Comparison of Posaconazole Pharmacodynamics in Neutropenic Murine Models of Sinopulmonary Aspergillosis and Mucormycosis

R. E. Lewis, N. D. Albert, D. P. Kontoyiannis

Author address: 

Univ. of Bologna, Bologna, ITALY; Univ. of Texas M.D Anderson Cancer Ctr., Houston, TX.

Abstract: 

BACKGROUND: Posaconazole is an established agent in prevention and treatment of invasive aspergillosis, however, its effectiveness and pharmacodynamics in mucormycosis are less well defined.METHODS: We used to two established neutropenic murine models of invasive pulmonary aspergillosis and mucormycosis to compare the posaconazole plasma exposures (AUC:MIC) required for efficacy in experimental pulmonary aspergillosis and mucormycosis, respectively. Posaconazole pharmacokinetics in infected animals over an oral dosing range previously reported to be effective in murine models of aspergillosis (1-50 mg/kg/day) were confirmed by HPLC. Sinopulmonary infection was induced through intranasal inoculation of 5 x10^6 A. fumigatus 293 (MIC 0.5 mg/L) or 1x10^6 Rhizopus oryzae 969 (MIC 2 mg/L) in neutropenic mice. Oral posaconazole treatment was started 12 hours later. The primary endpoint of treatment response was Aspergillus or Rhizopus conidial equivalent DNA (marker of fungal burden) in lungs harvested from infected mice analyzed by quantiative real-time PCR. RESULTS: Murine pharmacokinetics of oral posaconazole doses were linear with a terminal half-life of 14 hr. Posaconazole treatment resulted in dose-dependent reductions in AF293 and RO969 CE DNA in the lungs of mice, that maximized at doses above 15 mg/kg/day in the aspergillosis model and at 50 mg/kg/day in the mucormycosis model. POS ED50 were observed at an AUC:MIC of 115 for AF293 and 88 for RO969.CONCLUSIONS: Despite the enhanced virulence of RO versus AF, the plasma posaconazole exposures indexed to pathogen MIC required to suppress fungal proliferation in our neutropenic murine model of pulmonary mucormycosis were similar to that required for aspergillosis.
2013

abstract No: 

NULL

Full conference title: 

53rd Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC, 53rd (2013)