Pharmacokinetics And Pharmacodynamics Of Low-Dose Meropenem In Anuria Patients Treated By Continuous Veno-Venous Hemofiltration

Objective:Meropenem is a broad spectrum antibiotics, with strong activity and low toxicity, and it is frequently prescribed for the treatment of severe infections in critically ill patients. Meropenem is mainly eliminated by the kidney, and its dosage should be given an appropriate reduction in patients with renal dysfunction. Those patients often receive continuous renal replacement therapy, which can remove the drug, because meropenem molecules are small and easily permeate the semi-permeable membrane, and therefore it is necessary to give a supplement dose to those patients.This study is aimed to determine the concentration of meropenem in human plasma, and to investigate the pharmacokinetics characteristic of meropenem in anuria patients in ICU treated by continuous veno-venous hemofiltration, and to explore the pharmacodynamics of low-dose meropenem (1g/12h) in those patients in accordance with PK/PD theory, so as to promote security, economic and effective rational use of drugs.Method:The study was conducted in 6 anuria patients undergoing CVVH,including 4 men and 2 women, with an average age of (77.61±6.19) years, the mean body weight of (65.83±7.36) kg, and an average creatinine clearance rate of (18.26±7.60) ml/ min. During the CVVH period, those patients were given meropenem at 1g every 12 h (total daily doses of 2 g/day) by intravenous infusion over 30 min.Intravenous blood samples were collected before drug administration and at 0.5h, 1h,2h,4h,6h,8h, 10h, 12h after the start of the drug infusion. Drug concentrations were measured using high performance liquid chromatography method, and the pharmacokinetic data were processed by the drug pharmacokinetics calculation program DAS2.0.Results:The relevant pharmacokinetic parameters were obtained using non-compartment model analysis method-statistical moment analysis:peak concentration Cmax =(46.57±6.49)μg/mL, trough concentration Cmin= (3.83±1.16)μg/mL, the area under the concentration-time curve AUC= (188.03±37.33)μg/mL*h, the half-life T1/2=(3.72±0.86) h, the mean residence time MRT=(4.02±0.11)h, the apparent volume of distribution Vd=(25.55±5.33) L, the total clearance CL= (4.87±0.97) L/h.There were individual differences in different patient data. To compared with the data reported in the literature of both the healthy subjects and the critically ill patients with renal dysfunction,there were varying degrees of changes. In this study, the plasma concentrations within 10 hours of all patients were higher than 4μg/mL (the highest MIC value of sensitive bacteria). The average time above MIC was approximately (93.7±8.93)% of 12-hour dose interval,and 3 cases of all subjects achieved 100%, and the lowest one was 77.81%, which can also achieve the maximum bactericidal effect.Conclusions:1 The high performance liquid chromatography method used to determine the plasma concentrations of meropenem is simple, sensitive, accurate, specific and can be used in meropenem pharmacokinetics studies.2 To compared with the data reported in the literature of healthy subjects,the pharmacokinetic parameters of these critically ill patients undergoing CVVH were variable,including drug plasma concentration, half-life and the apparent volume of distribution increasing, and the total clearance rate lowering.These indicated that patients with renal dysfunction should be paid attention to give an appropriate reduction in dosage of meropenem.3 To compared with the data reported in the literature of critically ill patients with renal dysfuction but without CVVH, the pharmacokinetic parameters of these critically ill patients undergoing CVVH were variable, including drug plasma concentration,the area under the concentration-time curve, half-life and the apparent volume of distribution lowering, and the total clearance rate increasing. These indicated that meropenem can be removed by the CVVH and patients treated by CRRT should be paid attention to give a complement dose of meropenem.4 There were individual differences in research data, it indicated that a vast array of pathophysiological changes occur in critically ill patients that can complicate antibiotic dosing, thereby achieving individualized drug delivery is particularly important.5 The PK/PD parameter-T> MIC index of meropenem in these anuria critically ill patients undergoing CVVH showed that, the dosage regimen of 1g meropenem every 12h, can achieve maximum bactericidal activity, and then reduce the side effects, and also the economic burden.6 The pharmacokinetics and dosage adjustments of antimicrobial agents in critically ill patients treated by the continuous renal replacement therapy need more samples and more prolonged monitoring in order to give further research and discussion.