Clinical pharmacokinetics of 3-h extended infusion of meropenem in adult patients with severe sepsis and septic shock: implications for empirical therapy against Gram-negative bacteria

Abstract

Background: Optimal anti-bacterial activity of meropenem requires maintenance of its plasma concentration (Cp) above the minimum inhibitory concentration (MIC) of the pathogen for at least 40% of the dosing interval (fT > MIC > 40). We aimed to determine whether a 3-h extended infusion (EI) of meropenem achieves fT > MIC > 40 on the first and third days of therapy in patients with severe sepsis or septic shock. We also simulated the performance of the EI with respect to other pharmacokinetic (PK) targets such as fT > 4 × MIC > 40, fT > MIC = 100, and fT > 4 × MIC = 100.Methods: Arterial blood samples of 25 adults with severe sepsis or septic shock receiving meropenem 1000 mg as a 3-h EI eight hourly (Q8H) were obtained at various intervals during and after the first and seventh doses. Plasma meropenem concentrations were determined using a reverse-phase high-performance liquid chromatography assay, followed by modeling and simulation of PK data. European Committee on Antimicrobial Susceptibility Testing (EUCAST) definitions of MIC breakpoints for sensitive and resistant Gram-negative bacteria were used. Results:A 3-h EI of meropenem 1000 mg Q8H achieved fT > 2 µg/mL > 40 on the first and third days, providing activity against sensitive strains of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. However, it failed to achieve fT > 4 µg/mL > 40 to provide activity against strains susceptible to increased exposure in 33.3 and 39.1% patients on the first and the third days, respectively. Modeling and simulation showed that a bolus dose of 500 mg followed by 3-h EI of meropenem 1500 mg Q8H will achieve this target. A bolus of 500 mg followed by an infusion of 2000 mg would be required to achieve fT > 8 µg > 40. Targets of fT > 4 µg/mL = 100 and fT > 8 µg/mL = 100 may be achievable in two-thirds of patients by increasing the frequency of dosing to six hourly (Q6H). Conclusions:In patients with severe sepsis or septic shock, EI of 1000 mg of meropenem over 3 h administered Q8H is inadequate to provide activity (fT > 4 µg/mL > 40) against strains susceptible to increased exposure, which requires © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article' s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article' a bolus of 500 mg followed by EI of 1500 mg Q8H. While fT > 8 µg/mL > 40 require escalation of EI dose, fT > 4 µg/ mL = 100 and fT > 8 µg/mL = 100 require escalation of both EI dose and frequency.

Therapeutic Drug Monitoring of Meropenem and Piperacillin in Critical Illness—Experience and Recommendations from One Year in Routine Clinical Practice

“…We thought that the chosen high breakpoints for target attainment were necessary due to the high number of immunocompromised patients who underwent lung or liver transplantation and had special pathogens with higher MICs than other patients [31,32]. The number of subtherapeutic levels was comparable to those reported in the literature for meropenem [17,33,34]…”

“…We thought that the chosen high breakpoints for target attainment were necessary due to the high number of immunocompromised patients who underwent lung or liver transplantation and had special pathogens with higher MICs than other patients [31,32]. The number of subtherapeutic levels was comparable to those reported in the literature for meropenem [17,33,34], piperacillin [7,35,36], and other beta-lactam antibiotics like cefepime [37] or ceftriaxone [38]. Furthermore, the existing correlation between renal function and beta-lactam blood concentration has also been described in different studies [21,22].…”

500 mg as bolus followed by an extended infusion of 1500 mg of meropenem every 8 h failed to achieve in one-third of the patients an optimal PK/PD against non-resistant strains of these organisms: is CRRT responsible for this situation?

“…However, this dosing regimen failed to achieve a fraction of time (fT) > 4 μg/ mL > 40 for activity against non-resistant strains of these organisms in more than one-third of patients [1]. A bolus of 500 mg followed by EI of 1500 mg every 8 h was predicted to achieve this target in all patients [1]. The question is why was this the case in this study.…”

“…We read with great interest the recent paper by Kothekar et al who conclude that in patients with severe sepsis or septic shock, extended infusions (EI) of 1000 mg of meropenem over 3 h, administered every 8 h on the first and third days, provided adequate coverage against sensitive strains of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii [1]. However, this dosing regimen failed to achieve a fraction of time (fT) > 4 μg/ mL > 40 for activity against non-resistant strains of these organisms in more than one-third of patients [1]. A bolus of 500 mg followed by EI of 1500 mg every 8 h was predicted to achieve this target in all patients [1].…”

Evaluation of pharmacokinetic and pharmacodynamic parameters of meropenem in critically ill patients with acute kidney disease

“…The ft > 4MIC was calculated using series of pharmacokinetic formulas in appendix 1 . The optimal goal of ft was considered ≥ 80% for meropenem in Gram-negative bacterial infections [ 17 ]. In our study, measured concentrations were compared to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) of susceptible breakpoints for the Gram-negative organism, 2 μg/mL for meropenem.…”