A 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?

Design

• 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

Setting

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

Population

• 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.

Intervention

• 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

Control

• 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

Outcome

• 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

Strengths

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

Weaknesses

• 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

• [article] Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis
• [further reading] A multicenter randomized trial of continuous versus intermittent beta-lactam infusions in severe sepsis
• [further reading] Alternative dosing strategies for intravenous antibiotics to treat severe infections
• [further reading] LITFL CCC – Antimicrobial dosing and kill characteristics

Metadata

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