Pharmacodynamics of Caspofungin in a Murine Model of Systemic Candidiasis: Importance of Persistence of Caspofungin in Tissues to Understanding Drug Activity

Abstract

Pharmacokinetic and pharmacodynamic studies were conducted in a murine model of systemic candidiasis to determine the pharmacodynamic parameter linked with caspofungin efficacy. Additional studies defined the importance of persistent tissue drug concentrations to treatment outcome. The pharmacokinetics of caspofungin were determined in the serum and kidneys of infected mice over 96 h. Population pharmacokinetic analysis demonstrated a serum terminal half-life (t 1/2 ) for caspofungin of 20.2 h when only serum concentrations were considered, but the terminal t 1/2 increased to 59.2 h when serum and kidney concentration-time data were comodeled. In dose-range studies, the dose-response effect was well described by an inhibitory sigmoid curve for the exposure-effect killing caused by the drug (r 2 > 0.96; P Ͻ Ͻ 0.001). In dose-fractionation studies, fungal counts in kidneys were not statistically different for total doses given as one, two, or four equally divided doses over 96 h, indicating that the area under the concentration-time curve/MIC is the pharmacodynamic parameter that predicts caspofungin efficacy in our infection model. In a separate study, mice infected with Candida albicans 24 h after serum concentrations of caspofungin fell below the MIC for the fungal isolate had significant reductions in fungal densities in their kidneys compared with the growth of fungi in the kidneys of untreated controls (P ‫؍‬ 0.005). This in vivo biological assay demonstrates that therapeutic concentrations of caspofungin persist at the site of infection in kidney tissue well after serum concentrations fall below the MIC, underscoring the primacy of caspofungin levels in tissues on determining treatment outcome.

Correlation of MIC with Outcome for Candida Species Tested against Caspofungin, Anidulafungin, and Micafungin: Analysis and Proposal for Interpretive MIC Breakpoints

“…Caspofungin exhibits concentrationdependent killing that is optimized at a peak-to-MIC ratio of ϳ4:1 and produces a prolonged (Ͼ12 h) postantifungal effect (17,18,31). Louie et al (32) have noted the importance of the total drug exposure (AUC) for determining caspofungin efficacy in a murine infection model of invasive candidiasis. A formal examination of the target AUC/MIC has not been undertaken with caspofungin.…”

“…A formal examination of the target AUC/MIC has not been undertaken with caspofungin. The study of Louie et al (32) employed a single strain of C. albicans and found that the AUC/MIC ratio associated with a stasis endpoint was near 20. …”

“…PD investigations of caspofungin against Candida have been performed, and both in vitro and in vivo models have demonstrated a correlation between drug dose, organism MIC, and outcome (1,18,19,32). Caspofungin exhibits concentrationdependent killing that is optimized at a peak-to-MIC ratio of ϳ4:1 and produces a prolonged (Ͼ12 h) postantifungal effect (17,18,31).…”

“…The PD indices associated with treatment efficacy for the echinocandins include the area under the concentration-time curve (AUC)/MIC and time to maximum concentration of drug in serum (C max )/MIC ratios. The PD target associated with a stasis endpoint for echinocandins is equivalent to AUC/MIC and C max /MIC ratios near 10 and 1, respectively (2,3,20,24,32,64). Free (not bound to protein) echinocandin concentrations are considered in these estimates.…”

Current Concepts in Antifungal Pharmacology

“…Moreover, a recent study that examined the benefits of dosage escalation to 10 mg/ kg daily of liposomal amphotericin B in patients with proven or probable aspergillosis found that the escalated dosage provided no benefit over the 3 mg/kg daily dosage and nearly doubled the rate of nephrotoxicity and severe hypokalemia. 71 The concentration-dependent activity of echinocandins against Candida 72,73 and Aspergillus 74 species is optimized when the free-drug (non-protein-bound) serum area under the curve (AUC):MIC ratio approaches 20 for C albicans or 7 for less virulent isolates of C glabrata and Candida parapsilosis. 72 These pharmacokinetic-pharmacodynamic targets are generally achieved with currently recommended echinocandin dosages for greater than 90% of isolates with MICs less than 0.5 75 (Table 1).…”