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Repeated Piperacillin-Tazobactam Plasma Concentration Measurements in Severely Obese Versus Nonobese Critically Ill Septic Patients and the Risk of Under- and Overdosing
Jung B, Mahul M, Breilh D, et al. Crit Care Med. 2017; 45: e470-8.
Study Question: Are severely obese patients treated with continuous infusion piperacillin-tazobactam (PTZ) for severe sepsis or septic shock at higher risk for underdosing than their nonobese counterparts?
Study Description: This was a prospective, single-center study of medical-surgical critically ill adult patients treated for severe sepsis or septic shock with PTZ 4.5 g 1-hr bolus intravenous (IV) followed by a 0.75 g/hr IV continuous infusion. Nonobese patients were defined as a body mass index (BMI) <30 kg/m2, while severely obese was defined as BMI >35 kg/m2. Therapeutic drug monitoring (TDM) was completed at 12-hour increments after the initial bolus dose over a 7-day period. Total body clearance calculations and Monte Carlo simulations for three different PTZ dosing regimens were performed. The primary outcome was the steady-state pharmacokinetic parameters of piperacillin (PIP).
Results: Twelve nonobese and 11 severely obese patients were enrolled in the study. Pneumonia and peritonitis were the most common sources of sepsis, accounting for 79% of the cases. Nine patients in the cohort developed renal failure. The severely obese cohort had a statistically higher PIP clearance than the nonobese patients (23.72 ± 42.43 L/h vs. 14.27 ± 28.90 L/h; p=0.03). PIP concentrations demonstrated inter- and intra-patient variability with lower PIP levels in the severely obese (84.31 ± 47.14 mg/L vs. 140.11 ± 69.21 mg/L; p<0.01). The probability of attaining targeted minimum inhibitory concentrations (MICs) over the entire dosing interval was less likely in the severely obese. A targeted MIC of 16 mg/L or less was consistently achieved with the continuous PTZ 18 g/24 h infusion in both groups; however, the probability of attainment in severely obese patients dropped to 91% and 44% when the targeted MIC was 32 mg/L or 64 mg/L, respectively, compared to 100% and 44% in the nonobese patients.
Conclusion(s): Severely obese patients, treated with continuous PTZ for severe sepsis or septic shock, are at higher risk for underdosing than their nonobese counterparts.
Perspective: The findings from this study emphasize the variability in achieving satisfactory PTZ serum concentrations in this population. Altered volume of distribution and renal clearance of drug from multiple factors including sepsis, complications of sepsis and obesity play a role. Initiating appropriate antimicrobial therapy quickly and maximizing PIP concentrations above MICs are important to optimize clinical outcomes in severe sepsis and septic shock. PIP TDM (if available) may be necessary to ensure adequate PIP plasma concentrations are achieved in severely obese patients, while staying below the toxic threshold of 150 mg/L. Understanding of the clinical outcomes of these patients would also be beneficial in tailoring dosing recommendations to BMI.