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. 2020 Dec 21;9(12):931.
doi: 10.3390/antibiotics9120931.

Meropenem Plasma and Interstitial Soft Tissue Concentrations in Obese and Nonobese Patients-A Controlled Clinical Trial

Philipp Simon  1   2 , David Petroff  2   3 , David Busse  4   5 , Jana Heyne  1 , Felix Girrbach  1 , Arne Dietrich  2   6 , Alexander Kratzer  7 , Markus Zeitlinger  8 , Charlotte Kloft  4 , Frieder Kees  9 , Hermann Wrigge  1   2   10 , Christoph Dorn  7
Affiliations

Meropenem Plasma and Interstitial Soft Tissue Concentrations in Obese and Nonobese Patients-A Controlled Clinical Trial

Philipp Simon et al. Antibiotics (Basel). .

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.

Keywords: antibiotic dosing; concentrations; meropenem; microdialysis; obesity; pharmacodynamics; pharmacokinetics; soft tissue.

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Conflict of interest statement

H.W. received grants from Pfizer (Investigator Initiated Trial Program, Berlin, Germany) and InfectoPharm (Heppenheim, Germany), both for the clinical microdialysis trial. H.W. reports lecture fees from InfectoPharm (Heppenheim, Germany), MSD (Konstanz, Germany) and consultant honoraria from Dräger Medical (Lübeck, Germany). P.S. reports lecture fees from InfectoPharm (Heppenheim, Germany). C.K. reports grants from an industry consortium (AbbVie Deutschland GmbH & Co. KG, AstraZeneca GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Grünenthal GmbH, F. Hoffmann-La Roche Ltd., Merck KGaA and SANOFI) for the PharMetrX program, grants for the Innovative Medicines Initiative-Joint Undertaking (“DDMoRe”), Diurnal Ltd., the Federal Ministry of Education and Research within the Joint Programming Initiative on Antimicrobial Resistance Initiative (JPIAMR) and from the European Commission within in the Horizon 2020 framework programme (“FAIR”). M.Z. received funding for other investigator initiated trials from Pfizer (Wien, Austria). The other authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
CONSORT flow diagram. BMI = body mass index.
Figure 2
Figure 2
Semilogarithmic concentration–time course (mean and SD) of meropenem in the plasma and interstitial fluid of subcutaneous tissue in obese or nonobese surgical patients following an intravenous infusion of 1 g of meropenem. The dotted line indicates the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints for Pseudomonas aeruginosa and Enterobacteriaceae. ISF: interstitial fluid.
Figure 3
Figure 3
Correlation of the volume of distribution at the steady state (Vss) with the total body weight.
See this image and copyright information in PMC

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