Continuous versus intermittent β-lactam infusion in severe sepsis

A meta-analysis of individual patient data from randomized trials

Jason A. Roberts, Mohd Hafiz Abdul-Aziz, Joshua S. Davis, Joel M. Dulhunty, Menino O. Cotta, John Myburgh, Rinaldo Bellomo, Jeffrey Lipman

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    Rationale: Optimization of β-lactam antibiotic dosing for critically ill patients is an intervention that may improve outcomes in severe sepsis. 

    Objectives: In this individual patient data meta-analysis of critically ill patients with severe sepsis, we aimed to compare clinical outcomes of those treated with continuous versus intermittent infusion of β-lactam antibiotics. 

    Methods: We identified relevant randomized controlled trials comparing continuous versus intermittent infusion of β-lactam antibiotics in critically ill patients with severe sepsis. We assessed the quality of the studies according to four criteria. We combined individual patient data from studies and assessed data integrity for common baseline demographics and study endpoints, including hospital mortality censored at 30 days and clinical cure. We then determined the pooled estimates of effect and investigated factors associated with hospital mortality in multivariable analysis. 

    Measurements and Main Results: We identified three randomized controlled trials in which researchers recruited a total of 632 patients with severe sepsis. The two groups were well balanced in terms of age, sex, and illness severity. The rates of hospital mortality and clinical cure for the continuous versus intermittent infusion groups were 19.6% versus 26.3% (relative risk, 0.74; 95% confidence interval, 0.56-1.00; P = 0.045) and 55.4% versus 46.3% (relative risk, 1.20; 95% confidence interval, 1.03-1.40; P = 0.021), respectively. In a multivariable model, intermittent β-lactam administration, higher Acute Physiology and Chronic Health Evaluation II score, use of renal replacement therapy, and infection by nonfermenting gram-negative bacilli were significantly associated with hospital mortality. Continuous β-lactam administration was not independently associated with clinical cure. 

    Conclusions: Compared with intermittent dosing, administration of β-lactamantibioticsby continuous infusionincritically ill patientswith severe sepsis is associated with decreased hospital mortality.

    Original languageEnglish
    Pages (from-to)681-691
    Number of pages11
    JournalAmerican Journal of Respiratory and Critical Care Medicine
    Volume194
    Issue number6
    Early online date15 Mar 2016
    DOIs
    Publication statusPublished - 15 Sep 2016

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    Lactams
    Meta-Analysis
    Hospital Mortality
    Sepsis
    Critical Illness
    Anti-Bacterial Agents
    Randomized Controlled Trials
    Confidence Intervals
    APACHE
    Renal Replacement Therapy
    Bacillus
    Research Personnel
    Demography
    Infection

    Cite this

    Roberts, Jason A. ; Abdul-Aziz, Mohd Hafiz ; Davis, Joshua S. ; Dulhunty, Joel M. ; Cotta, Menino O. ; Myburgh, John ; Bellomo, Rinaldo ; Lipman, Jeffrey. / Continuous versus intermittent β-lactam infusion in severe sepsis : A meta-analysis of individual patient data from randomized trials. In: American Journal of Respiratory and Critical Care Medicine. 2016 ; Vol. 194, No. 6. pp. 681-691.
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    abstract = "Rationale: Optimization of β-lactam antibiotic dosing for critically ill patients is an intervention that may improve outcomes in severe sepsis. Objectives: In this individual patient data meta-analysis of critically ill patients with severe sepsis, we aimed to compare clinical outcomes of those treated with continuous versus intermittent infusion of β-lactam antibiotics. Methods: We identified relevant randomized controlled trials comparing continuous versus intermittent infusion of β-lactam antibiotics in critically ill patients with severe sepsis. We assessed the quality of the studies according to four criteria. We combined individual patient data from studies and assessed data integrity for common baseline demographics and study endpoints, including hospital mortality censored at 30 days and clinical cure. We then determined the pooled estimates of effect and investigated factors associated with hospital mortality in multivariable analysis. Measurements and Main Results: We identified three randomized controlled trials in which researchers recruited a total of 632 patients with severe sepsis. The two groups were well balanced in terms of age, sex, and illness severity. The rates of hospital mortality and clinical cure for the continuous versus intermittent infusion groups were 19.6{\%} versus 26.3{\%} (relative risk, 0.74; 95{\%} confidence interval, 0.56-1.00; P = 0.045) and 55.4{\%} versus 46.3{\%} (relative risk, 1.20; 95{\%} confidence interval, 1.03-1.40; P = 0.021), respectively. In a multivariable model, intermittent β-lactam administration, higher Acute Physiology and Chronic Health Evaluation II score, use of renal replacement therapy, and infection by nonfermenting gram-negative bacilli were significantly associated with hospital mortality. Continuous β-lactam administration was not independently associated with clinical cure. Conclusions: Compared with intermittent dosing, administration of β-lactamantibioticsby continuous infusionincritically ill patientswith severe sepsis is associated with decreased hospital mortality.",
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    Continuous versus intermittent β-lactam infusion in severe sepsis : A meta-analysis of individual patient data from randomized trials. / Roberts, Jason A.; Abdul-Aziz, Mohd Hafiz; Davis, Joshua S.; Dulhunty, Joel M.; Cotta, Menino O.; Myburgh, John; Bellomo, Rinaldo; Lipman, Jeffrey.

