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...

This dynamic model of IPA is a useful tool to address many remaining questions related to antifungal treatment of Aspergillus spp.

Amphotericin B is a first-line agent for the treatment of invasive aspergillosis. However, relatively little is known about the pharmacodynamics of amphotericin B for invasive pulmonary aspergillosis. We studied the pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAMB), amphotericin B lipid complex (ABLC), and liposomal amphotericin B (LAMB) by using a neutropenic-rabbit model of invasive pulmonary aspergillosis. The study endpoints were lung weight, infarct score, and levels of circulating galactomannan and (1¡3)-␤-D-glucan. Mathematical models were used to describe PK-PD relationships. The experimental findings were bridged to humans by Monte Carlo simulation. Each amphotericin B formulation induced a dose-dependent decline in study endpoints. Near-maximal antifungal activity was evident with DAMB at 1 mg/kg/day and ABLC and LAMB at 5 mg/kg/day. The bridging study suggested that the "average" patient receiving LAMB at 3 mg/kg/day was predicted to have complete suppression of galactomannan and ( Infections caused by Aspergillus fumigatus are a persistent public health problem. Diagnosis is slow and inaccurate, and there are still relatively few antifungal agents. The use of available compounds is difficult and requires specialist knowledge. The antiAspergillus triazoles (itraconazole, voriconazole, and posaconazole) and the polyenes have relatively narrow therapeutic indices (1). Suboptimal and toxic drug exposures are both potentially lethal. Both intrinsic and acquired forms of drug resistance to the triazoles are an ever-present concern (2) and are associated with a high mortality rate; in some centers, this has influenced local prescribing practices. There is an urgent requirement for the development of new antifungal compounds and a better understanding of the use of existing agents (1). Amphotericin B was first developed in 1957 (1). Despite this, there is still a relatively limited understanding of its pharmacokinetics (PK) and pharmacodynamics (PD) against A. fumigatus, and uncertainty surrounds the use of each of the formulations for the treatment of invasive pulmonary aspergillosis (IPA).Here, we provide further insight into the PD of three clinically licensed formulations of amphotericin B against A. fumigatus. Using a well-validated persistently-neutropenic-rabbit model of IPA (3), we linked concentrations of amphotericin B with levels of circulating galactomannan and (1¡3)-␤-D-glucan, both of which are licensed for the diagnosis of IPA and widely available in routine clinical microbiology laboratories. We linked the kinetics of these biomarkers with more basic measures of organism-mediated pulmonary injury (OPMI), such as lung weight and pulmonary infarct score. We describe the resultant exposure-response relationships and reflect on the adequacy of currently recommended antifungal regimens, as well as the potential limitations of fixed regimens.(This work was presented at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 5 t...