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• W3027962356 abstract "BackgroundPatients 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 QuestionWhat is the impact of delayed appropriate antibacterial therapy on clinical outcomes in patients with severe bacterial infections?Study Design and MethodsLiterature 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.ResultsThe 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.InterpretationAvoiding delayed appropriate therapy is essential to reduce mortality in patients with severe bacterial infections.Clinical Trial RegistrationPROSPERO; No.: CRD42018104669; URL: www.crd.york.ac.uk/prospero/ 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. What is the impact of delayed appropriate antibacterial therapy on clinical outcomes in patients with severe bacterial infections? 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. 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. Avoiding delayed appropriate therapy is essential to reduce mortality in patients with severe bacterial infections. PROSPERO; No.: CRD42018104669; URL: www.crd.york.ac.uk/prospero/ Severe bacterial infections requiring in-hospital treatment are associated with considerable mortality, morbidity, and health-care costs.1Battle S.E. Bookstaver P.B. Justo J.A. Kohn J. Albrecht H. Al-Hasan M.N. Association between inappropriate empirical antimicrobial therapy and hospital length of stay in gram-negative bloodstream infections: stratification by prognosis.J Antimicrob Chemother. 2017; 72: 299-304Crossref PubMed Scopus (44) Google Scholar, 2Gradel K.O. Jensen U.S. Schønheyder H.C. et al.Danish Collaborative Bacteraemia Network (DACOBAN)Impact of appropriate empirical antibiotic treatment on recurrence and mortality in patients with bacteraemia: a population-based cohort study.BMC Infect Dis. 2017; 17: 122Crossref PubMed Scopus (36) Google Scholar, 3Kumar A. Ellis P. Arabi Y. et al.Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock.Chest. 2009; 136: 1237-1248Abstract Full Text Full Text PDF PubMed Scopus (814) Google Scholar Choice of antibiotic therapy is usually guided by culture-based antimicrobial susceptibility testing; more rapid diagnostic techniques can reduce delays in identifying antimicrobial susceptibility, but are not currently routine.4Bauer K.A. Perez K.K. Forrest G.N. Goff D.A. Review of rapid diagnostic tests used by antimicrobial stewardship programs.Clin Infect Dis. 2014; 59: S134-S145Crossref PubMed Scopus (173) Google Scholar Physicians usually initiate antibiotic therapy before the causative pathogen and its drug resistance profile are known. Increasing antibiotic resistance makes empiric antibiotic selection more difficult as fewer appropriate treatments are available for resistant pathogens and there is heightened pressure to limit unnecessarily broad-spectrum antibiotic use in patients without resistant infections, to preserve antibiotic susceptibility.5Dellit T.H. Owens R.C. McGowan Jr., J.E. et al.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: 159-177Crossref PubMed Scopus (2442) Google Scholar This creates the challenge of providing early appropriate therapy while limiting unnecessary antibiotic use with limited diagnostic information. As a result, many patients with severe bacterial infections experience delays in receiving appropriate antibiotics. The negative consequences of delayed appropriate therapy are widely reported and accepted, and the importance of initiating prompt, appropriate, empiric antibiotic therapy is stressed in guidelines for several types of infection.6Levy M.M. Evans L.E. Rhodes A. The Surviving Sepsis Campaign bundle: 2018 update.Crit Care Med. 2018; 46: 997-1000Crossref PubMed Scopus (395) Google Scholar,7Kelly D.N. Martin-Loeches I. Comparing current US and European guidelines for nosocomial pneumonia.Curr Opin Pulm Med. 2019; 25: 263-270Crossref PubMed Scopus (10) Google Scholar In a retrospective analysis of 17,990 patients with severe sepsis and septic shock, time to first antimicrobial treatment was found to be important for survival.8Ferrer R. Martin-Loeches I. Phillips G. et al.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: 1749-1755Crossref PubMed Scopus (881) Google Scholar Delayed time to effective treatment of gram-negative infections has also been shown to impact negatively on hospital length of stay and costs.9Bonine N.G. Berger A. Altincatal A. et al.