The early use of Antibiotics for At-risk children with InfluEnza in Primary Care (the ARCHIE programme)
Authors: Wang Kay , Tonner Sharon , Semple Malcolm G , Wolstenholme Jane , Perera Rafael , Harnden Anthony 
Published: July 2023

Background
Influenza and influenza-like illness place significant burden on the NHS. Children with underlying health conditions are vulnerable to developing bacterial complications.

Objective
To strengthen the evidence base underlying antibiotic use in at-risk children with influenza-like illness.

Design
This programme comprised five separate work packages. Work package A investigated published and unpublished data from previously published literature and work package B explored attitudes of parents and general practitioners to influenza-like illness and antibiotics in at-risk children. This was followed by a clinical trial to assess the effectiveness of early co-amoxiclav (Augmentin®, GlaxoSmithKline UK) use at reducing reconsultation due to clinical deterioration (work package C), a nested sub-study to examine bacterial carriage indicators of antibiotic resistance (work package D) and a within-trial economic evaluation and clinical risk prediction analysis (work package E).

Setting
Interviews were conducted by telephone with general practitioners across the UK and parents/guardians in England (work package B). We conducted the clinical trial (work package C and nested work packages D and E) in general practices and ambulatory care services in England and Wales.

Participants
General practitioners and parents/guardians of at-risk children who previously had influenza-like illness participated in work package B. At-risk children with influenza-like illness aged 6 months to 12 years participated in work packages C and E and optionally in work package D.

Interventions
The intervention for the clinical trial was a 5-day course of co-amoxiclav 400/57 with dosing regimens based on British National Formulary guidance.

Main outcome measures
Hospital admission (work package A); findings from semi-structured interviews with patients and health-care professionals (work package B); proportion of patients who reconsulted owing to clinical deterioration (work package C); respiratory bacterial carriage and antibiotic resistance of potentially pathogenic respiratory tract bacteria at 3, 6, 9 and 12 months (work package D); and risk factors for reconsultation owing to clinical deterioration, quality of life (EuroQol-5 Dimensions, three-level youth version), symptoms (Canadian Acute Respiratory Infection and Flu Scale), health-care use and costs (work package E).

Review methods
For work package A, we searched the MEDLINE, MEDLINE In-Process, EMBASE, Science Citation Index and CINAHL (Cumulative Index to Nursing and Allied Health Literature) databases until 3 April 2013 with no language restrictions and requested unpublished data from authors of studies which had collected but not published relevant data. We included studies involving children up to 18 years of age with influenza or influenza-like illness from primary or ambulatory care settings. We used univariable meta-analysis methods to calculate odds ratios with 95% confidence intervals for individual risk factors. We reported our systematic review according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2009 statement.

Results
Work package A analysed data from 28 articles reporting data from 27 studies. Neurological disorders, sickle cell disease, immunosuppression, diabetes and an age of <2 years were risk factors for hospital admission. Work package B interviewed 41 general practitioners and found that decision-making in at-risk children with influenza-like illness varies considerably. Parents/guardians were interviewed for work package B and spoke of how quickly their at-risk child could deteriorate. They were supportive of antibiotic use while being aware of antibiotic resistance. The trial (work package C) recruited 271 at-risk children. Primary outcome data were available for 265 children. There was no evidence of benefit from treatment with co-amoxiclav versus placebo (adjusted risk ratio 1.16, 95% confidence interval 0.75 to 1.80). Work package D collected 285 additional throat swabs over 12 months. At 3 months, the proportion of Haemophilus influenzae isolates was greater in the placebo than co-amoxiclav group (29% vs. 18%). No association was found between antibiotic resistance and early co-amoxiclav use. No clinical features were significantly associated with risk of reconsultation due to clinical deterioration except respiratory rate (coefficient 0.046, 95% confidence interval 0.010 to 0.081). Work package E found no evidence that early co-amoxiclav treatment improves quality of life or reduces health-care use and costs. Total costs per patient were highly skewed in both groups (co-amoxiclav: median £4, range £4–5258; placebo: median £0, range £0–5177).

Limitations
We were not able to recruit our target sample size for the trial. This impacted the data available for microbiology, health economics and risk reduction score analyses.

Conclusions
Our results do not support early antibiotic prescribing to at-risk children with influenza-like illness during influenza season.

Future work
Further research is required to determine if antibiotic treatment would be beneficial during periods of higher influenza activity such as influenza pandemics, to identify children who would gain most clinical benefit and to better understand families’ reconsultation decisions.

Trial registration
This trial is registered as ISRCTN70714783 and EudraCT 2013-002822-21.

Funding
This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research and will be published in full in Programme Grants for Applied Research; Vol. 11, No. 1. See the NIHR Journals Library website for further project information.