Pharmacodynamics of empirical antibiotic monotherapies for an intensive care unit (ICU) population based on Canadian surveillance data

Abstract

Objectives: To evaluate, using Monte Carlo simulation, the pharmacodynamics (PD) of empirical antibiotic monotherapies for serious infections consistent with Canadian intensive care unit (ICU) surveillance data. Methods: Meropenem, piperacillin/tazobactam and cefepime, along with ceftobiprole, a broad-spectrum cephalosporin active against methicillin-resistant Staphylococcus aureus (MRSA), were tested at standard and highest recommended doses with and without prolonged infusion times (t′). Population pharmacokinetic models were used to simulate antibiotic serum concentrations (n=5000). Cumulative target attainment (CTA) at >50%, >75% and 100% fT>MIC (percentage of time free concentrations exceed the MIC) targets were determined based on ICU surveillance data including 4798 pathogens, most commonly methicillin-susceptible S. aureus (20.1%), Escherichia coli (15.2%) and Pseudomonas aeruginosa (12.3%). Results: With standard doses, ceftobiprole (500 mg every 8 h, t′ 2 h) had 0.90 CTA at the >50% fT>MIC target while meropenem (1 g every 8 h, t′ 0.5 h), piperacillin/tazobactam (3.375 g every 6 h, t′ 0.5 h) and cefepime (2 g every 12 h, t′ 0.5 h) reached .50% fT.>MIC in 0.79-0.82 of the population (0.84-0.88 when MRSA was excluded). Piperacillin/tazobactam had the largest reduction in CTA at the >75% and 100% fT>MIC targets requiring prolonged infusions to maintain comparable PD. For all agents, prolonged infusions and/or high doses were required to achieve >0.9 CTA at the lowest target, to reach higher targets or to cover less susceptible pathogens such as P. aeruginosa. Conclusions: This study provides important comparative data on empirical antibiotic monotherapies in an ICU setting including preliminary data on ceftobiprole. Ceftobiprole was most active overall, but similar to meropenem, piperacillin/tazobactam (lowest target only) and cefepime when MRSA was excluded. Prolonged infusions in particular and high doses were effective at improving antibiotic PD. © The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.