Pharmacokinetics of Imipenem/Cilastatin/Relebactam in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation (ECMO)
Phase: PHASE1
Conditions: Sepsis
Sponsor: Joseph L. Kuti, PharmD

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Center for Anti-Infective Research and Development 
Hartford Hospital 
 
 
Protocol 
 
 
Original Version Date: May 12, 2020 
Amendment 1 Version Date: July 7, 2021 
 
 
Pharmacokinetics of Imipenem/Cilastatin/Relebactam in Critically Ill Patients Receiving 
Extracorporeal Membrane Oxygenation (ECMO) 
 
 
NCT04493151 
 
 
Principal Investigator: Joseph L. Kuti, PharmD, FIDP, FCCP 
                                    Center for Anti-Infective Research and Development 
                                    Hartford Hospital 
                                    80 Seymour Street 
                                    Hartford, CT 06102 
                                    Tel: (860) 972-3612 
                                    Fax: (860) 545-3992 
                                    Email: joseph.kuti@hhchealth.org 
 
 
 

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Section #2- Core Protocol 
 
2.1 Objectives & 
Hypotheses  
 
 
 
 
1.0 PROTOCOL AMENDMENT 1: July 7, 2021 
 
1. Section 2.5 exclusion criteria #5 modified to remove valproic acid. 
2. Section 2.5 addition of criteria #6 excluding patients currently receiving or 
anticipated to receive valproic acid. The change in criteria 5 and 6 will 
allow for patients to receive imipenem-cilastatin-relebactam despite a 
prior recent history of valproic acid use. 
3. Section 2.5 screening/baseline: removal of urine analysis with microscopy 
due to unnecessary test not relating to patient safety.  
 
2.0 OBJECTIVES 
 
1. To determine the pharmacokinetics of imipenem and relebactam in critically 
ill adult patients supported by ECMO 
 
2.1.1 HYPOTHESES 
 
1. Imipenem and relebactam pharmacokinetics in critically ill patients receiving 
ECMO support will be consistent with parameters previously defined in 
critically ill adult patients not supported by ECMO 
 
2.2 Background & 
Rationale, 
Significance of 
Selected Topic & 
Preliminary Data  
 
Extracorporeal membrane oxygenation (ECMO) is a mechanical circulatory support 
device used temporary in critically ill patients with heart and/or respiratory failure 
unresponsive to maximal conventional therapy. Briefly, ECMO is a form of 
cardiopulmonary life-support where blood is extracted from the vascular system (i.e., 
peripheral or central vein) and circulated by a mechanical pump while it is 
oxygenated and re-infused into the patient’s circulation.   ECMO can be used in two 
different configurations depending on the patient’s requirement: veno-venous (VV-
ECMO) when only respiratory support is needed and veno-arterial (VA-ECMO) for 
cardiac and/or respiratory support (1). Although controversial until 2009, the clinical 
benefit of ECMO therapy was substantiated when the CESAR study, a multicenter, 
randomized controlled trial that included adult patients with respiratory failure, 
demonstrated an increased survival without disability at 6-month follow-up (2). Since 
then, ECMO has been increasingly used worldwide in pediatric and adult patients, 
and remarkable technological improvements (e.g., innovative device design, 
cannula, oxygenators) have been made, resulting in improved clinical outcomes (3). 
 
At our large tertiary care trauma center, we perform VV-ECMO or VA-ECMO in an 
increasing number of critically ill adult patients each year (n=60 in 2019). With more 
adult patients receiving ECMO support, there is a need to understand how ECMO 
circuits affect the pharmacokinetics (PK) and disposition of drugs. ECMO is not a 
disease-modifying treatment, and its effectiveness relies on the effect of other 
interventions, such as antibiotics in patients with severe infections where optimal 
exposure is crucial for treatment success. It is well known that critically ill patients 
may experience alterations in antibiotic PK, and as a result, dosing modifications are 
generally required (4). Multiple in vitro and in vivo studies have shown that ECMO 
may further alter the PK of certain antibiotics by resulting in lower plasma 
concentrations unable to achieve pharmacodynamic thresholds (5). Intrinsic drug 
properties such as lipophilicity and protein binding appear to be predictive of this 
artificial loss, presumably due to drug adsorption and sequestration within the 
oxygenator circuit, increases in compensatory volume of distribution and even 
changes in total body clearance (6-9). However, these specific drug properties may 

