Population Pharmacokinetics and Dose Optimization of Piperacillin/tazobactam in Critically Ill Patients During Extracorporeal Membrane Oxygenation (ECMO) and Weaned from ECMO

doi:10.21203/rs.3.rs-498132/v1

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Population Pharmacokinetics and Dose Optimization of Piperacillin/tazobactam in Critically Ill Patients During Extracorporeal Membrane Oxygenation (ECMO) and Weaned from ECMO

https://doi.org/10.21203/rs.3.rs-498132/v1

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Background: Piperacillin/tazobactam is commonly used for empirical or directed treatment of infections during extracorporeal membrane oxygenation therapy (ECMO). Critical illness and extracorporeal circulation, such as ECMO and continuous renal replacement therapy may alter the pharmacokinetic parameters. We aimed to develop a population pharmacokinetic model of piperacillin/tazobactam in ECMO patients and investigate the optimal dosage regimen to achieve a pharmacodynamics target.

Methods: This was a prospective observational study of 26 ECMO patients who received piperacillin/tazobactam. A population PK model was developed using non-linear mixed-effects models and simulations were performed to evaluate patient variables, MIC levels, and dosage regimens in relation to the probability of target attainment (PTA). The acceptable piperacillin PTA was set at ≥90% for 50%ƒT >16 mg/L.

Results: A total of 244 samples were collected (163 during ECMO and 81 weaned from ECMO). Thirteen patients (50%) underwent continuous venovenous hemodiafiltration (CVVHDF). In a 2-compartment model, clearance increased by 10.1% when patients weaned from ECMO. Because patients on CVVHDF had a significant residual renal function, CVVHDF was found non-relevant to clearance. Instead, volume overload which was main cause of CVVHDF and membrane adsorption might contribute to the increased volume of distribution. Creatinine clearance (CrCL) calculated by Cockcroft-Gault equation had a significant impact on clearance. Simulation demonstrated that extended infusion should be considered in ECMO patients with CrCL >60 mL/min. Our proposed regimen was extended infusion of 2/0.25 g q8h, 2/0.25 g 6h, 3/0.375 g q 6h, and 4/0.5g q6h for CrCL ≤40, 40–60, 60–130, and >130 mL/min, respectively. Furthermore, even a higher dose would be required when patients did not receive CVVHDF after weaning from ECMO, which was 4/0.5g q6h for CrCL >110 mL/min

Conclusions: Piperacillin/tazobactam PK changes observed in ECMO patients were associated with critical illness rather than ECMO itself. A recent guideline dose may result in underexposure against P.aeruginosa when ECMO patients have CrCL > 110 mL/min; therefore, close monitoring of renal clearance is crucial in ECMO patients who received piperacillin/tazobactam regardless of CVVHDF use to provide effective treatment of infections and promote recovery. Overall, this study provides preliminary insights into the incremental effects of critical illness, ECMO and CVVHDF on piperacillin/tazobactam PK.

Trial Registration: Clinicaltrials.gov NCT02581280, December 1st, 2014.

Critical Care & Emergency Medicine

extracorporeal membrane oxygenation

continuous renal replacement therapy

creatinine clearance

pharmacokinetics

pharmacodynamics

piperacillin

tazobactam

Extracorporeal membrane oxygenation (ECMO) is mechanical circulatory support for bridge to recovery or transplantation in patients with refractory cardiopulmonary failure, and its use has increased in recent years [1]. More than 60% of adult patients receiving ECMO develop nosocomial infections, which are related to the multiple invasive devices required for management, long-term mechanical ventilation, and hospital stays [2]. The infectious complications of ECMO increase the risk of death by 38–63% [3, 4]; therefore, prevention and treatment of infections are important.

Piperacillin/tazobactam is an intravenous β-lactam antibiotic commonly used for the empirical or directed treatment of infections in critically ill patients including ECMO patients [5]. Piperacillin exhibits activity against a broad range of gram-negative organisms including Acinetobacter baumannii, Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa and shows high tolerability [6]. For piperacillin/tazobactam, having a time-dependent activity pattern, the pharmacodynamics (PD) target is related to the percentage of time that the unbound drug concentration remains above the minimum inhibitory concentration (% fT > MIC) [7]. fT > MIC required for optimal bactericidal activity for piperacillin has been reported to be 50% [8].