    In: American Journal of Respiratory and Critical Care Medicine, Vol. 194, No. 6, 15.09.2016, p. 681-691.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Continuous versus intermittent β-lactam infusion in severe sepsis

    T2 - A meta-analysis of individual patient data from randomized trials

    AU - Roberts, Jason A.

    AU - Abdul-Aziz, Mohd Hafiz

    AU - Davis, Joshua S.

    AU - Dulhunty, Joel M.

    AU - Cotta, Menino O.

    AU - Myburgh, John

    AU - Bellomo, Rinaldo

    AU - Lipman, Jeffrey

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    N2 - Rationale: Optimization of β-lactam antibiotic dosing for critically ill patients is an intervention that may improve outcomes in severe sepsis. Objectives: In this individual patient data meta-analysis of critically ill patients with severe sepsis, we aimed to compare clinical outcomes of those treated with continuous versus intermittent infusion of β-lactam antibiotics. Methods: We identified relevant randomized controlled trials comparing continuous versus intermittent infusion of β-lactam antibiotics in critically ill patients with severe sepsis. We assessed the quality of the studies according to four criteria. We combined individual patient data from studies and assessed data integrity for common baseline demographics and study endpoints, including hospital mortality censored at 30 days and clinical cure. We then determined the pooled estimates of effect and investigated factors associated with hospital mortality in multivariable analysis. Measurements and Main Results: We identified three randomized controlled trials in which researchers recruited a total of 632 patients with severe sepsis. The two groups were well balanced in terms of age, sex, and illness severity. The rates of hospital mortality and clinical cure for the continuous versus intermittent infusion groups were 19.6% versus 26.3% (relative risk, 0.74; 95% confidence interval, 0.56-1.00; P = 0.045) and 55.4% versus 46.3% (relative risk, 1.20; 95% confidence interval, 1.03-1.40; P = 0.021), respectively. In a multivariable model, intermittent β-lactam administration, higher Acute Physiology and Chronic Health Evaluation II score, use of renal replacement therapy, and infection by nonfermenting gram-negative bacilli were significantly associated with hospital mortality. Continuous β-lactam administration was not independently associated with clinical cure. Conclusions: Compared with intermittent dosing, administration of β-lactamantibioticsby continuous infusionincritically ill patientswith severe sepsis is associated with decreased hospital mortality.

    AB - Rationale: Optimization of β-lactam antibiotic dosing for critically ill patients is an intervention that may improve outcomes in severe sepsis. Objectives: In this individual patient data meta-analysis of critically ill patients with severe sepsis, we aimed to compare clinical outcomes of those treated with continuous versus intermittent infusion of β-lactam antibiotics. Methods: We identified relevant randomized controlled trials comparing continuous versus intermittent infusion of β-lactam antibiotics in critically ill patients with severe sepsis. We assessed the quality of the studies according to four criteria. We combined individual patient data from studies and assessed data integrity for common baseline demographics and study endpoints, including hospital mortality censored at 30 days and clinical cure. We then determined the pooled estimates of effect and investigated factors associated with hospital mortality in multivariable analysis. Measurements and Main Results: We identified three randomized controlled trials in which researchers recruited a total of 632 patients with severe sepsis. The two groups were well balanced in terms of age, sex, and illness severity. The rates of hospital mortality and clinical cure for the continuous versus intermittent infusion groups were 19.6% versus 26.3% (relative risk, 0.74; 95% confidence interval, 0.56-1.00; P = 0.045) and 55.4% versus 46.3% (relative risk, 1.20; 95% confidence interval, 1.03-1.40; P = 0.021), respectively. In a multivariable model, intermittent β-lactam administration, higher Acute Physiology and Chronic Health Evaluation II score, use of renal replacement therapy, and infection by nonfermenting gram-negative bacilli were significantly associated with hospital mortality. Continuous β-lactam administration was not independently associated with clinical cure. Conclusions: Compared with intermittent dosing, administration of β-lactamantibioticsby continuous infusionincritically ill patientswith severe sepsis is associated with decreased hospital mortality.

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    KW - Meropenem

    KW - Pharmacodynamics

    KW - Pharmacokinetics

    KW - Piperacillin-tazobactam

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