Impact of time to antibiotics on clinical outcome in paediatric febrile neutropenia: a target trial emulation of 1685 episodes

Gabrielle M Haeusler^{1

2

3

4

5

6}, S Ghazaleh Dashti^{2

5}, Fiona James², Franz E Babl^{2

5

7}, Meredith L Borland^{8

9}, Julia E Clark^{10

11}, Bhavna Padhye^{12

13}, Heather Tapp¹⁴, Frank Alvaro¹⁵, Trisha Soosay Raj^{11

16}, Thomas Walwyn^{17

18}, David S Ziegler^{19

20

21}, Leanne Super^{22

23}, Lisa Hall^{4

24}, Daniel K Yeoh^{2

4

25}, Coen Butters^{2

5

26}, Brendan McMullan^{4

20

27}, Diane M T Hanna^{2

5

22}, Richard De Abreu Lourenco²⁸, Monica A Slavin^{3

4}, Bob Phillips^{29

30}, Karin A Thursky^{3

4

31}; Australian PICNICC and There is No Place Like Home study groups

Affiliations

¹ Department of Infectious Diseases, Royal Children's Hospital, Parkville, Victoria, Australia.
² Murdoch Children's Research Institute, Parkville, Victoria, Australia.
³ Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁴ NHMRC National Centre for Infections in Cancer, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
⁵ Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
⁶ The Paediatric Integrated Cancer Service, Victoria State Government, Parkville, Australia.
⁷ Emergency Department, Royal Children's Hospital, Parkville, Victoria, Australia.
⁸ Emergency Department, Perth Children's Hospital, Nedlands, Western Australia, Australia.
⁹ School of Medicine, Divisions of Emergency Medicine and Paediatrics, University of Western Australia, Crawley, Western Australia, Australia.
¹⁰ Infection Management, Queensland Children's Hospital, Brisbane, Queensland, Australia.
¹¹ Children's Health Queensland Clinical Unit, University of Queensland, Queensland, Australia.
¹² Cancer Centre for Children, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹³ Kids Research, Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹⁴ Department of Oncology, Women's and Children's Hospital, Adelaide, South Australia, Australia.
¹⁵ Children's Cancer and Blood Disorders, John Hunter Children's Hospital, Newcastle, New South Wales, Australia.
¹⁶ Oncology Services Group, Queensland Children's Hospital, Queensland, Australia.
¹⁷ Department of Oncology, Perth Children's Hospital, Perth, Western Australia, Australia.
¹⁸ Department of Paediatrics, Royal Hobart Hospital, Hobart, Tasmania, Australia.
¹⁹ Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, Australia.
²⁰ School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia.
²¹ Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia.
²² Children's Cancer Centre, Royal Children's Hospital, Parkville, Victoria, Australia.
²³ Children's Cancer Centre, Monash Children's Hospital, Clayton, Victoria, Australia.
²⁴ School of Public Health, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.
²⁵ Department of Infectious Diseases, Perth Children's Hospital, Nedlands, Western Australia, Australia.
²⁶ Department of General Paediatrics and Adolescent Medicine, John Hunter Children's Hospital, Australia.
²⁷ Department of Infectious Diseases, Sydney Children's Hospital Randwick, Sydney, New South Wales, Australia.
²⁸ Centre for Health Economics Research and Evaluation, University of Technology Sydney, Sydney, New South Wales, Australia.
²⁹ Centre for Reviews and Dissemination and Hull-York Medical School, York, UK.
³⁰ Regional Department of Haematology and Oncology, Leeds Children's Hospital, Leeds, UK.
³¹ NHMRC National Centre for Antimicrobial Stewardship, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.

PMID: 39553416
PMCID: PMC11566883
DOI: 10.1016/j.lanwpc.2024.101226

Impact of time to antibiotics on clinical outcome in paediatric febrile neutropenia: a target trial emulation of 1685 episodes

Gabrielle M Haeusler et al. Lancet Reg Health West Pac. 2024.

. 2024 Nov 2:53:101226.

doi: 10.1016/j.lanwpc.2024.101226. eCollection 2024 Dec.

