Background
Patients with severe bacterial infections often experience delay in receiving appropriate
treatment. Consolidated evidence of the impact of delayed appropriate treatment is
needed to guide treatment and improve outcomes.
Research Question
What is the impact of delayed appropriate antibacterial therapy on clinical outcomes
in patients with severe bacterial infections?
Study Design and Methods
Literature searches of MEDLINE and Embase, conducted on July 24, 2018, identified
studies published after 2007 reporting the impact of delayed appropriate therapy on
clinical outcomes for hospitalized adult patients with bacterial infections. Where
appropriate, results were pooled and analyzed with delayed therapy modeled three ways:
delay vs no delay in receiving appropriate therapy; duration of delay; and inappropriate
vs appropriate initial therapy. This article reports meta-analyses on the effect of
delay and duration of delay.
Results
The eligibility criteria were met by 145 studies, of which 37 contributed data to
analyses of effect of delay. Mortality was significantly lower in patients receiving
appropriate therapy without delay compared with those experiencing delay (OR, 0.57;
95% CI, 0.45-0.72). Mortality was also lower in the no-delay group compared with the
delay group in subgroups of studies reporting mortality at 20 to 30 days, during ICU
stay, or in patients with bacteremia (OR, 0.57 [95% CI, 0.43-0.76]; OR, 0.47 [95% CI,
0.27-0.80]; and OR, 0.54 [95% CI, 0.40-0.75], respectively). No difference was found
in time to appropriate therapy between those who died and those who survived (
P = .09), but heterogeneity between studies was high.
Interpretation
Avoiding delayed appropriate therapy is essential to reduce mortality in patients
with severe bacterial infections.
Clinical Trial Registration
PROSPERO; No.: CRD42018104669; URL:
www.crd.york.ac.uk/prospero/
Key Words
Abbreviations:
APACHE ( Acute Physiology and Chronic Health Evaluation), HR ( hazard ratio), I2 ( heterogeneity), Z ( overall effect size)To read this article in full you will need to make a payment
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References
- Association between inappropriate empirical antimicrobial therapy and hospital length of stay in gram-negative bloodstream infections: stratification by prognosis.J Antimicrob Chemother. 2017; 72: 299-304
- Impact of appropriate empirical antibiotic treatment on recurrence and mortality in patients with bacteraemia: a population-based cohort study.BMC Infect Dis. 2017; 17: 122
- Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock.Chest. 2009; 136: 1237-1248
- Review of rapid diagnostic tests used by antimicrobial stewardship programs.Clin Infect Dis. 2014; 59: S134-S145
- Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship.Clin Infect Dis. 2007; 44: 159-177
- The Surviving Sepsis Campaign bundle: 2018 update.Crit Care Med. 2018; 46: 997-1000
- Comparing current US and European guidelines for nosocomial pneumonia.Curr Opin Pulm Med. 2019; 25: 263-270
- Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program.Crit Care Med. 2014; 42: 1749-1755
- Impact of delayed appropriate antibiotic therapy on patient outcomes by antibiotic resistance status from serious gram-negative bacterial infections.Am J Med Sci. 2019; 357: 103-110
Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0. Updated March 2011. Cochrane Collaboration. https://handbook-5-1.cochrane.org/. Accessed June 13, 2020.
NHS Centre for Reviews and Dissemination. Undertaking Systematic Reviews of Research on Effectiveness: CRD’s Guidance for Those Carrying Out or Commissioning Reviews. CRD Report 4, 2nd ed. York, UK: University of York; 2001.
International Prospective Register of Systematic Reviews (PROSPERO). Systematic review on impact of delay in appropriate therapy in hospital for bacterial infections (impact of delay). CRD42018104669. National Institute for Health Research; 2018. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=104669. Accessed June 14, 2020.
- The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.
Higgins JPT, Altman D, Sterne J. Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0. Updated March 2011. Cochrane Collaboration. https://handbook-5-1.cochrane.org/chapter_8/8_assessing_risk_of_bias_in_included_studies.htm. Accessed June 13, 2020.
