","timestamp":1041379200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Clin Microbiol"],"published-print":{"date-parts":[[2003,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Strains of\n            <jats:italic>Cryptococcus neoformans<\/jats:italic>\n            expressing heteroresistance to fluconazole have been described previously. The present study was conducted to investigate the prevalence of heteroresistance among clinical isolates of\n            <jats:italic>C. neoformans<\/jats:italic>\n            and to characterize the heteroresistant phenotypes. A total of 107 clinical isolates of\n            <jats:italic>C. neoformans<\/jats:italic>\n            for which the MICs of fluconazole ranged from 0.25 to 32 \u03bcg\/ml were selected. The isolates were chosen to represent a broad geographic distribution. Of the 107\n            <jats:italic>C. neoformans<\/jats:italic>\n            isolates tested, 4 grew on medium containing fluconazole at concentrations that were four to eight times higher than the MICs for each strain. A fifth isolate, for which the fluconazole MIC was 32 \u03bcg\/ml, grew on agar with 64 \u03bcg of fluconazole per ml. These five isolates (4.7% of the total number) were confirmed to exhibit heteroresistant compositions by population analysis. The degree and frequency of resistance varied among the isolates. Stepwise selection by exposure to fluconazole resulted in subclones of all five strains for which the fluconazole MIC was &gt;64 \u03bcg\/ml. Subclones of three strains demonstrated a homogenous population of resistant cells on medium containing 64 \u03bcg of fluconazole\/ml. The resistance was sensitive to incubation temperature, that is, heteroresistance was demonstrable only at 30\u00b0C by agar-based tests, and was reversible through serial transfers on fluconazole-free medium over a period of 8 days. These results suggest that the fluconazole-heteroresistant phenotype of\n            <jats:italic>C. neoformans<\/jats:italic>\n            exists in a significant proportion of clinical isolates and that fluconazole resistance can be developed by selection from heteroresistant clones and induction by exposure to fluconazole.\n          <\/jats:p>","DOI":"10.1128\/jcm.41.1.267-272.2003","type":"journal-article","created":{"date-parts":[[2003,1,7]],"date-time":"2003-01-07T18:03:11Z","timestamp":1041962591000},"page":"267-272","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":58,"title":["Characterization of Heteroresistance to Fluconazole among Clinical Isolates of\n            <i>Cryptococcus neoformans<\/i>"],"prefix":"10.1128","volume":"41","author":[{"given":"T.","family":"Yamazumi","sequence":"first","affiliation":[{"name":"Medical Microbiology Division, Department of Pathology, University of Iowa College of Medicine, Iowa City"},{"name":"Kinki University School of Medicine, Ohnohigashi, Osakasayama, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. A.","family":"Pfaller","sequence":"additional","affiliation":[{"name":"Medical Microbiology Division, Department of Pathology, University of Iowa College of Medicine, Iowa City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. A.","family":"Messer","sequence":"additional","affiliation":[{"name":"Medical Microbiology Division, Department of Pathology, University of Iowa College of Medicine, Iowa City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. K.","family":"Houston","sequence":"additional","affiliation":[{"name":"Medical Microbiology Division, Department of Pathology, University of Iowa College of Medicine, Iowa City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Boyken","sequence":"additional","affiliation":[{"name":"Medical Microbiology Division, Department of Pathology, University of Iowa College of Medicine, Iowa City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. J.","family":"Hollis","sequence":"additional","affiliation":[{"name":"Medical Microbiology Division, Department of Pathology, University of Iowa College of Medicine, Iowa City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.","family":"Furuta","sequence":"additional","affiliation":[{"name":"Kinki University School of Medicine, Ohnohigashi, Osakasayama, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. N.","family":"Jones","sequence":"additional","affiliation":[{"name":"The JONES Group\/JMI Laboratories, North Liberty, Iowa"},{"name":"Tufts University School of Medicine, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"1337","volume":"23","year":"1996","unstructured":"Armengou, A., C. Porcar, J. Mascaro, and F. Garcia-Bragado. 1996. Possible development of resistance to fluconazole during suppressive therapy for AIDS-associated cryptococcal meningitis. Clin. Infect. Dis.23:1337-1338.","journal-title":"Clin. Infect. Dis."},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/0732-8893(95)00169-7"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.6.1578-1584.2000"},{"key":"e_1_3_2_5_2","first-page":"186","volume":"26","year":"1998","unstructured":"Berg, J., C. J. Clancy, and M. H. Nguyen. 1998. The hidden danger of primary fluconazole prophylaxis for patients with AIDS. Clin. Infect. Dis.26:186-187.","journal-title":"Clin. Infect. Dis."},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/174.4.812"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.11.3065-3069.2001"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.41.3.535"},{"key":"e_1_3_2_9_2","doi-asserted-by":"crossref","unstructured":"Casadevall A. and J. R. Perfect (ed.). 1998. Epidemiology p. 351-380. In Cryptococcus neoformans . American Society for Microbiology Washington D.C.","DOI":"10.1128\/9781555818241"},{"key":"e_1_3_2_10_2","unstructured":"Casadevall A. and J. R. Perfect (ed.). 1998. Therapy of cryptococcosis p. 457-518. In Cryptococcus neoformans . American Society for Microbiology Washington D.C."},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.10.4.781"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.34.4.848-852.1996"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.epirev.a036195"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.36.5.1330-1332.1998"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.42.10.2584"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.1.52-59.2001"},{"key":"e_1_3_2_17_2","first-page":"161","volume":"11","year":"1984","unstructured":"Matthews, P. R., and P. R. Stewart. 1984. Resistance heterogeneity in methicillin-resistant Staphylococcus aureus. FEMS Microbiol. Lett.11:161-166.","journal-title":"FEMS Microbiol. Lett."},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.8.4.515"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.8.1856"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.41.3.617"},{"key":"e_1_3_2_21_2","unstructured":"National Committee for Clinical Laboratory Standards. 1997. Reference method for broth dilution antifungal susceptibility testing of yeasts. Approved standard M27-A. National Committee for Clinical Laboratory Standards Wayne Pa."},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0732-8893(98)00095-9"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.1.169"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199503163321102"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1093\/clinids\/19.5.975-a"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.34.5.1280-1282.1996"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(97)00421-6"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.41.4.748"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.11.2.382"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.2.420-427.2001"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.10.2883-2886.2000"}],"container-title":["Journal of Clinical Microbiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JCM.41.1.267-272.2003","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JCM.41.1.267-272.2003","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T02:12:10Z","timestamp":1646446330000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/JCM.41.1.267-272.2003"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,1]]},"references-count":30,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2003,1]]}},"alternative-id":["10.1128\/JCM.41.1.267-272.2003"],"URL":"https:\/\/doi.org\/10.1128\/jcm.41.1.267-272.2003","relation":{},"ISSN":["0095-1137","1098-660X"],"issn-type":[{"value":"0095-1137","type":"print"},{"value":"1098-660X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2003,1]]},"assertion":[{"value":"2002-05-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2002-10-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2003-01-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}