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Purpose: To evaluate the population PK/PD of piperacillin, when administered with tazobactam by prolonged infusion (PI), in morbidly obese and non-obese patients.
Methods: Serial serum piperacillin concentrations (n=197) were collected at steady-state from 13 hospitalized patients with a BMI < 40 kg/m2 who received piperacillin/tazobactam 4.5 g q8h and from 14 hospitalized patients with a BMI > 40 kg/m2 who received piperacillin/tazobactam 4.5 g or 6.75 g q8h. All doses were infused over 4 h. Population PK/PD analyses were performed using NONMEM. 5,000-patient Monte Carlo simulations were performed to estimate piperacillin PK profiles for 4 PI (4-h infusion) regimens: 3.375 g q8h, 4.5 g q8h, 6.75 g q8h, and 9.0 g q8h. Probability of target attainment (PTA) for ≥ 50% fT>MIC was calculated at MICs ranging from 1-64 μg/ml.
Results: A 1-compartment model best fit the PK data. Creatinine clearance (CRCL), total body weight (TBW), and body mass index (BMI) were the most significant covariates affecting piperacillin PK. CRCL and TBW were significantly correlated with systemic clearance, and BMI was significantly correlated with volume of distribution. For patients with BMIs < 50 kg/m2, PTA was > 90% for regimens ≥ 4.5 g q8h at MICs ≤ 16 mg/ml, but only 9.0 g q8h achieved a PTA > 90% at an MIC of 32 mg/ml. For patients with BMIs > 50 kg/m2, PTA was > 90% for regimens ≥ 6.75 g q8h at MICs ≤ 16 mg/ml; however, no regimen achieved a PTA > 90% at an MIC of 32 mg/ml.
Conclusions: Piperacillin PK is altered in morbid obesity, and larger doses should be utilized in these patients. Based on this population PK/PD analysis, patients with a BMI > 50 kg/m2 and < 50 kg/m2 should be treated empirically with 4-h infusions of 6.75 g and 4.5 g q8h, respectively.