S. Christian Cheatham

Comparative Pharmacodynamics of Intermittent and Prolonged Infusions of Piperacillin/Tazobactam Using Monte Carlo Simulations and Steady-State Pharmacokinetic Data from Hospitalized Patients

Background: Prolonging the infusion of a β-lactam antibiotic enhances the time in which unbound drug concentrations remain above the minimum inhibitory concentration (fT>MIC). Objective: To compare the pharmacodynamics of several dosing regimens of piperacillin/tazobactam administered by intermittent and prolonged infusion using pharmacokinetic data from hospitalized patients. Methods: Steady-state pharmacokinetic data were obtained from 13 patients who received piperacillin/tazobactam 4.5 g every 8 hours, infused over 4 hours. Monte Carlo simulations (10,000 pts.) were performed to calculate pharmacodynamic exposures at 50% fT>MIC for 4 intermittent-infusion regimens (3.375 g every 4 and 6 h, 4.5 g every 6 and 8 h) and 4 prolonged-infusion regimens (2.25 g, 3.375 g. 4.5 g, and 6.75 g every 8 h [4-h infusion]) of piperacillin/tazobactam using pharmacokinetic data for piperacillin. Cumulative fraction of response (CFR) was calculated using MIC data for 6 gram-negative pathogens (Meropenem Yearly Susceptibility Test Information Collection, 2004-2007), and probability of target attainment (PTA) was calculated at MICs ranging from 1 μg/mL to 64 μ/g/mL Results: The CFR for 3.375 g every 4 hours (intermittent infusion) and 3.375–4.5 g every 8 hours (prolonged infusion) greater than or equal to 90.3% for Escherichia coli, Serratia marcescens, and Citrobacter spp. Increasing the prolonged-infusion dose to 6.75 g improved the CFR to greater than 90% for Enterobacter spp. For every regimen evaluated, the CFR was less than 90% for Klebsiella pneumoniae and Pseudomonas aeruginosa. At an MIC of 16 μg/mL, PTA was greater than 90% for one intermittent-infusion regimen (3.375 g every 4 h) and 3 prolonged-infusion regimens (≥3.375 g every 8 h). but no regimen achieved a PTA greater than 90% at an MIC of 64 μ/g/mL. Conclusions: At doses greater than or equal to 3.375 g every 8 hours, 4-hour infusions of piperacillin/tazobactam achieved excellent target attainment with lower daily doses compared with standard regimens at MICs less than or equal to 16 μg/mL

Steady-state pharmacokinetics and pharmacodynamics of piperacillin and tazobactam administered by prolonged infusion in obese patients.

The study objective was to evaluate steady-state pharmacokinetics and pharmacodynamics of piperacillin and tazobactam administered by prolonged infusion in obese patients. Fourteen hospitalised patients weighing >120kg received piperacillin/tazobactam 4.5 g every 8 h (q8h) or 6.75 g q8h infused over 4h. Blood samples were collected at steady-state and drug concentrations were determined. Pharmacokinetic parameters were estimated and 5000-patient Monte Carlo simulations were performed for four prolonged-infusion dosing regimens. The probability of target attainment (PTA) for ≥50% fT>MIC was calculated for piperacillin at various MICs, and the PTA for fAUC(0-24)≥96 mg h/L was calculated for tazobactam. Mean±S.D. patient demographics were: age 49±10 years; weight 161±29 kg; and body mass index 52.3±10.8 kg/m(2). For piperacillin and tazobactam, respectively, the mean±S.D. elimination rate was 0.440±0.177 h(-1) and 0.320±0.145 h(-1), volume of distribution was 33.4±14.0L (0.21±0.07L/kg) and 37.5±15.3L (0.23±0.08 L/kg), and systemic clearance was 13.7±5.2L/h and 11.1±4.2L/h. For piperacillin, the PTA was ≥91% for doses ≥4.5g q8h at MICs≤16 μg/mL. For tazobactam, the PTA was 57%, 84% and 94% for doses of 4.5, 6.75 and 9.0g q8h, respectively. The pharmacokinetics of piperacillin and tazobactam are altered in obese patients. To ensure adequate tazobactam concentrations for β-lactamase inhibition, it may be prudent to employ larger initial doses for empirical therapy in obese patients.

