Semin Respir Crit Care Med 2019; 40(04): 447-453
DOI: 10.1055/s-0039-1694970
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Early Antimicrobial Therapy for Sepsis: Does Each Hour Really Count?

Benoit Guery
1   Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
,
Thierry Calandra
1   Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
› Author Affiliations
Further Information

Publication History

Publication Date:
04 October 2019 (online)

Abstract

For the last decades, the timing of antimicrobial therapy has remained a hotly debated topic in sepsis as well as other infectious diseases like community-acquired pneumonia (CAP) or bacterial meningitis (CABM). In CAP, a relationship between the time to antibiotic administration and mortality was found only in the largest cohort, but all these studies were retrospective and of low quality. In CABM, the level of evidence remains also limited, but there is now a good body of evidence linking the delay to antibiotic administration to unfavorable outcome. The European guidelines strongly suggest that time period should not exceed 1 hour. Finally, in sepsis, if the 1-hour cut-off remains debatable for sepsis patients, early administration (within 3 hours) is recommended in sepsis and sepsis shock as suggested by the surviving sepsis campaign recommendations. To conclude, all these data are in favor of a potential link between the time to antibiotic administration and survival, but we still miss randomized controlled studies to give a definite answer.

 
  • References

  • 1 Rhodes A, Evans LE, Alhazzani W. , et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med 2017; 45 (03) 486-552
  • 2 Silber SH, Garrett C, Singh R. , et al. Early administration of antibiotics does not shorten time to clinical stability in patients with moderate-to-severe community-acquired pneumonia. Chest 2003; 124 (05) 1798-1804
  • 3 Waterer GW, Kessler LA, Wunderink RG. Delayed administration of antibiotics and atypical presentation in community-acquired pneumonia. Chest 2006; 130 (01) 11-15
  • 4 Lee JS, Primack BA, Mor MK. , et al. Processes of care and outcomes for community-acquired pneumonia. Am J Med 2011; 124 (12) 1175.e9-1175.e17
  • 5 Simonetti A, Viasus D, Garcia-Vidal C. , et al. Timing of antibiotic administration and outcomes of hospitalized patients with community-acquired and healthcare-associated pneumonia. Clin Microbiol Infect 2012; 18 (11) 1149-1155
  • 6 Cheng AC, Buising KL. Delayed administration of antibiotics and mortality in patients with community-acquired pneumonia. Ann Emerg Med 2009; 53 (05) 618-624
  • 7 Houck PM, Bratzler DW, Nsa W, Ma A, Bartlett JG. Timing of antibiotic administration and outcomes for Medicare patients hospitalized with community-acquired pneumonia. Arch Intern Med 2004; 164 (06) 637-644
  • 8 Meehan TP, Fine MJ, Krumholz HM. , et al. Quality of care, process, and outcomes in elderly patients with pneumonia. JAMA 1997; 278 (23) 2080-2084
  • 9 Wilson PA, Ferguson J. Severe community-acquired pneumonia: an Australian perspective. Intern Med J 2005; 35 (12) 699-705
  • 10 Marti C, John G, Genné D. , et al. Time to antibiotics administration and outcome in community-acquired pneumonia: secondary analysis of a randomized controlled trial. Eur J Intern Med 2017; 43: 58-61
  • 11 Bordon J, Aliberti S, Duvvuri P. , et al. 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 (05) e293-e298
  • 12 Dedier J, Singer DE, Chang Y, Moore M, Atlas SJ. Processes of care, illness severity, and outcomes in the management of community-acquired pneumonia at academic hospitals. Arch Intern Med 2001; 161 (17) 2099-2104
  • 13 Lee JS, Nsa W, Hausmann LRM. , et al. Quality of care for elderly patients hospitalized for pneumonia in the United States, 2006 to 2010. JAMA Intern Med 2014; 174 (11) 1806-1814
  • 14 Lee JS, Giesler DL, Gellad WF, Fine MJ. Antibiotic therapy for adults hospitalized with community-acquired pneumonia: a systematic review. JAMA 2016; 315 (06) 593-602
