No abstract

The study objective was to evaluate the population pharmacokinetics and pharmacodynamics of piperacillin and tazobactam administered by prolonged infusion in obese and nonobese patients. Twenty-seven patients (total body weight [TBW], 60 to 211 kg; body mass index [BMI], 19.6 to 72.9 kg/m(2) ) received 4.5 or 6.75 g every 8 hours, infused over 4 hours, and serum concentrations were measured at steady state. Population pharmacokinetic parameters were estimated using NONMEM, and Monte Carlo simulations were performed for three 4-hour dosing regimens to calculate probability of target attainment (PTA) at ≥50% fT>MIC.A 1-compartment linear-elimination model best fit the pharmacokinetic data for piperacillin and tazobactam. Creatinine clearance (CRCL), TBW, and BMI were significantly associated with piperacillin pharmacokinetics, and CRCL was significantly associated with tazobactam pharmacokinetics. Clearance and volume of distribution for piperacillin and tazobactam were significantly different between obese and nonobese patients (P < .05). At MICs ≤ 16 mg/L, PTA was >90% for dosing regimens ≥3.375 g every 8 hours in nonobese patients and ≥ 4.5 g every 8 hours in obese patients. Piperacillin and tazobactam pharmacokinetics are altered in obesity, and 4.5 g every 8 hours infused over 4 hours should be recommended for empiric therapy in obese patients.

The study objective was to evaluate meropenem pharmacokinetics and pharmacodynamics in morbid obesity. Nine patients hospitalized in an intensive care unit with a body mass index ≥40 kg/m(2) received meropenem 500 mg or 1 g q6h, infused over 0.5 hours. Pharmacokinetic parameters were estimated, and Monte Carlo simulations were performed for 5 dosing regimens (500 mg q8h, 1 g q8h, 2 g q8h, 500 mg q6h, 1 g q6h) infused over 0.5 and 3 hours. Probability of target attainment (PTA) was calculated using fT > MIC of 40% and 54%. Total body weight and body mass index were 152.3 ± 31.0 kg and 54.7 ± 8.6 kg/m(2) , respectively. Volume of distribution of the central compartment was 13.3 ± 6.7 L, volume of distribution at steady-state was 37.4 ± 14.7 L, and systemic clearance was 10.2 ± 5.0 L/h. At an MIC of 2 µg/mL, PTA was ≥90% for 4/5 and 2/5 regimens infused over 0.5 hours and for 5/5 and 4/5 regimens infused over 3 hours at 40% and 54% fT > MIC, respectively. Standard doses achieve adequate exposures for susceptible bacteria at a pharmacodynamic target of 40% fT > MIC. Higher doses or prolonged infusion regimens are needed at the higher pharmacodynamic target.

The study objective was to evaluate meropenem population pharmacokinetics and pharmacodynamics in nonobese, obese, and morbidly obese patients. Forty adult patients-11 nonobese (body mass index [BMI] < 30 kg/m ), 9 obese (30 kg/m ≤ BMI < 40 kg/m ), and 20 morbidly obese (BMI ≥ 40 kg/m )-received meropenem 500 mg every 6 hours (q6h), q8h, or q12h or 1 g q6h or q8h, infused over 0.5 hour. Population pharmacokinetic modeling was performed using NONMEM, and 5000-patient Monte-Carlo simulations were performed to calculate probability of target attainment (PTA) for 5 dosing regimens, infused over 0.5 and 3 hours, using fT>MIC of 40%, 54%, and 100% of the dosing interval. A 2-compartment linear-elimination model best described the serum concentration-time data, and creatinine clearance was significantly associated with systemic clearance. Pharmacokinetic parameters were not significantly different among patient groups. In patients with creatinine clearances ≥50 mL/min, all simulated dosing regimens achieved >90% PTA at 40% fT>MIC in all patient groups at MICs ≤2 mg/L. Only 500 mg q8h, infused over 0.5 hour, did not achieve >90% PTA at 54% fT>MIC in nonobese and morbidly obese patients. At 100% fT>MIC, 1 g q6h and 2 g q8h, infused over 3 hours, reliably achieved >90% PTA in all patient groups. Meropenem pharmacokinetics are comparable among nonobese, obese, and morbidly obese patients. Standard dosing regimens provide adequate pharmacodynamic exposures for susceptible pathogens at 40% and 54% fT>MIC, but prolonged infusions of larger doses are needed for adequate exposures at 100% fT>MIC. Dosage adjustments based solely on body weight are unnecessary.

Doripenem and meropenem pharmacokinetics differ in obesity. However, currently approved dosing regimens provide adequate pharmacodynamic exposures for susceptible bacteria in obese patients.