Guiva Annane1,2, Benoit Crevier3, Amélie Marsot1,2,4
1Laboratoire STP², Faculté de Pharmacie, Université de Montréal, 2Faculté de Pharmacie, Université de Montréal, 3CISSS de la Montérégie-Centre, Hôpital Charles-Le Moyne, 4CHU Sainte-Justine
Introduction/Objectives: Obesity is an urgent global health issue due to its strong association with chronic diseases such as diabetes, cardiovascular disorders, and metabolic syndrome [1, 2]. This condition is characterized by a body mass index (BMI) of 30 kg/m² or higher, a measure of excess body fat, such as the waist circumference, and the presence of symptoms of organ dysfunction [3]. Physiological changes in obese patients can also increase the risk of infections in this population [4]. Furthermore, obesity significantly alters drug pharmacokinetics (PK). This represents a challenge for clinicians, as suboptimal antibiotic dosing can lead to treatment failure, increased toxicity, and the emergence of antibiotic resistance [5, 6]. ß-lactam antibiotics, used in the treatment of gram-positive and gram-negative bacteria, rely on precise dosing regimens to maintain therapeutic efficacy [7]. However, pharmacokinetic data specific to obesity are limited, as this population is often under-represented in clinical studies [5, 8]. Considering that standard dosing strategies may not be adequate, special attention is required on obesity-related physiological and pharmacokinetic variations [5]. Population pharmacokinetic (popPK) modeling provides insights into drug behavior by accounting for inter-individual variability (IIV) and significant covariates. This review aims to synthesize popPK models for ß-lactam antibiotics prescribed in obese patients to identify significant covariates, current dosing strategies and the variability influencing therapeutic responses. Methods: A literature search was conducted using the MEDLINE, EMBASE, and PubMed databases from inception to February 2025. The search strategy incorporated a combination of keywords including ‘antibacterial agents’, ‘antiinfective agents’, ‘beta-lactams’ ‘obesity’, and ‘population pharmacokinetics’. The citations were also screened to identify and include additional relevant studies. Articles were selected based on predefined inclusion and exclusion criteria. Data extracted from each study included the dosing regimen, population characteristics, pharmacokinetic model parameters and structures, covariates and dosing recommendations. Results: A total of 22 studies met the selection criteria and were included in this review. These studies evaluated different subclasses of ß-lactam antibiotics such as penicillins (amoxicillin/clavulanic acid, piperacillin and piperacillin-tazobactam), cephalosporins (cefazolin, cefoxitin and ceftaroline) and carbapenems (doripenem, ertapenem and meropenem). One-, two- and three-compartment models were used to describe the PK of various ß-lactams. A few studies have used four- and five-compartment models to describe the PK of interstitial space fluid, peritoneal fluid or drug metabolite. The overall estimated clearance (CL) for all ß-lactams ranged from 1.79 to 32.4 L/h. As for central volume of distribution (Vd), the estimates (range) were 20.9 (8.25–49) L, 11.8 (5.2–25.1) L and 13.75 L (4.76–40) L for penicillins, cephalosporins and carbapenems, respectively. Key findings from these studies indicated that creatinine clearance and weight descriptors, such as total body weight (TBW) and BMI, were the most frequently identified covariates influencing ß-lactam pharmacokinetics. Other studies have used allometric scaling based on fat-free mass (FFM) instead of usual covariates. IIV was expressed with exponential models in all the articles. The IIV for CL ranged from 9.57 % to 72.14 %. As for Vd, the IIV ranged from 7.92 % to 79.36 %. Several studies suggested that standard dosing regimens may not achieve optimal pharmacodynamic (PD) targets in obese patients. And simulations showed that continuous or extended infusions allow for better attainment of PD targets. Conclusions: This review highlights the key aspects of popPK models in obese populations treated with ß-lactams. Despite the growing prevalence of obesity, there remains no universally accepted dosing strategy for this population, highlighting the challenges in optimizing ß-lactam therapy in this population.
[1] Federation WO. World Obesity Atlas 2024. London: World Obesity Federation; 2024. [2] Field AE, Coakley EH, Must A, Spadano JL, Laird N, Dietz WH, et al. Impact of overweight on the risk of developing common chronic diseases during a 10-year period. Arch Intern Med. 2001;161(13):1581-6. [3] The Lancet Diabetes E. Diagnosing clinical obesity. Lancet Diabetes Endocrinol. 2025. [4] Huttunen R, Syrjanen J. Obesity and the risk and outcome of infection. Int J Obes (Lond). 2013;37(3):333-40. [5] Castro-Balado A, Varela-Rey I, Mejuto B, Mondelo-Garcia C, Zarra-Ferro I, Rodriguez-Jato T, et al. Updated antimicrobial dosing recommendations for obese patients. Antimicrob Agents Chemother. 2024;68(5):e0171923. [6] Pinner NA, Tapley NG, Barber KE, Stover KR, Wagner JL. Effect of Obesity on Clinical Failure of Patients Treated With beta-Lactams. Open Forum Infect Dis. 2021;8(8):ofab212. [7] Fratoni AJ, Nicolau DP, Kuti JL. A guide to therapeutic drug monitoring of beta-lactam antibiotics. Pharmacotherapy. 2021;41(2):220-33. [8] Smit C, De Hoogd S, Bruggemann RJM, Knibbe CAJ. Obesity and drug pharmacology: a review of the influence of obesity on pharmacokinetic and pharmacodynamic parameters. Expert Opin Drug Metab Toxicol. 2018;14(3):275-85.
Reference: PAGE 33 (2025) Abstr 11323 [www.page-meeting.org/?abstract=11323]
Poster: Methodology - Other topics