{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T11:13:26Z","timestamp":1768475606165,"version":"3.49.0"},"reference-count":56,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2019,8,17]],"date-time":"2019-08-17T00:00:00Z","timestamp":1566000000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institute of Neurologic Diseases and Stroke","award":["R01NS086312"],"award-info":[{"award-number":["R01NS086312"]}]},{"name":"Fogarty International Institute","award":["K01TW010268"],"award-info":[{"award-number":["K01TW010268"]}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U01AI125003"],"award-info":[{"award-number":["U01AI125003"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["K23AI138851"],"award-info":[{"award-number":["K23AI138851"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["K08AI134262"],"award-info":[{"award-number":["K08AI134262"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Fluconazole is lifesaving for treatment and prevention of cryptococcosis; however, optimal dosing is unknown. Initial fluconazole doses of 100 mg to 2000 mg\/day have been used. Prevalence of fluconazole nonsusceptible Cryptococcus is increasing over time, risking the efficacy of long-established standard dosing. Based on current minimum inhibitory concentration (MIC) distribution, we modeled fluconazole concentrations and area under the curve (AUC) relative to MIC to propose a rational fluconazole dosing strategy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>We conducted a systematic review using the MEDLINE database for reports of fluconazole MIC distribution against clinical Cryptococcus isolates. Then, we utilized fluconazole concentrations from 92 Ugandans who received fluconazole 800mg\/day coupled with fluconazole\u2019s known pharmacokinetics to predict plasma fluconazole concentrations for doses ranging from 100 mg to 2000 mg via linear regression. The fluconazole AUC above MIC ratio were calculated using Monte Carlo simulation and using the MIC distribution elucidated during the systemic review.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We summarized 21 studies with 11 049 clinical Cryptococcus isolates. Minimum inihibitory concentrations were normally distributed with a geometric mean of 3.4 \u00b5g\/mL, median (MIC50) of 4 \u00b5g\/mL, and 90th percentile (MIC90) of 16 \u00b5g\/mL. The median MIC50 trended upwards from 4 \u00b5g\/mL in 2000\u20132012 to 8 \u00b5g\/mL in 2014\u20132018. Predicted subtherapeutic fluconazole concentrations (below MIC) would occur in 40% with 100 mg, 21% with 200 mg, and 9% with 400 mg. The AUC:MIC ratio &amp;gt;100 would occur in 53% for 400 mg, 74% for 800 mg, 83% for 1200 mg, and 88% for 1600 mg.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Currently recommended fluconazole doses may be inadequate for cryptococcosis. Further clinical studies are needed for rational fluconazole dose selection.<\/jats:p><\/jats:sec>","DOI":"10.1093\/ofid\/ofz369","type":"journal-article","created":{"date-parts":[[2019,8,17]],"date-time":"2019-08-17T02:25:06Z","timestamp":1566008706000},"source":"Crossref","is-referenced-by-count":23,"title":["Minimum Inhibitory Concentration Distribution of Fluconazole Against Cryptococcus Species and the Fluconazole Exposure Prediction Model"],"prefix":"10.1093","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3507-6411","authenticated-orcid":false,"given":"Supavit","family":"Chesdachai","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Minnesota, Minneapolis, Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Radha","family":"Rajasingham","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Minnesota, Minneapolis, Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5513-5509","authenticated-orcid":false,"given":"Melanie R","family":"Nicol","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David B","family":"Meya","sequence":"additional","affiliation":[{"name":"Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Felix","family":"Bongomin","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Faculty of Medicine, Gulu University, Gulu, Uganda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahsa","family":"Abassi","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Minnesota, Minneapolis, Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caleb","family":"Skipper","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Minnesota, Minneapolis, Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Kwizera","sequence":"additional","affiliation":[{"name":"Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0480-9646","authenticated-orcid":false,"given":"Joshua","family":"Rhein","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Minnesota, Minneapolis, Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David R","family":"Boulware","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Minnesota, Minneapolis, Minnesota"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,8,17]]},"reference":[{"key":"2020081004470652300_CIT0001","doi-asserted-by":"crossref","first-page":"e101","DOI":"10.1097\/QAI.0b013e31828e1e56","article-title":"Cost-effective diagnostic checklists for meningitis in resource-limited settings","volume":"63","author":"Durski","year":"2013","journal-title":"J Acquir Immune Defic Syndr"},{"key":"2020081004470652300_CIT0002","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/S1473-3099(17)30243-8","article-title":"Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis","volume":"17","author":"Rajasingham","year":"2017","journal-title":"Lancet Infect Dis"},{"key":"2020081004470652300_CIT0003","volume-title":"Guidelines for the diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children","author":"World Health Organization"},{"key":"2020081004470652300_CIT0004","doi-asserted-by":"crossref","first-page":"261","DOI":"10.3109\/13693786.2012.715763","article-title":"Fluconazole resistance in cryptococcal disease: emerging or intrinsic?","volume":"51","author":"Cheong","year":"2013","journal-title":"Med Mycol"},{"key":"2020081004470652300_CIT0005","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1128\/AAC.44.6.1544-1548.2000","article-title":"Correlation of fluconazole MICs with clinical outcome in cryptococcal infection","volume":"44","author":"Aller","year":"2000","journal-title":"Antimicrob Agents Chemother"},{"key":"2020081004470652300_CIT0006","doi-asserted-by":"crossref","first-page":"3065","DOI":"10.1128\/AAC.45.11.3065-3069.2001","article-title":"Trends in antifungal drug susceptibility of Cryptococcus neoformans isolates in the United States: 1992 to 1994 and 1996 to 1998","volume":"45","author":"Brandt","year":"2001","journal-title":". 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