%0 Journal Article %1 Dulhunty2013 %A Dulhunty, Joel M. %A Roberts, Jason A. %A Davis, Joshua S. %A Webb, Steven A R. %A Bellomo, Rinaldo %A Gomersall, Charles %A Shirwadkar, Charudatt %A Eastwood, Glenn M. %A Myburgh, John %A Paterson, David L. %A Lipman, Jeffrey %D 2013 %J Clin Infect Dis %K drug dosing safety drugresistance %N 2 %P 236--244 %R 10.1093/cid/cis856 %T Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial. %U http://dx.doi.org/10.1093/cid/cis856 %V 56 %X Beta-lactam antibiotics are a commonly used treatment for severe sepsis, with intermittent bolus dosing standard therapy, despite a strong theoretical rationale for continuous administration. The aim of this trial was to determine the clinical and pharmacokinetic differences between continuous and intermittent dosing in patients with severe sepsis.This was a prospective, double-blind, randomized controlled trial of continuous infusion versus intermittent bolus dosing of piperacillin-tazobactam, meropenem, and ticarcillin-clavulanate conducted in 5 intensive care units across Australia and Hong Kong. The primary pharmacokinetic outcome on treatment analysis was plasma antibiotic concentration above the minimum inhibitory concentration (MIC) on days 3 and 4. The assessed clinical outcomes were clinical response 7-14 days after study drug cessation, ICU-free days at day 28 and hospital survival.Sixty patients were enrolled with 30 patients each allocated to the intervention and control groups. Plasma antibiotic concentrations exceeded the MIC in 82\% of patients (18 of 22) in the continuous arm versus 29\% (6 of 21) in the intermittent arm (P = .001). Clinical cure was higher in the continuous group (70\% vs 43\%; P = .037), but ICU-free days (19.5 vs 17 days; P = .14) did not significantly differ between groups. Survival to hospital discharge was 90\% in the continuous group versus 80\% in the intermittent group (P = .47).Continuous administration of beta-lactam antibiotics achieved higher plasma antibiotic concentrations than intermittent administration with improvement in clinical cure. This study provides a strong rationale for further multicenter trials with sufficient power to identify differences in patient-centered endpoints.

@article{Dulhunty2013, abstract = {Beta-lactam antibiotics are a commonly used treatment for severe sepsis, with intermittent bolus dosing standard therapy, despite a strong theoretical rationale for continuous administration. The aim of this trial was to determine the clinical and pharmacokinetic differences between continuous and intermittent dosing in patients with severe sepsis.This was a prospective, double-blind, randomized controlled trial of continuous infusion versus intermittent bolus dosing of piperacillin-tazobactam, meropenem, and ticarcillin-clavulanate conducted in 5 intensive care units across Australia and Hong Kong. The primary pharmacokinetic outcome on treatment analysis was plasma antibiotic concentration above the minimum inhibitory concentration (MIC) on days 3 and 4. The assessed clinical outcomes were clinical response 7-14 days after study drug cessation, ICU-free days at day 28 and hospital survival.Sixty patients were enrolled with 30 patients each allocated to the intervention and control groups. Plasma antibiotic concentrations exceeded the MIC in 82\% of patients (18 of 22) in the continuous arm versus 29\% (6 of 21) in the intermittent arm (P = .001). Clinical cure was higher in the continuous group (70\% vs 43\%; P = .037), but ICU-free days (19.5 vs 17 days; P = .14) did not significantly differ between groups. Survival to hospital discharge was 90\% in the continuous group versus 80\% in the intermittent group (P = .47).Continuous administration of beta-lactam antibiotics achieved higher plasma antibiotic concentrations than intermittent administration with improvement in clinical cure. This study provides a strong rationale for further multicenter trials with sufficient power to identify differences in patient-centered endpoints.}, added-at = {2013-03-06T01:03:42.000+0100}, author = {Dulhunty, Joel M. and Roberts, Jason A. and Davis, Joshua S. and Webb, Steven A R. and Bellomo, Rinaldo and Gomersall, Charles and Shirwadkar, Charudatt and Eastwood, Glenn M. and Myburgh, John and Paterson, David L. and Lipman, Jeffrey}, biburl = {https://www.bibsonomy.org/bibtex/2864b7aac540c3c60361d80c4bc9c9f7d/aorchid}, description = {see page 81 of notebook 00002. Good study, poor paper. Even CI zosyn had only 70% time over MIC, though clearly this was bacteriocidal. See also Drusano2013 for comment.}, doi = {10.1093/cid/cis856}, file = {:ID_General/ClinInfectDis.56.236.pdf:PDF}, groups = {public}, institution = {Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, and Burns, Trauma and Critical Care Research Centre, University of Queensland, Brisbane. joel_dulhunty@health.qld.gov.au}, interhash = {cf691a7174c9f737e38a41e7d95d5449}, intrahash = {864b7aac540c3c60361d80c4bc9c9f7d}, journal = {Clin Infect Dis}, keywords = {drug dosing safety drugresistance}, language = {eng}, medline-pst = {ppublish}, month = Jan, number = 2, pages = {236--244}, pii = {cis856}, pmid = {23074313}, timestamp = {2013-03-06T01:03:42.000+0100}, title = {Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial.}, url = {http://dx.doi.org/10.1093/cid/cis856}, username = {aorchid}, volume = 56, year = 2013 }