Mi Xu,1,* Na Chen,2,* Yong-Wei Yu,1 Xiang-Ying Pan,1 Tong Li1 

1Department of Critical Care Medicine, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Clinical Pharmaceutical, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Tong Li, Department of Critical Care Medicine, The First Affiliated Hospital of Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, Zhejiang, People’s Republic of China, Tel +86 15067114620, Fax +86 057187236838, Email drli@zju.edu.cn

Purpose: With the development of extracorporeal membrane oxygenation (ECMO) technology, the duration of ECMO support has gradually increased, leading to an increased risk of ECMO-related bacterial resistance. Polymyxin B (PMB) is used to treat drug-resistant bacterial infections. However, the pharmacokinetic (PK) parameters of antibiotics may change during ECMO, resulting in over- or under-exposure. This study aimed to clarify the changes in PK parameters and identify factors influencing PMB levels in patients receiving venovenous or venoarterial ECMO.
Patients and Methods: A prospective PK study was performed in 11 patients receiving ECMO with resistant bacteria. After reaching a steady state, the drug concentrations of PMB pre- and post-oxygenator were measured. Nonlinear mixed-effects modelling was used to construct a population PK model for PMB. Microbial results were assessed using repeated cultures at the end of treatment. Semiquantitative microbial culture results were used to form clearance and uncleared groups.
Results: The PMB concentrations were not significantly different between pre- and post-oxygenator. A two-compartment model best described the PK of PMB. ECMO flow rate was included as a covariate of clearance (CL). Continuous renal replacement therapy (CRRT) were included as covariates on the volume of the central compartment. The PK parameters central compartment, volume of the peripheral compartment, CL, and inter-compartmental clearance or flow rate(Q) were 20.41 L, 9.86 L, 3.75 L/h, and 3.82 L/h. 7 patients (63.64%) had two consecutive negative bacterial cultures at discharge. The Css,avg shows a significant difference between clearance group (2.26± 0.72) and uncleared group (1.25± 0.24), P< 0.05.
Conclusion: There were no significant differences in PMB concentrations between pre- and post-oxygenator. The PK of PMB may be altered in patients receiving CRRT-ECMO. The ECMO flow rate is strongly correlated with the CL. The Css,avg is correlated with the bacterial clearance rate. In clinical practice, increasing the incidence of therapeutic drug monitoring may improve the clinical outcomes.
Plain Language Summary: The duration of ECMO support has gradually increased, leading to a heightened risk of ECMO-related bacterial resistance. PMB is used to treat drug-resistant bacterial infections. However, the PK parameters of antibiotics may change during ECMO, resulting to over- or under-exposure. CRRT in combination with ECMO may impact the PK of PMB. The ECMO flow rate is strongly correlated with CL. Css,avg is correlated with the pathogen bacterial clearance rate. In clinical practice, increasing the use of therapeutic drug monitoring may improve the clinical outcomes.

Keywords: antibacterial agents, pharmacokinetic, extracorporeal membrane oxygenation, polymyxin B, continuous renal replacement therapy