Administering ß-lactam antibiotics for sepsis or septic shock by continuous (also termed, prolonged) infusion was associated with lower 90-day mortality than with intermittent infusion, in a meta-analysis1 published concurrently with similar findings from the BLING III trial.
“The current evidence presents a high degree of certainty for clinicians to consider prolonged infusions as a standard of care in the management of sepsis and septic shock,” declared lead author Mohd Abdul-Aziz, BPharm, PhD, Centre for Clinical Research, University of Queensland, Brisbane, Australia, and colleagues.
The investigators identified 18 randomized clinical trials which compared outcomes between regimens in 9,108 critically ill adult participants with sepsis or septic shock.The primary outcome of the systematic review and meta-analysis was all-cause 90-day mortality; with secondary outcomes of ICU mortality, ICU length of stay, clinical cure, microbiologic cure and adverse events.
Prolonged infusion corresponded to sequential administrations of 6-, 8-, 12- or 24- hours; while intermittent infusions for the same total 24-hour dosage were each administered over 2 hours or less.Pre-specified subgroup analysis was conducted for: meropenem vs piperacillin-tazobactam; culture-positive vs negative infection; gram-negative vs gram positive infection; receiving or not receiving kidney replacement; lung vs other infections; sepsis vs septic shock; and male vs female.
Meropenem was studied in 11 of the trials; piperacillin-tazobactam in 8 trials; cefepime in 3 trials; ticarcillin-clavulanate in 2 trials; and amoxicillin-clavulanate, ampicillin-sulbactam, ceftriaxone, and imipenem-cilastatin in 1 trial each.The median duration of ß-lactam prolonged infusion treatment was 7 days, and was 9 days for the intermittent regimen.
Abdul-Aziz and colleagues reported a pooled estimated risk ratio (RR) for all-cause 90-day mortality for prolonged infusions compared to intermittent of 0.86 (95% CI, 0.72-0.98).They equated this to a 14 percentage-point reduction in the risk of 90-day mortality relative to intermittent infusion.The prolonged infusion was also associated with reduced risk of ICU mortality (RR 0.84 [0.70-0.97]); and an increase in clinical cure (RR 1.16 [1.07-1.31]).
The investigators found the association held in each subgroup analysis, includingpiperacillin-tazobactam or meropenem, and culture-positive or culture-negative infections.There was, however, no statistically significant difference between the regimens in regard to microbiologic cure, adverse events, or of ICU length of stay.
The investigators suggest there is a biologic rationale for prolonged infusions of ß-lactam antibiotics to be more effective than intermittent infusions.They note that pharmacokinetic-pharmacodynamic studies have demonstrated that prolonged infusions achieve exposures associated with maximal bacterial-killing more consistently than intermittent infusions.They acknowledge, however, that it is uncertain whether these differences in pharmacokinetics relate to different outcomes.
Abdul-Aziz and colleagues characterize this meta-analysis as providing “the most up-to-date evidence”; and contrast it to previous meta-analyses which have acknowledged including trials of varying quality.
“This review included trials that recruited critically ill adult participants with sepsis or septic shock to mitigate population heterogeneity reported in previous meta-analyses,” they remarked.”The addition of these trials has increased the sample size of the present analysis, providing greater confidence and precision in estimating the effects of prolonged infusions of ß-lactam antibiotics on clinically important outcomes.”