ABSTRACT
Fluconazole is frequently the only antifungal agent that is available for induction therapy for cryptococcal meningitis. There is relatively little understanding of the pharmacokinetics and pharmacodynamics (PK-PD) of fluconazole in this setting. PK-PD relationships were estimated with 4 clinical isolates of Cryptococcus neoformans. MICs were determined using Clinical and Laboratory Standards Institute (CLSI) methodology. A nonimmunosuppressed murine model of cryptococcal meningitis was used. Mice received two different doses of fluconazole (125 mg/kg of body weight/day and 250 mg/kg of body weight/day) orally for 9 days; a control group of mice was not given fluconazole. Fluconazole concentrations in plasma and in the cerebrum were determined using high-performance liquid chromatography (HPLC). The cryptococcal density in the brain was estimated using quantitative cultures. A mathematical model was fitted to the PK-PD data. The experimental results were extrapolated to humans (bridging study). The PK were linear. A dose-dependent decline in fungal burden was observed, with near-maximal activity evident with dosages of 250 mg/kg/day. The MIC was important for understanding the exposure-response relationships. The mean AUC/MIC ratio associated with stasis was 389. The results of the bridging study suggested that only 66.7% of patients receiving 1,200 mg/kg would achieve or exceed an AUC/MIC ratio of 389. The potential breakpoints for fluconazole against Cryptococcus neoformans follow: susceptible, ≤ 2 mg/liter; resistant, >2 mg/liter. Fluconazole may be an inferior agent for induction therapy because many patients cannot achieve the pharmacodynamic target. Clinical breakpoints are likely to be significantly lower than epidemiological cutoff values. The MIC may guide the appropriate use of fluconazole. If fluconazole is the only option for induction therapy, then the highest possible dose should be used.
Subject(s)
Antifungal Agents/pharmacokinetics , Antifungal Agents/therapeutic use , Cryptococcus neoformans/drug effects , Fluconazole/pharmacokinetics , Fluconazole/therapeutic use , Meningitis, Cryptococcal/drug therapy , Meningoencephalitis/drug therapy , Animals , Antifungal Agents/administration & dosage , Antifungal Agents/pharmacology , Area Under Curve , Disease Models, Animal , Fluconazole/administration & dosage , Fluconazole/pharmacology , Humans , Male , Meningitis, Cryptococcal/microbiology , Meningoencephalitis/microbiology , Mice , Microbial Sensitivity Tests/standards , Models, Biological , Treatment OutcomeABSTRACT
BACKGROUND: The aim of this study was to develop a simple organ score derived from the Critical Care Minimum Data Set (CCMDS) to compare with the Sequential Organ Failure Assessment (SOFA) score, a previously validated score of organ dysfunction. FINDINGS: The CCMDS collects data regarding the support of seven organ systems. To create a CCMDS derived score each level of organ support was allocated a numerical value. SOFA scores were collected retrospectively from each patient in the study. Data was collected in 50 sequential admissions over the first 5 days of their admission. This generated a total of 147 pairs of data for comparison.Scatter plots and Spearman's rank correlation coefficient suggest a weak positive association between our CCMDS-derived score and the SOFA score. Daily Bland-Altman plots reveal minimal bias between the score but wide limits of agreement. CONCLUSION: Our CCMDS-derived score cannot be regarded as an indicator of severity of organ dysfunction and cannot replace SOFA scores when a daily marker of organ dysfunction is required.
