Determination of susceptibility breakpoints for posaconazole and Aspergillus fumigatus using a pharmacokinetic-pharmacodynamic model

Elefanti, A.(1)*; Mavridou, E.(1); Mouton, J.(2); Verweij, P.E.(2); Meletiadis, J.(3);


Aspergillus fumigatus has become the most
widespread opportunistic fungal pathogen, causing
severe and commonly fatal invasive fungal infections in
neutropenic hosts. Posaconazole is a triazole antifungal
agent commonly used for prophylaxis and occasionally
for treatment of invasive aspergillosis.
The emergence of azole-resistant isolates is of great
concern since azole therapy against these isolates is
often associated with clinical failure. Reliable
susceptibility breakpoints for detecting these isolates
are on high demand.

Therefore, we investigated the pharmacokinetic (PK)
and pharmacodynamic (PD) properties of posaconazole
using an in vitro model simulating human PK. For this
purpose four clinical isolates of A. fumigatus with
different cyp51a mutations and in vitro susceptibility to
posaconazole were used. Human pharmacokinetics of
posaconazole were simulated in vitro and the Monte
Carlo analysis was applied for determination of
susceptibility breakpoints.



abstract No: