Association of time to antibiotics and clinical outcomes in patients with fever and neutropenia during chemotherapy for cancer: a systematic review

  • Christa KoenigEmail author
  • Christine Schneider
  • Jessica E. Morgan
  • Roland A. Ammann
  • Lillian Sung
  • Bob Phillips
Original Article



Prompt antibiotic therapy is standard of care for patients with fever and neutropenia (FN) during chemotherapy for cancer. We systematically reviewed the association between time to antibiotics (TTA) and clinical outcomes.


The search covered seven databases; confounding biases and study quality were assessed with the ROBINS-I tool. Safety (death, intensive care unit (ICU) admission, sepsis) and treatment adequacy (relapse of infection, persistence or recurrence of fever) were assessed as primary outcomes.


Of 6296 articles identified, 13 observational studies were included. Findings regarding safety were inconsistent. Three studies controlling for triage bias showed a possible association between longer TTA and impaired safety. Meta-analysis for TTA ≤ 60 min versus > 60 min was feasible on four studies, with three studies each reporting on death (OR 0.78, 95%CI 0.16–3.69) and on ICU admission (OR 1.43, 95%CI 0.57–3.60). No study reported data on treatment adequacy. Triage bias, i.e. faster treatment of patients with worse clinical condition, was identified as a relevant confounding factor.


There seems to be an association between longer TTA and impaired safety. More knowledge about TTA effects on safety are important to optimise treatment guidelines for FN. Controlling for triage and other biases is necessary to gain further evidence.

Trial registration

Registration: PROSPERO [].


Oncology Fever Neutropenia Time to antibiotics Cancer Chemotherapy Systematic review 



Krebsliga Schweiz, KFS-3645-02-2015, JM was funded during this research by an NIHR Clinical Lecturer Award and BP by an NIHR Post-doctoral Fellowship.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

520_2019_4961_MOESM1_ESM.pdf (529 kb)
ESM 1 (PDF 528 kb)


