Continuous versus intermittent infusions of antibiotics for the treatment of severe acute infections

Abstract

Background: Intravenous broad-spectrum antibiotics are indicated for the treatment of severe infections. However, the emergence of infections caused by multi-drug resistant organisms in conjunction with a lack of novel antibiotics has prompted the investigation of alternative dosing strategies to improve clinical efficacy and tolerability. To optimise pharmacokinetic and pharmacodynamic antibiotic parameters, continuous antibiotic infusions have been compared to traditional intermittent antibiotic infusions. Objectives: To compare the clinical efficacy and safety of continuous intravenous administration of concentration-dependent and time-dependent antibiotics to traditional intermittent intravenous administration in adults with severe acute bacterial infections. Search methods: The following electronic databases were searched in September 2012: The Cochrane Injuries Group Specialised Register, Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE (OvidSP), EMBASE (OvidSP), CINAHL, ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED), ISI Web of Science: Conference Proceedings Citation Index-Science (CPCI-S). The reference lists of all relevant material, the Internet and the trials registry www.clinicaltrials.gov for completed and ongoing trials were also searched. Selection criteria: Randomized controlled trials in adults with a bacterial infection requiring intravenous antibiotic therapy comparing continuous versus intermittent infusions of antibiotics were included. Both time-dependent and concentration-dependent antibiotics were considered. Data collection and analysis: Three independent authors performed data extraction for the included studies. All data was cross-checked and disagreements resolved by consensus. An intention to treat analysis was conducted using a random-effects model. Main results: Twenty-nine studies met inclusion criteria with a combined total of over 1,600 patients. The majority of included studies were judged to be at unclear or high risk of bias with regard to randomisation sequence generation, allocation concealment, blinding, management of incomplete outcome data, selective outcome reporting, and other potential threats to validity. No studies were judged to be at low risk of bias for all methodological quality items assessed. There were no differences in all-cause mortality (n=1241, RR 0.89, 95% CI 0.67 - 1.20, p=0.45), infection recurrence (n=398, RR 1.22, 95% CI 0.35 - 4.19, p=0.76), clinical cure (n=975, RR 1.00, 95% CI 0.93 - 1.08, p=0.98), and superinfection post-therapy (n=813, RR 1.08, 95% CI 0.60 - 1.94, p=0.79). There were no differences in safety outcomes including adverse events (n=575, RR 1.02, 95% CI 0.94 - 1.12, p=0.63), serious adverse events (n=871, RR 1.36, 95% CI 0.80 - 2.30, p=0.26), and withdrawal due to adverse events (n=871, RR 2.03, 95% CI 0.52 - 7.95, p=0.31). A difference was observed in the subgroup analyses of clinical cure in septic versus non-septic patients, where intermittent antibiotic infusions were favoured for clinical cure in septic patients. However, this effect was not consistent between random-effects and fixed-effects analyses. No differences were found in sensitivity analyses conducted. Authors' conclusions: There were no differences in mortality, infection recurrence, clinical cure, superinfection post-therapy, and safety outcomes when comparing continuous infusions of intravenous antibiotics to traditional intermittent infusions of antibiotics. However, the wide confidence intervals suggest that beneficial or harmful effects cannot be ruled out for all outcomes. Therefore, the current evidence is insufficient to recommend the widespread adoption of continuous infusion antibiotics in the place of intermittent infusions of antibiotics. Further large prospective randomised trials, with consistent and complete reporting of clinical outcome measures, conducted with concurrent pharmacokinetic and pharmacodynamic studies in special populations are required to determine whether adoption of continuous antibiotic infusions is warranted in specific circumstances.