Use of Monte Carlo Simulations to Determine Optimal Carbapenem Dosing in Critically Ill Patients Receiving Prolonged Intermittent Renal Replacement Therapy.

Pharmacokinetic/pharmacodynamic analyses with Monte Carlo simulations (MCSs) can be used to integrate prior information on model parameters into a new renal replacement therapy (RRT) to develop optimal drug dosing when pharmacokinetic trials are not feasible. This study used MCSs to determine initial doripenem, imipenem, meropenem, and ertapenem dosing regimens for critically ill patients receiving prolonged intermittent RRT (PIRRT). Published body weights and pharmacokinetic parameter estimates (nonrenal clearance, free fraction, volume of distribution, extraction coefficients) with variability were used to develop a pharmacokinetic model. MCS of 5000 patients evaluated multiple regimens in 4 different PIRRT effluent/duration combinations (4 L/h × 10 hours or 5 L/h × 8 hours in hemodialysis or hemofiltration) occurring at the beginning or 14-16 hours after drug infusion. The probability of target attainment (PTA) was calculated using ≥40% free serum concentrations above 4 times the minimum inhibitory concentration (MIC) for the first 48 hours. Optimal doses were defined as the smallest daily dose achieving ≥90% PTA in all PIRRT combinations. At the MIC of 2 mg/L for Pseudomonas aeruginosa, optimal doses were doripenem 750 mg every 8 hours, imipenem 1 g every 8 hours or 750 mg every 6 hours, and meropenem 1 g every 12 hours or 1 g pre- and post-PIRRT. Ertapenem 500 mg followed by 500 mg post-PIRRT was optimal at the MIC of 1 mg/L for Streptococcus pneumoniae. Incorporating data from critically ill patients receiving RRT into MCS resulted in markedly different carbapenem dosing regimens in PIRRT from those recommended for conventional RRTs because of the unique drug clearance characteristics of PIRRT. These results warrant clinical validation.

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.