NIHR Signal Intravenous antibiotics, administered over 3 hours, are linked to lower death rates in sepsis

Published on 31 January 2018

The risk of death in adults with sepsis was 30% lower when each dose of antibiotic was given intravenously over three hours compared to a bolus or less than 60 minutes.

This systematic review included adults on intensive care units with a range of ages, severity of sepsis and other symptoms. A variety of antibiotics of the anti-pseudomonal beta-lactam class were used in the trials. These included carbapenems, penicillins and cephalosporins.

In the UK, current guidance for intravenous use of these drugs is to give them over a period of up to 30 minutes. This review provides high-quality evidence that suggests that all patients should be given these intravenous infusions over a longer period.

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Why was this study needed?

Sepsis occurs in serious infections when a person’s immune system response becomes overactive and starts to cause damage to the body. There are about 123,000 cases of sepsis a year in England. Overall, around 37,000 people die each year because of the condition; that is up to four in every ten people with the condition.

If sepsis is identified and treated quickly, most people recover fully with no lasting problems. Increasing resistance to antibiotics means we need to find new antibiotics and also optimise the use of those that we already have.

This review aimed to assess the effectiveness of a common group of antibiotics when given by prolonged (more than three hours) versus short-term (less than 60 minutes) infusion on mortality of patients with sepsis.

What did this study do?

This systematic review and meta-analysis pooled the results of 22 randomised controlled trials involving 1,876 adults with sepsis. The trials compared prolonged versus short-term administration of any anti-pseudomonal beta-lactam. Carbapenems were studied in nine trials, penicillins in nine trials, and cephalosporins in eight trials.

Definitions of sepsis varied between the trials. Participants varied in age across the trials, with mean ages ranging from less than 45 years to older than 65 years. Total daily doses of antibiotics varied both within and between individual studies.

The review was well-conducted, and the included studies that reported on mortality were rated as high-quality evidence. None of the trials was carried out in the UK: 10 were done in Asia-Pacific, nine in Europe and three in the USA.

What did it find?

  • Prolonged infusion was associated with lower all-cause mortality than short-term infusion, with 13.6% deaths compared to 19.8% (risk ratio [RR] 0.70, 95% confidence interval [CI] 0.56 to 0.87; 17 studies, 1,597 participants).
  • There was no significant difference between prolonged and short-term infusion for clinical cure or improvement (RR 1.06, 95% CI 0.96 to 1.17; 11 studies, 1,219 participants).
  • There was no difference in reported adverse events between the groups (RR 0.88, 95% CI 0.71 to 1.09; seven studies, 980 participants).
  • Two trials had no incidence of antibiotic resistance, and two trials had no difference in resistance between the two methods of antibiotic administration (RR 0.60, 95% CI 0.15 to 2.38).

What does current guidance say on this issue?

The 2016 NICE guideline on the recognition, diagnosis and early management of sepsis doesn’t recommend a specific antibiotic or give a direction for administration. It recommends using an intravenous antimicrobial from the agreed local formulary and in line with local or national guidelines.

The British National Formulary indicates that drugs belonging to the beta-lactam groups (for example piperacillin with tazobactam or ceftazidime) should be given as intermittent intravenous infusion over 30 minutes.

What are the implications?

This review provides robust evidence that prolonged infusion should be considered when giving beta-lactams for sepsis patients in intensive care units. This appears to be the case for a range of beta-lactams, in different patient groups with different infections. People with kidney problems were excluded from the trials so these findings may not apply to them.

Prolonged infusion should be easy to apply in the intensive care setting, without the need for additional training or equipment.

Citation and Funding

Vardakas KZ, Voulgaris GL, Maliaros A, et al. Prolonged versus short-term intravenous infusion of antipseudomonal beta-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials. Lancet Infect Dis. 2018;18(1):108-20.

There was no funding source acknowledged for this study.

Bibliography

BNF. Ceftazidime. London: BMJ Group and Pharmaceutical Press; 2017.

