PK of antimicrobials in obese critically ill

17 May 2018

 

We are pleased to have completed a multi-centre Project 8 within the CRE REDUCE plan on the topic of antibiotic dosing in obese critically ill patients. The project was run by Prof Jason Roberts, Prof Jeffrey Lipman, Assoc Prof Sandra Peake and Assoc Prof Andrew Udy who supervised a PhD at the University of Queensland, by Dr Abdulaziz Alobaid. As part of his PhD, Dr Alobaid published three original research articles, one retrospective study and one overview article. Please access the details of these publications here.

The background for this topic is that the increasing numbers of critically ill obese patients in the intensive care unit (ICU) and the high frequency of antimicrobial prescription in these patients present a challenge for prescribing effective antimicrobial doses. Critically ill obese patients have greater infection-related morbidity and mortality than their non-obese counterparts. The underlying explanation for these inferior outcomes remains unclear, although sub-optimal antimicrobial dosing may be a contributing factor. Unfortunately, there is a paucity of research and no recognised guidelines to assist clinicians with dosing antimicrobials in these patients who commonly develop dramatic physiological changes that can lead to significantly altered drug concentrations, and therefore, sub-optimal treatment.

In Project 8, we investigated the effect of obesity on trough concentrations and achievement of target exposures for piperacillin and meropenem in 1400 obese and non-obese critically ill patients. We found that piperacillin concentrations were significantly affected by the presence of obesity, with no significant differences evident for meropenem.

To further explore the effect of obesity using a more descriptive approach, prospective pharmacokinetic studies were conducted with piperacillin/ tazobactam (n=37), meropenem (n=19) and fluconazole (n=21) in critically ill patients across different body mass index (BMI) classifications including non-obese (BMI 18.5 - 29.9 kg/m2), obese (BMI 30 - 39.9 kg/m2), and morbidly-obese (BMI ≥ 40 kg/m2. Using a population pharmacokinetic modelling approach, it was concluded that BMI only had a small effect on antimicrobial volume of distribution, whilst measured creatinine clearance had a significant effect on drug clearance. Using Monte Carlo dosing simulations, it was concluded that dose adjustment based on renal function (i.e. measured creatinine clearance) was the most important factor to be considered by clinicians for effective dosing in both obese and non-obese critically ill patients. For fluconazole, weight-based dosing was found to be most appropriate for achieving therapeutic drug exposures.

The overall results of Project 8 suggest that the weight or BMI do not have profound effects on antimicrobial dosing requirements for critically ill obese patients. Renal function was the major determinant of dosing requirements in individual patients. It can be concluded that although a higher than standard dose may be appropriate for the first 24-h of treatment, on subsequent days, dosing need only be based on robust estimates of renal function.

We are grateful for funding support provided by the National Health and Medical Research Council as well as the Royal Brisbane and Women’s Hospital Foundation and the University of Queensland.

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