Piperacillin/tazobactam is a minimally protein-bound and hydrophilic drug, which recovery from ex vivo ECMO circuits after 48 h was 71% [9]. Critical illness and ECMO itself can significantly alter the pharmacokinetics (PK) of piperacillin/tazobactam, which can result in subtherapeutic levels or accumulation associated with clinical failure. In addition, the use of continuous renal replacement therapy (CRRT) further complicates the PK of piperacillin/tazobactam [10]. To date, studies on the PK of piperacillin/tazobactam have enrolled patients receiving ECMO or CRRT separately.

In this study, we developed a population PK model of piperacillin/ tazobactam in ECMO patients and performed Monte Carlo simulations to evaluate various clinical covariates, MIC level, and dosing regimens in relation to fT > MIC, and finally suggested an optimal dosage regimen to achieve the PD target.

Study design and population

This prospective observational PK/PD study was conducted at the cardiac intensive care unit (CCU) in Severance Cardiovascular Hospital between November 2015 and January 2019. The protocol for the study was approved by the Institutional Review Board (IRB No. 4-2014-0919) of Severance Hospital and was registered at ClinicalTrials.gov (NCT02581280). Written informed consent was obtained from each patient or the legal representative of unconscious patients prior to enrolment. This study included critically ill patients aged 19 years or older who were admitted CCU for venoarterial -ECMO and were prescribed piperacillin/tazobactam. The exclusion criterion was the use of drugs known to change piperacillin/tazobactam plasma concentrations.

Details of ECMO and CRRT

The ECMO circuit included a centrifugal blood pump with a pump controller (Capiox® SP-101, Terumo Inc., Tokyo, Japan), an air-oxygen mixer (Sechrist® Ind., Anaheim, CA, USA), and conduit tubing (Capiox® EBS Circuit with X coating, Terumo Inc., Tokyo, Japan).

Patients underwent independent CRRT utilizing continuous venovenous haemodiafiltration (CVVHDF, Prismaflex^®; Baxter Inc., IL, USA). Prismaflex^® ST100 set configurations were used with the polyacrylonitrile AN 69 membrane of 1m²surface area. All CVVHDF settings were established at the discretion of the treating physician.

Dosing and sampling procedure

The standard empirical dose used at our institution for patients with normal renal function is 4/0.5 g of intravenous piperacillin/tazobactam every 6 h (q6h) or q8h infused over 40 min per dose. However, when creatinine clearance (CrCL) was <40 mL/min or the patient was receiving CRRT, the piperacillin/tazobactam dosage was reduced to 3/0.375 g or 2/0.25 g q6h.

Blood samples were collected from an existing arterial catheter just before piperacillin/tazobactam administration (time 0) and then 0–0.5, 0.5–1, 1–2, 2–4, 4–6, and 6–8 h afterward. The samples were collected between days 2 and 4 of VA ECMO. In the case of concomitant CRRT, the first sample was obtained at least 24 hours after CRRT initiation. Fourteen subjects received piperacillin/tazobactam after ECMO weaning, and blood samples were collected as indicated above between days 2 and 4 of VA ECMO weaning.

plasma concentration assay

Blood samples were added to EDTA tubes and centrifuged at 1,500 × g for 15 min within 1 h of collection and stored at –80 °C until analysis. Validated liquid chromatography–tandem mass spectrometry assays were used to quantify piperacillin and tazobactam concentrations [11]. The linear concentration ranges of piperacillin and tazobactam were 1 to 220 mg/L and 0.5 to 28 mg/L, respectively. The lower limit of quantification was 0.5 mg/L for both piperacillin and tazobactam. The intra-assay accuracies of the quality control samples (1, 3, 30, and 160 mg/L) ranged from 94.9% to 96.5% for piperacillin and from 90.0% to 94.7% for tazobactam.

Population PK analyses

Population PK analyses were conducted using non-linear mixed-effects modeling (NONMEM®; version 7.4; ICON Development Solutions, Ellicott, MD, USA) and the first-order conditional estimation with interaction method. We explored 1-, 2-, and 3-compartment models. Interindividual variability (IIV) was modeled exponentially, and additive, proportional, and combined residual error models were evaluated. Model selections were based on the decrease in objective function value (OFV), goodness-of-fit (GOF) plots, and the relative standard errors of the parameters. When adding another parameter to the model, a decrease in OFV greater than 3.84 points between two nested models was significant at P-values of 0.05.

