{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T19:56:55Z","timestamp":1791316615919,"version":"4.3.1"},"reference-count":35,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2019,12,3]],"date-time":"2019-12-03T00:00:00Z","timestamp":1575331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,12,24]],"date-time":"2019-12-24T00:00:00Z","timestamp":1577145600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Wellcome","award":["097377\/Z\/11\/Z"],"award-info":[{"award-number":["097377\/Z\/11\/Z"]}]},{"DOI":"10.13039\/501100000265","name":"UK Research and Innovation | Medical Research Council","doi-asserted-by":"publisher","award":["G1001760"],"award-info":[{"award-number":["G1001760"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2019,12,24]]},"abstract":"<jats:p>\n                    Cryptococcal meningitis is a lethal disease with few treatment options. The incidence remains high and intricately linked with the HIV\/AIDS epidemic. In many parts of the world, fluconazole is the only agent that is available for the initial treatment of cryptococcal meningitis despite considerable evidence that it is associated with suboptimal microbiological and clinical outcomes. Fluconazole has a fungistatic mode of action: it predominantly inhibits growth rather than causing fungal killing. Our work shows that the pattern of fluconazole activity is caused by the emergence of resistance in\n                    <jats:italic>Cryptococcus<\/jats:italic>\n                    not detected by standard susceptibility tests, with chromosomal duplication\/aneuploidy as the main mechanism. Resistance emergence is related to drug exposure and occurs with the use of clinically relevant regimens. Hence, fluconazole (and potentially other agents that target 14-alpha-demethylase) is compromised by an intrinsic property that limits its effectiveness. However, this resistance may be potentially overcome by dosage escalation or the use of combination therapy.\n                  <\/jats:p>","DOI":"10.1128\/mbio.02575-19","type":"journal-article","created":{"date-parts":[[2019,12,2]],"date-time":"2019-12-02T06:42:32Z","timestamp":1575268952000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":62,"title":["Fluconazole Monotherapy Is a Suboptimal Option for Initial Treatment of Cryptococcal Meningitis Because of Emergence of Resistance"],"prefix":"10.1128","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6187-878X","authenticated-orcid":false,"given":"William","family":"Hope","sequence":"first","affiliation":[{"name":"Antimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, Liverpool Health Partners, Liverpool, United Kingdom"},{"name":"Royal Liverpool Broadgreen University Hospital Trust, Liverpool Health Partners, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil R. H.","family":"Stone","sequence":"additional","affiliation":[{"name":"Antimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, Liverpool Health Partners, Liverpool, United Kingdom"},{"name":"Institute of Infection and Immunity, St. George\u2019s, University of London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Johnson","sequence":"additional","affiliation":[{"name":"Antimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, Liverpool Health Partners, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"McEntee","sequence":"additional","affiliation":[{"name":"Antimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, Liverpool Health Partners, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Farrington","sequence":"additional","affiliation":[{"name":"Antimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, Liverpool Health Partners, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anahi","family":"Santoro-Castelazo","sequence":"additional","affiliation":[{"name":"Antimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, Liverpool Health Partners, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Centre for Genomics Research, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Lucaci","sequence":"additional","affiliation":[{"name":"Centre for Genomics Research, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Hughes","sequence":"additional","affiliation":[{"name":"Centre for Genomics Research, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason D.","family":"Oliver","sequence":"additional","affiliation":[{"name":"F2G Ltd., Eccles, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Giamberardino","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Health, Duke University School of Medicine, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayoki","family":"Mfinanga","sequence":"additional","affiliation":[{"name":"National Institute of Medical Research, Dar es Salaam, Tanzania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas S.","family":"Harrison","sequence":"additional","affiliation":[{"name":"Institute of Infection and Immunity, St. George\u2019s, University of London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Perfect","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Health, Duke University School of Medicine, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tihana","family":"Bicanic","sequence":"additional","affiliation":[{"name":"Institute of Infection and Immunity, St. George\u2019s, University of London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","volume-title":"WHO guidelines for the diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children","author":"WHO","year":"2018","unstructured":"WHO. 2018. WHO guidelines for the diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children. WHO, Geneva, Switzerland. http:\/\/www.who.int\/hiv\/pub\/guidelines\/cryptococcal-disease\/en\/."},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(18)30493-6"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1086\/593194"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1086\/649861"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199201093260202"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1086\/516372"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1086\/518607"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00216-13"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000848"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1086\/507895"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.8.1856"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00694-13"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI124516"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/clinids\/22.2.322"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00885-18"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01909-17"},{"key":"e_1_3_3_18_2","volume-title":"Reference method for broth dilution antifungal susceptibility testing of yeasts: approved standard","author":"Clinical and Laboratory Standards Institute","year":"2008","unstructured":"Clinical and Laboratory Standards Institute. 2008. Reference method for broth dilution antifungal susceptibility testing of yeasts: approved standard, 3rd ed. Clinical and Laboratory Standards Institute, Wayne, PA.","edition":"3"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02177-15"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01315-18"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0b013e31825c4ba6"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10795"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1001815"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00205-17"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01290-18"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01520-05"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.riam.2009.02.001"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.44.6.1544-1548.2000"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02526-17"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1710922"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.14806\/ej.17.1.200"},{"key":"e_1_3_3_32_2","unstructured":"Joshi NA Fass JN. 2011. Sickle: a sliding-window adaptive quality-based trimming tool for FastQ files."},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107524.110"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.806"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr670"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.02575-19","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.02575-19","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T21:21:06Z","timestamp":1646688066000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mBio.02575-19"}},"subtitle":[],"editor":[{"given":"Tom","family":"Chiller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2019,12,24]]},"references-count":35,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2019,12,24]]}},"alternative-id":["10.1128\/mBio.02575-19"],"URL":"https:\/\/doi.org\/10.1128\/mbio.02575-19","relation":{},"ISSN":["2161-2129","2150-7511"],"issn-type":[{"value":"2161-2129","type":"print"},{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,24]]},"assertion":[{"value":"2019-09-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-10-23","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-12-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e02575-19"}}