BLISS Feature ImageA prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis

Abdul-Aziz. ICM 2016; doi:10.1007//s00134-015-4188-0

Clinical Question

  • In adult ICU patients with severe sepsis does the use of continuous infusion (CI) of beta-lactam antibiotics compared to intermittent bolus (IB) improve clinical outcomes?


  • Randomised, controlled trial
  • Prospective, two-centre, open-labelled
    • Computerised block randomisation
    • Unblinded staff prepared drugs
    • Unblinded staff provided care and management plans
    • Blinded investigators assess primary outcome
  • Sample size of 120 patients (60 in each group) to demonstrate a statistical significant difference in primary end point assuming 75% and 45% clinical cure rate in intervention and control group.
  • Intention-to-treat (ITT) analysis for primary outcome, in addition to:
    • Modified intention-to-treat (mITT) conducted in eligible patients who received at least one dose of study drug
    • Per protocol analysis of pts who received study drug for > 4 days


  • 2 ICUs in Malaysia
  • Recruitment from April 2013 to July 2014


  • Inclusion:
    • Adult (>18 years)
    • Severe sepsis (defined as presumed or confirmed infection with new organ dysfunction) in previous 48 hours
    • Indication for cefepime, meropenem or piperacillin/tazobactam with < 24 hr therapy at time of assessment
    • Expected ICU stay greater than 48 hrs
  • Exclusion:
    • Receiving renal replacement therapy
    • Impaired hepatic function (total bilirubin > 100umol/ml)
    • Patients receiving palliative care
    • Inadequate central venous catheter access
    • Death was deemed imminent
  • 220 patients screened, 140 eligible patients randomised. Main reason for exclusion – renal replacement therapy.


  • Continuous infusion (CI) of beta-lactam antibiotics
    • Loading dose of chosen antibiotic
    • Continuous infusion thereafter
      • 6gm Cefepime over 24 hours
      • 3g Meropenem over 24 hours
      • 18g Piperacillin-tazobactam over 24 hours


  • Intermittent bolus (IB) of beta-lactam antibiotics
    • Loading dose of chosen antibiotic
    • Intermittent infusion thereafter
      • Cefepime – 2gm every 8 hrs
      • Meropenem – 1gm every 8 hrs
      • Piperacillin-Tazobactam – 4.5gm every 6 hrs

Management common to both groups

  • Antibiotics administered until
    • Treating intensivists decided to stop drug
    • Pt withdrew from study
    • ICU discharge
    • ICU death
  • All other management plans (including addition of other antibiotics) at discretion of treating intensivists


  • Characteristics of the groups (CI vs IB)
    • APACHE II score: 21 [IQR 17-26] vs 21 [IQR 15-26]
    • Pre-randomisation antibiotic therapy: 74% vs 80%
    • Median duration of drug treatment: 7 days [IQR 5-9] vs 7 days [IQR 5-9]
    • Choice of antibiotic:
      • Cefepime: 16% vs 3%
      • Meropenem: 30% vs 30%
      • Piperacillin-tazobactam: 54% vs 67%
    • Concomitant use of antibiotic: 47% in both groups
    • No difference in 24hr dose of antibiotics in both groups
  • Primary outcome: Higher clinical cure rate at 14 days after antibiotic cessation in CI vs IB
    • Continuous infusion: 56%
    • Intermittent bolus: 34%
    • P-value: 0.011
  • Secondary outcome:
    • PK/PD target attainment: Significantly higher in CI
      • Continuous infusion: 100% fT>MIC 97% on day 3
      • Intermittent bolus: 100% fT>MIC 68% on day 3
    • ICU-free days at 28 days: No significant difference
    • Ventilator-free days at 28 days: Favours CI group
      • Continuous infusion: 22 days
      • Intermittent bolus: 14 days
      • P-value: 0.043
    • Survival at 14 days: No significant difference
    • Survival at 30 days: No significant difference
    • Time to white cell count normalisation: Favours CI group
      • Continuous infusion: 3 days
      • Intermittent bolus: 8 days
      • P-value: <0.001
  • Modified-intention-to-treat analysis did not change outcomes

Authors’ Conclusions

  • In critically ill patients with severe sepsis not receiving RRT, CI administration was associated with higher clinical cure rates and better PK/PD target attainment compared to IB dosing for three common beta-lactam antibiotics


  • Inclusion of a pragmatic, heterogenous ICU population
  • Pharmacokinetic measurements included as secondary endpoints


  • Unblinded staff deciding management plans although assessors for primary outcome were blinded
  • Exclusion of patients requiring renal replacement therapy
  • Additional treatment at discretion of treating intensivists; significant use of concomitant antibiotics
  • No follow up beyond ICU stay
  • Clinical cure rate much lower in both groups compared to that used to power the study

The Bottom Line

  • This study confirms that CI has a superior PK/PD profile compared to IB regiments
  • The higher clinical cure rate, ventilator free days and faster resolution of white cell count in the CI group did not translate to a mortality benefit at both 14 and 30 days
  • Given the weakness in this study and the simplicity of IB regiment, I will continue to use this in my daily practice

External Links


Summary author: @avkwong
Summary date: 21 January 2016
Peer-review editor: @DuncanChambler


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