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not always be predictive; a recent ex vivo study with ceftolozane observed 92% loss 
in the circuit over 24 hours even though this antibiotic is neither lipophilic nor highly 
protein bound (10).  Other factors related with the ECMO circuit itself such as the 
type of pump and presence of oxygenator have been also associated with antibiotic 
loss (9,10).  In contrast, some investigators largely conclude that antibiotic 
exposures are minimally altered by ECMO and thus antibiotic dosing should be 
consistent with critically ill patients not supported by ECMO (11-13). In light of this 
inconsistent data, the sequestration and clinical PK of individual antibiotics should be 
assessed to confirm optimal dosing in this patient population.  
 
Imipenem/cilastatin/relebactam (Recarbrio®, Merck & Co, Inc, Kenilworth, NJ) is a 
novel carbapenem/β-lactamase inhibitor combination recently approved by the U.S. 
Food and Drug Administration (FDA). Imipenem/cilastatin/relebactam has enhanced 
activity against multidrug resistant Gram-negative bacteria, including imipenem 
resistant strains (14). As a result of its potent activity against multidrug-resistant 
pathogens, it is reasonable to surmise that imipenem/cilastatin/relebactam will be 
prescribed to treat serious infections in critically ill patients, including those who are 
supported on ECMO. Optimizing the dosing regimen in critically ill patients receiving 
ECMO will be paramount to achieving successful clinical response and minimizing 
the risk of resistance development. Both imipenem and relebactam have low protein 
binding (~20%) and low octanoal/partition coefficients (Log P: -3.8 to -0.86 and -3.1 
to -1.1, respectively), which suggests that drug disposition should be minimally 
affected by ECMO (15-17). However, Jaruratanasirikul and colleagues compared 
imipenem PK parameters between 10 critically ill patients on ECMO and 18 similarly 
ill patients not supported by ECMO (18). They observed that ECMO, or the 
underlying physiological state produced by it, resulted in a significantly higher total 
volume of distribution (33.4 ± 13.9 L vs. 21.3 ± 15.0 L) and significantly lower total 
body clearance (10.0 ± 10.5 L/h vs. 21.5 ± 9.6 L/h). The authors suggest that these 
alterations may require dosing modifications (i.e., 1 g q6h) to maintain optimal 
pharmacodynamic exposure. It should be noted, however, that the PK parameters in 
the studied ECMO patients were within the range of imipenem PK values observed 
in other critically ill patients without ECMO, suggesting that the patients may not 
have been evenly matched for comparison (19). Moreover, there are currently no 
data evaluating the disposition of relebactam in patients supported by ECMO. We 
propose a clinical pharmacokinetic study to determine imipenem and relebactam 
exposure in critically ill patients supported by ECMO.  
 
2.3 Study Design 
 
The study will be a prospective, open-label, single-center, phase 1b PK study of 
imipenem/cilastatin/relebactam in eight critically ill adult patients receiving ECMO 
support at Hartford Hospital. PK analyses will be conducted to assess exposure 
attainment in these eight ECMO patients. 
 
The study protocol and informed consent documents will be reviewed and 
approved by the Institutional Review Board (IRB) at Hartford Healthcare.   All study 
subjects, or their next of kin, will be required to provide written consent in order to 
participate in the study. Imipenem/cilastatin/relebactam will not be given as a 
treatment. Therefore, all patients will receive other antibiotics as necessary to treat 
any ongoing infection if present.   
 
2.4 Study Flowchart 
 
Not Applicable 
2.5 Study 
Procedures 
Study Location 
This study will take place at Hartford Hospital, an 867 bed, tertiary care hospital in 
Hartford, CT. ECMO is prescribed in approximately 60 critically ill adult patients each 
year, split between use of VV-ECMO and VA-ECMO.    We anticipate that the 

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majority of patients with sepsis who qualify for this study to be receiving VV-ECMO. 
 
