Minimum Inhibitory Concentration Distribution of Fluconazole Against Cryptococcus Species and the Fluconazole Exposure Prediction Model

Supavit Chesdachai, Radha Rajasingham, Melanie R. Nicol, David B. Meya, Felix Bongomin, Mahsa Abassi, Caleb Skipper, Richard Kwizera, Joshua Rhein, David R. Boulware

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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: 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: 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: Currently recommended fluconazole doses may be inadequate for cryptococcosis. Further clinical studies are needed for rational fluconazole dose selection.

Original languageEnglish (US)
Article numberofz369
JournalOpen Forum Infectious Diseases
Volume6
Issue number10
DOIs
StatePublished - Oct 1 2019

Bibliographical note

Funding Information:
Acknowledgments. The authors thank the support from the National Institute of Neurologic Diseases and Stroke (R01NS086312) and Fogarty International Institute (K01TW010268) and the National Institute of Allergy and Infectious Diseases (U01AI125003, K23AI138851, K08AI134262).

Funding Information:
The authors thank the support from the National Institute of Neurologic Diseases and Stroke (R01NS086312) and Fogarty International Institute (K01TW010268) and the National Institute of Allergy and Infectious Diseases (U01AI125003, K23AI138851, K08AI134262).

Publisher Copyright:
© 2019 The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

Keywords

  • Cryptococcus
  • cryptococcal meningitis
  • fluconazole
  • fungal drug resistance
  • systematic review

PubMed: MeSH publication types

  • Journal Article

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