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

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

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 CL(CR) 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13318-020-00643-3) contains supplementary material, which is available to authorized users.