The relationship between individual PK parameter estimates and the covariates (sex, age, weight, total plasma protein, glomerular filtration rate, blood urea nitrogen, serum creatinine, CrCL, total bilirubin, use of CRRT, CRRT blood flow rate, CRRT dialysate flow rate, CRRT duration, use of ECMO, ECMO pump speed, ECMO flow rate, ECMO duration) were investigated in scatter plots and a biologically plausible explanation for altering PKs were explored. Continuous covariates were centered at the median value of the population. Based on the ꭓ2 test, stepwise covariate modeling with forward inclusion (P <0.05, OFV decrease of 3.84 points) and backward deletion (P <0.01, OFV increase of 6.64 points) was performed. Reduced inter-individual and residual variabilities, precision of the parameter estimates, and diagnostic plots and shrinkage were also considered. The extent of shrinkage, as a measure of model over-parameterization, was calculated for each PK parameter with associated IIV.

Validation of the final model was conducted using the bootstrap method (n = 5,000 runs) and prediction-corrected visual predictive checks (pc–VPCs). The median and 95% confidence intervals for the bootstrap results were compared with the estimated PK parameters from the final model. By using pc-VPCs, 1000 datasets were simulated from the final model parameter estimates, and the 95% CIs for the 5^th, 50^th, and 95^th percentiles based on the simulated datasets were calculated and overlaid with prediction corrected observed concentration for visual inspection [12].

Monte Carlo simulations

Monte Carlo simulations (n = 1,000) were conducted for segmented CrCL level (20–150 mL/min) in four cases: concomitant use of ECMO and CVVHDF, receiving ECMO only, weaning from ECMO and receiving CVVHDF, weaning from ECMO and not receiving CVVHDF. The dosing regimen was created based on a total daily piperacillin/tazobactam dose of 16/2, 12/1.5, 9/1.125, 8/1, or 6/0.75 g, with an inter-dose interval of 6 or 8 h and duration of infusion of 0.5 h (intermittent bolus), 3 or 4 h (extended infusion equal to half of the dosing interval). Proportion of time between two infusions with piperacillin concentrations above the concentration threshold (ranging from 2 to 64 mg/L) was determined. The PK/PD target for piperacillin was set to 50% fT >MIC of 16 mg/L, which is the clinical breakpoint for P.aeruginosa defined by the European Committee on Antimicrobial Susceptibility Testing [13], and considered successful if the PTA ≥90% [14, 15]. The PTA for 63% fT >2 mg/L of free tazobactam was also evaluated, and the acceptable PTA level was set at ≥50% [16, 17].

Study population

The study included 26 ECMO patients, of which 19 (73.1%) were male; the median age was 57 (range 20–89) years, and the median body weight was 70 (range 40.8–92.5) kg. Thirteen patients (50%) received CVVHDF, with the median blood flow rate of 150 (range 100–160) mL/min and the median dialysate flow rate of 1200 (range 700–1400) mL/h. CrCL was estimated with the Cockcroft–Gault equation on the day of the study with median of 40.5 (range18.0–111) mL/min on CVVHDF, and 63.2 (16.2–157) mL/min not on CVVHDF.

All 26 patients provided samples for PK analysis while they were on ECMO. Among them, 14 patients who were weaned from ECMO were able to provide samples to explore ECMO effect on piperacillin/tazobactam PK. A total of 244 piperacillin/tazobactam plasma concentration measurements were available—67 during concomitant use of ECMO and CVVHDF, 96 during ECMO only, 27 weaning from ECMO and receiving CVVHDF, and 54 weaning from ECMO and not receiving CVVHDF. The demographic characteristics are presented in Table 1.

