Affiliation:
1. Facility for Anti-infective Drug Development and Innovation, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
2. School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York
3. Ordway Research Institute, Albany, New York
Abstract
ABSTRACT
Colistin plays a key role in treatment of serious infections by
Pseudomonas aeruginosa
. The aims of this study were to (i) identify the pharmacokinetic/pharmacodynamic (PK/PD) index (i.e., the area under the unbound concentration-time curve to MIC ratio [ƒAUC/MIC], the unbound maximal concentration to MIC ratio [ƒ
C
max
/MIC], or the cumulative percentage of a 24-h period that unbound concentrations exceed the MIC [ƒ
T
>MIC
]) that best predicts colistin efficacy and (ii) determine the values for the predictive PK/PD index required to achieve various magnitudes of killing effect. Studies were conducted in a one-compartment
in vitro
PK/PD model for 24 h using
P. aeruginosa
ATCC 27853, PAO1, and the multidrug-resistant mucoid clinical isolate 19056 muc. Six intermittent dosing intervals, with a range of ƒ
C
max
colistin concentrations, and two continuous infusion regimens were examined. PK/PD indices varied from 0.06 to 18 for targeted ƒ
C
max
/MIC, 0.36 to 312 for ƒAUC/MIC, and 0 to 100% for ƒ
T
>MIC
. A Hill-type model was fit to killing effect data, which were expressed as the log
10
ratio of the area under the CFU/ml curve for treated regimens versus control. With ƒ
C
max
values equal to or above the MIC, rapid killing was observed following the first dose; substantial regrowth occurred by 24 h with most regimens. The overall killing effect was best correlated with ƒAUC/MIC (
R
2
= 0.931) compared to ƒ
C
max
/MIC (
R
2
= 0.868) and ƒ
T
>MIC
(
R
2
= 0.785). The magnitudes of ƒAUC/MIC required for 1- and 2-log
10
reductions in the area under the CFU/ml curve relative to growth control were 22.6 and 30.4, 27.1 and 35.7, and 5.04 and 6.81 for ATCC 27853, PAO1, and 19056 muc, respectively. The PK/PD targets identified will assist in designing optimal dosing strategies for colistin.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
143 articles.
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