BNF. Piperacillin with tazobactam. London: BMJ Group and Pharmaceutical Press; 2017.

NHS Choices. Sepsis. London: Department of Health; updated 2016.

NICE. Sepsis: recognition, diagnosis and early management. NG51. London: National Institute for Health and Care Excellence; updated 2017.

Why was this study needed?

Sepsis occurs in serious infections when a person’s immune system response becomes overactive and starts to cause damage to the body. There are about 123,000 cases of sepsis a year in England. Overall, around 37,000 people die each year because of the condition; that is up to four in every ten people with the condition.

If sepsis is identified and treated quickly, most people recover fully with no lasting problems. Increasing resistance to antibiotics means we need to find new antibiotics and also optimise the use of those that we already have.

This review aimed to assess the effectiveness of a common group of antibiotics when given by prolonged (more than three hours) versus short-term (less than 60 minutes) infusion on mortality of patients with sepsis.

What did this study do?

This systematic review and meta-analysis pooled the results of 22 randomised controlled trials involving 1,876 adults with sepsis. The trials compared prolonged versus short-term administration of any anti-pseudomonal beta-lactam. Carbapenems were studied in nine trials, penicillins in nine trials, and cephalosporins in eight trials.

Definitions of sepsis varied between the trials. Participants varied in age across the trials, with mean ages ranging from less than 45 years to older than 65 years. Total daily doses of antibiotics varied both within and between individual studies.

The review was well-conducted, and the included studies that reported on mortality were rated as high-quality evidence. None of the trials was carried out in the UK: 10 were done in Asia-Pacific, nine in Europe and three in the USA.

What did it find?

  • Prolonged infusion was associated with lower all-cause mortality than short-term infusion, with 13.6% deaths compared to 19.8% (risk ratio [RR] 0.70, 95% confidence interval [CI] 0.56 to 0.87; 17 studies, 1,597 participants).
  • There was no significant difference between prolonged and short-term infusion for clinical cure or improvement (RR 1.06, 95% CI 0.96 to 1.17; 11 studies, 1,219 participants).
  • There was no difference in reported adverse events between the groups (RR 0.88, 95% CI 0.71 to 1.09; seven studies, 980 participants).
  • Two trials had no incidence of antibiotic resistance, and two trials had no difference in resistance between the two methods of antibiotic administration (RR 0.60, 95% CI 0.15 to 2.38).

What does current guidance say on this issue?

The 2016 NICE guideline on the recognition, diagnosis and early management of sepsis doesn’t recommend a specific antibiotic or give a direction for administration. It recommends using an intravenous antimicrobial from the agreed local formulary and in line with local or national guidelines.

The British National Formulary indicates that drugs belonging to the beta-lactam groups (for example piperacillin with tazobactam or ceftazidime) should be given as intermittent intravenous infusion over 30 minutes.

What are the implications?

This review provides robust evidence that prolonged infusion should be considered when giving beta-lactams for sepsis patients in intensive care units. This appears to be the case for a range of beta-lactams, in different patient groups with different infections. People with kidney problems were excluded from the trials so these findings may not apply to them.

Prolonged infusion should be easy to apply in the intensive care setting, without the need for additional training or equipment.

Citation and Funding

Vardakas KZ, Voulgaris GL, Maliaros A, et al. Prolonged versus short-term intravenous infusion of antipseudomonal beta-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials. Lancet Infect Dis. 2018;18(1):108-20.

There was no funding source acknowledged for this study.

Bibliography

BNF. Ceftazidime. London: BMJ Group and Pharmaceutical Press; 2017.

BNF. Piperacillin with tazobactam. London: BMJ Group and Pharmaceutical Press; 2017.

NHS Choices. Sepsis. London: Department of Health; updated 2016.

NICE. Sepsis: recognition, diagnosis and early management. NG51. London: National Institute for Health and Care Excellence; updated 2017.

Prolonged versus short-term intravenous infusion of antipseudomonal beta-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials

Published on 6 November 2017

Vardakas, K. Z.,Voulgaris, G. L.,Maliaros, A.,Samonis, G.,Falagas, M. E.