Steady‐state pharmacokinetics and pharmacodynamics of meropenem in morbidly obese patients hospitalized in an intensive care unit

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/m2 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/m2, 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 pharmacokinetics and pharmacodynamics in morbid obesity. Nine patients hospitalized in an intensive care unit with a body mass index ≥40 kg/m2 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/m2, 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.

Steady-state pharmacokinetics and pharmacodynamics of piperacillin/tazobactam administered by prolonged infusion in hospitalised patients ☆

The objective of this study was to evaluate the steady-state pharmacokinetics and pharmacodynamics of piperacillin/tazobactam, administered by prolonged infusion, in hospitalised patients requiring antimicrobial therapy. Thirteen patients received 4.5 g every 8 h (q8h), infused over 4 h, and pharmacokinetic parameters were determined by non-compartmental methods. Monte Carlo simulations (10,000 patients) were performed to calculate the cumulative fraction of response (CFR) for seven gram-negative pathogens using minimum inhibitory concentration (MIC) data from the Meropenem Yearly Susceptibility Test Information Collection (2004-2007, USA) as well as the probability of target attainment (PTA) at MICs ranging from 1 microg/mL to 64 microg/mL. The pharmacodynamic target was free piperacillin concentration remaining above the MIC for 50% of the dosing interval. Mean+/-standard deviation maximum and minimum serum concentrations, half-life, volume of distribution at steady-state and systemic clearance of piperacillin were 108.2+/-31.7 microg/mL, 27.6+/-26.3 microg/mL, 2.1+/-1.2 h, 22.1+/-4.0 L and 8.6+/-3.0 L/h, respectively. The CFR was > 90% for Escherichia coli, Serratia marcescens and Citrobacter spp., 88.6% for Enterobacter spp., 87% for Klebsiella pneumoniae, 85.5% for Pseudomonas aeruginosa and 52.8% for Acinetobacter spp. The PTA was 100%, 81.1% and 12.3% at MICs of < or = 16 microg/mL, 32 microg/mL and 64 microg/mL, respectively. Piperacillin/tazobactam 4.5 g q8h infused over 4 h provides excellent target attainment for bacterial pathogens with MICs < or = 16 microg/mL. However, the CFR was < 90% for four of the seven gram-negative pathogens evaluated.

Comparative Pharmacokinetics and Pharmacodynamics of Doripenem and Meropenem in Obese Patients

Background: Antimicrobial pharmacokinetic and pharmacodynamic data are limited in obesity. Objective: To evaluate the steady-state pharmacokinetics and pharmacodynamics of doripenem and meropenem in obese patients hospitalized on a general ward. Methods: Patients with a body mass index (BMI) ≥40 kg/m2 or total body weight (TBW) ≥100 pounds over their ideal body weight randomly received doripenem 500 mg (1-hour infusion) or meropenem 1 g (0.5-hour infusion) every 8 hours. Differences in pharmacokinetic parameters were determined by unpaired t test. Monte Carlo simulations were performed for 500 mg and 1 g every 8 hours, infused over 1 and 4 hours for doripenem and 0.5 and 3 hours for meropenem. Probability of target attainment (PTA) was calculated using a pharmacodynamic target of 40% fT > MIC (free drug concentrations above the minimum inhibitory concentration [MIC]), and cumulative fraction of response (CFR) was calculated using MIC data for 8 Gram-negative pathogens. Results: Twenty patients were studied. Volume of distribution at steady state, corrected for TBW, was significantly larger (0.18 ± 0.04 vs 0.13 ± 0.05 L/kg, P = .048) and systemic clearance was significantly faster for doripenem (11.7 ± 4.1 vs 8.1 ± 2.6 L/h, P = .03). PTA was >90% for all regimens at MICs ≤2 µg/mL. CFR was >90% for all regimens against 6 enteric Gram-negative pathogens and for 3 of 4 regimens for each drug against Pseudomonas aeruginosa. Conclusions: Doripenem and meropenem pharmacokinetics differ in obesity. However, currently approved dosing regimens provide adequate pharmacodynamic exposures for susceptible bacteria in obese patients.