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: 103-110Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar A consolidated systematic review of the effect of delayed appropriate antibiotic therapy is not currently available; evidence is needed to help physicians identify the likelihood of negative outcomes and guide treatment decisions to optimize prompt appropriate antibiotic therapy for patients most at risk. The objective of this systematic review was to assess the impact of delayed appropriate antibacterial therapy on outcomes of patients hospitalized with severe bacterial infections. Outcomes of interest included mortality, treatment success/failure, duration and progress of infection, length of hospital/ICU stay, and health-care costs. This article focuses on the impact of delay and time to appropriate antibiotic therapy. This systematic review was undertaken according to the principles in the Cochrane handbook and guidance from the Centre for Reviews and Dissemination.10Higgins 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.Google Scholar,11NHS 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.Google Scholar The protocol was published in the PROSPERO database.12International 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.Google Scholar Studies were eligible for inclusion if they reported the impact of delayed appropriate antibiotic therapy for hospitalized adult patients with severe bacterial infections, including but not limited to urinary tract infections, nosocomial pneumonia, bacteremia, intraabdominal infections, CNS infections, skin and soft tissue infections, and endocarditis. Studies were required to report the appropriateness of antibiotic therapy, an identifiable delay to initiation of appropriate therapy, and at least one of the following outcomes: mortality, treatment success, infection progression, clinical cure, microbiological eradication, duration of antibiotic treatment, length of hospital or ICU stay, or health-care cost. Randomized controlled trials, nonrandomized comparative studies, and observational studies were eligible. Studies involving patients less than 18 years of age or patients with prostatitis, cystic fibrosis, infection with Clostridium difficile, or sexually transmitted infections were excluded. Systematic reviews and meta-analyses were included in the search for study identification purposes but were excluded from analysis. To reflect contemporary practice, reports published before 2007 were excluded, as were those not in English. MEDLINE and Embase were searched on July 24, 2018, using a strategy structured as follows: (nonspecific infections or specific infections) and treatment delay and (hospitalization or named disease severity scores) (see e-Table 1). Database searches were supplemented by a methodical citation search (see e-Appendix 1; Supplementary materials and methods). Reference lists of relevant systematic reviews were also checked for eligible studies. Two reviewers (S. K., J. V. P., or K. W.) independently screened titles and abstracts for inclusion and assessed potentially relevant full texts against the eligibility criteria. A third reviewer resolved conflicts. Where results for one study were reported in more than one article, related articles were grouped to ensure participants were included only once. One person (S. K. or J. V. P.) extracted data from eligible studies, using a piloted data extraction form, and a second reviewer verified every data point. A third reviewer resolved conflicts. Data elements for which data were sought are detailed in e-Table 1. The risk of bias was assessed with the relevant tool (Newcastle Ottawa Scale, CRD Cohort Study Checklist, or Cochrane Risk of Bias Tool).11NHS 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.Google Scholar,13Wells G. Shea B. O’Connell D. Peterson J. Welch V. Loso M. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.http://www.ohri.ca/programs/clinical_epidemiology/oxford.aspDate: 2014Date accessed: June 13, 2020Google Scholar,14Higgins 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.Google Scholar Results were grouped according to the comparison reported: delay vs no delay in receiving appropriate antibiotic therapy, time to appropriate therapy, and appropriate vs inappropriate therapy (see e-Appendix 1; Supplementary materials and methods for examples). Definitions of appropriate antibiotics varied between studies, but usually included therapy to which the microorganism was susceptible, and could also specify appropriate dosing or concordance with guidelines. Where a study reported different definitions of adequate therapy, the most conservative was used. Cutoff times reported for the definition of delay varied between studies and ranged from > 1 h to > 5 days (e-Table 2). Where a study reported several cutoff times, the time point closest to 24 h was selected. Where a study reported several time points for an outcome, specific time points (eg, “at 24 h”) were selected in preference to periods varying between participants (eg, “in hospital”), and the earliest specific time point was selected. Raw data for the number of events and sample size for each outcome were extracted from each article, and the presented ORs for each study were calculated during meta-analyses using a random effects model. Where