The Impact of Beta-Lactam Antibiotic Timing on Patient Outcomes in Post-Operative Sepsis Management: A Multi-Center Analysis of Orthopedic and General Surgery Cases
DOI:
https://doi.org/10.52783/jns.v14.2097Keywords:
Post-operative sepsis, Beta-lactam antibiotics, Antibiotic timing, Surgical infection, Orthopedic surgery, General surgery, Mortality, Pharmacokinetics, Antimicrobial stewardship, Quality improvementAbstract
Background: Post-operative sepsis remains a significant cause of morbidity and mortality in surgical patients. While the importance of timely antibiotic administration in sepsis is established, the specific impact of beta-lactam timing on outcomes in post-operative sepsis has not been well characterized across different surgical populations.
Methods: We conducted a multi-center retrospective cohort study of 150 patients (75 orthopedic and 75 general surgery) who developed sepsis within 30 days following surgery at five tertiary care hospitals between 2020-2023. The primary exposure was time from sepsis recognition to beta-lactam administration, categorized as ≤1 hour, 1-3 hours, 3-6 hours, and >6 hours. The primary outcome was 30-day mortality. Secondary outcomes included ICU and hospital length of stay, time to resolution of organ dysfunction, and functional status.
Results: Median time to beta-lactam administration was 2.4 hours (IQR 1.3-4.7), with only 18.7% of patients receiving antibiotics within 1 hour. Thirty-day mortality was 19.3% overall, with a clear dose-response relationship across timing categories: 7.1% (≤1 hour), 15.3% (1-3 hours), 23.8% (3-6 hours), and 38.1% (>6 hours). In multivariable analysis, each hour delay in beta-lactam administration was associated with a 20% increase in the odds of 30-day mortality (adjusted OR 1.20, 95% CI 1.09-1.33, p<0.001). This association was stronger in general surgery patients (adjusted OR 1.28, 95% CI 1.13-1.46) compared to orthopedic surgery patients (adjusted OR 1.12, 95% CI 1.01-1.24). Delayed administration was also associated with prolonged ICU stay, hospital length of stay, and slower resolution of organ dysfunction. In the subset of patients with plasma drug measurements, achieving therapeutic concentrations within 2 hours was associated with improved survival (88.2% vs. 62.5%, p=0.027).
Conclusions: In post-operative sepsis, each hour delay in beta-lactam administration is associated with a 20% increase in 30-day mortality, with a more pronounced effect in general surgery patients. These findings highlight the critical importance of early recognition and prompt antibiotic therapy for post-operative sepsis and suggest potential benefits from specialized sepsis protocols for surgical patients
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Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810.
Shankar-Hari M, Phillips GS, Levy ML, et al. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock. JAMA. 2016;315(8):775-787.
Bateman BT, Schmidt U, Berman MF, Bittner EA. Temporal trends in the epidemiology of severe postoperative sepsis after elective surgery: a large, nationwide sample. Anesthesiology. 2010;112(4):917-925.
Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-377.
Tamma PD, Han JH, Rock C, et al. Carbapenem therapy is associated with improved survival compared with piperacillin-tazobactam for patients with extended-spectrum β-lactamase bacteremia. Clin Infect Dis. 2015;60(9):1319-1325.
Cho JC, Zmarlicka MT, Shaeer KM, Pardo J. Meropenem/Vaborbactam, the First Carbapenem/β-Lactamase Inhibitor Combination. Ann Pharmacother. 2018;52(8):769-779.
Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26(1):1-10.
MacVane SH, Kuti JL, Nicolau DP. Prolonging β-lactam infusion: a review of the rationale and evidence, and guidance for implementation. Int J Antimicrob Agents. 2014;43(2):105-113.
Roberts JA, Abdul-Aziz MH, Lipman J, et al. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis. 2014;14(6):498-509.
Gonçalves-Pereira J, Póvoa P. Antibiotics in critically ill patients: a systematic review of the pharmacokinetics of β-lactams. Crit Care. 2011;15(5):R206.
Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063-e1143.
Pea F, Viale P. Bench-to-bedside review: Appropriate antibiotic therapy in severe sepsis and septic shock--does the dose matter? Crit Care. 2009;13(3):214.
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(1):194.
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(4):623-629.
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(6):1589-1596.
Prescott HC, Angus DC. Enhancing Recovery From Sepsis: A Review. JAMA. 2018;319(1):62-75.