- Timing of antimicrobial therapy after identification of ventilator-associated condition is not associated with mortality in patients with ventilator-associated pneumonia: a cohort study.PLoS One. 2014; 9e97575
- The clinical features, diagnosis, treatment, and prognosis of neuroinvasive listeriosis: a multinational study.Eur J Clin Microbiol Infect Dis. 2015; 34: 1213-1221
- Treatment and outcomes for patients with bacteremic pneumococcal pneumonia.Medicine. 2008; 87: 160-166
- Clinical and microbiological characteristics of bloodstream infections due to AmpC β-lactamase producing Enterobacteriaceae: an active surveillance cohort in a large centralized Canadian region.BMC Infect Dis. 2014; 14: 647
- Factors associated with 30-day mortality rate in respiratory infections caused by Streptococcus pneumoniae.Clin Infect Dis. 2017; 66: 1282-1285
- Epidemiology of methicillin-resistant Staphylococcus aureus infection and empirical antibiotic therapy for MRSA infection: multicenter investigation.Chin Med J. 2013; 126: 3745-3749
- Impact of early appropriate antimicrobial therapy on survival in Acinetobacter baumannii bloodstream infections.Int J Antimicrob Agents. 2009; 34: 575-579
- Initial management of and outcome in patients with pneumococcal bacteremia: a retrospective study at a Swiss university hospital, 2003-2009.Infection. 2011; 39: 519-526
- Predictive factors for metastatic infection in patients with bacteremia caused by methicillin-sensitive Staphylococcus aureus.Am J Med Sci. 2015; 349: 24-28
- Delay in the administration of appropriate antimicrobial therapy in Staphylococcus aureus bloodstream infection: a prospective multicenter hospital-based cohort study.Infection. 2013; 41: 979-985
- Impact of a computerized alert system for bacteremia notification on the appropriate antibiotic treatment of Staphylococcus aureus bloodstream infections.Eur J Clin Microbiol Infect Dis. 2013; 32: 937-945
- Independent predictors for mortality in patients with positive Stenotrophomonas maltophilia cultures.Ann Acad Med Singapore. 2008; 37: 826-830
- The determinants of hospital mortality among patients with septic shock receiving appropriate initial antibiotic treatment.Crit Care Med. 2012; 40: 2016-2021
- Timing of appropriate empirical antimicrobial administration and outcome of adults with community-onset bacteremia.Crit Care. 2017; 21: 119
- Delay of active antimicrobial therapy and mortality among patients with bacteremia: impact of severe neutropenia.Antimicrob Agents Chemother. 2008; 52: 3188-3194
- Impact of inappropriate empiric antimicrobial therapy on mortality of septic patients with bacteremia: a retrospective study.Interdiscip Perspect Infect Dis. 2012; 2012: 765205
- Initial management of pneumonia and sepsis: factors associated with improved outcome.Eur Respir J. 2012; 39: 156-162
- Prognostic value of timing of antibiotic administration in patients with septic shock treated with early quantitative resuscitation.Am J Med Sci. 2015; 349: 328-333
- Impact of the initiation time of colistin treatment for Acinetobacter infections.J Infect Chemother. 2013; 19: 703-708
- Predictors of mortality in patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae and impact of appropriate antimicrobial treatment.Clin Microbiol Infect. 2011; 17: 1798-1803
- Time is of the essence: the impact of delayed antibiotic therapy on patient outcomes in hospital-onset enterococcal bloodstream infections.Clin Infect Dis. 2016; 62: 1242-1250
- Ventilator-associated pneumonia: epidemiology and prognostic indicators of 30-day mortality.Jpn J Infect Dis. 2015; 68: 181-186
- Blood stream infections due to OXA-48-like carbapenemase-producing Enterobacteriaceae: treatment and survival.Int J Infect Dis. 2014; 26: 51-56
- Time to antibiotic therapy and outcome in bacterial meningitis: a Danish population-based cohort study.BMC Infect Dis. 2016; 16: 392
- Early administration of the first antimicrobials should be considered a marker of optimal care of patients with community-acquired pneumonia rather than a predictor of outcomes.Int J Infect Dis. 2013; 17: e293-e298
