Elucidation of the Pharmacokinetic/Pharmacodynamic Determinant of Colistin Activity against Pseudomonas aeruginosa in Murine Thigh and Lung Infection Models

Abstract

Colistin is increasingly used as last-line therapy againstwere examined by using an inhibitory sigmoid maximum-effect model. Nonlinearity in the PKs of colistin, including its plasma protein binding, was observed. The PK/PD index that correlated best with its efficacy was fAUC/MIC in both the thigh infection model (R 2 ‫؍‬ 87%) and the lung infection model (R 2 ‫؍‬ 89%). The fAUC/MIC targets required to achieve 1-log and 2-log kill against the three strains were 15.6 to 22.8 and 27.6 to 36.1, respectively, in the thigh infection model, while the corresponding values were 12.2 to 16.7 and 36.9 to 45.9 in the lung infection model. The findings of this in vivo study indicate the importance of achieving adequate time-averaged exposure to colistin. The results will facilitate efforts to define the more rational design of dosage regimens for humans.

Systematic review of the evidence for rational dosing of colistin

“…However, extended dosing intervals may lead to periods of low colistin concentrations allowing for resistant subpopulations to occur within a microbial population susceptible to colistin (heteroresistance). [28][29][30]34] Small, uncontrolled studies report good efficacy, without significant renal toxicity, of high-dose CMS regimens given 12-hourly [35] or daily. [31] There are no randomised, controlled, clinical trials (RCTs) evaluating the efficacy and safety of once-, twice-and thrice-daily dosing of colistin.…”

“…This AUC/ MIC of 60 would be expected to result in a suboptimal pharmacodynamic effect of somewhere between stasis and 1 log 10 kill for most susceptible bacteria. The authors acknowledge that there are limitations to their estimates as free concentrations of colistin were measured in the murine infection models [29][30] and there are no human data on the protein binding of colistin. Peak concentrations of at least 4 mg/l (four times the MIC) were needed to eliminate P. aeruginosa in one study, but in critically ill patients this concentration was only reached with doses of 9 MU of CMS.…”

“…[28] Murine studies showed that the most predictive index for antibacterial effect against P. aeruginosa and A. baumannii was the ratio of the area under the curve to the minimum inhibitory concentration (AUC/MIC). [29][30] Extrapolating from murine AUC/MIC colistin data, Garonzik et al [17] estimated that in humans a total colistin AUC/ MIC of 60 is the average achieved using currently recommended doses. This AUC/ MIC of 60 would be expected to result in a suboptimal pharmacodynamic effect of somewhere between stasis and 1 log 10 kill for most susceptible bacteria.…”

Optimizing Antibiotic Pharmacodynamics for Clinical Practice

“…More recently, the pharmacodynamics of the older polymyxin class of antibiotics has been found to observe concentration-dependent killing, where the fAUC/MIC ratio is predictive of antibacterial effect against Gram-negative bacteria [37]. in vitro and in vivo thigh infection studies indicate that the fAUC/MIC required for 1-to 2-log reductions against P. aeruginosa range from 15.6 to 22.8 and from 27.6 to 36.1, respectively; in the lung infection model, those requirements ranged from 12.2 to 16.7 and 36.9 to 45.9, respectively [38]. Similar targets were required for 1-log reduction against A. baumannii isolates, although more variability was noted in the lung infection models [37].…”

Polymyxins for the treatment of extensively-drug-resistant Gram-negative bacteria: from pharmacokinetics to bedside

“…And although many questions are still unresolved, there is consistent evidence that clinicians may apply when prescribing the initial and maintenance doses of both polymyxin B and CMS. It has been shown that free (unbound) area under the concentration-time curve (fAUC)/MIC is the PK/pharmacodynamic (PD) index that best predicts polymyxins activity against GNB [5][6][7]. It means that achieving an adequate time-averaged exposure to polymyxins is necessary to their optimal bactericidal action [3,4].…”