Continuous versus intermittent bolus dosing of beta-lactam antibiotics in a South African multi-disciplinary intensive care unit: A randomized controlled trial

Abstract

Background

Beta-lactams exhibit time-dependent bactericidal effects with continuous infusion (CI) suggested to provide superior antibiotic concentrations compared to intermittent bolus (IB).

Objective

To determine whether beta-lactam CI improves day 14 clinical cure compared to IB in a South African, multi-disciplinary intensive care unit (ICU).

Methods

Adult patients with sepsis receiving amoxicillin-clavulanate, piperacillin-tazobactam, imipenem-cilastatin and meropenem were randomized to 24-hour CI or IB. On screening, patients who received study antibiotics for more than 24 h, pregnant patients or patients on renal replacement therapy were excluded. The primary outcome, clinical cure, was defined as completion of antibiotics by day 14 without recommencement within 48 h. Secondary outcomes included ICU length of stay (LOS), ICU, day 28 and day 90 mortality.

Results

We enrolled 122 patients. The groups were balanced for baseline age, weight, sex, severity of illness, organ support, HIV status, diagnostic category and site of infection. Median antibiotic duration, CI group, 7 days (IQR 5–8.5) vs. IB group, 6 days (IQR 4–8), p=0.191, and median ICU LOS, CI, 9.5 days (IQR 6–15.5) vs. IB, 9 days (IQR 5–16), p= 0.575, were similar. Clinical cure in the CI group was 81% (52/64) vs. 74.1% (43/58) in the IB group), p=0.345. Day 90 relative risk of death was 0,57, 95% Confidence Interval 0.32 – 1.01) for the CI group compared to IB.

Conclusion

Among critically ill patients meeting the sepsis-3 definition, this study could not demonstrate the superiority of continuous infusion of beta-lactam antibiotics compared to intermittent bolus in achieving a clinical cure.