Minimum Inhibitory Concentration Distribution of Fluconazole against Cryptococcus Species and the Fluconazole Exposure Prediction Model.
Cryptococcus
Cryptococcal meningitis
Fluconazole
Fungal drug resistance
Systematic review
Journal
Open forum infectious diseases
ISSN: 2328-8957
Titre abrégé: Open Forum Infect Dis
Pays: United States
ID NLM: 101637045
Informations de publication
Date de publication:
01 Oct 2019
01 Oct 2019
Historique:
received:
21
05
2019
pubmed:
20
8
2019
medline:
20
8
2019
entrez:
18
8
2019
Statut:
ppublish
Résumé
Fluconazole is lifesaving for treatment and prevention of cryptococcosis; however, optimal dosing is unknown. Initial fluconazole doses of 100mg to 2000mg/day have been used. Prevalence of fluconazole non-susceptible Cryptococcus is increasing over time, risking the efficacy of long-established standard dosing. Based on current minimum inhibitory concentration (MIC) distribution, we modeled fluconazole concentration and area under the curve (AUC) relative to MIC to propose a rational fluconazole dosing strategy. First, we conducted a systematic review using MEDLINE database for reports of fluconazole MIC distribution against clinical Cryptococcus isolates. Second, we utilized fluconazole concentrations from 92 Ugandans who received fluconazole 800mg/day coupled with fluconazole's known pharmacokinetics to predict plasma fluconazole concentrations for doses ranging from 100mg to 2000mg via linear regression. Third, the fluconazole AUC above MIC ratio were calculated using Monte Carlo simulation and using the MIC distribution elucidated during the systemic review. We summarized 21 studies with 11,049 clinical Cryptococcus isolates. MICs were normally distributed with geometric mean of 3.4 μg/mL, median (MIC50) of 4 μg/mL, and 90th percentile (MIC90) of 16 μg/mL. The median MIC50 trended upwards from 4 μg/mL in 2000-2012 to 8 μg/mL in 2014-2018. Predicted sub-therapeutic fluconazole concentrations (below MIC) would occur in 40% with 100mg, 21% with 200mg, and 9% with 400mg. AUC/MIC ratio >100 would occur in 53% for 400mg, 74% for 800mg, 83% for 1200mg, and 88% for 1600mg. Currently recommended fluconazole doses may be inadequate for cryptococcosis. Further clinical studies are needed for rational fluconazole dose selection.
Sections du résumé
BACKGROUND
BACKGROUND
Fluconazole is lifesaving for treatment and prevention of cryptococcosis; however, optimal dosing is unknown. Initial fluconazole doses of 100mg to 2000mg/day have been used. Prevalence of fluconazole non-susceptible Cryptococcus is increasing over time, risking the efficacy of long-established standard dosing. Based on current minimum inhibitory concentration (MIC) distribution, we modeled fluconazole concentration and area under the curve (AUC) relative to MIC to propose a rational fluconazole dosing strategy.
METHODS
METHODS
First, we conducted a systematic review using MEDLINE database for reports of fluconazole MIC distribution against clinical Cryptococcus isolates. Second, we utilized fluconazole concentrations from 92 Ugandans who received fluconazole 800mg/day coupled with fluconazole's known pharmacokinetics to predict plasma fluconazole concentrations for doses ranging from 100mg to 2000mg via linear regression. Third, the fluconazole AUC above MIC ratio were calculated using Monte Carlo simulation and using the MIC distribution elucidated during the systemic review.
RESULTS
RESULTS
We summarized 21 studies with 11,049 clinical Cryptococcus isolates. MICs were normally distributed with geometric mean of 3.4 μg/mL, median (MIC50) of 4 μg/mL, and 90th percentile (MIC90) of 16 μg/mL. The median MIC50 trended upwards from 4 μg/mL in 2000-2012 to 8 μg/mL in 2014-2018. Predicted sub-therapeutic fluconazole concentrations (below MIC) would occur in 40% with 100mg, 21% with 200mg, and 9% with 400mg. AUC/MIC ratio >100 would occur in 53% for 400mg, 74% for 800mg, 83% for 1200mg, and 88% for 1600mg.
CONCLUSIONS
CONCLUSIONS
Currently recommended fluconazole doses may be inadequate for cryptococcosis. Further clinical studies are needed for rational fluconazole dose selection.
Identifiants
pubmed: 31420668
pii: 5550889
doi: 10.1093/ofid/ofz369
pmc: PMC6767974
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : NINDS NIH HHS
ID : R01 NS086312
Pays : United States
Organisme : NIAID NIH HHS
ID : K23 AI138851
Pays : United States
Organisme : NIAID NIH HHS
ID : U01 AI125003
Pays : United States
Organisme : FIC NIH HHS
ID : K01 TW010268
Pays : United States
Organisme : Medical Research Council
ID : MR/M007413/1
Pays : United Kingdom
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
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