Pharmacokinetics (PK) and Pharmacodynamics (PD) of Micafungin in Experimental Hematogenous Candida Meningoencephalitis (HCME).

W. W. HOPE1, D. MICKIENE 1,2, V. PETRAITIS 1,2, R. PETRAITIENE 1,2, A. KELAHER 1, J. HUGHES 1, M. COTTON 1, J. BACHER 3, A. H. GROLL 4, T. J. WALSH 1;

Author address: 

1NCI, Bethesda, MD, 2SAIC-Frederick Inc., Frederick, MD, 3ORS NIH, Bethesda, MD, 4Children’s Univ. Hosp., Muenster, Germany.

Abstract: 

Background: We sought to describe the PK and PD of micafungin in a rabbit model of HCME. Methods: A non-neutropenic rabbit model of HCME was used. Micafungin was administered 48 h post inoculation of C. albicans. The concentrations (concs.) of micafungin in serum, cerebrum (C), cerebellum (CE), spinal cord (SC), CSF, meninges (M), aqueous (AH), vitreous (VH) and choroid (CO) were measured using HPLC. Serum PK and tissue concs. were compared in infected and non-infected rabbits. The effect of micafungin 0.25, 0.5, 1, 2, 4, 8 and16 mg/kg administered daily for 7 days was studied. Serum PK were determined using a population methodology. Individual AUC0-144.5 were calculated using the Bayesian estimates of the PK parameters and correlated with CNS tissue concs. PD data were analyzed using an inhibitory sigmoid Emax model by defining CFU/g with no drug (Econ), maximum effect (Emax), slope (H) and dose at which effect was half maximal (E50). Results: The micafungin PK of non-infected rabbits was: V 0.71 L; Kcp 0.51 h-1, Kpc 0.29 h-1, SCL 0.18 L/h and for infected rabbits was: V 0.59 L, Kcp 0.61 h-1, Kpc 0.45 h-1, SCL 0.14 L/h. The AUC in infected rabbits was 29.3% higher than uninfected animals. Micafungin was not reliably detected in the CSF. Micafungin 16 mg/kg resulted in mean concs. in the C, CE, SC, M, AH, VH and CO of 3.15, 3.64, 1.50, 27.62, 0.58, 0.05 and 6.94 mg/L, respectively. There were no significant differences in non-infected rabbits. The PD model revealed: Econ (log10CFU/g) 3.21, Emax (log10CFU/g) 2.79, H 1.28, E50 2.79 mg/kg. 15.5 mg/kg was required for a 90% reduction in burden in the cerebrum and cerebellum. Conclusions: Micafungin penetrates the CNS and has activity in non-neutropenic HCME. Infection results in higher systemic drug-exposure but does not directly influence the penetration of drug into the CNS.
2006

abstract No: 

M-301

Full conference title: 

46th Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 46th