Parametric and nonparametric population pharmacokinetic analysis of fluconazole in critically ill patients and dosing simulations for Candida infections.

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  • Additional Information
    • Source:
      Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 0315061 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-6596 (Electronic) Linking ISSN: 00664804 NLM ISO Abbreviation: Antimicrob Agents Chemother Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, American Society for Microbiology
    • Subject Terms:
      Fluconazole*/pharmacokinetics ; Fluconazole*/therapeutic use ; Fluconazole*/pharmacology ; Critical Illness* ; Antifungal Agents*/pharmacokinetics ; Antifungal Agents*/therapeutic use ; Antifungal Agents*/pharmacology ; Microbial Sensitivity Tests* ; Candidiasis*/drug therapy ; Candidiasis*/microbiology; Humans ; Female ; Retrospective Studies ; Male ; Middle Aged ; Aged ; Adult ; Candida/drug effects ; Candida glabrata/drug effects ; Area Under Curve
    • Abstract:
      Large pharmacokinetic (PK) variability of fluconazole has been reported in critically ill patients, but the implications for fluconazole dosing remain unclear. The objectives of this study were to evaluate the population PK of fluconazole and identify appropriate dosage regimens by simulations. This was a retrospective analysis of fluconazole PK data from patients hospitalized in critical care and infectious disease departments. Both parametric and nonparametric population approaches were used. Various loading and maintenance fluconazole doses were evaluated by simulations, with computation of the probabilities of PK/pharmacodynamic (PD) target attainment (PTA) and cumulative fractions of response (CFR) based on international and local minimum inhibitory concentration (MIC) distributions of Candida sp. Data from 36 critically ill patients and 16 non-critically ill patients were available for model building ( n = 202 concentrations). The final model adequately described the data, including the external data set (13 patients). After 24 h of therapy, 65% and 74% of patients had trough and area under the concentration-time curve values below the usual targets. Standard dosages were associated with low PTA for MIC >1 mg/L at 24 h. Higher loading doses administered two times daily improved PTA. CFR were >90% for C. albicans with standard dosages, while they were very low for C. glabrata , even with high dosages. Candida species and associated MIC distributions strongly influence fluconazole dosage requirements. Higher loading doses may be necessary for the achievement of PK/PD targets up to MIC breakpoints. The use of fluconazole for invasive C. glabrata infection should be discouraged because of poor PK/PD target attainment.
      Competing Interests: The authors declare no conflict of interest.
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    • Contributed Indexing:
      Keywords: antifungal; critical care; fluconazole; pharmacokinetics; therapeutic drug monitoring
    • Accession Number:
      8VZV102JFY (Fluconazole)
      0 (Antifungal Agents)
    • Publication Date:
      Date Created: 20240926 Date Completed: 20241106 Latest Revision: 20241108
    • Publication Date:
      20241108
    • Accession Number:
      PMC11539208
    • Accession Number:
      10.1128/aac.00991-24
    • Accession Number:
      39324800