Pharmacokinetic/pharmacodynamic investigation of colistin against Pseudomonas aeruginosa using an in vitro model

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 [fAUC/MIC], the unbound maximal concentration to MIC ratio [fC(max)/MIC], or the cumulative percentage of a 24-h period that unbound concentrations exceed the MIC [fT(>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 fC(max) colistin concentrations, and two continuous infusion regimens were examined. PK/PD indices varied from 0.06 to 18 for targeted fC(max)/MIC, 0.36 to 312 for fAUC/MIC, and 0 to 100% for fT(>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 fC(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 fAUC/MIC (R(2) = 0.931) compared to fC(max)/MIC (R(2) = 0.868) and fT(>MIC) (R(2) = 0.785). The magnitudes of fAUC/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.

FIG. 1.

Typical microbiological responses observed in the in vitro PK/PD model simulating the colistin pharmacokinetics of different dosage regimens using ATCC 27853 (MIC = 1 μg/ml) (A), PAO1 (MIC = 1 μg/ml) (B), and the MDR clinical isolate 19056 muc (MIC = 0.5 μg/ml) (C). The y axis starts from the limit of counting, and the limit of quantification is indicated by the horizontal broken line.

FIG. 2.

Relationship between killing effect (log area ratio) against P. aeruginosa ATCC 27853 (solid line and open circles), PAO1 (dashed line and solid triangles), and 19056 muc (dotted line and crosses) as a function of three PK/PD indices: ƒAUC/MIC (A), ƒC_max/MIC (B), and ƒT_>MIC (C). Each data point represents the result from a single treatment run. Lines represent model-generated fits using modeling approach iii (see Materials and Methods and Table 2).