Evaluation of the Dialytic Clearance of the Combination of Peracillin and Tazobactam

Overview

Severe bacterial infections, often responsible for sepsis and septic shock, are a major challenge in critical care: approximately 50% of patients are affected, with a mortality rate of up to 40%. Their initial management consists of antibiotic therapy with an adapted spectrum of activity and dose. One of the most widely used antibiotic therapies in intensive care is the piperacillin-tazobactam (pip-taz) combination, a beta-lactam combined with a beta-lactamase inhibitor, which is indicated probabilistically in many infections (pneumopathies, intra-abdominal infections, urinary tract infections, etc.). Mortality rates of up to 40%. Their initial management consists of antibiotic therapy with an appropriate spectrum of activity and dose. One of the most widely used antibiotic therapies in intensive care is the piperacillin-tazobactam (pip-taz) combination, a beta-lactam combined with a beta-lactamase inhibitor, which is indicated probabilistically in many infections (pneumonia, intra-abdominal infections, urinary tract infections, etc.). Intensive care patients with septic shock exhibit specific pharmacokinetics with an increased volume of distribution, notably due to significant capillary leakage, often disrupted hepatic metabolism, possible hypoalbuminemia, the presence of renal hyperclearance in the initial phase or conversely, the onset of renal failure with altered glomerular filtration rate, sometimes leading to extrarenal clearance, changes that have consequences for the efficacy and toxicity of the administered antibiotic therapy. Sepsis itself also causes renal dysfunction, with the main pathophysiological hypotheses being an alteration of microcirculation, cellular metabolic reprogramming, and deregulation of the inflammatory response. It is therefore essential to focus on the dosages administered and the pharmacokinetics of these patients. Indeed, underdosing is associated with the emergence of resistance and a poorer prognosis in intensive care patients: increased risk of treatment failure, length of stay and mortality. Conversely, significant overdoses can be associated with a poorer renal prognosis, seizures, encephalopathy which can lead to delayed awakening, prolonged duration of mechanical ventilation and intensive care stay.

Pip-taz is administered intravenously due to non-absorption via the oral route. It is weakly bound to plasma proteins (21%), inducing good clearance of extrarenal clearance (fraction extracted in 4 hours: 23.6% of the administered dose). Its plasma half-life is 60 minutes. This molecule is not metabolized, and is therefore independent of liver function. It is eliminated mainly in active form in the urine (65%) and bile (35%). Thus, the main determinant of pip-taz clearance is renal clearance, or continuous extrarenal clearance (CER) in dialysis patients in intensive care. Pip-taz is characterized by time-dependent pharmacodynamics, with better coverage with continuous infusions compared to discontinuous infusions. However, there is no well-defined pattern in patients undergoing continuous extra-renal purification. Despite recommendations regarding antibiotic dosages for use in intensive care, the lack of data regarding patients undergoing continuous renal replacement therapy (CRRE) remains a major and complex problem in optimizing treatment, as these patients present with unique pharmacokinetics, with an increased risk of treatment failure and mortality. Furthermore, there has been a change in practices in recent years, with pip-taz being administered by continuous infusion and increasingly less by discontinuous infusion, in accordance with the latest recommendations. To our knowledge, few studies have examined the pharmacokinetics of the pip-taz combination in patients undergoing cCRRE in intensive care. Most of these rare studies did not use standard pip-taz dosages, did not examine the clinical and biological variables influencing pip-taz clearance, and none have examined the impact of any preserved diuresis. Furthermore, there are no data on the kinetics of tazobactam in this population. It therefore seems relevant, given the frequent use of this antibiotic therapy in patients undergoing cERE, to accurately assess the clearance of piperacillin and tazobactam in this population. From a precision medicine perspective, these data could contribute to the construction of a pharmacokinetic model using a population approach, based on blood, urine, and effluent samples, in order to provide a tool to assist in the prescription of this antibiotic therapy in intensive care to reduce iatrogenicity and optimize its effectiveness.