The Imipenem’s Plasma Concentration Of Pharmacokinetic Changes In Severe Infection Patients Complicating Acute Renal Injury With Continuous Renal Replacement Therapy

Background: The frequency of infection and associated mortalityrates in patients requiring continue renal replacement therapy (CRRT) ishigh[1].Thus,optimizing antibiotic therapy is a priority[2]. This optimizationcan be problematic because critically ill patients without renal dysfunctionhave significant pharmacokinetic derangements compared with noncriticallyill patients and require an altered approach to antibiotic dosing[3]. This problemis exacerbated by a patient’s increasing severity of illness and the presence ofacute kidney injury (AKI) requiring CRRT[4,5].The most common approachremains empirical dosing.Instead, rational changes to the dose regimen aredesirable to minimize the risk of therapeutic failure from inadequate antibioticdosing or adverse reactions from excessive exposure.CRRT is widely used for the treatment of severe AKI in critically illpatients[6].Antibiotic dosing during CRRT is particularly complex and currentapproaches are imprecise. Antibiotic elimination is influenced by patientfactors(the increase of apparent volume of distribution, the level of protein inblood, the changing of tissue permeability),drug factors, and CRRT technique.The influences through CRRT maily include:the modalities of therapeutic,doseof treatment,types of membrane and duration of treatment, etc[7,8].Imipenem-cilastatin is frequently used in critically ill patients due to itsbroad spectrum of potent antimicrobial activity against many commongram-positive and gram-negative pathogens, that has been maintained throughmany years of clinical use[9].the main PK/PD index that correlates with itstherapeutic efficacy is the t>MIC. their optimal bactericidal effect whenunbound drug concentration is maintained above the MIC for the longestperiod of time. Antibacterial activity may be maximal when the antibiotic is four-times to five-times MIC of the bacteria for the duration of the dosinginterval[10,11].In addition, Tam VH[12]et al.reported that optimal killingproperties have been observed in critically ill patients when concentrations aremaintained at4×MIC.A number of published studies have evaluated thepharmacokinetics of imipenem in critically ill patients with severe acuterenalfailure undergoing CRRT[13,14].But today, as the changes of the technology,the recommended therapeutic dose in the previous literature may notapply.First of all, high flux, high adsorption and larger membrane area of thefilter makes the removal of small molecule material increased significantlycompared with before, for imipenem, the clearance could also increase.Second, in previous studies, the therapeutic dose and treatment mode are notunified,the recommended dosage in past is also different.Besides,withunderstanding of the positive liquid recovery deeply, the increase of drugapparent volume of distribution, will also affect plasma drug pharmacokinetics.These factors may make the level of plasma drug concentration below theforecast level, led to the anti-infection treatment failure.Objective: The purpose of this Observational study was to investigatethat the removal efficiency of imipenem in critically ill adult intensive careunit patients during currently used CRRT regimens,and want to know if theconcentration of imipenem in plasma could achieve effectivel evels ofanti-infection.at the same time,exploring the cleaning efficiency during CRRTtreatment, in order to guide clinical.Methods: This was a prospective open-label study.All adult patientsgreater than18years of age who were hospital inpatients in the Fourthhospital of hebei medical university.who were prescribed imipenem-cilastatinas part of their required medical care, and who were receiving CRRT fortreatment of acute kidney injury. The total number of all the subjects was13,including7males and7females.Dosing regimens were determined by thephysicians caring for the patients and selected based on clinical indication,Imipenem-cilastatin regimens thus consisted of0.5g doses administeredintravenously every6h to8h. Imipenem-cilastatin doses were infused over30 minutes. In order to obtain plasma imipenem concentrations at or near steadystate, pharmacokinetic sampling was performed at least24h after initiation ofdrug therapy and the therapy of CRRT has begun. Pre-and postmembranevenous blood samples were obtained at time zero (just before the beginning ofthe drug infusion),0.25h,0.5h,0.75h,1h,2h,5h,6h or8h after the completionof the drug infusion in all patients. Samples (4ml) were taken from the in-lineblood access port in the extracorporeal circuit and collected into tubescontaining EDTA as an anticoagulant.Because imipenem is rapidly hydrolyzedin plasma, blood samples were centrifuged immediately after collection andaliquots of plasma were mixed1:1with0.5M morpholinoethanesulfonic acid.ultrafiltrate samples (2ml) were obtained simultaneous with bloodsamples.ultrafiltrate samples were collected from the CRRT apparatus directlyinto labeled polyethylene containers containing0.5M MES(2ml). Bufferedplasma,and ultrafiltrate samples were frozen at80℃immediately afterprocessing and kept frozen until assayed.LC-MS/MS was used to measureconcentration in plasma and ultrafiltrate.SPSS13.0was empoied in dataanalyses.Result:1With the Application of Prismaflex blood filtration system andAN69-M100filter,the elimination of imipenem in patient throughingCRRT(mode:CVVH) was2.387±0.595L/h when the delivered dose was31.63±1.48ml/kg/h,accounting for38%±17%of the total drug clearance.2In6hours interval dosage regimen,The percentages of the t>4×MIC atspecific4×MIC of2and8μg/ml of imipenem for more than40%of the dosinginterva.But, In the8hours interval dosage regimen,when above the4×MIC of6μg/ml,maintaining time will drop below40%of the dosinginterval.Differences had statistically significant((p＜0.05).3In a short period of time,the sieving coefficient of imipenem throughAN69-M100filter is not affected by anticoagulation measures and timefactor,cleaning efficiency will not decline.Differences by the repeated measure analysis hadn’t statistically significant((p>0.05).Conclusion: Froming the prospective open-label study,we have foundthat the clearance rate of imipenem.then, affecting the level of plasma drugconcentration, so need to adjust the dosage regimen, satisfies the requirementof anti-infection therapy.To shorten the time of the dosing interval, theconcentration of imipenem in patients plasma could be increasedsignificantly, and the pathogenic bacteria with high value of MIC could bekilled effectively.In a short period of time,the csieving coefficient of imipenemthrough AN69filter is not affected by anticoagulation measures and timefactor,cleaning efficiency will not decline.