{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:42:04Z","timestamp":1792114924120,"version":"4.4.0"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T00:00:00Z","timestamp":1643241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100004916","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Amazonas","doi-asserted-by":"publisher","award":["001\/2017"],"award-info":[{"award-number":["001\/2017"]}],"id":[{"id":"10.13039\/501100004916","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,3,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:label\/>\n                  <jats:p>Heteroresistance, defined as the occurrence of apparently homogeneous subpopulations of microbial cells showing different levels of antimicrobial susceptibility is a problem that has been associated with therapeutical failure in cryptococcosis. The purpose of the study was an investigation on the level of heteroresistance to fluconazole (LHF) as observed in clinical and environmental C. neoformans\/C. gattii complex species isolates from Amazonas State (AM), Brazil. A total of 45 isolates and 9 type strains were analyzed. The assessments comprised testing for minimal inhibitory concentrations (MICs), for LHFs, for the strains\u2019 capacity of adaptation to high fluconazole (FLC) concentrations above the LHF, and for the stability of the heteroresistance phenomenon. The mean MICs for clinical isolates of C. gattii (6.4\u00a0\u00b5g\/ml) were higher than those observed for environmental C. gattii strains (1.7\u00a0\u00b5g\/ml) and clinical (3.7\u00a0\u00b5g\/ml) as well as environmental (1.5\u00a0\u00b5g\/ml) C. neoformans isolates. The phenomenon of heteroresistance to FLC was recorded for all isolates. On average, the LHF (8\u2013256\u00a0\u00b5g\/ml) of the isolates was 16 times higher than the FLC MICs (0.5\u201316\u00a0\u00b5g\/ml) and a proportion of 85% isolates showed LHFs\u00a0\u2265\u00a016\u00a0\u00b5g\/ml, 40% even\u00a0\u2265\u00a032\u00a0\u00b5g\/ml. According to the adaptation assay, a considerable number of isolates (58%) showed the capacity of adaptation to MICs even higher than the initially recorded LHF. After the adaptation experiment, the adaptative-LHF values (8\u2013512\u00a0\u00b5g\/ml) were about 60 times higher than the original MIC values. After nine subsequent passages in drug-free broth, the isolates had their adaptative-LHF reduced. However, the LHF did not revert to the initially measured level. Our findings challenge the clinical interpretation of the antifungal MIC testing and motivate future studies correlating the levels of heteroresistance and parameters like LHF and adaptative-LHF with cryptococcosis-associated morbidity and mortality.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Lay summary<\/jats:title>\n                  <jats:p>Cryptococcosis affects many people and is caused by fungi of the Cryptococcus neoformans\/Cryptococcus gattii complexes. These agents appear to become more resistant to antifungals when exposed to increasing concentrations of antifungals due to a phenomenon called heteroresistance.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/mmy\/myac005","type":"journal-article","created":{"date-parts":[[2022,1,24]],"date-time":"2022-01-24T20:12:13Z","timestamp":1643055133000},"source":"Crossref","is-referenced-by-count":23,"title":["Investigation of fluconazole heteroresistance in clinical and environmental isolates of <i>Cryptococcus neoformans<\/i> complex and <i>Cryptococcus gattii<\/i> complex in the state of Amazonas, Brazil"],"prefix":"10.1093","volume":"60","author":[{"given":"Izabela de Mesquita B\u00e1rcia","family":"Moreira","sequence":"first","affiliation":[{"name":"Graduate Program in Pharmaceutical Sciences, Federal University of Amazonas- UFAM, 69080-900, Manaus, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Cl\u00e1udia Alves","family":"Cortez","sequence":"additional","affiliation":[{"name":"Laboratory of Mycology, Coordination of Society, Environment and Health, National Institute for Amazonian Research-INPA, 69060-001, Manaus, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c9rica Simpl\u00edcio","family":"de Souza","sequence":"additional","affiliation":[{"name":"Superior School of Technology, Amazon State University- UEA, 69050-020, Manaus, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silviane Bezerra","family":"Pinheiro","sequence":"additional","affiliation":[{"name":"Graduate Program in Genetics, Conservation and Evolutionary Biology, National Institute for Amazonian Research- INPA, 69060-001, Manaus, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana Gomes","family":"de Souza Oliveira","sequence":"additional","affiliation":[{"name":"Collection of Microorganisms of Medical Interest, Coordination of Society, 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Carvalho","family":"Melhem","sequence":"additional","affiliation":[{"name":"Mycology Department, Adolfo Lutz Institute, 01246-902, S\u00e3o Paulo, SP, Brazil"},{"name":"School of Medicine, Federal University of Mato Grosso do Sul, 79070-900, Campo Grande, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hagen","family":"Frickmann","sequence":"additional","affiliation":[{"name":"Microbiology and Hospital Hygiene, Bundeswehr Hospital Hamburg, 22049, Hamburg, Germany"},{"name":"Institute for Medical Microbiology, Virology and Hygiene, University Medicine Rostock, 18057, Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3163-7499","authenticated-orcid":false,"given":"Jo\u00e3o Vicente Braga","family":"de Souza","sequence":"additional","affiliation":[{"name":"Laboratory of Mycology, Coordination of Society, Environment and Health, National Institute for Amazonian Research-INPA, 69060-001, Manaus, 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