An investigation of the pharmacokinetics of piperacillin, meropenem and fluconazole in critically ill obese patients

Abstract

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. Critical illness pathologies, such as sepsis and septic shock are reported to alter the pharmacokinetics of many antimicrobials, including piperacillin, meropenem and fluconazole. Along with the alterations in the pharmacokinetics of these agents caused by obesity, sub-therapeutic concentrations of these drugs are likely in critically ill obese patients. This Thesis addresses the limitations of current knowledge by describing the plasma pharmacokinetics of piperacillin, meropenem and fluconazole in critically ill non-obese, obese and morbidly obese patients. The Thesis then provides dosing recommendations which can be used for more effective antibiotic dosing. Firstly a structured review of the effect of obesity on the pharmacokinetics of antimicrobials in critically ill patients was performed. The review concluded that the presence of obesity augments the pharmacokinetic changes of antimicrobials in critical illness. Furthermore, this chapter also provides suggested dosing regimens for use in critically ill obese patients based on the published literature. To investigate the effect of obesity on antimicrobial trough concentrations and achievement of target exposures in obese and non-obese critically ill patients, a large retrospective study (n = 1400) of therapeutic drug monitoring data of piperacillin and meropenem was performed. This study 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). The included patients had widely varying BMIs, but typical age and sex distributions as encountered in ICUs. 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 this Thesis suggest that the BMI does not have a profound effect on antimicrobial dosing requirements for critically ill obese patients. Renal function, which was best described by creatinine clearance, 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.