Pharmacokinetics and Pharmacodynamics of Fluconazole for Cryptococcal Meningoencephalitis: Implications for Antifungal Therapy andIn VitroSusceptibility Breakpoints

Abstract

dFluconazole 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. Cryptococcal meningoencephalitis is a leading cause of global infectious morbidity and mortality (1). There are approximately one million cases per year in the world and 600,000 deaths (1). The majority of the global disease burden occurs in subSaharan Africa, where cryptococcal meningoencephalitis is intricately linked with the extensive and persistent AIDS epidemic. There are relatively few therapeutic options, and little information on the pharmacokinetics and pharmacodynamics (PK-PD) of currently available antifungal agents for the treatment of this neglected fungal disease.In many parts of the world, fluconazole is the only antifungal agent that is available for treatment of cryptococcal meningoencephalitis. While there is extensive information on the use of fluconazole for consolidation and suppressive therapy, there is less information on optimal induction regimens. Recent clinical trials suggest that higher dosages (e.g., 1,200 to 2,000 mg/day) result in improved antifungal activity (2, 3), although further antifungal activity is evident with the addition of flucytosine, suggesting that this dosage may sti...

Population Pharmacokinetics and Cerebrospinal Fluid Penetration of Fluconazole in Adults with Cryptococcal Meningitis

“…neoformans isolates. This is consistent with the findings of Sudan et al (11). Approximately half of patients will fail therapy because they are not able to generate the drug exposure required to prevent progressive fungal growth.…”

Antifungal Pharmacokinetics and Pharmacodynamics

“…An additional study has examined the fluconazole PD target in a murine cryptococcal meningitis model (Sudan et al 2013). Therapy against a group of three Cryptococcus neoformans isolates produced a stasis end point with a fluconazole AUC/MIC value near 400, which, interestingly, is higher than is observed for other pathogens.…”

Antifungal Drug Susceptibility and Phylogenetic Diversity among Cryptococcus Isolates from Dogs and Cats in North America

“…Among dogs, purebred animals are most commonly affected, and an increased risk for breeds such as American cocker spaniels suggests an underlying genetic immunodeficiency (6). In general, cryptococcosis in humans is treated with a combination of amphotericin B and flucytosine (5FC), but high-dose (1,200 mg/day) fluconazole monotherapy is often used in resource-poor health care settings, such as among humans with HIV in sub-Saharan Africa (7). Similarly, cats and dogs with cryptococcosis are often treated with fluconazole monotherapy because of its relatively low cost, ease of administration, and favorable pharmacokinetic properties.…”

“…Susceptibilities were determined using the Sensititre YeastOne (SYO) method (YO-9; Trek Diagnostic Systems, Inc., Cleveland, OH), because it is widely used for yeast susceptibility testing in commercial diagnostic laboratories (26). We also sought to determine whether fluconazole area-under-the-curve (AUC)/MIC ratios for the isolates in this study would be likely to achieve or exceed the target ratio (Ն389.3) to prevent progressive fungal growth in the central nervous system (CNS), which was previously determined using a mouse meningoencephalitis model (7).…”