Steady-state pharmacokinetics and pharmacodynamics of cefepime administered by prolonged infusion in hospitalised patients

The objective of this study was to evaluate the steady-state pharmacokinetics and pharmacodynamics of cefepime administered by prolonged infusion in hospitalised patients requiring antimicrobial therapy. Nine patients received 1g every 8h (q8h), infused over 4h, and steady-state pharmacokinetic parameters were determined by non-compartmental and compartmental methods. Using these pharmacokinetic parameters, 5000-patient Monte Carlo simulations were performed to estimate the pharmacokinetic profiles for six prolonged-infusion dosing regimens. The probability of target attainment (PTA) was calculated at minimum inhibitory concentrations (MICs) ranging from 0.06 μg/mL to 32 μg/mL, and the cumulative fraction of response (CFR) was calculated for six Gram-negative pathogens using MIC data from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) (2005-2007, USA). The pharmacodynamic target was free cefepime concentrations remaining above the MIC for 60% of the dosing interval (60% fT>MIC). Mean ± standard deviation maximum and minimum serum concentrations, terminal elimination half-life, elimination rate constant, volume of distribution and systemic clearance of cefepime were 32.5 ± 13.5 μg/mL, 9.5 ± 5.2 μg/mL, 2.4 ± 0.7h, 0.316 ± 0.116 h(-1), 21.3 ± 6.5L and 6.6 ± 3.6L/h, respectively. At the susceptibility breakpoint of 8 μg/mL, the PTA was >90% for 1g and 2g q8h (4-h infusion) and 1g and 2g every 6h (q6h) (3-h infusion). For Pseudomonas aeruginosa, the CFR was 88.6% for 1g q8h (4-h infusion) and ≥ 92.7% for 2g q8h (4-h infusion) and 1g and 2g q6h (3-h infusion). Cefepime 1g q8h infused over 4h provides excellent target attainment for susceptible bacterial pathogens with MICs ≤8 μg/mL.

Steady-State Pharmacokinetics and Pharmacodynamics of Meropenem in Hospitalized Patients

Study Objective. To evaluate the steady‐state pharmacokinetics and pharmacodynamics of meropenem 500 mg every 6, 8, and 12 hours, based on renal function, in hospitalized patients.

Population pharmacokinetics and pharmacodynamics of piperacillin and tazobactam administered by prolonged infusion in obese and nonobese patients

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/m2) 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.

Population Pharmacokinetics and Pharmacodynamics of Meropenem in Nonobese, Obese, and Morbidly Obese Patients

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] 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.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/m2), 9 obese (30 kg/m2 ≤ BMI < 40 kg/m2), and 20 morbidly obese (BMI ≥ 40 kg/m2)—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.

Population Pharmacokinetics and Pharmacodynamics of Doripenem in Obese, Hospitalized Patients

Background: Doripenem population pharmacokinetics and dosing recommendations are limited in obesity. Objective: To evaluate the population pharmacokinetics and pharmacodynamics of doripenem in obese patients. Methods: Hospitalized adults with a body mass index (BMI) ≥ 40 kg/m2 or total body weight (TBW) ≥45.5 kg over their ideal body weight received doripenem 500 mg every 8 hours, infused over 1 hour. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed for 5 intermittent and prolonged infusion dosing regimens to calculate probability of target attainment (PTA) at 40% and 100% fT>MIC (free drug concentrations above the minimum inhibitory concentration). Results: A total of 20 patients were studied: 10 in an intensive care unit (ICU) and 10 in a non-ICU. A 2-compartment model with first-order elimination best described the serum concentration-time data. Doripenem clearance (CL) was significantly associated with creatinine CL (CRCL), volume of the central compartment with TBW and ICU residence, and volume of the peripheral compartment with TBW (P < 0.05). Using 40% fT>MIC, PTA was >90% for all simulated dosing regimens at MICs ≤2 mg/L. Using 100% fT>MIC, prolonged infusions of 1 g every 6 hours and 2 g every 8 hours achieved >90% PTA at MICs ≤2 mg/L. Conclusions: CRCL, ICU residence, and TBW are significantly associated with doripenem pharmacokinetics. Currently approved dosing regimens provide adequate pharmacodynamic exposures at 40% fT>MIC for susceptible bacteria in obese patients. However, prolonged infusions of larger doses are needed if a higher pharmacodynamic target is desired.