Authors

Affiliations

¹ Department of Infectious Diseases, Royal Children's Hospital, Parkville, Victoria, Australia.
² Murdoch Children's Research Institute, Parkville, Victoria, Australia.
³ Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁴ NHMRC National Centre for Infections in Cancer, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
⁵ Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
⁶ The Paediatric Integrated Cancer Service, Victoria State Government, Parkville, Australia.
⁷ Emergency Department, Royal Children's Hospital, Parkville, Victoria, Australia.
⁸ Emergency Department, Perth Children's Hospital, Nedlands, Western Australia, Australia.
⁹ School of Medicine, Divisions of Emergency Medicine and Paediatrics, University of Western Australia, Crawley, Western Australia, Australia.
¹⁰ Infection Management, Queensland Children's Hospital, Brisbane, Queensland, Australia.
¹¹ Children's Health Queensland Clinical Unit, University of Queensland, Queensland, Australia.
¹² Cancer Centre for Children, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹³ Kids Research, Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹⁴ Department of Oncology, Women's and Children's Hospital, Adelaide, South Australia, Australia.
¹⁵ Children's Cancer and Blood Disorders, John Hunter Children's Hospital, Newcastle, New South Wales, Australia.
¹⁶ Oncology Services Group, Queensland Children's Hospital, Queensland, Australia.
¹⁷ Department of Oncology, Perth Children's Hospital, Perth, Western Australia, Australia.
¹⁸ Department of Paediatrics, Royal Hobart Hospital, Hobart, Tasmania, Australia.
¹⁹ Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, Australia.
²⁰ School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia.
²¹ Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia.
²² Children's Cancer Centre, Royal Children's Hospital, Parkville, Victoria, Australia.
²³ Children's Cancer Centre, Monash Children's Hospital, Clayton, Victoria, Australia.
²⁴ School of Public Health, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.
²⁵ Department of Infectious Diseases, Perth Children's Hospital, Nedlands, Western Australia, Australia.
²⁶ Department of General Paediatrics and Adolescent Medicine, John Hunter Children's Hospital, Australia.
²⁷ Department of Infectious Diseases, Sydney Children's Hospital Randwick, Sydney, New South Wales, Australia.
²⁸ Centre for Health Economics Research and Evaluation, University of Technology Sydney, Sydney, New South Wales, Australia.
²⁹ Centre for Reviews and Dissemination and Hull-York Medical School, York, UK.
³⁰ Regional Department of Haematology and Oncology, Leeds Children's Hospital, Leeds, UK.
³¹ NHMRC National Centre for Antimicrobial Stewardship, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.

PMID: 39553416
PMCID: PMC11566883
DOI: 10.1016/j.lanwpc.2024.101226

Abstract

Background: Prompt antibiotic administration for febrile neutropenia (FN) is standard of care, and targets of time to antibiotics (TTA) <60 min are common. We sought to determine the effect of TTA ≥60 versus <60 min on adverse outcomes (intensive care unit (ICU) admission or death) in children with cancer and FN. Effect modification by a decision rule that predicts infection (AUS-rule) and bacteraemia were also investigated.

Methods: The prospective, multi-centre (n = 8), Australian PICNICC study dataset was analysed. To control for confounding, we used outcome regression adjusted for propensity score modelled as restricted cubic spline with two degrees of freedom. The propensity score was estimated from a logistic regression model for the exposure on the confounders, identified a priori (age, sex, severely unwell, disease, chemotherapy intensity and site). TTA was defined as time from from emergency triage to first antibiotic dose.

Findings: 1685 FN episodes in 976 patients were included. Median TTA was 53 min (IQR 37-77 min, 1542 (92%) <120 min). An adverse outcome occurred in 43 (2.6%) episodes (39 ICU; 5 deaths). The confounder-adjusted point estimate suggested a lower risk for adverse outcome associated with TTA ≥60 min (RR 0.62, 95% CI 0.32-1.21), but the wide 95% CI precluded definitive judgement about strength and direction of the effect (unadjusted RR 0.52; 95% CI 0.26, 1.05). Similarly, although the point estimates were suggestive of a null association or reduced risk for adverse outcome associated with TTA ≥60 min for all comparisons across bacteraemia or AUS-rule strata, the 95% CIs were imprecise.

Interpretation: For children with FN, there was no definite evidence that TTA ≥60 min from hospital triage (but within 2 h), increased risk of adverse outcome or prolonged hospital admission. This study has important implications for FN TTA mandates, suggesting a more nuanced approach is required.

Funding: National Health and Medical Research Council and Medical Research Future Fund.

Keywords: Children with cancer; Febrile neutropenia (FN); Time to antibiotics (TTA).

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Conflict of interest statement

There are no conflicts of interest to disclose.

Figures

**Fig. 1**
Estimated average causal effect on primary outcome (ICU admission or death) for time to antibiotics (≥60 versus <60 min) overall, for the subset with known absolute neutrophil count, and by AUS-rule score or presence of bacteraemia, and for time to antibiotics since fever onset at home (≥180 versus <180 min) for the subset with available data. FN, febrile neutropenia; TTA, time to antibiotics; RR, risk ratio; CI, confidence interval.

See this image and copyright information in PMC

References

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Impact of time to antibiotics on clinical outcome in paediatric febrile neutropenia: a target trial emulation of 1685 episodes

Affiliations

Impact of time to antibiotics on clinical outcome in paediatric febrile neutropenia: a target trial emulation of 1685 episodes

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources

Miscellaneous