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Monitoring and impact of fluconazole serum and cerebrospinal fluid concentration in HIV-associated cryptococcal
W Manosuthi1, P Chetchotisakd, T L Nolen
1Department of Medicine, Bamrasnaradura Infectious Diseases Institute, Nonthaburi, Thailand. drweerawat@hotmail.com
Objectives:
The aim of the present study was to assess fluconazole pharmacokinetic measures in serum and cerebrospinal fluid (CSF); and the correlation of these measures with clinical outcomes of invasive fungal infections.
Methods:
A randomized trial was conducted in HIV-infected patients receiving three different regimens of fluconazole plus amphotericin B (AmB) for the treatment of cryptococcal meningitis. Regimens included fluconazole 400 mg/day+AmB (AmB+Fluc400) or fluconazole 800 mg/day+AmB (AmB+Fluc800) (14 days followed by fluconazole alone at the randomized dose for 56 days); or AmB alone for 14 days followed by fluconazole 400 mg/day for 56 days. Serum (at 24 h after dosing) and CSF samples were taken at baseline and days 14 and 70 (serum only) for fluconazole measurement, using gas-liquid chromatography.
Results:
Sixty-four treated patients had fluconazole measurements: 11 in the AmB group, 12 in the AmB+Fluc400 group and 41 in the AmB+Fluc800 group. Day 14 serum concentration geometric means were 24.7 mg/L for AmB+Fluc400 and 37.0 mg/L for AmB+Fluc800. Correspondingly, CSF concentration geometric means were 25.1 mg/L and 32.7 mg/L. Day 14 Serum and CSF concentrations were highly correlated with AmB+Fluc800 (P<0.001, r=0.873) and AmB+Fluc400 (P=0.005, r=0.943). Increased serum area under the curve (AUC) appears to be associated with decreased mortality at day 70 (P=0.061, odds ratio=2.19) as well as with increased study composite endpoint success at days 42 and 70 (P=0.081, odds ratio=2.25 and 0.058, 2.89, respectively).
Conclusion:
High fluconazole dosage (800 mg/day) for the treatment of HIV-associated cryptococcal meningitis was associated with high serum and CSF fluconazole concentration. Overall, high serum and CSF concentration appear to be associated with increased survival and primary composite endpoint success.
Insights
Higher fluconazole doses (800 mg/day) improved serum and cerebrospinal fluid (CSF) concentrations in HIV patients with cryptococcal meningitis. These higher drug levels correlated with better survival and treatment success.
Area of Science:
- Infectious Diseases
- Pharmacology
- Clinical Medicine
Background:
- Cryptococcal meningitis is a significant opportunistic infection in HIV-infected individuals.
- Optimizing antifungal therapy, such as fluconazole, is crucial for improving patient outcomes.
Purpose of the Study:
- To evaluate fluconazole pharmacokinetics in serum and cerebrospinal fluid (CSF).
- To correlate fluconazole concentrations with clinical outcomes in patients with invasive fungal infections.
Main Methods:
- A randomized trial involving HIV-infected patients treated for cryptococcal meningitis.
- Comparison of three regimens: fluconazole (400 or 800 mg/day) plus amphotericin B (AmB), or AmB alone followed by fluconazole.
- Measurement of serum and CSF fluconazole concentrations using gas-liquid chromatography.
Main Results:
- Higher fluconazole doses (800 mg/day) resulted in significantly higher serum and CSF concentrations.
- Strong positive correlation observed between serum and CSF fluconazole levels.
- Increased serum area under the curve (AUC) was associated with reduced mortality and improved treatment success.
Conclusions:
- High-dose fluconazole (800 mg/day) achieves favorable concentrations in serum and CSF for treating HIV-associated cryptococcal meningitis.
- Elevated fluconazole levels are linked to enhanced survival and successful treatment outcomes.
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