appropriate, results were statistically pooled for outcomes of interest. Because of heterogeneity between studies, random effects models were used for meta-analyses to estimate the mean of the distribution of true effects, weighting studies according to their size and variance. The OR, overall effect (Z), and heterogeneity (I2) were calculated. Pairwise meta-analyses to pool evidence from comparisons of two interventions were performed using standard frequentist approaches.10Higgins 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.Google Scholar RevMan (version 5.3) was used to conduct the analyses. Subgroup analyses were explored by infection site where data permitted. Further subgroup analyses based on pathogens and infection severity were planned but were unfeasible with the data identified. Literature searches identified 10,800 unique records for screening; 10,320 were excluded after assessment of the title and abstract. The full texts of 480 documents were assessed and 145 studies, reported in 147 records, were eligible for inclusion. Of these, 37 studies reported comparison of delay vs no delay in receiving appropriate therapy15Amaral A.C. Holder M.W. 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; 9e97575Crossref PubMed Scopus (12) Google Scholar, 16Arslan F. Meynet E. Sunbul M. et al.The clinical features, diagnosis, treatment, and prognosis of neuroinvasive listeriosis: a multinational study.Eur J Clin Microbiol Infect Dis. 2015; 34: 1213-1221Crossref PubMed Scopus (55) Google Scholar, 17Berjohn C.M. Fishman N.O. Joffe M.M. Edelstein P.H. Metlay J.P. Treatment and outcomes for patients with bacteremic pneumococcal pneumonia.Medicine. 2008; 87: 160-166Crossref PubMed Scopus (33) Google Scholar, 18Chaubey V.P. Pitout J.D.D. Dalton B. Gregson D.B. Ross T. Laupland K.B. 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: 647Crossref PubMed Scopus (14) Google Scholar, 19Cheng M.P. Bogoch II, Green K. et al.Factors associated with 30-day mortality rate in respiratory infections caused by Streptococcus pneumoniae.Clin Infect Dis. 2017; 66: 1282-1285Crossref Scopus (2) Google Scholar, 20Deng L. Wu X. Kang Y. Xu Y. Zhou J. Wang D. Epidemiology of methicillin-resistant Staphylococcus aureus infection and empirical antibiotic therapy for MRSA infection: multicenter investigation.Chin Med J. 2013; 126: 3745-3749PubMed Google Scholar, 21Erbay A. Idil A. Gözel M.G. Mumcuoğlu I. Balaban N. Impact of early appropriate antimicrobial therapy on survival in Acinetobacter baumannii bloodstream infections.Int J Antimicrob Agents. 2009; 34: 575-579Crossref PubMed Scopus (76) Google Scholar, 22Giner A.M. Kuster S.P. Zbinden R. Ruef C. Ledergerber B. Weber R. Initial management of and outcome in patients with pneumococcal bacteremia: a retrospective study at a Swiss university hospital, 2003-2009.Infection. 2011; 39: 519-526Crossref PubMed Scopus (16) Google Scholar, 23Horino T. Sato F. Hosaka Y. et al.Predictive factors for metastatic infection in patients with bacteremia caused by methicillin-sensitive Staphylococcus aureus.Am J Med Sci. 2015; 349: 24-28Abstract Full Text Full Text PDF PubMed Google Scholar, 24Kaasch A.J. Rieg S. Kuetscher J. et al.Delay in the administration of appropriate antimicrobial therapy in Staphylococcus aureus bloodstream infection: a prospective multicenter hospital-based cohort study.Infection. 2013; 41: 979-985Crossref PubMed Scopus (30) Google Scholar, 25Kim J. Joo E.-J. Ha Y.E. et al.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: 937-945Crossref PubMed Scopus (12) Google Scholar, 26Kwa A.L. Low J.G. Lim T.P. Leow P.C. Kurup A. Tam V.H. Independent predictors for mortality in patients with positive Stenotrophomonas maltophilia cultures.Ann Acad Med Singapore. 2008; 37: 826-830PubMed Google Scholar, 27Labelle A. Juang P. Reichley R. et al.The determinants of hospital mortality among patients with septic shock receiving appropriate initial antibiotic treatment.Crit Care Med. 2012; 40: 2016-2021Crossref PubMed Scopus (60) Google Scholar, 28Lee C.C. Lee C.H. Hong M.Y. Tang H.J. Ko W.C. Timing of appropriate empirical antimicrobial administration and outcome of adults with community-onset bacteremia.Crit Care. 2017; 21: 119Crossref PubMed Scopus (55) Google Scholar, 29Lin M.Y. Weinstein R.A. Hota B. Delay of active antimicrobial therapy and mortality among patients with bacteremia: impact of severe neutropenia.Antimicrob Agents Chemother. 