Please cite this article in press as: Alobaid AS, et al. Effect of obesity on the pharmacokinetics of antimicrobials in critically ill patients: A structured review. Int J Antimicrob Agents (2016), http://dx.doi.org/10.1016/j.ijantimicag.2016.01.009 ARTICLE IN PRESS G Model ANTAGE-4748; No. of Pages 10 International Journal of Antimicrobial Agents xxx (2016) xxx–xxx Contents lists available at ScienceDirect International Journal of Antimicrobial Agents j o ur nal ho me pag e: http://www.elsevier.com/locate/ijantimicag Review Effect of obesity on the pharmacokinetics of antimicrobials in critically ill patients: A structured review Abdulaziz S. Alobaid a , Maya Hites b , Jeffrey Lipman a,c , Fabio Silvio Taccone d , Jason A. Roberts a,c,e,∗ a Burns, Trauma & Critical Care Research Centre, The University of Queensland, Brisbane, QLD, Australia b Department of Infectious Diseases, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium c Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia d Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium e School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia a r t i c l e i n f o Article history: Received 20 November 2015 Accepted 22 January 2016 Keywords: Antifungal Fluconazole Pharmacodynamics Non-obese patients Obesity Morbidly obese patients a b s t r a c t The increased prevalence of obesity presents challenges for clinicians aiming to provide optimised antimi- crobial dosing in the intensive care unit. Obesity is likely to exacerbate the alterations to antimicrobial pharmacokinetics when the chronic diseases associated with obesity exist with the acute pathophys- iological changes associated with critical illness. The purpose of this paper is to review the potential pharmacokinetic (PK) changes of antimicrobials in obese critically ill patients and the implications for appropriate dosing. We found that hydrophilic antimicrobials (e.g. -lactams, vancomycin, daptomycin) were more likely to manifest altered pharmacokinetics in critically ill patients who are obese. In par- ticular for -lactam antibiotics, obesity is associated with a larger volume of distribution (V d ). In obese critically ill patients, piperacillin is also associated with a lower drug clearance (CL). For doripenem, these PK changes have been associated with reduced achievement of pharmacodynamic (PD) targets when standard drug doses are used. For vancomycin, increases in V d are associated with increasing total body weight (TBW), meaning that the loading dose should be based on TBW even in obese patients. For daptomycin, an increased V d is not considered to be clinically relevant. For antifungals, little data exist in obese critically ill patients; during fluconazole therapy, an obese patient had a lower V d and higher CL than non-obese comparators. Overall, most studies suggested that standard dosage regimens of most commonly used antimicrobials are sufficient to achieve PD targets. However, it is likely that larger doses would be required for pathogens with higher minimum inhibitory concentrations. © 2016 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. 1. Introduction Obesity is a growing public health concern and is associated with increased morbidity and mortality compared with non-obese indi- viduals [1–3]. Obesity is a well known risk factor for community- and hospital-acquired infections as well as hospital and inten- sive care unit (ICU) admission [4–6]. Critically ill obese patients in particular are at a higher risk of infection and commonly require antimicrobial therapy [7,8]. However, delivering optimal antimi- crobial therapy in this population is considered to be a great challenge. To date, there are few studies summarising the published ∗ Corresponding author. Present address: Burns, Trauma & Critical Care Research Centre, The University of Queensland, Level 3 Ned Hanlon Building, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia. Tel.: +61 736464108. E-mail address: j.roberts2@uq.edu.au (J.A. Roberts). data and providing clinical guidance for effective dosing in these patients. Understanding antimicrobial pharmacokinetic (PK) behaviour is crucial to optimise antimicrobial therapy for critically ill obese patients. However, antimicrobial pharmacokinetics is often altered by the pathophysiology associated with critical illness [9,10] and may be further changed in the presence of obesity. Both antimicro- bial volume of distribution (V d ) and clearance (CL) can be highly variable in critically ill and obese patients [11,12]. Standard dosage regimens of antimicrobials, particularly those that are mainly elim- inated through the kidneys, may result in fluctuations of plasma concentrations in critically ill patients that may require dosing regimen adjustments to ensure optimal antimicrobial concentra- tions are achieved [13]. Optimised antimicrobial dosing in the ICU requires an understanding of antimicrobial pharmacokinet- ics/pharmacodynamics and possible PK changes caused by critical illness. http://dx.doi.org/10.1016/j.ijantimicag.2016.01.009 0924-8579/© 2016 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.