Study population 
The study population will include eight critically ill adult patients (>/= 18 years of age) 
receiving ECMO support in the medical or surgical intensive care units at Hartford 
Hospital. Patients with documented or presumed infection are eligible. Any patient 
with infection will be treated with standard antibiotics by the attending provider. To 
ensure representation of patients across the renal function spectrum to be included 
in the study, half of the enrolled patients with have a creatinine clearance ≥60 ml/min 
at screening and half will have a value between 15 and 59 ml/min. 
 
Inclusion Criteria: Patients eligible to participate in the study must meet all of the 
following criteria prior to any study-related procedure: 
• 
Age 18 years or older; 
• 
On support with VV- or VA-ECMO; 
• 
Documented infection or presumed infection as confirmed by the presence 
of at least one of the following criteria within the past 72 hours: 
o 
Documented fever (oral, rectal, tympanic, or core temperature > 
38.5° C) 
o 
Hypothermia (oral, rectal, tympanic, or core temperature < 35.0° C) 
o 
An elevated white blood cell (WBC) count ≥ 12,000 cells/mm3 
 
Exclusion Criteria: Patients will be considered ineligible if they meet any of the 
following criteria: 
• 
If female, currently pregnant or breast feeding; 
• 
History of any moderate or severe hypersensitivity or allergic reaction to any 
β-lactam agent (a history of mild rash to a β-lactam followed by uneventful 
re-exposure is not a contraindication); 
• 
Severe renal dysfunction defined as a creatinine clearance < 15 mL/min 
(calculated by the Cockcroft-Gault equation using actual body weight) or 
requirement for continuous renal replacement therapy or hemodialysis; 
• 
Hemoglobin less than 8 mg/dL at baseline; 
• 
Use of probenecidor imipenem within 3 days before study drug infusion; 
• 
Current use of valproic acid or anticipated use during study enrollment. 
• 
Acute liver injury, defined as aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) > 5 times the upper limit of normal, or AST or ALT > 
3 times the upper limit of normal with an associated total bilirubin > 2 times 
upper limit of normal; 
• 
Any rapidly-progressing disease or immediately life-threatening illness 
(defined as imminent death within 48 hours in the opinion of the 
investigator); 
• 
Any condition or circumstance that, in the opinion of the investigator, would 
compromise the safety of the patient or the quality of study data; 
Planned or prior participation in any other interventional drug study within 30 
days. 
Study Procedures 
Screening/Baseline 
Screening/Baseline assessments and procedures must be completed within 24 
hours before the start of the study drug infusion. Potential subjects who do not meet 
enrollment criteria may, as appropriate, repeat the screening assessments once at a 
later time for possible enrollment into the study.  Local laboratory results will be used 
to determine subject eligibility for study enrollment. Any protocol-required eligibility 
laboratory evaluations already done as part of the patient’s regular medical care 
within 24 hours before the start of the study drug infusion on Study Day 1 do not 

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have to be repeated for purposes of determining eligibility for this study. 
 
• 
Obtain informed consent in writing from patient, legal authorized 
representative, or next of kin, according to local regulations. 
• 
Clinical Assessments: 
• 
Obtain a complete medical and surgical history, including: a) all active 
conditions and all conditions diagnosed within the previous 1 year 
• 
Perform a complete physical examination (general/appearance; head, eyes, 
ears, nose, and throat [HEENT]; neurological; pulmonary; cardiovascular; 
gastrointestinal; musculoskeletal; and skin) 
• 
Record height and weight 
• 
Record resting pulse, blood pressure, and respiratory rate; oxygen saturation 
(by pulse oximeter), including rate of supplemental oxygen (i.e., FiO2); 
ventilator support; and highest (or lowest if hypothermia) daily temperature 
(oral, rectal, tympanic, or core) measured 
• 
Record total fluid balance including total fluid intake and total fluid output for 
the period encompassing the signing of the ICF to the start of the study drug 
infusion 
• 
Record each component of the Acute Physiology and Chronic Health 
Evaluation II (APACHE II) assessment at Screening/Baseline 
• 
Record ECMO settings 
• 
Record all prior medications taken or received within 3 days before study 
drug infusion 
• 
Identify, assess, and record any new adverse events or Serious Adverse 
Events (SAE) after signing of informed consent 
• 
Laboratory Assessments: 
• 
Collect the following labs within 24 hours of study dose administration: 
serum creatinine, blood urea nitrogen, glucose, sodium, potassium, chloride, 
bicarbonate, albumin, total protein, complete blood count (CBC) with 
differential, total bilirubin, direct bilirubin, alkaline phosphate, alanine 
aminotransferase, and aspartame aminotransferase.  A serum hCG test will 
be collected for females of child-bearing potential. 
• 
Calculation of CrCL using Cockcroft-Gault based on screening/baseline 
serum creatinine: 
 
