In Vitro Evaluation of the Efficacy of Voriconazole (VOR) in Combination with Amphotericin B (AMB) against Aspergillus fumigatus (AFM) Using a Novel Pharmacokinetic/Pharmacodynamic (PK/PD) Model

Ref ID: 18707

Author:

M. Siopi, MS – PhD student, A. Elefanti, MS – PhD student, N. Siafakas, PhD – Lecturer, L. Zerva, MD – Professor, J. Meletiadis, PhD – Lecturer;

Author address:

Attikon Univ. Gen. Hosp., Athens, Greece.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: Despite its use in treatment of invasive aspergillosis, the benefit of polyene-triazole combination is questionable because of conflicting data from in vitro and in vivo combination studies. We therefore investigate the combination of VCZ with AMB against AFM using a new in vitro PK/PD model simulating human pharmacokinetics of these two drugs.
Methods: A clinical AFM isolate with VCZ and AMB CLSI MICs of 0.5 and 1 mg/L, respectively, was used. AMB and VOR dosages were simulated in a new in vitro PK simulation system with half-life 6h and 24h, respectively and twelve different combinations were investigated with AMB fCmax 2.4, 0.6, 0.3, 0.1 mg/l and VOR fCmax 7.2, 3.4, 1.7 mg/l including monotherapies and drug-free control. The in vitro model consists of an internal compartment (IC, a 10 mL dialysis tube made out of semi-permeable cellulose membrane allowing the free diffusion of molecules with MW <20kDa) placed inside an external compartment (EC, a 700 mL glass beaker) whose content is diluted with a peristaltic pump at the same rate as the clearance of the drug in human plasma. The IC was inoculated with a conidial suspension (10^3 CFU/mL), while drug solutions were injected in both compartments (VCZ every 12h, AMB every 24h). Drug levels were determined by a microbiological diffusion assay and fungal growth by measuring galactomannan concentrations in the IC with a sandwich-ELISA. The interactions were analyzed based on the Bliss independence model. Results: The model simulated well AMB and VOR human pharmacokinetics. The combination of VCZ plus AMB exerted antagonistic effects (-4 to -13%) in most of the simulated dosages tested in vitro, except the lowest AMB and VOR dosages with fCmax 0.1 mg/l and 1.7 mg/l respectively where synergistic interactions (26%) were observed. Extrapolating to human dosages taking into account the protein binding of AMB (95%) and VOR (58%), the latter fCmaxs can be achieved in human plasma after standard dosing of AMB (1 mg/kg) and VOR (4 mg/kg). Conclusions: The AMB+VCZ combination was antagonistic at a wide range of concentrations and may be synergistic at clinically relevant dosages.

Abstract Number: A-1939

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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