However, the trend was not seen at day 14. To date, clinical trials attempting to predict adequate antifungal CNS pharmacokinetics for the treatment of CNS fungal infections have been limited [3]. BAMSG 3-01 demonstrated that fluconazole concentrations in the brain closely paralleled serum levels. The median percentage

of CSF compared with serum fluconazole concentrations for the AmB+Fluc800 and AmB+Fluc400 PD0325901 arms were 93.7% and 94.6%, respectively, after 14 days of antifungal treatment. These concentration ratios are consistent with previous results [3,7] but are higher than 70%, which is achieved in the absence of meningeal inflammation [8]. Furthermore, CSerum14 and CCSF14 were found to be highly correlated. Therefore, we can surmise that the steady state of metabolism in both serum and CSF had been achieved. The increased serum concentration in patients receiving fluconazole 800 mg/day compared with those receiving a standard dose of fluconazole over time may be explained by the elimination half-life of fluconazole after zero order kinetics and only 10% of elimination because of the buy Y-27632 metabolism [9]. Fluconazole renal clearance has

been found to be positively correlated with eGFR [9]. In the model for AUCSerum, decreased baseline eGFR was associated with high AUCSerum; however, the impact of baseline eGFR decreased as the dose received increased, suggesting that non-renal elimination pathways may become increasingly important as the fluconazole dose increases. The other subject characteristics, including age and BMI, were not associated with pharmacokinetic parameters (data not shown). Major factors affecting fluconazole pharmacokinetics identified previously included renal insufficiency, ageing and drug–drug interactions from concurrent medication use [2,9]. Of note, increased pharmacokinetic concentration was associated with decreased

day 14 CSF WBC count in BAMSG 3-01. Normally, the CSF WBC GPX6 count increases as a result of inflammation of the CNS and disruption of the blood–brain barrier. The CSF profiles of HIV- and non-HIV-infected patients are similar for conventional bacterial meningitis, but not cryptococcal meningitis. HIV-infected patients with cryptococcal meningitis are more likely to have a low CSF WBC count and are more likely to have a positive CSF culture [1]. During the course of therapy, risk factors for death or poor clinical outcome for cryptococcal meningitis that have been identified previously included abnormal mental status, high CSF cryptococcal antigen titre, low CSF WBC count, disseminated cryptococcal infection, CSF fungal burden in the CSF and lack of flucytosine treatment [10,11]. While this study was not designed to formally assess the association between pharmacokinetic concentration and cryptococcal meningitis outcome, the findings revealed a tendency of association between high levels of fluconazole and favourable outcomes at days 42 and 70.