  1. 1.
    Bodey GP, Buckley M, Sathe YS, Freireich EJ (1966) Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 64:328–340CrossRefGoogle Scholar
  2. 2.
    Pizzo PA (1981) Infectious complications in the child with cancer. I. Pathophysiology of the compromised host and the initial evaluation and management of the febrile cancer patient. J Pediatr 98:341–354CrossRefGoogle Scholar
  3. 3.
    McCavit TL, Winick N (2012) Time-to-antibiotic administration as a quality of care measure in children with febrile neutropenia: a survey of pediatric oncology centers. Pediatr Blood Cancer 58:303–305CrossRefGoogle Scholar
  4. 4.
    Kapil P, MacMillan M, Carvalho M, Lymburner P, Fung R, Almeida B, van Dorn L, Enright K (2016) Assessment of fever advisory cards (FACs) as an initiative to improve febrile neutropenia management in a regional cancer center emergency department. J Oncol Pract 12:e858–e863CrossRefGoogle Scholar
  5. 5.
    Fletcher M, Hodgkiss H, Zhang S, Browning R, Hadden C, Hoffmann T et al (2013) Prompt administration of antibiotics is associated with improved outcomes in febrile neutropenia in children with cancer. Pediatr Blood Cancer 60:1299–1306CrossRefGoogle Scholar
  6. 6.
    Koenig C, Morgan J, Ammann RA, Sung L, Phillips B (2019) Protocol for a systematic review of time to antibiotics (TTA) in patients with fever and neutropenia during chemotherapy for cancer (FN) and interventions aiming to reduce TTA. Syst Rev 8:82CrossRefGoogle Scholar
  7. 7.
    Klastersky J, de Naurois J, Rolston K, Rapoport B, Maschmeyer G, Aapro M, Herrstedt J (2016) Management of febrile neutropaenia: ESMO clinical practice guidelines. Ann Oncol 27:v111–v1v8CrossRefGoogle Scholar
  8. 8.
    Taplitz RA, Kennedy EB, Bow EJ, Crews J, Gleason C, Hawley DK, Langston AA, Nastoupil LJ, Rajotte M, Rolston K, Strasfeld L, Flowers CR (2018) Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America clinical practice guideline update. J Clin Oncol 36:1443–1453CrossRefGoogle Scholar
  9. 9.
    Lehrnbecher T, Robinson P, Fisher B, Alexander S, Ammann RA, Beauchemin M, Carlesse F, Groll AH, Haeusler GM, Santolaya M, Steinbach WJ, Castagnola E, Davis BL, Dupuis LL, Gaur AH, Tissing WJE, Zaoutis T, Phillips R, Sung L (2017) Guideline for the management of fever and neutropenia in children with cancer and hematopoietic stem-cell transplantation recipients: 2017 update. J Clin Oncol 35:2082–2094CrossRefGoogle Scholar
  10. 10.
    Deutsche Gesellschaft für Pädiatrische Infektologie (DGPI) und Gesellschaft Pädiatrische Onkologie und Hämatologie (GPOH) (2016) AWMF S2K Leitlinie: Diagnostik und Therapie bei Kindern mit onkologischer Grunderkrankung, Fieber und Granulozytopenie (mit febriler Neutropenie) außerhalb der allogenen Stammzelltransplantation. AWMF-Registernummer 048/14, finale Version 23.01.2016. Accessed 18.04.2018Google Scholar
  11. 11.
    Sterling SA, Miller WR, Pryor J, Puskarich MA, Jones AE (2015) The impact of timing of antibiotics on outcomes in severe sepsis and septic shock: a systematic review and meta-analysis. Crit Care Med 43:1907–1915CrossRefGoogle Scholar
  12. 12.
    Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, Suppes R, Feinstein D, Zanotti S, Taiberg L, Gurka D, Kumar A, Cheang M (2006) Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 34:1589–1596CrossRefGoogle Scholar
  13. 13.
    Proulx N, Frechette D, Toye B, Chan J, Kravcik S (2005) Delays in the administration of antibiotics are associated with mortality from adult acute bacterial meningitis. QJM 98:291–298CrossRefGoogle Scholar
  14. 14.
    Bodilsen J, Dalager-Pedersen M, Schønheyder HC, Nielsen H (2016) Time to antibiotic therapy and outcome in bacterial meningitis: a Danish population-based cohort study. BMC Infect Dis 16:392CrossRefGoogle Scholar
  15. 15.
    Keng MK, Thallner EA, Elson P, Ajon C, Sekeres J, Wenzell CM, Seastone DJ, Gallagher EM, Weber CM, Earl MA, Mukherjee S, Pohlman B, Cober E, Foster VB, Yuhas J, Kalaycio ME, Bolwell BJ, Sekeres MA (2015) Reducing time to antibiotic administration for febrile neutropenia in the emergency department. J Oncol Pract 11:450–455CrossRefGoogle Scholar
  16. 16.
    Van Vliet M, Potting CM, Sturm PD, Donnelly JP, Blijlevens NM (2011) How prompt is prompt in daily practice? Earlier initiation of empirical antibacterial therapy for the febrile neutropenic patient. Eur J Cancer Care 20:679–285CrossRefGoogle Scholar
  17. 17.
