Pharmacokinetics and Monte Carlo Dosing Simulations of Imipenem in Critically Ill Patients with Life-Threatening Severe Infections During Support with Extracorporeal Membrane Oxygenation

Sutep Jaruratanasirikul, Veerapong Vattanavanit, Wibul Wongpoowarak, Monchana Nawakitrangsan, Maseetoh Samaeng, Sutep Jaruratanasirikul, Veerapong Vattanavanit, Wibul Wongpoowarak, Monchana Nawakitrangsan, Maseetoh Samaeng

Abstract

Background: Extracorporeal membrane oxygenation (ECMO), a cardiopulmonary bypass device, has been found to increase the profound pathophysiological changes associated with life-threatening severe infections in patients with multiple comorbidities, which results in alterations of pharmacokinetic patterns for antibiotics.

Objectives: The aims of this study were (1) to determine the pharmacokinetics of imipenem and (2) to assess the probability of target attainment (PTA) for imipenem in critically ill patients with life-threatening severe infections during support with ECMO.

Methods: The pharmacokinetic studies were carried out following administration of 0.5 g of imipenem every 6 h on the 4th dose of drug administration in 10 patients and a Monte Carlo simulation was performed to determine the PTA of achieving 40% exposure time during which the plasma drug concentrations remained above minimum inhibitory concentration (T > MIC) and 80% T > MIC.

Results: The median values of volume of distribution and total clearance (CL) of imipenem in these patients were 13.98 L and 9.78 L/h, respectively. A high PTA (≥ 90%) for a target of 80% with a MIC of 4 μg/mL in patients with CLCR 60-120 mL/min and flow rate of ECMO circuit 3-5.5 L/min was observed when imipenem was administered by a 4-h infusion of 1 g every 6 h.

Conclusions: A high dosage regimen such as 1 g every 6 h of imipenem may be required to achieve pharmacodynamic targets against less susceptible pathogens in this patient population. CLINICALTRIAL.

Gov identifier: NCT03776305, date of registration: 11 December 2018.

Conflict of interest statement

Sutep Jaruratanasirikul, Veerapong Vattanavanit, Wibul Wongpoowarak, Monchana Nawakitrangsan and Maseetoh Samaeng have no conflicts of interest that are relevant to the content of this paper.

Figures

Fig. 1
Fig. 1
Probability of target attainment (PTA) for imipenem regimens achieving (a) 40% T > MIC at flow rate 3–5.5 L/min, with CLCR 60–120 mL/min, (b) 80% T > MIC at flow rate 3–5.5 L/min, with CLCR 60–120 mL/min, (c) 40% T > MIC at flow rate 1–2.99 L/min, with CLCR 60–120 mL/min and (d) 80% T > MIC at flow rate 1–2.99 L/min, with CLCR 60–120 mL/min at specific minimum inhibitory concentrations (MICs) in 10 critically ill patients with life-threatening severe infections during support with ECMO after administration of a 1-h infusion of 0.5 g every 6 h (open diamond), a 4-h infusion of 0.5 g every 6 h (close diamond), a 1-h infusion of 1 g every 8 h (open triangle), a 4-h infusion of 1 g every 8 h (close triangle), a 1-h infusion of 1 g every 6 h (open circle), a 4-h infusion of 1 g every 6 h (close circle). The broken line represents 90% PTA. T > MIC, time that concentrations in tissue and serum were above the MIC

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