{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:34:11Z","timestamp":1790724851144,"version":"4.1.0"},"reference-count":35,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[1999,8,1]],"date-time":"1999-08-01T00:00:00Z","timestamp":933465600000},"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":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[1999,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            <jats:italic>Cryptococcus neoformans<\/jats:italic>\n            isolates that exhibited unusual patterns of resistance to fluconazole and voriconazole were isolated from seven isolates from two different geographical regions: one isolate from an Israeli non-AIDS patient and six serial isolates from an Italian AIDS patient who had suffered six recurrent episodes of cryptococcal meningitis. Each isolate produced cultures with heterogeneous compositions in which most of the cells were susceptible, but cells highly resistant to fluconazole (MICs, \u226564 \u03bcg\/ml) were recovered at a variable frequency (7 \u00d7 10\n            <jats:sup>\u22123<\/jats:sup>\n            to 4.6 \u00d7 10\n            <jats:sup>\u22122<\/jats:sup>\n            ). Evidence showed that this type of resistance is innate and is unrelated to drug exposure since the Israeli patient had never been treated with azoles or any other antimycotic agents. Analysis of clonal subpopulations of these two strains showed that they exhibited heterogeneous patterns of resistance. The number of subpopulations which grew on fluconazole or voriconazole agar declined progressively with increasing azole concentration without a sharp cutoff point. For the Italian serial isolates, the number of clonal populations resistant to fluconazole (64 \u03bcg\/ml) and voriconazole (1 \u03bcg\/ml) increased steadily, yielding the highest number for the isolate from the last episode. Attempts to purify a sensitive subpopulation failed, but clones highly resistant to fluconazole (100 \u03bcg\/ml) and moderately resistant to voriconazole (1 \u03bcg\/ml) always produced a homogeneous population of resistant cells. Upon maintenance on drug-free medium, however, the majority of the homogeneously resistant cells of these subclones lost their resistance and returned to the stable initial heteroresistant phenotype. The pattern of heteroresistance was not affected by the pH or osmolarity of the medium but was influenced by temperature. The resistance appeared to be suppressed at 35\u00b0C and was completely abolished at 40\u00b0C. Although heterogeneity in azole resistance among subpopulations of single isolates has been reported for\n            <jats:italic>Candida<\/jats:italic>\n            species, the transient changes in expression of resistance under different growth conditions reported here have not been observed in fungal pathogens.\n          <\/jats:p>","DOI":"10.1128\/aac.43.8.1856","type":"journal-article","created":{"date-parts":[[2018,10,9]],"date-time":"2018-10-09T00:35:20Z","timestamp":1539045320000},"page":"1856-1861","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":128,"title":["Heteroresistance to Fluconazole and Voriconazole in\n            <i>Cryptococcus neoformans<\/i>"],"prefix":"10.1128","volume":"43","author":[{"given":"P.","family":"Mondon","sequence":"first","affiliation":[{"name":"<!--label omitted: 1-->Molecular Microbiology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 208921;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Petter","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Molecular Microbiology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 208921;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Amalfitano","sequence":"additional","affiliation":[{"name":"<!--label omitted: 2-->University Hospital of Verona, Verona, Italy2; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Luzzati","sequence":"additional","affiliation":[{"name":"<!--label omitted: 2-->University Hospital of Verona, Verona, Italy2; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Concia","sequence":"additional","affiliation":[{"name":"<!--label omitted: 2-->University Hospital of Verona, Verona, Italy2; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.","family":"Polacheck","sequence":"additional","affiliation":[{"name":"<!--label omitted: 3-->Hadassah Medical Center, Jerusalem, Israel3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. J.","family":"Kwon-Chung","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Molecular Microbiology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 208921;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/clinids\/23.6.1337-a"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/517056"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1177\/095646249500600510"},{"key":"e_1_3_2_5_2","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1093\/infdis\/174.4.812","article-title":"Molecular subtypes and antifungal susceptibilities of serial Cryptococcus neoformans isolates in human immunodeficiency virus-associated cryptococcosis.","volume":"174","author":"Brandt M. E.","year":"1996","unstructured":"Brandt M. E. Pfaller M. A. Hajjeh R. A. Graviss E. A. Rees J. Spitzer E. D. Pinner R. W. Mayer L. W. Cryptococcal Disease Active Surveillance Group Molecular subtypes and antifungal susceptibilities of serial Cryptococcus neoformans isolates in human immunodeficiency virus-associated cryptococcosis. J. Infect. Dis. 174 1996 812 820","journal-title":"J. Infect. Dis."},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.41.3.535"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.37.6.1383"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.10.4.781"},{"key":"e_1_3_2_9_2","doi-asserted-by":"crossref","first-page":"S13","DOI":"10.1007\/BF02389872","article-title":"Genetic control of population structure in heterogeneous strains of methicillin resistant Staphylococcus aureus.","volume":"12","author":"DeLencastre H.","year":"1993","unstructured":"DeLencastre H. Figuiredo A. M. S. Tomasz A. Genetic control of population structure in heterogeneous strains of methicillin resistant Staphylococcus aureus. Eur. J. Clin. Microbiol. Infect. Dis. 12 1993 S13 S17","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"e_1_3_2_10_2","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1111\/j.1574-6968.1996.tb08394.x","article-title":"Impact of sar and arg on methicillin-resistance in Staphylococcus aureus.","volume":"141","author":"Duran S. P.","year":"1996","unstructured":"Duran S. P. Kayser F. H. Berger-Bachi B. Impact of sar and arg on methicillin-resistance in Staphylococcus aureus. FEMS Microbiol. Lett. 141 1996 255 260","journal-title":"FEMS Microbiol. 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NCCLS document M27-A.\n          1997\n          National Committee for Clinical Laboratory Standards\n          Wayne Pa"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.42.2.471"},{"key":"e_1_3_2_22_2","unstructured":"Orni-Wasserlauf\n              R.\n              Siegman-Igra\n              Y.\n              Izkhakov\n              E.\n              Bash\n              E.\n              Polacheck\n              I.\n              Giladi\n              M.\n          Fluconazole-resistant Cryptococcus neoformans isolated from an immunocompetent patient without prior exposure to fluconazole abstr. J-24\n          Program and abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy.\n          1998\n          458\n          American Society for Microbiology\n          Washington D.C"},{"key":"e_1_3_2_23_2","first-page":"431","article-title":"Increased fluconazole resistance of Cryptococcus neoformans isolated from a patient with AIDS and recurrent meningitis.","volume":"17","author":"Paugam A.","year":"1993","unstructured":"Paugam A. Dupouy-Camet J. Blanche P. Gangneux J. P. Tourte-Schaefer C. Sicard D. Increased fluconazole resistance of Cryptococcus neoformans isolated from a patient with AIDS and recurrent meningitis. Clin. Infect. Dis. 17 1993 431 436","journal-title":"Clin. Infect. 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