Conventional amphotericin B (AMB) activity against Aspergillus species in an in vitro pharmacokinetic (PK)-pharmacodynamic(PD) model

Ref ID: 19257

Author:

A. Elefanti, M. Siopi, N. Siafakas, L. Zerva, J. Meletiadis

Author address:

Attikon Univ. Hosp., Athens, GREECE

Full conference title:

53rd Interscience Conference on Antimicrobial Agents and Chemotherapy

Date: 10 September 2014

Abstract:

Background: Since most clinical data on AMB efficacy against invasive aspergillosis obtained from infections by A. fumigatus (AFM), little information exists for other Aspergillus species. Although isolates with CLSI MICs >1 mg/l are considered resistant, detection of AMB resistance is a challenge with CLSI method. We therefore investigated AMB activity in an in vitro PKPD model simulating human plasma PKs of different AMB dosing regimens against AFM, A. flavus (AFL) and A. terreus (AT). Methods: Three clinical strains of Aspergillus spp. with CLSI MICs of AMB 1mg/L were used. Several clinically relevant doses of AMB were simulated in an in vitro PKPD model simulating the biphasic 24h-plasma concentration profile of AMB in humans with free (f) Cmax 0.1-2.4 mg/l and t1/2 of <2h (alpha phase) and 7-10h(beta phase) administered once a day for three days. Drug levels were measured with a bioassay and Aspergillus growth was monitored over time by galactomannan production and the area under the galactomannan index-time curve (AUCGI) were used as a surrogate marker of fungal growth for each dose and isolate compared to the AUCGI of drug free control. Fungal growth (PD) was associated with the fCmax (PK) for each species. In vitro PKPD relationship was analyzed based on sigmoid Emax model with variable slope and the PKPD index fCmax/MIC associated with 50% growth was linked with human PK after standard AMB dosing with 1 mg/kg (Cmax 2.83±1.17 mg/l, Ayestaran et al AAC 1996) taking into account the 95% protein binding. PKs of 1000 patients were simulated and % patients attained the PKPD target was calculated for each species with different MICs. Results: Complete inhibition of galactomannan production was observed for AFM at AMB Cmax≥ 0.3 mg/l and for AFL and AFL at AMB Cmax≥ 0.8 mg/l. The in vitro PKPD relationship followed a sigmoid pattern (global R2=0.96) with fCmax/MIC (95%CI) associated with 50% growth of 0.15 (0.13-0.16) for AFM, 0.63 (0.38-1.06) for AFL and 0.65 (0.45-0.95) AT (P<0.05). The % target attainment was 42%, 84% and 96% for AFM and 0%, 1% and 38% for AFL and AT isolates with CLSI MICs of 1, 0.5 and 0.25 mg/l, respectively. Conclusions:AMB was more active in the in vitro PKPD model against AFM than AFL and AT for which higher drug exposures may be required in order to obtain high % target attainment even for isolates with CLSI MIC <1mg/l.

Abstract Number: NULL

Conference Year: 2013

Link to conference website: NULL

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