Calculated CrCL =  (140 - age in years) × ideal body weight (kg)a,b,c 
    72 × SCr (mg/dL) 
 
Multiply by 0.85 for female patients 
 
a Ideal body weight (IBW, kg): Males = 50 + [2.3 × (Height (in) - 60)]; Females = 45.5 
+ [2.3 × (Height (in) - 60)] 
b For patients with total body weight (TBW) that is greater than 20% over IBW, use 
adjusted body weight (ABW, kg): IBW + 0.4*(TBW-IBW) 
c If TBW is less than IBW, use TBW in equation 
 
Imipenem/cilastatin/relebactam Administration 
Imipenem/cilastatin/relebactam will be dosed according to current prescribing 
information based on creatinine clearance (20). Four to six doses of 
imipenem/cilastatin/relebactam, each infused over 0.5 hours, will be administered to 
achieve steady-state. The dose will be prepared according to manufacturer 
recommendations 
in 
precisely 
100 
ml 
of 
0.9% 
sodium 
chloride.  
Imipenem/cilastatin/relebactam must be administered through 
a peripheral 
intravenous catheter, peripherally inserted central catheter, central line, or port-a-
catheter, whichever is determined to be most appropriate by the local investigator 
and care provider for each participant.  Participants will also receive standard 
intravenous antibiotic therapy (excluding generic or branded intravenous imipenem) 
to treat their suspected infection, as determined by the responsible provider.  No 

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other 
intravenous 
medications 
will 
be 
co-administered 
with 
imipenem/cilastatin/relebactam. 
 
 
Study Day 1  
• 
Vital signs (temperature, heart rate, blood pressure, respiratory rate) will be 
recorded within 15 minutes prior to starting the study drug infusion. 
• 
Participants will receive imipenem/cilastatin/relebactam as described above. 
Exact start and stop times will be recorded in military time.   
• 
Identify, assess, and record any new adverse events or Serious Adverse 
Events (SAE) 
• 
Concomitant medications will be recorded. 
• 
Blood samples will be collected as described below. 
 
Study Day 2 
• 
Participants will receive imipenem/cilastatin/relebactam as described above. 
Exact start and stop times will be recorded in military time.   
• 
Blood samples will be collected as described below. 
• 
Concomitant medications will be recorded. 
• 
Clinical Assessments: 
• 
Perform a complete physical examination 
• 
Record resting pulse, blood pressure, and respiratory rate; oxygen saturation 
(by pulse oximeter), including rate of supplemental oxygen (i.e., FiO2); 
ventilator support; and highest (or lowest if hypothermia) daily temperature 
(oral, rectal, tympanic, or core) measured 
• 
Identify, assess, and record any new adverse events or SAE 
• 
Laboratory Assessments: 
• 
Collect the following labs within 24 hours after completion of last blood 
sample collection: serum creatinine, blood urea nitrogen, glucose, sodium, 
potassium, chloride, bicarbonate, albumin, total protein, complete blood 
count (CBC) with differential, total bilirubin, direct bilirubin, alkaline 
phosphate, alanine aminotransferase, aspartame aminotransferase, and 
urine analysis with microscopy.   
 
Sample Collection 
Blood samples (4 mL) will be collected in K2EDTA vacutainers before the first 
imipenem/cilastatin/relebactam dose (i.e., blank), and at 0.5 and 6 hours following 
the first dose, and then at 0, 0.5, 0.75, 1, 2, 4, 5, and 6 hours after the start of the 
final dose, when concentrations are expected to be at steady-state. All blood 
samples will be collected pre-oxygenator. Additionally, protein binding will be 
determined at the 0.5 hour time point of the final dose. The timing of all blood 
samples should be +/- 5 minutes of protocol defined time, except for the 0.5 hour 
(peak concentration), which can be +5 minutes the end of infusion and should be 
collected as close to the end of the infusion as possible.  
 
