Efficacy of intravenous posaconazole for the treatment of azole-resistant invasive aspergillosis

Authors

• X-X Nguyen
• H Zarkoob
• MJ Song
• K Sung
• M Ferrer

Abstract

Objectives: In the current study we aimed to evaluate the efficacy of the new intravenous formulation of POS in a non-neutropenic murine model of invasive aspergillosis (IA) using POS-susceptible and POS-resistant A. fumigatus isolates.

Methods: A total of 240 outbred CD-1® female mice were randomized into groups of 10. The treatment groups consisted of intravenous POS monotherapy at 0.25, 1, 4, 16 and 64 mg/kg/day for seven consequtive days. The control mice received PBS via intravenous injection. The in vivo efficacy of inravenous formulation of POS was assessed against infection with two isolates: a wild type (MIC, 0.031mg/L) and an azole-resistant A. fumigatus (MIC, 0.5 mg/L) harboring TR34/L98H mutation in Cyp-51A gene.

Results: The efficacy of posaconazole treatment at the dosing regimens ≤ 4 mg/kg/day depended on the MIC. However, the maximum effect (100% survival at day 14 post infection) was achieved with a POS dose of ≥ 16 mg/kg for both wild-type and mutant isolates, and histopathological slides revealed limited number of inflammatory foci with or without detectable fungal elements in the Kidneys. The Hill-type model with a variable slope fitted the relationship between the dose and 14-day survival well (R2 of 0.99 for wild type, and 0.95 for TR34/L98H isolate).

Conclusion: Overall, treatment with intravenous formulation of posaconazole improved the survival of the mice in a dose-dependent manner. A dose-response relationship was observed regardless of the underlying azole-resistance mechanism. These results show intravenous formulation of posaconazole provide higher exposure than the oral suspension for treatment of azole-resistant IA.

Scientific Focus Area: Microbiology and Infectious Diseases

This page was last updated on Monday, September 25, 2023