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 Talazoparib in vitro 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. Cryptococcus
neoformans Cyclopamine cost can cause significant morbidity and mortality in the immuno-compromised host, and invasion of the central nervous system (CNS) may lead to devastating consequences . Fluconazole is a triazole antifungal agent that has a long half-life and excellent bioavailability, exhibits low serum protein binding and achieves high levels in multiple tissues, including the CNS . This medication is excreted unchanged in the urine; the hepatic CYP2C9 enzyme plays a minor role . Treatment of CNS infections is often
difficult because the blood–brain barrier limits diffusion of the drug into the CNS; however, the ability of fluconazole to penetrate cerebrospinal fluid (CSF) increases during meningeal inflammation. Furthermore, tissue efflux pumps can reduce CNS drug accumulation . To date, data regarding the relationship between the pharmacokinetics of fluconazole in serum and CSF, and in the correlation of these pharmacokinetic measures with clinical outcomes of invasive fungal infections in humans are limited . BAMSG 3-01 was a Phase II, multicentre, randomized clinical trial designed to RG7420 mw investigate the safety and efficacy of a combination therapy of amphotericin B (AmB) plus fluconazole for the treatment of HIV-associated cryptococcal meningitis . A secondary objective was to assess fluconazole pharmacokinetics and pharmacodynamics by (1) examining the relationship between serum and CSF concentrations in subjects receiving high-dose fluconazole, (2) identifying baseline characteristics influencing serum and CSF concentrations and (3) determining the relationship of serum and CSF drug concentrations with fluconazole dosing, efficacy measures and post-baseline characteristics of interest. Standard therapy consisted of AmB (0.