S K B Sy1, L Zhuang1, H Xia2, V J Schuck3, W W Nichols3, H Derendorf4. 1. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA. 2. Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, USA. 3. AstraZeneca, Waltham, MA, USA. 4. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA. Electronic address: hartmut@cop.ufl.edu.
Abstract
OBJECTIVE: The aim of the present work was to use a semi-mechanistic pharmacokinetic-pharmacodynamic (PK/PD) model developed from in vitro time-kill measurements with P. aeruginosa to compare different pharmacodynamic indices derived from simulated human avibactam exposures, with respect to their degree of correlation with the modelled bacterial responses. METHODS: A mathematical model of the effect of ceftazidime-avibactam on the growth dynamics of P. aeruginosa was used to simulate bacterial responses to modelled human exposures from fractionated avibactam dosing regimens with a fixed ceftazidime dosing regimen (2 or 8 g q8h as a 2-h infusion). The relatedness of the 24-h change in bacterial density and avibactam exposure parameters was evaluated to determine exposure parameter that closely correlated with bacterial growth/killing responses. RESULTS: Frequent dosing was associated with higher efficacy, resulting in a reduction of avibactam daily dose. The best-fit PD index of avibactam determined from the simulation was fT > CT of 1 mg/L avibactam and q8h was the longest dosing interval able to achieve 2-log kill: 41-87% (3.3 h to 7.0 h out of 8-h interval, respectively). The avibactam exposure magnitude required to achieve a 2-log kill in the simulations was dependent on the susceptibility of the bacterial isolate to ceftazidime. CONCLUSIONS: Avibactam activity in combination with ceftazidime against multidrug resistant P. aeruginosa correlated with fT > CT. Setting a threshold avibactam concentration to 1 mg/L, superimposed over a simulated human-like exposure of ceftazidime, achieved at least 2-log kill for the clinical dose of 500 mg q8h avibactam as a 2-h infusion, depending on the minimum inhibitory concentration of ceftazidime alone.
OBJECTIVE: The aim of the present work was to use a semi-mechanistic pharmacokinetic-pharmacodynamic (PK/PD) model developed from in vitro time-kill measurements with P. aeruginosa to compare different pharmacodynamic indices derived from simulated humanavibactam exposures, with respect to their degree of correlation with the modelled bacterial responses. METHODS: A mathematical model of the effect of ceftazidime-avibactam on the growth dynamics of P. aeruginosa was used to simulate bacterial responses to modelled human exposures from fractionated avibactam dosing regimens with a fixed ceftazidime dosing regimen (2 or 8 g q8h as a 2-h infusion). The relatedness of the 24-h change in bacterial density and avibactam exposure parameters was evaluated to determine exposure parameter that closely correlated with bacterial growth/killing responses. RESULTS: Frequent dosing was associated with higher efficacy, resulting in a reduction of avibactam daily dose. The best-fit PD index of avibactam determined from the simulation was fT > CT of 1 mg/L avibactam and q8h was the longest dosing interval able to achieve 2-log kill: 41-87% (3.3 h to 7.0 h out of 8-h interval, respectively). The avibactam exposure magnitude required to achieve a 2-log kill in the simulations was dependent on the susceptibility of the bacterial isolate to ceftazidime. CONCLUSIONS:Avibactam activity in combination with ceftazidime against multidrug resistant P. aeruginosa correlated with fT > CT. Setting a threshold avibactam concentration to 1 mg/L, superimposed over a simulated human-like exposure of ceftazidime, achieved at least 2-log kill for the clinical dose of 500 mg q8h avibactam as a 2-h infusion, depending on the minimum inhibitory concentration of ceftazidime alone.
Authors: James Albiero; Josmar Mazucheli; Juliana Pimenta Dos Reis Barros; Marcia Maria Dos Anjos Szczerepa; Sheila Alexandra Belini Nishiyama; Floristher Elaine Carrara-Marroni; Serubbabel Sy; Matthew Fidler; Sherwin K B Sy; Maria Cristina Bronharo Tognim Journal: Antimicrob Agents Chemother Date: 2019-05-24 Impact factor: 5.191
Authors: Craig R Rayner; Patrick F Smith; David Andes; Kayla Andrews; Hartmut Derendorf; Lena E Friberg; Debra Hanna; Alex Lepak; Edward Mills; Thomas M Polasek; Jason A Roberts; Virna Schuck; Mark J Shelton; David Wesche; Karen Rowland-Yeo Journal: Clin Pharmacol Ther Date: 2021-03-09 Impact factor: 6.875