Abstract
Background: This controlled clinical study aimed to investigate the impact of obesity on plasma and tissue pharmacokinetics of meropenem. Methods: Obese (body mass index (BMI) ≥ 35 kg/m2) and age-/sex-matched nonobese (18.5 kg/m2 ≥ BMI ≤ 30 kg/m2) surgical patients received a short-term infusion of 1000-mg meropenem. Concentrations were determined via high performance liquid chromatography-ultraviolet (HPLC-UV) in the plasma and microdialysate from the interstitial fluid (ISF) of subcutaneous tissue up to eight h after dosing. An analysis was performed in the plasma and ISF by noncompartmental methods. Results: The maximum plasma concentrations in 15 obese (BMI 49 ± 11 kg/m2) and 15 nonobese (BMI 24 ± 2 kg/m2) patients were 54.0 vs. 63.9 mg/L (95% CI for difference: −18.3 to −3.5). The volume of distribution was 22.4 vs. 17.6 L, (2.6–9.1), but the clearance was comparable (12.5 vs. 11.1 L/h, −1.4 to 3.1), leading to a longer half-life (1.52 vs. 1.31 h, 0.05–0.37) and fairly similar area under the curve (AUC)8h (78.7 vs. 89.2 mg*h/L, −21.4 to 8.6). In the ISF, the maximum concentrations differed significantly (12.6 vs. 18.6 L, −16.8 to −0.8) but not the AUC8h (28.5 vs. 42.0 mg*h/L, −33.9 to 5.4). Time above the MIC (T > MIC) in the plasma and ISF did not differ significantly for MICs of 0.25–8 mg/L. Conclusions: In morbidly obese patients, meropenem has lower maximum concentrations and higher volumes of distribution. However, due to the slightly longer half-life, obesity has no influence on the T > MIC, so dose adjustments for obesity seem unnecessary.
Highlights
Meropenem is a carbapenem with a broad spectrum of activity against Gram-positive andGram-negative bacteria, including multiresistant pathogens, and is recommended for the calculated therapy of patients with sepsis [1,2]
We studied obese and nonobese patients undergoing elective abdominal surgery in a controlled setting, measuring meropenem concentrations in the plasma, as well as in subcutaneous tissue, via microdialysis
Fifteen obese patients scheduled for bariatric surgery and 15 nonobese patients undergoing elective abdominal surgery, mainly tumour resection (11 patients underwent gynaecological operations, and the remaining four operations involved the stomach, liver, kidneys or appendix), were included in the study
Summary
Meropenem is a carbapenem with a broad spectrum of activity against Gram-positive andGram-negative bacteria, including multiresistant pathogens, and is recommended for the calculated therapy of patients with sepsis [1,2]. Recommended daily doses of antibiotics are based on pharmacokinetic (PK) studies performed almost exclusively in nonobese patients [5]. Data to characterize the pharmacokinetics (PK) in obese compared with nonobese patients are increasingly important to assess whether effective meropenem concentrations are reached in this growing population. Recent studies indicate that the current standard dosage of meropenem in obese patients is sufficient [6,7,8], and there are no recommendations for weight-dependent dosing [9]. This controlled clinical study aimed to investigate the impact of obesity on plasma and tissue pharmacokinetics of meropenem. The volume of distribution was 22.4 vs. 17.6 L, (2.6–9.1), but the clearance was comparable (12.5 vs. 11.1 L/h, −1.4 to 3.1), leading to a longer half-life (1.52 vs. 1.31 h, 0.05–0.37) and fairly similar area under the curve (AUC)8h (78.7 vs. 89.2 mg·h/L, −21.4 to 8.6)
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