Yersultan Mirasbekov 1,2, Davide Bindellini 1,2, Stefanie Nothofer 3, Philipp Simon 3,4, Robin Michelet 1, Christoph Dorn 5, Markus Zeitlinger 6, Hermann Wrigge 7, Wilhelm Huisinga 2,8, Charlotte Kloft 1,2
1 Freie Universität Berlin (Berlin, Germany), 2 Graduate Research Training Programme, PharMetrX (Berlin, Germany), 3 Anesthesiology and Intensive Care, Faculty of Medicine, University of Augsburg (Augsburg, Germany), 4 Germany and Integrated Research and Treatment Center (IFB), Adiposity Diseases, University of Leipzig (Leipzig, Germany), 5 Department of Pharmaceutical an Medicinal Chemistry, University of Regensburg (Regensburg, Germany), 6 Department of Clinical Pharmacology, Medical University of Vienna (Vienna, Austria), 7 Department of Anaesthesiology, Intensive Care and Emergency Medicine, Pain Therapy, Bergmannstrost Hospital Halle (, Germany), 8 Institute of Mathematics, University of Potsdam (Potsdam, Germany)
Introduction:
To prevent surgical site infections (SSI) caused by anaerobic bacteria, thus optimising perioperative care, a flat dose of 500 mg of metronidazole is administered intravenously before intra-abdominal surgery [1,2]. Obese patients are at a higher risk of developing SSIs, yet current metronidazole dosing recommendations lack evidence on whether dose adjustment is needed for obese patients [3,4]. As exposure in plasma and the target-site (in this case, interstitial fluid, ISF) may differ in obese compared to nonobese patients, this study aimed to evaluate the need for dose adjustments in obese patients using model-based analysis of metronidazole pharmacokinetics (PK).
Methods:
The clinical trial included 15 obese (BMI in the range of 39.5-69.3 kg/m²) and 15 nonobese (18.7-29.8 kg/m²) patients [2,5]. All patients received a single 30-minute intravenous infusion of 500 mg metronidazole. Drug concentrations were measured in plasma (n_total=240; n_unbound=124) and ISF (n=572, 2 catheters/patient) for up to 8 hours post-dose. ISF concentrations were obtained via microdialysis, followed by a retrodialysis calibration (n=104) to calculate the relative recovery [6]. Using nonlinear mixed-effects modelling, various compartmental PK models were compared, with log-normally distributed IIV tested on all structural parameters. The interindividual differences were examined via stepwise covariate model-building (SCM+) using various body size descriptors, such as BMI and lean body weight (LBW) [7,8]. Model performance was evaluated based on OFV/AIC metrics, precision of parameter estimates, GOF and VPC plots.
The developed PK model was applied to simulate scenarios of a 30-minute intravenous infusion of a standard (500 mg) and a high (1500 mg) dose in obese and nonobese reference patients. The probability of target attainment (PTA; threshold of 90%) was calculated based on PK/PD index of the percentage of time that unbound concentrations were above the minimum inhibitory concentration (MIC) within 8h (target: fT>MIC,0-8h=100%). These results were weighted against MIC distribution of Bacteroides fragilis, the most common anaerobic pathogen in SSIs, to obtain a cumulative fraction of response (CFR; threshold of 90%) analysis [9].
Results:
The concentration-time profiles of metronidazole were best described by a two-compartment model characterized by first-order elimination, linear plasma protein binding, and rapid, extensive distribution. The typical parameter values (CV%; IIV) were CL=4.49 L/h (29.4%), Vc=14.6 L (35%), Q=160 L/h (69.4%), Vp=52.2 L (13.7%) and fu=93.2%. Microdialysis measurements were connected to the peripheral compartment using tissue factor of 80.9% (43.4%; IIV) and relative recovery (RR) of 43.8% (90.8%; inter-catheter variability). Proportional RUV models were used for plasma (6.14%), microdialysis (21.2%) and retrodialysis (35.3%) measurements. BMI and LBW were identified to influence Vc and Vp parameters, respectively, via linear (slope of 0.033 m²/kg) and power (exponent of 0.827) relationships. LBW was also found to have a significant effect on RR (power relationship, exponent of −0.911). Parameters were precisely estimated, with RSE of 0.756-20.7%. GOF and VPC plots showed good agreement between model predictions and observations.
Concentration-time profiles of unbound metronidazole in plasma and ISF were simulated for typical obese (BMI, 52.6 kg/m²; LBW, 69.4 kg) and nonobese (26.0 kg/m²; 45.6 kg) patients. Based on unbound plasma exposure, the standard dose achieved adequate PTA for MIC ≤2 mg/L. While the PTA reduced at MIC of 4 mg/L (10.3% and 60.8% for obese and nonobese patients, respectively), CFR remained at 94.1% and 97.0%, indicating a favourable prophylactic target attainment. Contrarily, PTA at the target-site (ISF) was significantly lower. The standard dose was only adequate for highly susceptible strains (MIC ≤0.25 mg/L for obese; ≤0.5 mg/L for nonobese), causing CFR to drop below the threshold for both groups. Simulation results of the high dosing showed increased chances of prophylaxis at the target-site, raising CFR to 62.9% and 87.9% for obese and nonobese reference patients, respectively.
Conclusion:
A model was developed to describe metronidazole PK in plasma and target-site to evaluate standard and high-dose regimens in obese and nonobese populations. While standard dosing appeared sufficient based on unbound plasma concentrations, ISF analysis revealed a significant risk of surgical antibiotic prophylaxis, particularly in obese patients, where drug exposure at the infection site is substantially reduced. Therefore, the current metronidazole dosage may be insufficient to achieve ISF exposure needed to prevent SSIs caused by Bacteroides fragilis. These findings suggest that alternative dosing regimens might be necessary, and further investigation is required to establish clinical recommendations.
References:
References:
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Reference: PAGE 34 (2026) Abstr 11882 [www.page-meeting.org/?abstract=11882]
Poster: Drug/Disease Modelling - Infection