Lancet Infect Dis , 2017

BACKGROUND: The findings of randomised controlled trials (RCT), observational studies, and meta-analyses vary regarding the effectiveness of prolonged beta-lactam infusion. We aimed to identify the effectiveness of prolonged versus short-term infusion of antipseudomonal beta-lactams in patients with sepsis. METHODS: We did a systematic review and meta-analysis to compare prolonged versus short-term intravenous infusion of antipseudomonal beta-lactams in patients with sepsis. Two authors independently searched PubMed, Scopus, and the Cochrane Library of clinical trials until November, 2016, without date or language restrictions. Any RCT comparing mortality or clinical efficacy of prolonged (continuous or >/=3 h) versus short-term (</=60 min) infusion of antipseudomonal beta-lactams for the treatment of patients with sepsis was eligible. Studies were excluded if they were not RCTs, the antibiotics in the two arms were not the same, neither mortality nor clinical efficacy was reported, only pharmacokinetic or pharmacodynamic outcomes were reported, or if ten or fewer patients were enrolled or randomised. Data were extracted in prespecified forms and we then did a meta-analysis using a Mantel-Haenszel random-effects model. The primary outcome was all-cause mortality at any timepoint. This meta-analysis is registered with the PROSPERO database, number CRD42016051678, and is reported according to PRISMA guidelines. FINDINGS: 2196 articles were identified and screened, and 22 studies (1876 patients) were included in the meta-analysis. According to the Grading of Recommendations Assessment, Development, and Evaluation tool, the quality of evidence for mortality was high. Carbapenems, penicillins, and cephalosporins were studied. Patients with variable age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, severity of sepsis and renal function were enrolled. Prolonged infusion was associated with lower all-cause mortality than short-term infusion (risk ratio [RR] 0.70, 95% CI 0.56-0.87). Heterogeneity was not observed (p=0.93, I2=0%). The funnel plot and the Egger's test (p=0.44) showed no evidence of publication bias. INTERPRETATION: Prolonged infusion of antipseudomonal beta-lactams for the treatment of patients with sepsis was associated with significantly lower mortality than short-term infusion. Further studies in specific subgroups of patients according to age, sepsis severity, degree of renal dysfunction, and immunocompetence are warranted. FUNDING: None.

Expert commentary

Prompt and aggressive antibiotic therapy is now seen as the cornerstone of effective sepsis care. But are we getting the most out of these drugs?

Established practice of short-term infusions (intermittent bolus dosing) may not be the most efficacious method of delivery. This secondary research compared prolonged (continuous or more than 3 hours) against short-term infusions in over 1,800 randomised patients and demonstrated a significant reduction in mortality overall, with prolonged infusion of the most commonly used broad-spectrum antibiotics in sepsis.

Further validation is needed, but this important work may lead a slow but steady revolution in prescribing practice.

Daniel Horner, Professor of the Royal College of Emergency Medicine; Consultant in Emergency and Intensive Care Medicine, Salford Royal NHS Foundation Trust

Expert commentary

Intravenous broad-spectrum antibiotics may be administered to patients with sepsis as a bolus over a short amount of time, typically less than 30 minutes or as a prolonged infusion over many hours.

The prolonged infusion of intravenous broad-spectrum antibiotics to patients with sepsis is associated with lower mortality. The beneficial effects of prolonged infusions of intravenous broad-spectrum antibiotics are particularly evident in older and more unwell patients.

Prolonged infusions of intravenous broad-spectrum antibiotics may be a more effective method of administering Intravenous broad-spectrum antibiotics to patients with sepsis. A randomised clinical trial [Beta-Lactam InfusioN Group Study (BLING III)] of continuous versus bolus infusions of antibiotics is currently underway.

Dr Timothy Felton, Consultant in Intensive Care and Respiratory Medicine, University Hospital of South Manchester; Senior Lecturer in the Division of Infection, Immunity and Respiratory Medicine, University of Manchester