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A Multicenter Randomized Trial of Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis

Dulhunty. Am J Respir Crit Care Med. First published online 22 Jul 2015. DOI: 10.1164/rccm.201505-0857OC

Clinical Question

  • In adult ICU patients on beta-lactam antibiotics, does continuous infusion compared to intermittent bolus increase survival?

Design

  • Randomised, controlled trial
  • Double-blind with double-dummy preparations
    • Unblinded staff prepared drugs and consecutively labelled sealed opaque envelopes
    • Study participants, clinicians and data investigators remained blinded
  • Pilot trial conducted to guide power calculation
    • Sample size of 420 required to achieve 90% power to detect a 3 day difference in the primary outcome
  • Intention-to-treat (ITT) analysis for primary end points, in addition to:
    • Modified intention-to-treat (mITT) conducted in eligible patients who received a study drug
    • A priori per protocol analysis in those who received 3 or more days of a study drug

Setting

  • 25 Intensive Care Units (17 in Australia, 7 in New Zealand and 1 in Hong Kong)
  • July 2012 to April 2014

Population

  • Inclusion: adults with severe sepsis commenced on any of:
    • Piperacillin-tazobactam
    • Ticarcillin-clavulanate
    • Meropenem
  • Exclusion:
    • Received beta-lactam for more than 24 hours duration prior to randomisation
    • Pregnancy
    • Allergy to study drugs
    • No central venous line with >= 3 lumens
    • Palliative treatment only, limits to care, death is imminent or death is likely within 90 days due to underlying process
  • 2630 patients screened, 432 eligible patients were randomised (ITT), 422 received a study drug (mITT)
    • Pathogen isolated in blood cultures in 83 patients

Intervention

  • Continuous infusion of beta-lactam antibiotics
    • Loading dose of chosen antibiotic
    • Continuous infusion thereafter
      • 1g in 100ml Meropenem over 24 hours
      • 13.5g in 250ml Piperacillin-tazobactam over 24 hours
      • 12.4g in 250ml Ticarcillin-clavulanate over 24 hours
    • Administered with a normal saline dummy intermittent infusion

Control

  • Intermittent infusion of beta-lactam antibiotics
    • Loading dose of chosen antibiotic
    • Intermittent infusion thereafter
      • 1g in 20ml Meropenem once daily
      • 4.5g in 20ml Piperacillin-tazobactam three times daily
      • 3.1g in 20ml Ticarcillin-clavulanate four times daily
    • Administered with a normal saline dummy continuous infusion

Management common to both groups

  • Infusions were administered via a primed central venous line
  • A change between the three beta-lactam antibiotics or to flucloxacillin was permitted within 14 days
    • If flucloxacillin was introduced, a non-blinded loading dose was administered followed by blinded administration as per the patient’s allocation
  • Total dose over 24 hours was the same regardless of group allocation

Outcome

  • Characteristics of the groups (continuous vs intermittent)
    • APACHE II score: 21 [IQR 17-26] vs 20 [IQR 16-25]
    • Median antibiotic administration prior to randomisation: 13 hours vs 12 hours
    • Median duration of blinded study drug treatment: 3.2 days [IQR 1.9-6.0] vs 3.7 days [IQR 1.9-5.9]
    • Median total course of beta-lactam antibiotic: 5.3 days [IQR 2.9-7.7] vs 5.0 days [IQR 3.1-8.0]
    • Change in antibiotic: 9.4% patients vs 11.8% patients
    • Choice of antibiotic:
      • Piperacillin-tazobactam: 69.3% vs 71.4%
      • Meropenem: 29.7% vs 27.3%
      • Ticarcillin-clavulanate: 0.9% vs 1.4%
  • Primary outcome: no difference was demonstrated in alive ICU-free days at 28 days
    • Continuous group: 18 days [IQR 2-24]
    • Intermittent: 20 days [IQR 3-24]
    • P-value: 0.38
  • Secondary outcome:
    • ICU-free days at 90 days: no difference found
      • Hazard ratio: 0.91 (95% CI 0.63-1.31; p-value = 0.61)
    • Clinical cure at 14 days after antibiotic cessation: no difference found
      • Odds ratio: 1.12 (95% CI 0.77-1.63; p-value 0.56)
  • Modified Intention-to-treat and per-protocol analysis
    • Differences remained non-significant for these two a priori defined populations

Authors’ Conclusions

  • In a heterogenous Intensive Care Unit population, continuous and intermittent infusion of beta-lactams appear to have equivalent outcomes

Strengths

  • Inclusion of a pragmatic, heterogenous ICU population including those on renal replacement therapy
  • Appropriate randomisation, concealment and blinding
  • Double-blind and double-dummy administration removes possible bias, which is particularly important given that the treating clinicians could influence the outcome measure (early or late discharge from ICU)

Weaknesses

  • Not powered to detect mortality differences; this study used alive ICU-free days at 28 days as a surrogate
  • Relatively short antibiotic courses were used, and so may not represent all ICU practice
  • Very few patients received ticarcillin-clavulanate, so the results may not be representative for this antibiotic
  • Clinical cure was assessed subjectively by blinded clinician

The Bottom Line

  • In ICU patients, with underlying pathophysiological changes of sepsis and organ dysfunction, there appears to be no benefit from continuous infusion of beta-lactam antibiotics compared to intermittent bolus infusion
  • Given the simplicity of an intermittent bolus infusion, this should be the preferred method for these antibiotics in this patient group

External Links

Metadata

Summary author: @DuncanChambler
Summary date: 2 October 2015
Peer-review editor: @avkwong

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