Processing of clinical samples 
Blood samples will be immediately stored on ice and centrifuged within 30 minutes 
of collection at 4º C and 1300 x g for 10 minutes to separate the plasma. 
Immediately after centrifugation, 1.0 mL of plasma from each sample will be 
transferred (using a 1.0 mL pipette) to a previously labeled cryovial containing 1.0 
mL of plasma stabilizer (2-(N-morpholino) ethanesulfonic acid (MES)). A second 1.0 
mL of plasma will be added to a second cryovial (labeled with stabilizer) to have a 
back-up sample. Thereafter, cryovials will be capped and inverted at least six times 
to mix the plasma with the stabilizer. The cryovials will be stored at -80º C until 
concentration determination. No more than 60 minutes should elapse between the 
blood draw and freezing of plasma sample.  

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Protein Binding determination 
An additional 10ml blood sample will be collected for imipenem and relebactam 
protein binding determination at time points described above. Plasma will be 
separated by centrifugation as previously explained. Approximately 0.9 mL of plasma 
will be loaded in an ultrafiltration device (Centrifree®, Merck Millipore Ltd., Ireland) 
and centrifuged for 45 minutes at 10º C at 2,000 x g to obtain an ultrafiltrate 
containing only free-drug concentrations. Protein binding will be conducted in 
triplicate.  The ultrafiltrate volume will be measured, transferred to a cryovial and 
then, an equal volume of the stabilizer will be added (confirmation of processing 
instructions for protein-free imipenem and relebactam will be provided by Q2 
Solutions, Ithaca, NY). The cryovials will be stored at -80º C until concentration 
determination. The final protein percentage will be calculated by dividing the free 
concentration by the total plasma concentration and subtracting from 100 (%).  
 
2.6 Study Duration 
IRB Submission and Contracting: 2 months 
Patient Enrollment: 8 months 
Data Analyses: 2 months 
Final Report: 2 months 
 
2.7 Statistical 
Analysis and 
Sample Size 
Justification  
Data Collection 
Patient demographics, medical/surgical history, concomitant medications, and 
adverse event data will be collected throughout the study on a provided case report 
form.  Protected Health Information (PHI) will be maintained at CAIRD.   
 
Imipenem and Relebactam Concentration Determination 
Cryovials containing plasma and protein free filtrate will be overnight shipped on 
dry ice to Q2 Solutions (Ithaca, NY) for imipenem and relebactam concentration 
determination.  The back-up vial will be shipped separately.  Imipenem and 
relebactam concentrations will be determined by a liquid chromatography mass 
spectrometry assay.   
 
 
Pharmacokinetic Analyses 
Non-compartmental 
Non-compartmental modeling will be conducted using WinNonlin (Pharsight 
Corporation, Cary, NC) using the latest version licensed for the laboratory.  All 
concentration time curves will be plotted for visual inspection.  The following 
pharmacokinetic parameters will be estimated for imipenem and relebactam in each 
of the 8 participants.  The maximum concentration (Cmax) will be the highest 
concentration observed for the concentration time profile of each participant.  The 
time to maximum concentration (Tmax) will be the observed sampling time of the Cmax.  
The minimum concentration (Cmin) will be the lowest concentration observed for the 
concentration time profile of each participant that occurs after the observed Cmax.  
Lambda (z) will be the resulting slope of the regression line of best fit.  Half-life (T1/2) 
will be calculated as ln(2)/z.  Area under the curve for the dosing interval (AUC0-) 
will be calculated by the linear/log trapezoidal rule (linear during increasing 
concentrations, log during decreasing concentrations), where  is the dosing interval 
for the drug studied. The AUC to infinity (AUCINF) will be calculated as the AUC 
extrapolated to infinity by the equation: AUC + Clast/z. Clearance (CL) will be 
estimated by Dose/AUC0-.  The volume of distribution based on the terminal 
elimination phase (Vz) will be estimated by Dose/(z*AUC0-).   
 
