A phase IIb randomised controlled trial of continuous beta-lactam infusion compared with intermittent beta-lactam dosing in critically ill patients BLING II

In critically ill patients with severe sepsis, how does continuous beta-lactam infusion compared with intermittent beta-lactam bolus dosing affect ICU-free days up to Day 28?Beta-lactam antibiotics are the class of antibiotics most commonly used to treat infection in patients with severe sepsis. In a recent point prevalence study of antibiotic usage in Australia and New Zealand conducted in conjunction with the Extended Study on Prevalence of Infection in Intensive Care (EPIC II), among ICU patients being treated for infection, 4 of the 5 most commonly used antibiotics were beta-lactams. The three most commonly prescribed beta-lactams were ticarcillin-clavulanate (23% of all antibiotics), meropenem (20% of all antibiotics), and piperacillin-tazobactam (13% of all antibiotics). Routine use of continuous infusions for beta-lactam administration was extremely low; with a point prevalence estimate of 1.8% for all beta-lactam antibiotics used in Australian and New Zealand ICUs. The theoretical rationale for administration of beta-lactams via continuous infusion is well recognised. Bacterial killing is related to the duration of time that bacteria are exposed to a concentration of antibiotic that exceeds the Minimum Inhibitory Concentration (MIC). It is well established that administration of beta-lactam antibiotics by infusion produces higher blood and tissue serum levels. While continuous infusion is superior to bolus administration in animal and in vitro models of infection in the absence of an effective immune response, two meta-analyses of the human trials conducted to date have not demonstrated that continuous infusion is superior to intermittent administration in terms of clinical cure and survival. These human trials, however, have been underpowered, even when pooled, and primarily conducted in non-critically ill patients. In addition, 13 of the 14 studies included in the meta-analysis by Roberts et al. used higher doses in the intermittent arm. The beta-lactam antibiotic chosen by the treating physician will be randomised to continuous infusion or intermittent bolus administration. The dose and dosing interval of the antibiotic will be chosen by the treating physician so as to reflect body size and estimated drug clearance. The dose of antibiotic will be the same regardless of treatment group allocation and antibiotic dosing can be modified during the study based on predicted or actual changes to renal clearance. Dosing will continue as per clinician's discretion, ICU discharge or to a maximum of 14 days.