Pharmacokinetics and Monte Carlo Dosing Simulations of Imipenem in Critically Ill Patients with Life-Threatening Severe
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ORIGINAL RESEARCH ARTICLE
Pharmacokinetics and Monte Carlo Dosing Simulations of Imipenem in Critically Ill Patients with Life‑Threatening Severe Infections During Support with Extracorporeal Membrane Oxygenation Sutep Jaruratanasirikul1 · Veerapong Vattanavanit1 · Wibul Wongpoowarak2 · Monchana Nawakitrangsan1 · Maseetoh Samaeng1
© Springer Nature Switzerland AG 2020
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.
1 Introduction Extracorporeal membrane oxygenation (ECMO), a cardiopulmonary bypass device, provides temporary cardiorespiratory support for patients with severe respiratory and/or cardiac failure refractory to conventional therapy [1, 2]. This device was previously used primarily for lifesaving support in pediatric patients; however, in the past decade, it has been Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13318-020-00643-3) contains supplementary material, which is available to authorized users. * Sutep Jaruratanasirikul [email protected] 1
Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai 90110, Songkla, Thailand
Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai 90110, Songkla, Thailand
2
increasingly used for both respiratory and cardiac failure in adult patients [1–3]. The severity of multiple comorbidities in critically ill patients and life-threatening severe infections as well as the impact
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