Population PK analysis

A two-compartment PK model with first-order linear elimination and proportional residual variability best described the observed concentration data for piperacillin. IIVs were included for clearance (CL), central volume of distribution (V1), and peripheral volume of distribution (V2). The full model supported the inclusion of CrCL and presence of ECMO as covariates for CL, and total bilirubin and presence of CVVHDF as covariates for V1. In the backward elimination, extracting the total bilirubin from V1 increased OFV <6.63 (P >0.01). The final PK model is described as follows:

CL (L/h) = 9.4 × (1 − 0.092 × ECMO) + [0.115 × (CrCL − 54.7)]

V1 (L) = 6.56 × (1 + 1.46 × CVVHDF)

V2 (L) = 14.2

Q (intercompartmental clearance, L/h) = 17.2

A two-compartment PK model with first-order linear elimination and combined residual variability was the best fit for the tazobactam concentration–time data. IIVs were included for CL and V1. After forward selection and backward elimination, CrCL and presence of ECMO were identified as the significant covariates of CL. The final PK model is described as follows:

CL (L/h) = 7.93 × EXP (−0.0723 × ECMO) + 0.104 × (CrCL − 54.7)

V1 (L) = 8.58

V2 (L) = 10.5

Q (L/h) = 17.1

The population parameters of the final models for piperacillin and tazobactam are presented in Table 2 and 3, respectively. All estimates were within the 95% CIs obtained by 5,000 bootstrap runs. The GOF plots for piperacillin and tazobactam are presented in the Figure 1 and 2, respectively. The individual-fitted and population-fitted concentrations were unbiased and did not show any model misspecification. The pc–VPC plot revealed that the 5th to 95th percentiles of the predicted data overlaid most of the observed data, indicating good predictive power (Figure 3 and 4). These results confirmed that this final model was sufficiently robust to simulate concentration–time profiles.

Monte Carlo simulations

Simulated mean free piperacillin concentration-time courses are shown in Figure 5. Dosing regimen was established based on a total daily piperacillin dose of 12 g. Use of CVVHDF results in lower peak and higher trough concentration than without CVVHDF.

The piperacillin PTA of 50% fT >16 mg/L is calculated in Table 4. The calculated PTA decreased after weaning from ECMO, and increased in patients who received CVVHDF than in patients who did not receive CVVHDF. The strong relationship between CrCL and piperacillin clearance is directly reflected in the PTA. The range of PTA reduction as CrCL increased was greater with intermittent bolus than with extended infusion. It would be more appropriate to administer frequently even with the same total daily dose (3 g q6h was better than 4 g q8h) with extended infusion. The tazobactam PTA of 63% fT >2 mg/L was also calculated (Table 5).

We have recommended dosing regimens based on the achievement of 90% PTA (50% ƒT >16 mg/L) for piperacillin and 50% PTA (63% ƒT >2 mg/L) for tazobactam in four cases (Table 6). Considering the possibility of toxicity, the lowest possible dose with frequent administration was chosen. In patients with CrCL >60 mL/min, extended infusion should be considered because intermittent bolus could not achieve 90% PTA for piperacillin even at a dose of 4 g q6h. For extended infusion, all four cases required similar dosage which were 2/0.25 g q8h, 2/0.25 g q6h, 3/0.375 g q6h, and 4/0.5 g q6h for CrCL ≤40 mL/min, 40–60 mL/min, 60-130 mL/min, and >130 mL/min, respectively (in case of weaning from ECMO and not receiving CVVHDF, 4/0.5 g q6h for CrCL >110 mL/min).

The piperacillin PTAs against concentration threshold of 2–64 mg/L according to four CrCL levels (20, 60, 90, and 130 mL/min) during ECMO are presented in Figure 6. Five dosage regimens that comprised only the extended infusion method were evaluated. For MIC ranges from 2 to 8 mg/L, all extended infusion dosage could achieve 90% PTA in CrCL 20–130; however, for MIC 32 mg/L (also same as 4 × MIC of 8 mg/L) and 64 mg/L (also same as 4 × MIC of 16 mg/L), extended infusion of 4g q6h could not achieve 90% PTA in CrCL >60 mL/min and >20 mL/min, respectively.

To the best of our knowledge, our current work is the first large prospective PK/PD study of piperacillin/tazobactam in ECMO patients. Two case-control studies showed that the PK of piperacillin/tazobactam did not differ significantly between ECMO and critically ill patients; however, this conclusion was reached by simple PK analysis using the therapeutic drug monitoring results [18], or PK modeling that only explored ECMO as a covariate [19]. In this study, we used piperacillin/tazobactam plasma concentration data from four different cases (concomitant use of ECMO and CVVHDF, receiving ECMO only, weaning from ECMO and receiving CVVHDF, weaning from ECMO and not receiving CVVHDF) to provide preliminary insights into the incremental effects of critical illness, ECMO and CRRT on piperacillin/tazobactam PK. It could reflect a balance between the independent changes in volume of distribution and clearance in the presence of various clinical factors. Furthermore, we proposed an optimal dosage regimen for piperacillin/tazobactam.

