Pharmacokinetic Characteristics and Limited Sampling Strategies for Therapeutic Drug Monitoring of Colistin in Patients With Multidrug-Resistant Gram-Negative Bacterial Infections

Abstract

Background: Colistin is increasingly used as the last therapeutic option for the treatment of multidrug-resistant, Gram-negative bacterial infections. To ensure safe and efficacious use of colistin, therapeutic drug monitoring (TDM) is needed due to its narrow therapeutic window. This study aimed to evaluate the pharmacokinetic (PK) characteristics of colistin and to guide TDM in colistin-treated patients in Korea. Methods: In a prospective study, we analyzed PK characteristics in 15 patients who intravenously received colistin methanesulfonate twice per day. Colistin methanesulfonate doses were adjusted based on renal function of the subjects. The appropriate blood sampling points for TDM were evaluated by analyzing the correlations between the PK parameters and the plasma concentrations at each time point. Results: The mean values for the minimum, maximum, and average concentrations (Cmin, Cmax, and Caverage) of colistin at steady state were 2.29, 5.5, and 3.38 mg/L, respectively. The dose-normalized Cmin, Cmax, Caverage, and area under the plasma concentration–time curve from 0 to the last measurable concentration (AUClast) showed negative correlations with the creatinine clearance. The combination of the 0- and 2-hour post-dose plasma concentrations was evaluated as the appropriate sampling point for TDM. Two patients reported nephrotoxic adverse events during colistin administration. Conclusions: Our study clarifies the PK characteristics of successful colistin treatment using TDM. Further evaluations in a larger patient population are needed to confirm the clinical usefulness of colistin TDM.

Population Pharmacokinetics and Limited Sampling Strategy for Therapeutic Drug Monitoring of Polymyxin B in Chinese Patients With Multidrug-Resistant Gram-Negative Bacterial Infections

“…The 4point models (C 1h , C 1.5h , C 4h , and C 8h ), which included the absorption, distribution, and elimination phases, were the best predictor of polymyxin B AUC 0-12h . Additionally, it was reported a 2-point model including C 0h , and C 2h was appropriate for colistin TDM (r 2 = 0.98) because the C 0h sample had an association with renal toxicity and the C 2h sample was essential to monitor efficacy (Kim et al, 2019). This result was in agreement with that of model 16 in this study.…”

“…To solve this problem, the limited sampling strategy (LSS), estimating AUC with one or a few samples, would be suitable in the clinic (David and Johnston, 2000). It has been proposed for TDM of many drugs, such as mycophenolate mofetil and colistin (Zhang et al, 2018;Kim et al, 2019;Van Der Galiën et al, 2020). However, no LSS report is available for polymyxin B at present.…”

Antimicrobial therapeutic drug monitoring in critically ill adult patients: a Position Paper#

“…For the estimation of derived PK parameters, such as the AUC, and PK/PD targets, such as the fT >MIC , an optimised PK sampling schedule is suggested for unbiased and precise parameter estimation. A limited sampling strategy (LSS), which uses the most "informative" concentration-time points (commonly 1-3 sampling time points) to describe a drug's PK, is relatively easy to be performed and may provide accurate estimates of full drug exposure [23,24]. The optimal sampling time points for a drug can be identified during "limited sampling" studies where these time points will be estimated or calculated using PK models and Monte Carlo simulations.…”

Polymyxin Acute Kidney Injury: Dosing and Other Strategies to Reduce Toxicity

“…As discussed above, the very substantial inter-patient variability in the apparent clearance of colistin (and, hence, the plasma colistin C ss,avg achieved from a particular daily dose of colistimethate) and the narrow therapeutic window impose limitations on the application of the algorithm [54]. It is highly desirable that ongoing therapy with colistimethate is guided by reliable measurement of the plasma colistin concentration via timely access to a therapeutic drug monitoring/management (TDM) service [51], as available in some settings [80,81,82,83]. Knowledge of the plasma colistin concentration enables the optimization of the daily dose of colistimethate to maximize the likelihood of a desired antibacterial outcome, while minimizing the risk of nephrotoxicity.…”