We used two established neutropenic murine models of
pulmonary aspergillosis and
mucormycosis to explore the association between the
posaconazole area under the concentration-time curve (AUC)-to-MIC ratio (AUC/MIC) and treatment outcome.
Posaconazole serum pharmacokinetics were verified in infected mice to ensure that the studied doses reflected human exposures with the oral
suspension, delayed-release
tablet, and intravenous formulations of
posaconazole. Sinopulmonary
infections were then induced in groups of neutropenic mice with Aspergillus fumigatus strain 293 (
posaconazole MIC, 0.5 mg/liter) or Rhizopus oryzae strain 969 (
posaconazole MIC, 2 mg/liter) and treated with escalating daily dosages of oral
posaconazole, which was designed to achieve AUCs ranging from 1.10 to 392 mg · h/liter. After 5 days of treatment, lung fungal burden was analyzed by quantitative real-time PCR. The relationships of the total
drug AUC/MIC and the treatment response were similar in both models, with 90% effective concentrations (EC90s) corresponding to an AUC/MIC threshold of 76 (95% confidence interval [CI], 46 to 102) for strain 293 versus 87 (95% CI, 66 to 101) for strain 969. Using a provisional AUC/MIC target of >100, these exposures correlated with minimum serum
posaconazole concentrations (Cmins) of 1.25 mg/liter for strain 293 and 4.0 mg/liter for strain 969. The addition of
deferasirox, but not liposomal
amphotericin or
caspofungin, improved the activity of a suboptimal
posaconazole regimen (AUC/MIC, 33) in animals with pulmonary
mucormycosis. However, no combination was as effective as the high-dose
posaconazole monotherapy regimen (AUC/MIC, 184). Our analysis suggests that
posaconazole pharmacodynamics are similar for A. fumigatus and R. oryzae when indexed to pathogen MICs.