The PK of piperacillin and tazobactam in our study was best described by two-compartment models with linear elimination with CL of 8.54 L/h (receiving ECMO; standardized CrCL 54.7 mL/min), V1 of 6.56 L (not receiving CVVHDF), V2 of 14.2 L, and Q of 17.2 L/h. Our final model showed that the CL increased by 10.1% when patients weaned from ECMO, and the V1 increased by 146% in patients on CVVHDF compared with those not on CVVHDF.

For ECMO, despite initial concerns about drug adsorption in the circuit, this sequestration does not appear to occur significantly in piperacillin and tazobactam, which are hydrophilic and low protein binding. Instead, decreased clearance during ECMO may reflect a relatively higher severity of illness when patients received ECMO.

Piperacillin/tazobactam is predominantly eliminated through renal excretion and their clearance was usually dependent on renal function and CRRT [20, 21]. Interestingly, inclusion of CVVHDF intensity (dialysate flow rate) and CVVHDF duration on clearance did not improve the models’ performance. Previous studies did not yield conclusive data on the effect of CRRT on piperacillin/tazobactam PK, which might be attributed to patient baseline differences and variation in CRRT modality. Recent evidence has suggested that CRRT affects clearance only in patients with significantly impaired renal function (CrCL ≤ 10 mL/min or urine output < 20 mL/h) [22, 23]. Since our patients on CVVHDF had residual renal function (median CrCL before starting CVVHDF, 34.4 mL/min), CVVHDF was found to be non-relevant to CL. Instead, volume overload which was main cause of CVVHDF might have contributed to the increased V1 of piperacillin. The initiation of CVVHDF occurred a median of 27.3 (range 24.2–36.2) h before the first sample was obtained. Also, CVVHDF membrane, polyacrylonitrile, could be responsible for adsorption of piperacillin/tazobactam [24]. In the final model, CrCL calculated by the Cockcroft–Gault equation was included as a covariate on CL, which could indirectly reflect the clearing effect of CVVHDF. The influence of serum creatinine, blood urea nitrogen, and glomerular filtration rate was also tested but showed a less significant impact.

Three piperacillin PK/PD targets are regularly used in the literature in critically ill patients:50% fT > MIC, 50% fT > 4 × MIC, and 100% fT > MIC [25, 26]. When 50% ƒT > 4 × MIC of 16 mg/L was evaluated for piperacillin in consideration of conservative target, extended infusion of 4 g q6h could not achieve the desirable PTA in patients with CrCL > 20 mL/min; however, 50% fT > 16 mg/L reflects the worst-case associated with bacterial susceptibility in empirical treatment, and previous studies have shown these targets to be clinically meaningful [27].

According to the Stanford Health Care Antimicrobial Dosing Reference Guide 2020 [28], 3/0.375 to 4/0.5 g q6h intermittent bolus or 3/0.375 to 4/0.5 g q8h extended infusion was suitable for patients with CrCL > 40 mL/min or patients who receive CRRT. In our simulation, however, in patients with CrCL > 60 mL/min, intermittent bolus could not achieve 90% PTA for piperacillin even at a dose of 4 g q6h. Also, with extended infusion of 4 g q8h, 50% ƒT > 16 mg/L was achieved <90% of patients with CrCL >110 mL/min. This is especially relevant in critically ill patients who have augmented renal clearance for many reasons. It could be induced by hyperdynamic conditions in sepsis or by use of hemodynamically active drugs [29]. We proposed extended infusion of 3/0.375 g q6h and 4/0.5 g q6h in patients with CrCL 110–130 and >130 mL/min, respectively. Furthermore, even a higher dose would be required when patients did not receive CVVHDF after weaning from ECMO, which was 4/0.5g q6h for CrCL >110 mL/min (Table 6). In tazobactam simulation, our recommended doses of tazobactam in the piperacillin/tazobactam formulation were sufficient for bacterial stasis when the target was 63% fT >MIC of 2 mg/L.