  • 15 Yu KT, Wyer PC. Evidence-based emergency medicine/critically appraised topic. Evidence behind the 4-hour rule for initiation of antibiotic therapy in community-acquired pneumonia. Ann Emerg Med 2008; 51 (05) 651-662 , 662.e1–662.e2
  • 16 Welker JA, Huston M, McCue JD. Antibiotic timing and errors in diagnosing pneumonia. Arch Intern Med 2008; 168 (04) 351-356
  • 17 Yahav D, Leibovici L, Goldberg E, Bishara J, Paul M. Time to first antibiotic dose for patients hospitalised with community-acquired pneumonia. Int J Antimicrob Agents 2013; 41 (05) 410-413
  • 18 Pines JM, Isserman JA, Hinfey PB. The measurement of time to first antibiotic dose for pneumonia in the emergency department: a white paper and position statement prepared for the American Academy of Emergency Medicine. J Emerg Med 2009; 37 (03) 335-340
  • 19 Mandell LA, Wunderink RG, Anzueto A. , et al; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 (02) (Suppl. 02) S27-S72
  • 20 Lim WS, Baudouin SV, George RC. , et al; Pneumonia Guidelines Committee of the BTS Standards of Care Committee. BTS guidelines for the management of community acquired pneumonia in adults: update 2009. Thorax 2009; 64 (Suppl. 03) iii1-iii55
  • 21 Cartwright K, Reilly S, White D, Stuart J. Early treatment with parenteral penicillin in meningococcal disease. BMJ 1992; 305 (6846): 143-147
  • 22 Aronin SI, Peduzzi P, Quagliarello VJ. Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med 1998; 129 (11) 862-869
  • 23 Dzupova O, Rozsypal H, Prochazka B, Benes J. Acute bacterial meningitis in adults: predictors of outcome. Scand J Infect Dis 2009; 41 (05) 348-354
  • 24 Grindborg Ö, Naucler P, Sjölin J, Glimåker M. Adult bacterial meningitis-a quality registry study: earlier treatment and favourable outcome if initial management by infectious diseases physicians. Clin Microbiol Infect 2015; 21 (06) 560-566
  • 25 Bodilsen J, Brandt CT, Sharew A. , et al. Early versus late diagnosis in community-acquired bacterial meningitis: a retrospective cohort study. Clin Microbiol Infect 2018; 24 (02) 166-170
  • 26 Køster-Rasmussen R, Korshin A, Meyer CN. Antibiotic treatment delay and outcome in acute bacterial meningitis. J Infect 2008; 57 (06) 449-454
  • 27 Miner JR, Heegaard W, Mapes A, Biros M. Presentation, time to antibiotics, and mortality of patients with bacterial meningitis at an urban county medical center. J Emerg Med 2001; 21 (04) 387-392
  • 28 van de Beek D, Cabellos C, Dzupova O. , et al. ESCMID guideline: diagnosis and treatment of acute bacterial meningitis. Clin Microbiol Infect 2016; 22 (Suppl. 03) S37-S62
  • 29 Singer M, Deutschman CS, Seymour CW. , et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315 (08) 801-810
  • 30 Rhee C, Dantes R, Epstein L. , et al; CDC Prevention Epicenter Program. Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009-2014. JAMA 2017; 318 (13) 1241-1249
  • 31 Lamontagne F, Briel M, Duffett M. , et al. Systematic review of reviews including animal studies addressing therapeutic interventions for sepsis. Crit Care Med 2010; 38 (12) 2401-2408
  • 32 Efron PA, Mohr AM, Moore FA, Moldawer LL. The future of murine sepsis and trauma research models. J Leukoc Biol 2015; 98 (06) 945-952
  • 33 Greisman SE, DuBuy JB, Woodward CL. Experimental gram-negative bacterial sepsis: prevention of mortality not preventable by antibiotics alone. Infect Immun 1979; 25 (02) 538-557
  • 34 Kumar A, Haery C, Paladugu B. , et al. The duration of hypotension before the initiation of antibiotic treatment is a critical determinant of survival in a murine model of Escherichia coli septic shock: association with serum lactate and inflammatory cytokine levels. J Infect Dis 2006; 193 (02) 251-258
  • 35 Lewis AJ, Griepentrog JE, Zhang X, Angus DC, Seymour CW, Rosengart MR. Prompt administration of antibiotics and fluids in the treatment of sepsis: a murine trial. Crit Care Med 2018; 46 (05) e426-e434
  • 36 Ferrer R, Artigas A, Suárez D. , et al; Edusepsis Study Group. Effectiveness of treatments for severe sepsis: a prospective, multicenter, observational study. Am J Respir Crit Care Med 2009; 180 (09) 861-866