2008; 52: 3188-3194Crossref PubMed Scopus (87) Google Scholar, 30Lueangarun S. Leelarasamee A. Impact of inappropriate empiric antimicrobial therapy on mortality of septic patients with bacteremia: a retrospective study.Interdiscip Perspect Infect Dis. 2012; 2012: 765205Crossref PubMed Scopus (35) Google Scholar, 31Menendez R. Torres A. Reyes S. et al.Initial management of pneumonia and sepsis: factors associated with improved outcome.Eur Respir J. 2012; 39: 156-162Crossref PubMed Scopus (62) Google Scholar, 32Ryoo S.M. Kim W.Y. Sohn C.H. et al.Prognostic value of timing of antibiotic administration in patients with septic shock treated with early quantitative resuscitation.Am J Med Sci. 2015; 349: 328-333Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 33Tigen E.T. Koltka E.N. Dogru A. Orhon Z.N. Gura M. Vahaboglu H. Impact of the initiation time of colistin treatment for Acinetobacter infections.J Infect Chemother. 2013; 19: 703-708Abstract Full Text PDF PubMed Scopus (11) Google Scholar, 34Zarkotou O. Pournaras S. 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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: 647Crossref PubMed Scopus (14) Google Scholar,22Giner A.M. Kuster S.P. Zbinden R. Ruef C. Ledergerber B. Weber R. Initial management of and outcome in patients with pneumococcal bacteremia: a retrospective study at a Swiss university hospital, 2003-2009.Infection. 2011; 39: 519-526Crossref PubMed Scopus (16) Google Scholar,27Labelle A. Juang P. Reichley R. et al.The determinants of hospital mortality among patients with septic shock receiving appropriate initial antibiotic treatment.Crit Care Med. 2012; 40: 2016-2021Crossref PubMed Scopus (60) Google Scholar,30Lueangarun S. Leelarasamee A. Impact of inappropriate empiric antimicrobial therapy on mortality of septic patients with bacteremia: a retrospective study.Interdiscip Perspect Infect Dis. 2012; 2012: 765205Crossref PubMed Scopus (35) Google Scholar,32Ryoo S.M. Kim W.Y. Sohn C.H. et al.Prognostic value of timing of antibiotic administration in patients with septic shock treated with early quantitative resuscitation.Am J Med Sci. 2015; 349: 328-333Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar,35Zasowski E.J. Claeys K.C. Lagnf A.M. Davis S.L. Rybak M.J. 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: 1242-1250Crossref PubMed Scopus (74) Google Scholar,37Balkan I.I. Aygün G. 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Epidemiology of methicillin-resistant Staphylococcus aureus infection and empirical antibiotic therapy for MRSA infection: multicenter investigation.Chin Med J. 2013; 126: 3745-3749PubMed Google Scholar,24Kaasch A.J. Rieg S. Kuetscher J. et al.Delay in the administration of appropriate antimicrobial therapy in Staphylococcus aureus bloodstream infection: a prospective multicenter hospital-based cohort study.Infection. 2013; 41: 979-985Crossref PubMed Scopus (30) Google Scholar,31Menendez R. Torres A. Reyes S. et al.Initial management of pneumonia and sepsis: factors associated with improved outcome.Eur Respir J. 2012; 39: 156-162Crossref PubMed Scopus (62) Google Scholar 32 retrospective cohort studies,15Amaral A.C. Holder M.W. 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; 9e97575Crossref PubMed Scopus (12) Google Scholar, 16Arslan F. Meynet E. Sunbul M. et al.The clinical features, diagnosis, treatment, and prognosis of neuroinvasive listeriosis: a multinational study.Eur J Clin Microbiol Infect Dis. 2015; 34: 1213-1221Crossref PubMed Scopus (55) Google Scholar, 17Berjohn C.M. Fishman N.O. Joffe M.M. Edelstein P.H. Metlay J.P. Treatment and outcomes for patients with bacteremic pneumococcal pneumonia.Medicine. 2008; 87: 160-166Crossref PubMed Scopus (33) Google Scholar, 18Chaubey V.P. Pitout J.D.D. Dalton B. Gregson D.B. Ross T. Laupland K.B. 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: 647Crossref PubMed Scopus (14) Google Scholar, 19Cheng M.P. Bogoch II, Green K. et al.Factors associated with 30-day mortality rate in respiratory infections caused by Streptococcus pneumoniae.Clin Infect Dis. 2017; 66: 1282-1285Crossref Scopus (2) Google Scholar,21Erbay A. Idil A. Gözel M.G. Mumcuoğlu I. Balaban N. Impact of early appropriate antimicrobial therapy on survival in Acinetobacter baumannii bloodstream infections.Int J Antimicrob Agents. 2009; 34: 575-579Crossref PubMed Scopus (76) Google Scholar, 22Giner A.M. Kuster S.P. Zbinden R. Ruef C. Ledergerber B. Weber R. Initial management of and outcome in patients with pneumococcal bacteremia: a retrospective study at a Swiss university hospital, 2003-2009.Infection. 2011; 39: 519-526Crossref PubMed Scopus (16) Google Scholar, 23Horino T. Sato F. Hosaka Y. et al.Predictive factors for metastatic infection in patients with bacteremia caused by methicillin-sensitive Staphylococcus aureus.Am J Med Sci. 2015; 349: 24-28Abstract Full Text Full Text PDF PubMed Google Scholar,25Kim J. Joo E.-J. Ha Y.E. et al.Impact of a computerized alert system for bacteremia notification on the appropriate antibiotic treatment of Staph" @default.
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• W3027962356 title "A Systematic Review of the Effect of Delayed Appropriate Antibiotic Treatment on the Outcomes of Patients With Severe Bacterial Infections" @default.
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