Yang Y, Yang KS, Hsann YM, Lim V, Ong BC. The effect of comorbidity and age on hospital mortality and length of stay in patients with sepsis. J Crit Care. 2010;25(3):398-405.
Szakmany T, Lundin RM, Sharif B, et al. Sepsis Prevalence and Outcome on the General Wards and Emergency Departments in Wales: Results of a Multi-Centre, Observational, Point Prevalence Study. PLoS One. 2016;11(12):e0167230.
Arens C, Bajwa SA, Koch C, et al. Sepsis-induced long-term immune paralysis--results of a descriptive, explorative study. Crit Care. 2016;20(1):93.
Levy MM, Rhodes A, Phillips GS, et al. Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study. Intensive Care Med. 2014;40(11):1623-1633.
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.
Bloos F, Rüddel H, Thomas-Rüddel D, et al. Effect of a multifaceted educational intervention for anti-infectious measures on sepsis mortality: a cluster randomized trial. Intensive Care Med. 2017;43(11):1602-1612.
Paul M, Lador A, Grozinsky-Glasberg S, Leibovici L. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev. 2014;2014(1):CD003344.
Puskarich MA, Trzeciak S, Shapiro NI, et al. Association between timing of antibiotic administration and mortality from septic shock in patients treated with a quantitative resuscitation protocol. Crit Care Med. 2011;39(9):2066-2071.
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(7):856-863.
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377-381.
Seymour CW, Liu VX, Iwashyna TJ, et al. Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):762-774.
Tolsma V, Schwebel C, Azoulay E, et al. Sepsis severe or septic shock: outcome according to immune status and immunodeficiency profile. Chest. 2014;146(5):1205-1213.
Mathes T, Buehn S, Prengel P, Pieper D. Registry-based randomized controlled trials merged the strength of randomized controlled trials and observational studies and give rise to more pragmatic trials. J Clin Epidemiol. 2018;93:120-127.
Kahan BC, Rehal S, Cro S. Risk of selection bias in randomised trials. Trials. 2015;16:405.
Boyd JH, Russell JA, Fjell CD. The meta-analysis of sepsis and septic shock trials. Crit Care Med. 2008;36(7):2156-2157.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383.
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655.
Suding P, Jensen E, Abramson MA, Itani K, Wilson SE. Definitive risk factors for anastomotic leaks in elective open colorectal resection. Arch Surg. 2008;143(9):907-912.
Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Med. 1996;22(7):707-710.
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(3):486-552.
Baron EJ, Miller JM, Weinstein MP, et al. A guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2013 recommendations by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM). Clin Infect Dis. 2013;57(4):e22-e121.
Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing. 30th ed. CLSI supplement M100. Wayne, PA: Clinical and Laboratory Standards Institute; 2020.
Roberts JA, Paul SK, Akova M, et al. DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014;58(8):1072-1083.
Wong G, Brinkman A, Benefield RJ, et al. An international, multicentre survey of β-lactam antibiotic therapeutic drug monitoring practice in intensive care units. J Antimicrob Chemother. 2014;69(5):1416-1423.
Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120(4):c179-c184.
Mahoney FI, Barthel DW. Functional Evaluation: The Barthel Index. Md State Med J. 1965;14:61-65.
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727-1736.
Ferrer 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(8):1749-1755.
Bland JM, Altman DG. The logrank test. BMJ. 2004;328(7447):1073.
Vittinghoff E, McCulloch CE. Relaxing the rule of ten events per variable in logistic and Cox regression. Am J Epidemiol. 2007;165(6):710-718.
Harrell FE Jr, Lee KL, Pollock BG. Regression models in clinical studies: determining relationships between predictors and response. J Natl Cancer Inst. 1988;80(15):1198-1202.
Laird NM, Ware JH. Random-effects models for longitudinal data. Biometrics. 1982;38(4):963-974.
Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York, NY: John Wiley & Sons; 1987.
Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. J R Stat Soc Series B Stat Methodol. 1995;57(1):289-300.
Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c869.
Kumar 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(5):1237-1248.
Ferrer 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(8):1749-1755.
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.
Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control. 2008;36(5):309-332.
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(9):1907-1915.
Ramos JGR, Dias RD, do Brasil PEAA, de Moura EB, Neto MC, da Silva MVS. Antibiotic Timing and Outcomes in Sepsis. Am J Med Sci. 2019;358(6):417-423.
