CJIDMM Canadian Journal of Infectious Diseases and Medical Microbiology 1712-9532 Pulsus Group Inc 971701 10.1155/2011/971701 Original Article Pharmacodynamic Profiling of Antimicrobials against Gram-negative Respiratory Isolates from Canadian Hospitals Keel Rebecca A. 1 Zhanel George G. 2 Zelenitsky Sheryl 2 Nicolau David P. dnicola@harthosp.org 1 1 Center for Anti-Infective Research and Development Connecticut USA 2 University of Manitoba Bannatyne Campus Winnipeg, Manitoba USA umanitoba.ca 2011 22 4 132 136 2011 Copyright © 2011 Hindawi Publishing Corporation. This open-access article is distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC) (http://creativecommons.org/licenses/by-nc/4.0/), which permits reuse, distribution and reproduction of the article, provided that the original work is properly cited and the reuse is restricted to noncommercial purposes.

The objective of this study was to assess the profile of a variety of dosing regimens for common intravenous antibiotics against contemporary Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa isolates collected in Canada during 2009, using pharmacodynamic modelling techniques. Monte Carlo simulation was conducted for standard and/or prolonged infusion regimens of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, doripenem, ertapenem, meropenem and piperacillin/tazobactam. The cumulative fraction of response (CFR) was calculated using bactericidal targets for each regimen against each species. All cefepime, doripenem, ertapenem and meropenem regimens achieved optimal exposures against Enterobacteriaceae, whereas target attainment was organism and dose dependent for the other agents. These results support that the currently recommended antimicrobial dosing regimens generally attain acceptable exposures to achieve the requisite pharmacodynamic targets against the Enterobacteriaceae species; however, they fall short of obtaining optimal bactericidal exposures against P aeruginosa.

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.

Canada Gram negative Monte Carlo simulation Pharmacodynamics Respiratory