piperacillin--tazobactam-drug-combination and Obesity--Morbid

To evaluate the steady-state pharmacokinetic and pharmacodynamic parameters of piperacillin in morbidly obese, surgical intensive care patients.. Open-label single-center prospective study.. Level I trauma center and university-affiliated teaching institution.. Nine morbidly obese (body mass index [BMI] 40.0 kg/m² or higher) hospitalized patients admitted to the trauma and surgical intensive care service who were treated with piperacillin-tazobactam between December 15, 2010, and April 18, 2012.. Patients received intravenous piperacillin-tazobactam 4.5 g every 6 hours, administered as a 30-minute infusion.. Patients' blood samples were collected after the administration of the fourth, fifth, or sixth dose (i.e., at steady state). Serum piperacillin concentrations were determined by using a validated high-performance liquid chromatography assay; these concentrations were used to estimate pharmacokinetic parameters, and 5000-patient Monte Carlo simulations were performed. The probability of target attainment for 50% or higher of the dosing interval during which free (unbound) drug concentrations exceeded the minimum inhibitory concentration (%fT > MIC) of likely pathogens was calculated for piperacillin at various MICs. Patient demographic and clinical characteristics included a mean ± SD total body weight of 164 ± 50 kg, BMI of 57 ± 15.3 kg/m², and age 57 ± 11 years, and a median Acute Physiology and Chronic Health Evaluation II score of 22 (interquartile range 21-26). Compared with values previously reported in other populations, the volume of distribution was increased in the study patients, and total system clearance was decreased. The net result was a mean ± SD half-life of 3.7 ± 1.2 hours compared with ~1 hour reported in other populations. This contributed to an extended %fT > MIC for likely pathogens. Results from all nine patients showed %fT > MIC of 100% at the susceptibility breakpoint MIC of 16 mg/L and 85% or higher at an MIC of 32 mg/L.. The pharmacokinetics of piperacillin is altered in morbidly obese, surgical intensive care patients. The use of standard-dosage piperacillin-tazobactam 4.5 g intravenously every 6 hours was shown to be an appropriate dosage for this study population.

Topics: Aged; Anti-Bacterial Agents; Critical Illness; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Obesity, Morbid; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prospective Studies

Topics: Abscess; Anti-Bacterial Agents; Debridement; Diabetes Mellitus, Type 2; Disease Susceptibility; Empyema, Pleural; Hematoma; Humans; Male; Middle Aged; Obesity, Morbid; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pleural Effusion; Smoking; Streptococcal Infections; Streptococcus agalactiae; Thoracic Injuries; Wound Infection; Wounds, Nonpenetrating

Complicated intra-abdominal infections (cIAI) are a common problem in surgical practice. The effect of body mass index (BMI) on the outcome is poorly understood. We compared the association of BMI and type of antibiotic therapy for cIAI described in a previously published trial of ertapenem vs. piperacillin-tazobactam (Namias N, Solomkin JS, Jensen EH, et al. Randomized, multicenter, double-blind study of efficacy, safety, and tolerability of intravenous ertapenem versus piperacillin/tazobactam in treatment of complicated intra-abdominal infections in hospitalized adults. Surg Infect 2007;8:15-28).. A post-hoc analysis was performed using data obtained from the published study. The effect of BMI and type of antibiotic used for therapy were calculated for clinically favorable outcomes at early follow-up assessment (EFA).. The 231 patients who were microbiologically evaluable at EFA were stratified by BMI (<30 or ≥30 kg/m(2)). Twelve patients were excluded because of missing BMI data, leaving 219 patients for analysis. There were some differences in baseline characteristics between patients with a BMI <30 kg/m(2), including the source of intra-abdominal infection (more appendicitis in BMI <30 group; p=0.01) and gender (more men in the BMI <30 group; p=0.03). There was no difference in cure rates between the groups (82.9% for BMI <30 kg/m(2) vs. 74.5% for those with BMI ≥30 kg/m(2); 8% difference in proportions, 95% confidence interval [CI] -5%, 25%). There was an 80% favorable clinical response to ertapenem in the BMI <30 group compared with an 81% favorable rate in the BMI ≥30 group (-1% difference in proportions; 95% CI -22%, 19%). This compared with an 86% favorable response rate to piperacillin-tazobactam in the BMI <30 group vs. a 65% favorable clinical response rate in the BMI ≥30 group (21% difference in proportions; 95% CI -1%, 47%).. There was no difference in the cure rate of patients with cIAI in the BMI <30 and BMI ≥30 kg/m(2) groups. There were no statistically significant differences in the likelihood of response to an antibiotic regimen. However, there was a nominally 21% lower cure rate in the high BMI group receiving piperacillin-tazobactam (86% vs. 65%; 21% difference in proportions; 95% CI -1%, 47%), whereas there was only a 1% difference in the cure rate between BMI groups in the patients receiving ertapenem. This difference may be related to gender and etiology of infection. Although limited by the small number of high BMI patients and post-hoc methodology, these results merit consideration of the design of future prospective antibiotic trials to include stratification for BMI and consideration of the effect of BMI on pharmacokinetics and pharmacodynamics.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; beta-Lactams; Body Mass Index; Ertapenem; Female; Humans; Intraabdominal Infections; Male; Middle Aged; Multicenter Studies as Topic; Obesity, Morbid; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Randomized Controlled Trials as Topic; Young Adult