- Impact of sepsis classification and multidrug-resistance status on outcome among patients treated with appropriate therapy.Crit Care Med. 2015; 43: 1580-1586
- Bacteremic pneumonia caused by extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae: appropriateness of empirical treatment matters.J Microbiol Immunol Infect. 2016; 49: 208-215
- Risk factors and outcome of infections with Klebsiella pneumoniae carbapenemase-producing K. pneumoniae in kidney transplant recipients.Infection. 2015; 43: 315-323
- Prognostic impact of left ventricular diastolic function in patients with septic shock.Ann Intensive Care. 2016; 6: 36
- Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT): a retrospective cohort study.Lancet Infect Dis. 2017; 17: 726-734
- Delay of adequate empiric antibiotic therapy is associated with increased mortality among solid-organ transplant patients.Am J Transplant. 2009; 9: 1657-1665
- Appropriate antibiotic administration in critically ill patients with pneumonia.Indian J Pharm Sci. 2015; 77: 299-305
- Predictors of 30-day mortality and hospital costs in patients with ventilator-associated pneumonia attributed to potentially antibiotic-resistant gram-negative bacteria.Chest. 2008; 134: 281-287
- Predictors of 30-day mortality among patients with Pseudomonas aeruginosa bloodstream infections: impact of delayed appropriate antibiotic selection.Antimicrob Agents Chemother. 2007; 51: 3510-3515
- Empiric antibiotic therapy for Staphylococcus aureus bacteremia may not reduce in-hospital mortality: a retrospective cohort study.PLoS One. 2010; 5e11432
- Multifaceted antibiotic treatment analysis of methicillin-sensitive Staphylococcus aureus bloodstream infections.Int J Antimicrob Agents. 2016; 48: 674-679
- Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with Enterobacteriaceae urinary tract infection, pneumonia and sepsis.BMC Infect Dis. 2017; 17: 279
- Outcome of ventilator-associated pneumonia: impact of antibiotic therapy and other factors.Australas Med J. 2012; 5: 135-140
- Diagnosis of ambulatory community-acquired pneumonia: comparison of clinical assessment versus chest X-ray.Scand J Prim Health Care. 2003; 21: 57-60
- Rapid phenotypic methods to improve the diagnosis of bacterial bloodstream infections: meeting the challenge to reduce the time to result.Clin Microbiol Infect. 2018; 24: 935-943
- How to accelerate antimicrobial susceptibility testing.Clin Microbiol Infect. 2019; 25: 1347-1355
- Current and emerging methods of antibiotic susceptibility testing.Diagnostics (Basel). 2019; 9: 49
- Rapid susceptibility testing methods.Clin Lab Med. 2019; 39: 333-344
- Clinical outcomes of prolonged infusion (extended infusion or continuous infusion) versus intermittent bolus of meropenem in severe infection: a meta-analysis.PLoS One. 2018; 13e0201667
European Committee on Antimicrobial Susceptibility Testing. Clinical Breakpoints and Dosing of Antibiotics. January 2020. https://eucast.org/clinical_breakpoints/. Accessed June 13, 2020.
Clinical Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing, 30th ed. CLSI supplement M100. Wayne, PA: Clinical Laboratory Standards Institute; 2020. https://clsi.org/meetings/microbiology/. Accessed June 13, 2020.
- Counterpoint: should broad-spectrum antibiotics be routinely administered to all patients with sepsis as soon as possible? No.Chest. 2019; 156: 647-649
- Broad-spectrum antibiotic use and poor outcomes in community-onset pneumonia: a cohort study.Eur Respir J. 2019; 54: 1900057
European Centre for Disease Prevention and Control (ECDC). Surveillance of Antimicrobial Resistance in Europe 2017. Stockholm: ECDC; 2017. https://www.ecdc.europa.eu/en/publications-data/surveillance-antimicrobial-resistance-europe-2017. Accessed June 13, 2020.
Article Info
Publication History
Published online: May 21, 2020
Footnotes
FUNDING/SUPPORT: This study was funded by Shionogi BV.
Identification
Copyright
© 2020 Published by Elsevier Inc under license from the American College of Chest Physicians.
