Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial.
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.
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
Joel M
JM
Dulhunty
Jason A
JA
Roberts
Joshua S
JS
Davis
Steven A R
SA
Webb
Rinaldo
R
Bellomo
Charles
C
Gomersall
Charudatt
C
Shirwadkar
Glenn M
GM
Eastwood
John
J
Myburgh
David L
DL
Paterson
Jeffrey
J
Lipman
D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D018805:Sepsis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D016896:Treatment Outcome; D047090:beta-Lactams / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000900:Anti-Bacterial Agents; D047090:beta-Lactams