This is a Phase 4, interventional, multi-center pharmacokinetics (PK) study in up to 200 adult patients who are residing in an ICU. This study will compare the abilities of Cystatin C (CysC) and CysC-based estimated Glomerular Filtration Rate (eGFR) equations to characterize the PK profiles of meropenem and cefepime relative to Serum Creatinine (SCR), Serum Creatinine based Equation (SCRE), and iohexol in critically ill patients with suspected or documented AMR Gram-negative infections. We hypothesize that CysC and CysC-based eGFR equations will characterize the PK profiles of meropenem and cefepime at the population and individual levels with greater accuracy and precision than SCR and SCREs. Iohexol will be administered to patients enrolled in the study and serve as the reference indicator of measured Glomerular Filtration Rate (mGFR), which is the gold standard assessment of kidney function. We further hypothesize that the predictive performances of CysC and CysC-based eGFR equations in estimating the PK profiles of meropenem and cefepime at the population and individual levels will be comparable to iohexol. Firstly, population PK (PopPK) modeling will be used to develop meropenem and cefepime PopPK models informed by CysC, CysC-based eGFR equations, SCR, and SCREs (renal function biomarkers), and iohexol clearance. Secondly, model diagnostics will then be used to compare the predictive performances of the renal function biomarkers PopPK models for each antibiotic relative to iohexol PopPK model. Lastly, Monte Carlo simulation (MCS) will be used to design PK/ pharmacodynamics (PD) optimized meropenem and cefepime dosing schemes based on the renal function biomarker PopPK model with the best predictive performance for use in the treatment of critically ill adult patients with suspected or documented AMR Gram-negative infections and varying degrees of renal function. The primary objective of this study is to compare the abilities of renal function biomarkers (CysC, CysC-based eGFR equations, SCR, SCREs) relative to iohexol to characterize the PK profiles of meropenem and cefepime in critically ill adult patients with suspected or documented AMR Gram-negative infections.
Age >/=18 years at the time of enrollment.
Residing in an ICU.
Documented or suspected Antimicrobial Resistant (AMR) Gram-negative infection for which the prospective participant is receiving meropenem or cefepime as part of their clinical management.
Expectation that the prospective participant will reside in the ICU and receive meropenem or cefepime for the duration of the study, and that all study procedures will be completed.
Prospective participant has a documented hypersensitivity or allergic reaction to iohexol, any contrast agents, or iodine.
Prospective participant has a documented prior history of severe cutaneous reactions to iohexol, any contrast agents, or iodine.
Prospective participant received iohexol on the calendar day of enrollment or the expectation that they will receive iohexol for clinical care (i.e., Standard of Care [SOC]) during the study.
Prospective participant had a major surgery within one calendar day prior to enrollment.
Single group
Iohexol
DrugIohexol,N,N´ -Bis(2,3-dihydroxypropyl)-5-\[N-(2,3-dihydroxypropyl)-acetamido\]-2,4,6-triiodoisophthalamide, is a non-ionic, water-soluble radiographic contrast medium with a molecular weight of 821.14 (iodine content 46.36%)
Clearance (Cl)
Composite Euclidean distance score
Summarizes predictive precision, accuracy, and bias of the cefepime or meropenem renal function biomarker population pharmacokinetic (PopPK) model relative to the corresponding iohexol clearance PopPK model using the validation dataset.
Intercompartment rate constant
Volume of distribution (Vd)
Pharmacokinetic/pharmacodynamics (PK/PD) optimized meropenem and cefepime dosing schemes
For PopPK models
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