This study has limitations that should be noted. First, this was a single-center study and caution is advised against the extrapolation of the dosage regimen to any patient falling outside the characteristics of the studied cohort. Second, because of the absence of urine data we could not explore measured creatinine clearance or residual diuresis as a potential covariate of CL in our PK model. we measured neither pre- and post-filter concentrations nor dialysate concentrations which could conclude about the clearance of the CVVHDF. Third, CVVHDF status was used as a binary covariate. We tested the CVVHDF duration, dialysate flow rate and blood flow rate as covariates, but these did not improve the model. This might because all the samples during ongoing CVVHDF was obtained 24.2–36.2 h, and a consistent setting of CVVHDF was applied to most of study patients. Kohama et al. found that blood flow rate and blood purification rate could affect piperacillin clearance [30]. Future studies should further investigate the effects of duration, mode and intensity of CRRT on piperacillin/tazobactam PK during ECMO. Nevertheless, the major strengths of this study are its large sample size (26 patients) and the rich sampling scheme.

In conclusion, we revealed that piperacillin/tazobactam PK changes observed in ECMO patients were associated with critical illness rather than ECMO itself. CVVHDF did not affect clearance in patients with residual renal function, and creatinine clearance had a significant impact on clearance and PK/PD target attainment. A recent guideline dose may result in underexposure against P.aeruginosa when ECMO patients have CrCL >110 mL/min.; therefore, extended infusion of 3/0.375 g q6h and 4/0.5 g q6h in patients with CrCL 110–130 and >130 mL/min seem to be appropriate. Close monitoring of renal clearance is crucial in ECMO patients who received piperacillin/tazobactam regardless of CVVHDF use to provide effective treatment of infections and promote recovery.

CCU, cardiac intensive care unit; CL, clearance; CrCL, creatinine clearance; CRRT, continuous renal replacement therapy; CVVHDF, continuous venovenous hemodiafiltration; ECMO, extracorporeal membrane oxygenation; GOF, goodness-of-fit; IIV, interindividual variability; NONMEM, non-linear mixed-effects modeling; OFV, objective function value; pc-VPC, prediction-corrected visual predictive checks; PD, pharmacodynamics; PK, pharmacokinetics; PTA, probability of target attainment; Q, intercompartmental clearance; V1, central volume of distribution; V2, peripheral volume of distribution

Ethics approval and consent to participate

The study was approved by the Institutional Review Board (IRB No.: 4-2014-0919) of Severance Hospital and was registered at Clinicaltrials.gov (NCT02581280). Written informed consent was obtained from the patients or the legal surrogates of unconscious patients.

Consent for publication

Written informed consent was obtained from the patients’ legal representatives for publication of their individual details in this manuscript. The consent form is held by the authors’ institution and is available for review by the Editor.

Availability of data and materials

The datasets generated and/or analyzed during the current study are not publicly available due to privacy concerns and institutional policy, but are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (Ministry of Science, ICT & Future Planning) [No. 2020R1A6A3A0110036711], and the National Research Foundation of Korea (NRF) grant funded by the Korean Government (Ministry of Science, ICT & Future Planning) [No. 2021R1F1A1070549].

Authors' contributions

JH, JW, and MJC designed the study, performed the population PK analysis, interpreted the results of the analysis, and drafted the manuscript. JW and MJC supervised the design, conducted the study, and revised the manuscript. SY, KLM, DK, and BHJ collected the blood sample and patient data. SY and KLM assisted technical PK modeling. CP conducted the drug concentration assay and validation. MSP interpreted the study results and revised the manuscript. All authors read and approved the final manuscript. JH, JW, and MJC designed the study and interpreted the results of the analysis. JH performed the population PK analysis and drafted the manuscript. JW and MJC revised the manuscript. KLM, DK, BHJ and SY collected the blood sample and patient data. KLM and SK assisted in technical PK modeling. MSP interpreted the study results and revised the manuscript. All authors read and approved the final manuscript.

Acknowledgements

We would like to acknowledge all the staff of the cardiac care unit at Severance Cardiovascular Hospital for their routine support and patient care, which was crucial for the successful completion of this study.

