Meropenem PK/PD Variability and Renal Function: "We Go Together"

Abstract

Background: Meropenem is a carbapenem antibiotic widely employed for serious bacterial infections. Therapeutic drug monitoring (TDM) is a strategy to optimize dosing, especially in critically ill patients. This study aims to show how TDM influences the management of meropenem in a real-life setting, not limited to intensive care units.

Methods: From December 2021 to February 2022, we retrospectively analyzed 195 meropenem serum concentrations (Css). We characterized patients according to meropenem exposure, focusing on the renal function impact.

Results: A total of 36% (n = 51) of the overall observed patients (n = 144) were in the therapeutic range (8-16 mg/L), whereas 64% (n = 93) required a meropenem dose modification (37 patients (26%) underexposed; 53 (38%) overexposed). We found a strong relationship between renal function and meropenem concentrations (correlation coefficient = -0.7; p-value < 0.001). We observed different dose-normalized meropenem exposure (Css/D) among renal-impaired (severe and moderate), normal, and hyperfiltrating patients, with a median (interquartile range) of 13.1 (10.9-20.2), 7.9 (6.1-9.5), 3.8 (2.6-6.0), and 2.4 (1.6-2.7), respectively (p-value < 0.001).

Conclusions: Meropenem TDM in clinical practice allows modification of dosing in patients inadequately exposed to meropenem to maximize antibiotic efficacy and minimize the risk of antibiotic resistance, especially in renal alterations despite standard dose adaptations.

Keywords: antibiotics; antimicrobial resistance; clinical pharmacology; continuous infusion; critical illness; dose optimization; meropenem; pharmacokinetic; renal function; therapeutic drug monitoring.

Figure 1

Patients’ exposure to meropenem: (a) Meropenem serum concentration and PK/PD target attainment at the first therapeutic drug monitoring required for patients treated with meropenem. Red dotted lines represent the therapeutic range for meropenem. (b) Prevalence of patients who achieved the PK/PD target and who did not. Target classification according to meropenem serum concentration: <8 mg/L = underexposed patients; 8–16 mg/L = at target patients; 17–44.5 mg/L = overexposed patients; >44.5 mg/L = patients exposed to meropenem toxic concentration. Css = meropenem serum concentrations at the steady state. Data are reported as median and percentile. Circles represent outliers.

Figure 2

The correlation between creatinine clearance and meropenem exposure: (a) The distribution of meropenem steady-state concentrations normalized for the administered dose (Css/D) in relation to the serum creatinine clearance. The dotted lines represent the linear regression equation (in red) and the 95% CI (in black). (b) The direct correlation between the CLCr and the meropenem clearance. The dotted lines represent the linear regression equation (in red) and the 95% CI (in black). CLCr = creatinine clearance.

Figure 3

The meropenem exposure in the groups of patients stratified by different glomerular filtration: (a) The distribution of meropenem steady-state concentrations normalized for the administered dose (C/D) among patients with different renal functions estimated by creatinine clearance. (b) The meropenem clearance among patients with different renal functions estimated by creatinine clearance. The y-axis is represented on a log2 scale both in (a) and in (b). Median and interquartile range are presented. Black circles represent outliers.

Figure 4

The PK/PD meropenem target attainment among the groups of patients stratified by different glomerular filtration and the pertinent meropenem daily dose: (a) The distribution of meropenem steady-state concentrations at the first therapeutic drug monitoring required for patients treated with meropenem. Red dotted lines represent the therapeutic range for meropenem. (b) The meropenem daily dose administered as a continuous infusion among patients with different renal functions. The y-axis is represented on a log2 scale both in (a) and in (b). Median and interquartile range are presented. Black circles represent outliers.

Figure 5

The prevalence of patients achieving the PK/PD meropenem target among different glomerular filtration classes. (a) Number of patients reporting serum meropenem concentrations under the therapeutic target concentrations (white columns), within the therapeutic range (lined columns), and over the therapeutic target concentrations (black columns). Patients were grouped according to their renal function: impaired (CLCr < 50 mL/min), normal (CLCr 50–120 mL/min), and augmented (>120 mL/min) renal function. (b) Number of patients reporting serum meropenem therapeutic concentrations (black bar) and not reporting serum meropenem therapeutic concentrations (gray bar). All patients were grouped in normal function in case of CLCr between 50 mL/min and 120 mL/min and altered in case of CLCr < 50 mL/min or > 120 mL/min. CLCr = creatinine clearance.

Figure 6

Sankey plots of pharmacological target attainment of meropenem between the first and the second therapeutic drug monitoring. Meropenem serum target concentrations: 8–16 mg/L; underexposure: <8 mg/L; overexposure: >16 mg/L.