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. 2022 May;88(5):2156-2168.
doi: 10.1111/bcp.15138. Epub 2021 Dec 9.

Meropenem pharmacokinetics in critically ill patients with or without burn treated with or without continuous veno-venous haemofiltration

Daniel J Selig  1 , Kevin S Akers  2 , Kevin K Chung  3 , Kaitlin A Pruskowski  2 , Jeffrey R Livezey  3 , Elaine D Por  1
Affiliations

Meropenem pharmacokinetics in critically ill patients with or without burn treated with or without continuous veno-venous haemofiltration

Daniel J Selig et al. Br J Clin Pharmacol. 2022 May.

Abstract

Introduction: Severe burn injury involves widespread skin and tissue damage leading to systemic inflammation, hypermetabolism and multi-organ failure. The hypermetabolic phase of burn injury has been associated with increased systemic antibiotic clearance; however, critical illness in the absence of burn may also induce similar physiologic changes. Continuous renal replacement therapy (CRRT) is often implemented in critically ill patients and may also affect antibiotic clearance. Although the pharmacokinetics (PK) of meropenem has been described in both the burn and non-burn critically ill populations, direct comparative data is lacking.

Methods: For this study, we evaluated PK parameters of meropenem from 23 critically ill patients, burn or non-burn, treated with or without continuous veno-venous haemofiltration (CVVH) to determine the contribution of burn and CVVH to the variability of therapeutic meropenem levels.

Results: A two-compartment model best described the data and revealed creatinine clearance (CrCl) and total burn surface area (TBSA) as significant covariates on clearance (CL) and peripheral volume of distribution (Vp), respectively. Of interest, non-burn patients on CVVH displayed an overall lower inherent CL as compared to burn patients on CVVH (6.43 vs. 12.85 L/h). Probability of target attainment (PTA) simulations revealed augmented renal clearance (ARC) may necessitate dose adjustments, but TBSA and CVVH would not.

Conclusions: We recommend a standard dose of 1000 mg every 8 hours; however, if ARC is suspected, or the severity of illness requires a more stringent therapeutic target, we recommend a loading dose of 1000-2000 mg infused over 30 minutes to 1 hour followed by continuous infusion (3000-6000 mg over 24 hours), or intermittent infusion of 2000 mg every 8 hours.

Keywords: burns; continuous renal replacement therapy; critical illness; meropenem; pharmacokinetics.

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Conflict of interest statement

The authors have no conflicts of interest to report. Material has been reviewed by the Walter Reed Army Institute of Research, the Uniformed Services University of the Health Sciences and the United States Institute of Surgical Research. There is no objection to its presentation and/or publication. The views expressed in this article are those of the authors and do not reflect the official policy or position of the US Army Medical Department, Department of the Army, DoD or the US Government.

Figures

FIGURE 1
FIGURE 1
Goodness‐of‐fit plots
FIGURE 2
FIGURE 2
Mean simulations in a patient with LBM = 56 kg, CrCl = 125 and without CVVH. Figure 2(A) demonstrates the typical pharmacokinetic profiles when dosing meropenem 1000 mg every 8 hours at steady state with various infusion times. Figure 2(B) shows the time to reach steady state in a continuous infusion of 1500 mg every 12 hours, compared to a 1000 mg loading dose over 30 minutes followed by the same continuous infusion starting 1 hour later
FIGURE 3
FIGURE 3
PTA results from simulations with meropenem 1000 mg Q8 hours infused over 1 hour, 3 hours or continuous infusion of 1500 mg Q12 hours. Patients (1000 per group) were simulated with varying degrees of total burn surface area (TBSA), normal renal function (NRF, CrCl = 100–130 mL/min) or augmented renal clearance (ARC, 150–250 mL/min) and fixed lean body mass (LBM) = 56 kg
FIGURE 4
FIGURE 4
PTA results from simulations with meropenem 1000 mg Q8 hours infused over 1 hour, 3 hours or continuous infusion of 1500 mg Q12 hours. Patients (1000 per group) were simulated with varying prescriptions of CVVH (0 mL/kg/h, 42.9 mL/kg/h and 71.4 mL/kg/h), normal renal function (NRF, CrCl = 100–130 mL/min) or augmented renal clearance (ARC, 150–250 mL/min) and fixed lean body mass (LBM) = 56 kg
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