Continuous infusion of beta-lactam antibiotics in severe sepsis: A multicenter double-blind, randomized controlled trial

Joel Dulhunty, Jason Roberts, Joshua Davis, Steven Webb, Rinaldo Bellomo, Charles Gomersall, Charudatt Shirwadkar, Glenn Eastwood, David PATERSON, Jeffrey Lipman

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Background: 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.

    Methods:
    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.

    Results: 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).

    Conclusions: 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. � 2012 The Author. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.
    Original languageEnglish
    Pages (from-to)236-244
    Number of pages9
    JournalJournal of Infectious Diseases
    Volume56
    Issue number2
    DOIs
    Publication statusPublished - 2013

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