    Gavidia R, Fuentes SL, Vasquez R, Bonilla M, Ethier MC, Diorio C, Caniza M, Howard SC, Sung L (2012) Low socioeconomic status is associated with prolonged times to assessment and treatment, sepsis and infectious death in pediatric fever in El Salvador. PLoS One 7:e43639CrossRefGoogle Scholar
  18. 18.
    Rosa RG, Goldani LZ (2014) Cohort study of the impact of time to antibiotic administration on mortality in patients with febrile neutropenia. Antimicrob Agents Chemother 58:3799–3803CrossRefGoogle Scholar
  19. 19.
    De la Maza V, Simian D, Castro M, Torres JP, Lucero Y, Sepúlveda F et al (2015) Administration time for the first dose of antimicrobials in episodes of fever and neutropenia in children with cancer. Pediatr Infect Dis J 34:1069–1073CrossRefGoogle Scholar
  20. 20.
    Salstrom JL, Coughlin RL, Pool K, Bojan M, Mediavilla C, Schwent W, Rannie M, Law D, Finnerty M, Hilden J (2015) Pediatric patients who receive antibiotics for fever and neutropenia in less than 60 min have decreased intensive care needs. Pediatr Blood Cancer 62:807–815CrossRefGoogle Scholar
  21. 21.
    Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M et al (2016) ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 355:i4919CrossRefGoogle Scholar
  22. 22.
    Viechtbauer W (2010) Conducting meta-analyses in R with the metafor package. J Stat Softw 36:1–48CrossRefGoogle Scholar
  23. 23.
    R Core Team (2018) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna Google Scholar
  24. 24.
    Butts AR, Bachmeier CC, Dressler EV, Liu M, Cowden A, Talbert J, Adams VR (2017) Association of time to antibiotics and clinical outcomes in adult hematologic malignancy patients with febrile neutropenia. J Oncol Pharm Pract 23:278–283CrossRefGoogle Scholar
  25. 25.
    Daniels LM, Durani U, Barreto JN, O’Horo JC, Siddiqui MA, Park JG, Tosh PK (2019) Impact of time to antibiotic on hospital stay, intensive care unit admission, and mortality in febrile neutropenia. Support Care Cancer.
  26. 26.
    Johannesmeyer HJ, Seifert CF (2019) A retrospective analysis of clinical acuity markers on hospital length of stay in patients with febrile neutropenia. J Oncol Pharm Pract 25:535–543CrossRefGoogle Scholar
  27. 27.
    Ko BS, Ahn S, Lee YS, Kim WY, Lim KS, Lee JL (2015) Impact of time to antibiotics on outcomes of chemotherapy-induced febrile neutropenia. Support Care Cancer 23:2799–2804CrossRefGoogle Scholar
  28. 28.
    Lee SJ, Kim JH, Han SB, Paik JH, Durey A (2018) Prognostic factors predicting poor outcome in cancer patients with febrile neutropenia in the emergency department: usefulness of qSOFA. J Oncol 2183179Google Scholar
  29. 29.
    Lynn JJ, Chen KF, Weng YM, Chiu TF (2013) Risk factors associated with complications in patients with chemotherapy-induced febrile neutropenia in emergency department. Hematol Oncol 31:189–196CrossRefGoogle Scholar
  30. 30.
    Perron T, Emara M, Ahmed S (2014) Time to antibiotics and outcomes in cancer patients with febrile neutropenia. BMC Health Serv Res 14:162CrossRefGoogle Scholar
  31. 31.
    Sammut SJ, Mazhar D (2012) Management of febrile neutropenia in an acute oncology service. QJM 105:327–236CrossRefGoogle Scholar
  32. 32.
    World Bank Country and Lending Groups (2018) Word Bank list of economies (June 2018). Accessed 18 April 2019
  33. 33.
    Haeusler GM, Phillips RS, Lehrnbecher T, Thursky KA, Sung L, Ammann RA (2015) Core outcomes and definitions for pediatric fever and neutropenia research: a consensus statement from an international panel. Pediatr Blood Cancer 62:483–489CrossRefGoogle Scholar
  34. 34.
    Mattison G, Bilney M, Haji-Michael P, Cooksley T (2016) A nurse-led protocol improves the time to first dose intravenous antibiotics in septic patients post chemotherapy. Support Care Cancer 24:5001–5005CrossRefGoogle Scholar
  35. 35.
    Lim C, Bawden J, Wing A, Villa-Roel C, Meurer DP, Bullard MJ, Rowe BH (2012) Febrile neutropenia in EDs: the role of an electronic clinical practice guideline. Am J Emerg Med 30(1):5–11 e15CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Pediatric Hematology/Oncology, Department of Pediatrics, Inselspital, Bern University HospitalUniversity of BernBernSwitzerland
  2. 2.Centre for Reviews and DisseminationUniversity of YorkYorkUK
  3. 3.Leeds Children’s HospitalLeedsUK
  4. 4.The Hospital for Sick ChildrenUniversity of TorontoTorontoCanada

Personalised recommendations