Pharmacodynamic Profiling of Antimicrobials against Gram-negative Respiratory Isolates from Canadian Hospitals

Abstract

With diminishing antimicrobial potency, the choice of effective empirical therapy has become more challenging. Thus, the pharmacodynamic evaluation of potential therapies is essential to identify optimal agents, doses and administration strategies. Monte Carlo simulation was conducted for standard and/or prolonged infusion regimens of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, doripenem, ertapenem, meropenem and piperacillin/tazobactam. Minimum inhibitory concentrations were obtained for Escherichia coli (n=64 respiratory isolates), Enterobacter cloacae (n=53), Klebsiella pneumoniae (n=75) and Pseudomonas aeruginosa (n=273) throughout Canada. The cumulative fraction of response (CFR) was calculated using bactericidal targets for each regimen against each species. A CFR ≥90% was defined as optimal. All cefepime, doripenem, ertapenem and meropenem regimens achieved optimal exposures against Enterobacteriaceae, whereas target attainment was organism and dose dependent for the other agents. Prolonged infusion doripenem and meropenem 1 g and 2 g every 8 h, along with standard infusion doripenem and meropenem 2 g every 8 h, were the only regimens to attain optimal exposures against P aeruginosa. Ciprofloxacin had the lowest CFR against P aeruginosa, followed by cefepime. Among the P aeruginosa isolates collected in the intensive care unit (ICU) compared with the wards, differences of 0.5% to 10% were noted in favour of non-ICU isolates for all agents; however, marked differences (10% to 15%) in CFR were observed for ciprofloxacin in favour of ICU isolates. Standard dosing of cefepime, doripenem, ertapenem and meropenem has a high likelihood of obtaining optimal pharmacodynamic indexes against these Enterobacteriaceae. For P aeruginosa, aggressive treatment with high-dose and/or prolonged infusion regimens are likely required to address the elevated resistance rates of respiratory isolates from Canada.