| Popis: |
Background Fluconazole is lifesaving for the 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 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 the MEDLINE database for reports of fluconazole MIC distribution against clinical Cryptococcus isolates. Second, we utilized fluconazole concentrations from 92 Ugandans who received fluconazole 800 mg/day coupled with fluconazole’s known pharmacokinetics to predict plasma fluconazole concentrations for doses ranging from 100 mg to 2000 mg 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 11,094 clinical Cryptococcus isolates. MICs were normally distributed with geometric mean of 3.4 mg/mL, median (MIC50) of 4 mg/mL, and 90th percentile (MIC90) of 16 mg/mL. The median MIC50 trended upwards from 4 mg/mL in 2000–2012 to 8 mg/mL in 2014–2018. Predicted sub-therapeutic fluconazole concentrations (below MIC) would occur in 38% with 100 mg, 20% with 200 mg, and 8% with 400 mg. AUC/MIC ratio > 100 would occur in 53% for 400 mg, 74% for 800 mg, 84% for 1200 mg, and 88% for 1,600 mg. Conclusion Currently recommended fluconazole doses may be inadequate for cryptococcosis. Further clinical studies are needed for rational fluconazole dose selection. Disclosures All authors: No reported disclosures. |
