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Published in: Supportive Care in Cancer 3/2020

01-03-2020 | Septicemia | Original Article

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

Authors: Christa Koenig, Christine Schneider, Jessica E. Morgan, Roland A. Ammann, Lillian Sung, Bob Phillips

Published in: Supportive Care in Cancer | Issue 3/2020

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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 [http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018092948].
Appendix
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Literature
1.
go back to reference Bodey GP, Buckley M, Sathe YS, Freireich EJ (1966) Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 64:328–340CrossRef Bodey GP, Buckley M, Sathe YS, Freireich EJ (1966) Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 64:328–340CrossRef
2.
go back to reference 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 98:341–354CrossRef 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 98:341–354CrossRef
3.
go back to reference 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 58:303–305CrossRef 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 58:303–305CrossRef
4.
go back to reference 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–e863CrossRef 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–e863CrossRef
5.
go back to reference 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 60:1299–1306CrossRef 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 60:1299–1306CrossRef
6.
go back to reference 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 8:82CrossRef 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 8:82CrossRef
7.
go back to reference 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–v1v8CrossRef 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–v1v8CrossRef
8.
go back to reference 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 36:1443–1453CrossRef 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 36:1443–1453CrossRef
9.
go back to reference 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 35:2082–2094CrossRef 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 35:2082–2094CrossRef
10.
go back to reference 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. https://www.awmf.org/uploads/tx_szleitlinien/048-014l_S2k_onkologische_Grunderkrankung_Fieber_Granulozytopenie_2016-04-verlaengert.pdf. Accessed 18.04.2018 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. https://​www.​awmf.​org/​uploads/​tx_​szleitlinien/​048-014l_​S2k_​onkologische_​Grunderkrankung_​Fieber_​Granulozytopenie​_​2016-04-verlaengert.​pdf.​ Accessed 18.04.2018
11.
go back to reference 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 43:1907–1915CrossRef 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 43:1907–1915CrossRef
12.
go back to reference 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 34:1589–1596CrossRef 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 34:1589–1596CrossRef
13.
go back to reference 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 98:291–298CrossRef 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 98:291–298CrossRef
14.
go back to reference 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 16:392CrossRef 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 16:392CrossRef
15.
go back to reference 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 11:450–455CrossRef 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 11:450–455CrossRef
16.
go back to reference 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 20:679–285CrossRef 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 20:679–285CrossRef
17.
go back to reference 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:e43639CrossRef 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:e43639CrossRef
18.
go back to reference 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 58:3799–3803CrossRef 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 58:3799–3803CrossRef
19.
go back to reference 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 34:1069–1073CrossRef 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 34:1069–1073CrossRef
20.
go back to reference 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 62:807–815CrossRef 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 62:807–815CrossRef
21.
go back to reference 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:i4919CrossRef 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:i4919CrossRef
22.
go back to reference Viechtbauer W (2010) Conducting meta-analyses in R with the metafor package. J Stat Softw 36:1–48CrossRef Viechtbauer W (2010) Conducting meta-analyses in R with the metafor package. J Stat Softw 36:1–48CrossRef
24.
go back to reference 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 23:278–283CrossRef 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 23:278–283CrossRef
26.
go back to reference 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 25:535–543CrossRef 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 25:535–543CrossRef
27.
go back to reference 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 23:2799–2804CrossRef 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 23:2799–2804CrossRef
28.
go back to reference 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 2183179 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 2183179
29.
go back to reference 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 31:189–196CrossRef 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 31:189–196CrossRef
30.
go back to reference Perron T, Emara M, Ahmed S (2014) Time to antibiotics and outcomes in cancer patients with febrile neutropenia. BMC Health Serv Res 14:162CrossRef Perron T, Emara M, Ahmed S (2014) Time to antibiotics and outcomes in cancer patients with febrile neutropenia. BMC Health Serv Res 14:162CrossRef
31.
go back to reference Sammut SJ, Mazhar D (2012) Management of febrile neutropenia in an acute oncology service. QJM 105:327–236CrossRef Sammut SJ, Mazhar D (2012) Management of febrile neutropenia in an acute oncology service. QJM 105:327–236CrossRef
33.
go back to reference 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 62:483–489CrossRef 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 62:483–489CrossRef
34.
go back to reference 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 24:5001–5005CrossRef 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 24:5001–5005CrossRef
35.
go back to reference 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 e15CrossRef 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 e15CrossRef
Metadata
Title
Association of time to antibiotics and clinical outcomes in patients with fever and neutropenia during chemotherapy for cancer: a systematic review
Authors
Christa Koenig
Christine Schneider
Jessica E. Morgan
Roland A. Ammann
Lillian Sung
Bob Phillips
Publication date
01-03-2020
Publisher
Springer Berlin Heidelberg
Published in
Supportive Care in Cancer / Issue 3/2020
Print ISSN: 0941-4355
Electronic ISSN: 1433-7339
DOI
https://doi.org/10.1007/s00520-019-04961-4

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