Population Pharmacokinetic Analyses 
Imipenem and relebactam concentrations will be co-modeled using the non-
parametric adaptive grid program (NPAG) with adaptive gamma in the Pmetrics 

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package for R (Laboratory of Applied Pharmacokinetics and Bioinformatics, Los 
Angeles, CA) using either a one or two compartment model.  Appropriate model 
selection will be based on visual inspection, observed versus predicted plots, and 
Akaike Information Criterion (AIC). The effect of specific body size descriptors 
(actual body weight, ideal body weight, body mass index, body surface area),  
calculated CrCL, and ECMO flow rate will be analyzed for correlation with 
pharmacokinetic parameters (i.e., CL and volume of distribution). By including a 
similar proportion of participants with creatinine clearance above and below 60 
ml/min, a variable range of clearance values will be represented in the population 
analyses. 
 
Pharmacodynamic Analysis 
The free imipenem and relebactam concentration of each of the eight participants 
will be assessed for free time above the MIC (fT>MIC, applied for imipenem) and 
free area under the curve to MIC (fAUC/MIC, applied for relebactam) exposure using 
the imipenem susceptibility breakpoint of 2 µg/mL for Pseudomonas aeruginosa.  
 
Sample Size 
No target sample size is provided statistically as this will be a descriptive and 
exploratory study.  Therefore, this study will enroll eight critically ill adult patients on 
ECMO support based primarily on empirical considerations and feasibility. This 
number is considered sufficient to meet the study objectives.  
2.8 Specific Drug 
Supply 
Requirements  
Recarbrio® (Imipenem/cilastatin/relebactam) 1.25g vials (n=50 vials)  
2.9 Adverse 
Experience 
Reporting 
Safety and Adverse Event Monitoring 
Participants will be monitored for any sign or symptom of adverse events (AE) 
throughout the course of the study. Unanticipated, life-threatening or fatal adverse 
events will be reported to the IRB, the manufacturer, and the Food and Drug 
Administration according to federal guidelines. All adverse events requiring medical 
attention will be treated by the study physician and will be recorded by the 
investigator.  For the purpose of this study, an adverse event will be defined as any 
pathologic or unintended change in the structure (signs), function (symptoms), or 
chemistry (laboratory values) of the body associated with the use of the study drug, 
whether or not considered drug related, and will be categorized as one of the 
following:   
 
• 
MILD – present, but easily tolerated 
• 
MODERATE – discomfort that interferes with usual activities 
• 
SEVERE – incapacitating, inability to work or do usual activities 
 
Relationship of the AE to the study medication (i.e., causality) will be evaluated 
according to the investigator’s opinion, as one of the following: 
 
• 
Concurrent condition – unrelated to study drug 
• 
REMOTE adverse drug event – little or no temporal relationship to study 
drug 
• 
POSSIBLE adverse drug event – temporal relationship to study drug 
• 
PROBABLE adverse drug event – commonly associated with study drug 
• 
DEFINTE adverse drug event – reappeared on re-challenge of study 
drug 
 
All SAEs will be reported to the Institutional Review Board, sponsor, and the Food 