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Table 1. Demographic characteristics

	N (%) or median [range] (n = 26)
Age (years)	57 [20–89]
Male	19 (73.1)
Body weight (kg)	70 [40.8–92.5]
Body mass index (kg/m²)	26 [18.1–31.3]
APACHE II	32 [6–46]
Indication for VA-ECMO
Cardiomyopathy Valvular heart disease	3 4
ST-elevation myocardial infarction	16
Non-ST-elevation myocardial infarction	3
Duration of VA-ECMO (h)	135 [52.1–264]
ECMO flow rate (L/min)	3.0 [0.3–4.1]
Use of continuous CVVHDF	13
Blood flow rate (mL/min) Dialysate flow rate (mL/h)	150 [100–160] 1200 [800–1400]
Blood chemistry, serum levels
Total plasma protein (g/dL)	4.9 [2.7–6.8]
Albumin (g/dL)	2.9 [1.4–3.7]
Total bilirubin (mg/dL)	2.1 (0.5–8.1]
Blood urea nitrogen (mg/dL)	23.1 [7–64.2]
Serum creatinine (mg/dL)	1.4 [0.37–5.22]
CrCL^a (mL/min) CrCL^a when receiving CVVHDF (mL/min) CrCL^a when not receiving CVVHDF (mL/min)	54.7 [16.2-157] 40.5 [18.0–111] 63.2 [16.2–157]
Lactate (mmol/L)	1.6 [0.8–20.0]
Partial pressure of carbon dioxide (mmHg)	29.1 [13.5–46.7]
Tympanic body temperature (°C)	36.9 [33–38.7]
Piperacillin/tazobactam dosage (intermittent bolus) 2/0.25 g every 6 hours (q 6h) 3/0.375 g q 6h 4/0.5 g q 6h 4/0.5 g q 8h	9 4 9 4

Data are presented as number (percentage) or median (range). ^aCreatinine clearance estimated using the Cockroft–Gault equation. APACHE II, Acute Physiology and Chronic Health Evaluation II; CrCL, creatinine clearance; CVVHDF, continuous venovenous hemodiafiltration; VA-ECMO, venoarterial extracorporeal membrane oxygenation therapy

Table 4. Simulated probability of target attainments for piperacillin (pharmacodynamic target: 50% fT > 16 mg/L)

PTAs above 90% are highlighted in yellow. ECMO, extracorporeal membrane oxygenation therapy; CVVHDF, continuous venovenous hemodiafiltration; CrCL, creatinine clearance; IB, intermittent bolus; EI, extended infusio

Table 5. Simulated probability of target attainments for tazobactam (Pharmacodynamic target: 63% fT > 2 mg/L)

PTAs above 50% are highlighted in yellow. ECMO, extracorporeal membrane oxygenation therapy; CrCL, creatinine clearance; IB, intermittent bolus; EI, extended infusion

Table 6. Proposed dosage regimen of piperacillin/tazobactam in ECMO patients

Category of patients		Concomitant use of ECMO and CVVHDF		Receiving ECMO only OR Weaning from ECMO and receiving CVVHDF		Weaning from ECMO (not receiving CVVHDF)
Infusion method		Intermittent bolus	Extended infusion	Intermittent bolus	Extended infusion	Intermittent bolus	Extended infusion
CrCL (mL/min)	20	2/0.25 g q 8h	2/0.25 g q 8h	2/0.25 g q 8h	2/0.25 g q 8h	2/0.25 g q 8h	2/0.25 g q 8h
	20–40	2/0.25 g q 6h		3/0.375 g q 8h		3/0.375 g q 6h
	40–60	3/0.375 g q 6h	2/0.25 g q 6h	4/0.5 g q 6h	2/0.25 g q 6h	4/0.5 g q 6h	2/0.25 g q 6h
	60-90		3/0.375 g q 6h		3/0.375 g q 6h		3/0.375 g q 6h
	90-110
	110-130						4/0.5 g q 6h
	>130		4/0.5 g q 6h		4/0.5 g q 6h

Dosing regimens suggestion was based on the achievement of 90% PTA (PD target: 50% ƒT > 16 mg/L) for piperacillin and 50% PTA (PD target: 63% ƒT > 2 mg/L) for tazobactam. ECMO, extracorporeal membrane oxygenation therapy; CVVHDF, continuous venovenous hemodiafiltration; CrCL, creatinine clearance

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Population Pharmacokinetics and Dose Optimization of Piperacillin/tazobactam in Critically Ill Patients During Extracorporeal Membrane Oxygenation (ECMO) and Weaned from ECMO

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