  • 37 Bloos F, Thomas-Rüddel D, Rüddel H. , et al; MEDUSA Study Group. Impact of compliance with infection management guidelines on outcome in patients with severe sepsis: a prospective observational multi-center study. Crit Care 2014; 18 (02) R42
  • 38 Puskarich MA, Trzeciak S, Shapiro NI. , et al; Emergency Medicine Shock Research Network (EMSHOCKNET). Association between timing of antibiotic administration and mortality from septic shock in patients treated with a quantitative resuscitation protocol. Crit Care Med 2011; 39 (09) 2066-2071
  • 39 de Groot B, Ansems A, Gerling DH. , et al. The association between time to antibiotics and relevant clinical outcomes in emergency department patients with various stages of sepsis: a prospective multi-center study. Crit Care 2015; 19 (01) 194
  • 40 Alam N, Oskam E, Stassen PM. , et al; PHANTASi Trial Investigators and the ORCA (Onderzoeks Consortium Acute Geneeskunde) Research Consortium the Netherlands. Prehospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomised trial. Lancet Respir Med 2018; 6 (01) 40-50
  • 41 Jalili M, Barzegari H, Pourtabatabaei N. , et al. Effect of door-to-antibiotic time on mortality of patients with sepsis in emergency department: a prospective cohort study. Acta Med Iran 2013; 51 (07) 454-460
  • 42 Ryoo SM, Kim WY, Sohn CH. , 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 (04) 328-333
  • 43 Kumar A, Roberts D, Wood KE. , et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34 (06) 1589-1596
  • 44 Seymour CW, Gesten F, Prescott HC. , et al. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med 2017; 376 (23) 2235-2244
  • 45 Liu VX, Fielding-Singh V, Greene JD. , et al. The timing of early antibiotics and hospital mortality in sepsis. Am J Respir Crit Care Med 2017; 196 (07) 856-863
  • 46 Ferrer R, Martín-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 (08) 1749-1755
  • 47 Gaieski DF, Mikkelsen ME, Band RA. , et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med 2010; 38 (04) 1045-1053
  • 48 Joo YM, Chae MK, Hwang SY. , et al. Impact of timely antibiotic administration on outcomes in patients with severe sepsis and septic shock in the emergency department. Clin Exp Emerg Med 2014; 1 (01) 35-40
  • 49 Seymour CW, Kahn JM, Martin-Gill C. , et al. Delays from first medical contact to antibiotic administration for sepsis. Crit Care Med 2017; 45 (05) 759-765
  • 50 Whiles BB, Deis AS, Simpson SQ. Increased time to initial antimicrobial administration is associated with progression to septic shock in severe sepsis patients. Crit Care Med 2017; 45 (04) 623-629
  • 51 Wisdom A, Eaton V, Gordon D, Daniel S, Woodman R, Phillips C. INITIAT-E.D.: Impact of timing of INITIation of Antibiotic Therapy on mortality of patients presenting to an Emergency Department with sepsis. Emerg Med Australas 2015; 27 (03) 196-201
  • 52 Yokota PKO, Marra AR, Martino MDV. , et al. Impact of appropriate antimicrobial therapy for patients with severe sepsis and septic shock--a quality improvement study. PLoS One 2014; 9 (11) e104475-e10
  • 53 Zhang D, Micek ST, Kollef MH. Time to appropriate antibiotic therapy is an independent determinant of postinfection ICU and hospital lengths of stay in patients with sepsis. Crit Care Med 2015; 43 (10) 2133-2140
  • 54 Sterling SA, Miller WR, Pryor J, Puskarich MA, Jones AE. The impact of timing of antibiotics on outcomes in severe sepsis and septic shock: a systematic review and meta-analysis. Crit Care Med 2015; 43 (09) 1907-1915
  • 55 Johnston ANB, Park J, Doi SA. , et al. Effect of immediate administration of antibiotics in patients with sepsis in tertiary care: a systematic review and meta-analysis. Clin Ther 2017; 39 (01) 190-202.e6
  • 56 Henriksen DP, Laursen CB, Hallas J, Pedersen C, Lassen AT. Time to initial antibiotic administration, and short-term mortality among patients admitted with community-acquired severe infections with and without the presence of systemic inflammatory response syndrome: a follow-up study. Emerg Med J 2015; 32 (11) 846-853