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and Drug Administration according to Federal and local guidelines. A serious 
adverse event will be defined as any adverse event that results in death, is 
immediately life-threatening, requires or prolongs hospitalization, or is an important 
medical event that may jeopardize the participant or may require medical 
intervention to prevent one of the previously mentioned outcomes. 
2.10 Itemized Study 
Budget  
See Proposed Budget 
2.11 References 
1. 
Fraser JF, Shekar K, Diab S et al. ECMO - the clinician’s view. ISBT 
Science Series 2012;7:82-88. 
2. 
Peek GJ, Mugford M, Tiruvoipati R et al. Efficacy and economic assessment 
of conventional ventilatory support versus extracorporeal membrane 
oxygenation for severe adult respiratory failure (CESAR): a multicentre 
randomised controlled trial. The Lancet 2009;374:1351-1363. 
3. 
Makdisi G, Wang IW. Extra Corporeal Membrane Oxygenation (ECMO) 
review of a lifesaving technology. J Thorac Dis 2015;7:E166-76. 
4. 
Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in the critically 
ill patient. Crit Care Med 2009;37:840-51; quiz 859. 
5. 
Dzierba AL, Abrams D, Brodie D. Medicating patients during extracorporeal 
membrane oxygenation: the evidence is building. Crit Care 2017;21:66. 
6. 
Shekar K, Roberts JA, McDonald CI et al. Sequestration of drugs in the 
circuit may lead to therapeutic failure during extracorporeal membrane 
oxygenation. Crit Care 2012;16:R194. 
7. 
Shekar K, Roberts JA, McDonald CI et al. Protein-bound drugs are prone to 
sequestration in the extracorporeal membrane oxygenation circuit: results 
from an ex vivo study. Crit Care 2015;19:164. 
8. 
Shekar K, Roberts JA, Barnett AG et al. Can physicochemical properties of 
antimicrobials be used to predict their pharmacokinetics during 
extracorporeal membrane oxygenation? Illustrative data from ovine models. 
Crit Care 2015;19:437. 
9. 
Wildschut ED, Ahsman MJ, Allegaert K, Mathot RA, Tibboel D. Determinants 
of drug absorption in different ECMO circuits. Intensive Care Med 
2010;36:2109-16. 
10. 
Cies JJ, Moore WS, 2nd, Giliam N, Low T, Enache A, Chopra A. Oxygenator 
Impact on Ceftolozane and Tazobactam in Extracorporeal Membrane 
Oxygenation Circuits. Pediatr Crit Care Med 2019. 
11. 
Abdul-Aziz MH, Roberts JA. Antibiotic dosing during extracorporeal 
membrane oxygenation: does the system matter? Curr Opin Anaesthesiol 
2020;33:71-82. 
12. 
Dhanani JA, Lipman J, Pincus J et al. Pharmacokinetics of Total and 
Unbound Cefazolin during Veno-Arterial Extracorporeal Membrane 
Oxygenation: A Case Report. Chemotherapy 2019;64:115-118. 
13. 
Argudo E, Riera J, Luque S et al. Effects of the extracorporeal membrane 
oxygenation circuit on plasma levels of ceftolozane. Perfusion 
2019:267659119864813. 
14. 
Lapuebla A, Abdallah M, Olafisoye O et al. Activity of Imipenem with 
Relebactam against Gram-Negative Pathogens from New York City. 
Antimicrob Agents Chemother 2015;59:5029-31. 
15. 
Rizk ML, Rhee EG, Jumes PA et al. Intrapulmonary Pharmacokinetics of 
Relebactam, a Novel beta-Lactamase Inhibitor, Dosed in Combination with 
Imipenem-Cilastatin in Healthy Subjects. Antimicrob Agents Chemother 
2018;62. 
16. 
Imipenem Monohydrate. https://www.drugbank.ca/salts/DBSALT002429. 

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17. 
Relebactam. https://www.drugbank.ca/drugs/DB12377. 
18. 
Jaruratanasirikul S, Vattanavanit V, Samaeng M, Nawakitrangsan M, 
Sriwiriyajan S. Pharmacokinetics of Imipenem in Critically Ill Patients with 
Life-threatening Severe Infections During Support with Extracorporeal 
Membrane Oxygenation. Clin Drug Investig 2019;39:787-798. 
19. 
Goncalves-Pereira J, Povoa P. Antibiotics in critically ill patients: a 
systematic review of the pharmacokinetics of beta-lactams. Crit Care 
2011;15:R206. 
20. 
Recarbrio (Imipenem-relebactam) for Injection. Full Prescribing Information 
2019;Merck Sharp & Dohme Corp. 
 
2.12 Publication 
Plan 
The Center for Anti-Infective Research and Development will provide a Final Report 
at the completion of the study in format acceptable for submission to peer review 
literature.  Target journals include Antimicrobial Agents and Chemotherapy and 
Journal of Antimicrobial Chemotherapy. An abstract will also be generated for 
presentation at international meeting such as IDWeek, ASM Microbe or ECCMID.  
 
2.13 Curriculum 
Vitae 
 
Investigator should provide curriculum vitae in English and a listing of references to 
MSD. 
2.13 Protocol 
Submission for 
Investigator-
Initiated Studies  
U.S. protocols should be submitted by US investigators directly to Visiontracker at 
https://msd.envisionpharma.com/vt_msd/   
 
Non U.S. protocols should be submitted to the MSD office by the investigators.