Wang HE, Seymour CW, Yealy DM, Shapiro NI. Antibiotic Administration in the Emergency Department for Sepsis: Timing and Appropriateness. J Emerg Med. 2014;47(5):628-633.
Mazuski JE, Tessier JM, May AK, et al. The Surgical Infection Society Revised Guidelines on the Management of Intra-Abdominal Infection. Surg Infect (Larchmt). 2017;18(1):1-76.
Sartelli M, Chichom-Mefire A, Labricciosa FM, et al. The management of intra-abdominal infections from a global perspective: 2017 WSES guidelines for management of intra-abdominal infections. World J Emerg Surg. 2017;12:29.
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(7):856-863.
van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG. The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol. 2017;17(7):407-420.
Roberts JA, Paul SK, Akova M, et al. DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014;58(8):1072-1083.
Udy AA, Roberts JA, Lipman J. Implications of augmented renal clearance in critically ill patients. Nat Rev Nephrol. 2011;7(9):539-543.
Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, et al. 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. Intensive Care Med. 2016;42(10):1535-1545.
Sjövall F, Perner A, Hylander Møller M. Empirical mono- versus combination antibiotic therapy in adult intensive care patients with severe sepsis - A systematic review with meta-analysis and trial sequential analysis. J Infect. 2017;74(4):331-344.
Abdul-Aziz MH, Lipman J, Akova M, et al. Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort. J Antimicrob Chemother. 2016;71(1):196-207.
Jones SL, Ashton CM, Kiehne L, et al. Reductions in Sepsis Mortality and Costs After Design and Implementation of a Nurse-Based Early Recognition and Response Program. Jt Comm J Qual Patient Saf. 2015;41(11):483-491.
Hatfield KM, Dantes RB, Baggs J, et al. Assessing Variability in Hospital-Level Mortality Among U.S. Medicare Beneficiaries With Hospitalizations for Severe Sepsis and Septic Shock. Crit Care Med. 2018;46(11):1753-1760.
Nathens AB, Jurkovich GJ, Maier RV, et al. Relationship between trauma center volume and outcomes. JAMA. 2001;285(9):1164-1171.
Roberts JA, Abdul-Aziz MH, Lipman J, et al. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis. 2014;14(6):498-509.
Veiga RP, Paiva JA. Pharmacokinetics-pharmacodynamics issues relevant for the clinical use of beta-lactam antibiotics in critically ill patients. Crit Care. 2018;22(1):233.
Rhee C, Kadri SS, Danner RL, et al. Diagnosing sepsis is subjective and highly variable: a survey of intensivists using case vignettes. Crit Care. 2016;20:89.
Vardakas KZ, Voulgaris GL, Maliaros A, Samonis G, Falagas ME. Prolonged versus short-term intravenous infusion of antipseudomonal β-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials. Lancet Infect Dis. 2018;18(1):108-120.
Rhodes A, Phillips G, Beale R, et al. The Surviving Sepsis Campaign bundles and outcome: results from the International Multicentre Prevalence Study on Sepsis (the IMPreSS study). Intensive Care Med. 2015;41(9):1620-1628.
Prescott HC, Osterholzer JJ, Langa KM, Angus DC, Iwashyna TJ. Late mortality after sepsis: propensity matched cohort study. BMJ. 2016;353:i2375.
Hiengrach P, Panoi N, Wattanathum A, Guntawongwan K, Boonbaichaiyapruck S, Piyayotai D. The usefulness of modified sequential organ failure assessment score in predicting the risk of 28-day mortality in patients with sepsis at emergency room. J Med Assoc Thai. 2016;99(5):S47-55.
Henry KE, Hager DN, Pronovost PJ, Saria S. A targeted real-time early warning score (TREWScore) for septic shock. Sci Transl Med. 2015;7(299):299ra122.
Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, et al. 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. Intensive Care Med. 2016;42(10):1535-1545.
Banerjee D, Opal SM. Age, exercise, and the outcome of sepsis. Crit Care. 2017;21(1):286.
Peltan ID, Mitchell KH, Rudd KE, et al. Physician Variation in Time to Antimicrobial Treatment for Septic Patients Presenting to the Emergency Department. Crit Care Med. 2017;45(6):1011-1018.
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