Journal Pone 0302302

PLOS ONE
STUDY PROTOCOL
Rapid respiratory microbiological point-of-

care-testing and antibiotic prescribing in
primary care: Protocol for the RAPID-TEST
randomised controlled trial
Samantha Elizabeth Abbs ID1‡*, Lindsay Armstrong-Buisseret1‡, Kathy Eastwood2,
Stephen Granier3, Athene Lane1, Mandy Lui ID1, Chris Metcalfe ID1, Paul Mitchell4,
Peter Muir ID5, Matthew Ridd6, Jodi Taylor1, Lucy Yardley7,8, Grace Young1, Alastair
D. Hay6
a1111111111
1 Bristol Trials Centre, Bristol Medical School, University of Bristol, Bristol, United Kingdom, 2 Patient
a1111111111
Representative, United Kingdom, 3 Whiteladies Medical Group, Bristol, United Kingdom, 4 Bristol Medical
a1111111111 School, University of Bristol, Bristol, United Kingdom, 5 UKHSA South West Regional Laboratory,
a1111111111 Southmead Hospital, Bristol, United Kingdom, 6 Centre for Academic Primary Care, Bristol Medical School,
a1111111111 University of Bristol, Bristol, United Kingdom, 7 School of Psychological Science, University of Bristol, Bristol,
United Kingdom, 8 School of Psychology, University of Southampton, Southampton, United Kingdom
‡ SEA and LAB are Joint first authors on this work.

* [email protected]
OPEN ACCESS
Citation: Abbs SE, Armstrong-Buisseret L,

Eastwood K, Granier S, Lane A, Lui M, et al. (2024)
Abstract
Rapid respiratory microbiological point-of-care-
testing and antibiotic prescribing in primary care:
Protocol for the RAPID-TEST randomised Background
controlled trial. PLoS ONE 19(5): e0302302.
Antibiotics are prescribed for over 50% of respiratory tract infections in primary care, despite
https://doi.org/10.1371/journal.pone.0302302
good evidence of there being no benefit to the patient, and evidence of over prescribing driv-
Editor: Jianhong Zhou, PLOS: Public Library of
ing microbial resistance. The high treatment rates are attributed to uncertainty regarding
Science, UNITED STATES
microbiological cause and clinical prognosis. Point-of-care-tests have been proposed as
Received: March 21, 2024
potential antibiotic stewardship tools, with some providing microbiological results in 15 min-
Accepted: March 28, 2024 utes. However, there is little research on their impact on antibiotic use and clinical outcomes
Published: May 20, 2024 in primary care.
Peer Review History: PLOS recognizes the
benefits of transparency in the peer review Methods
process; therefore, we enable the publication of
This is a multi-centre, individually randomised controlled trial with mixed-methods investiga-
all of the content of peer review and author
responses alongside final, published articles. The
tion of microbial, behavioural and antibiotic mechanisms on outcomes in patients aged 12
editorial history of this article is available here: months and over presenting to primary care in the UK with a suspected respiratory tract
https://doi.org/10.1371/journal.pone.0302302 infection, where the clinician and/or patient thinks antibiotic treatment may be, or is, neces-
Copyright: © 2024 Abbs et al. This is an open sary. Once consented, all participants are asked to provide a combined nose and throat
access article distributed under the terms of the swab sample and randomised to have a rapid microbiological point-of-care-test or no point-
Creative Commons Attribution License, which
of-care-test. For intervention patients, clinicians review the result of the test, before contact-
permits unrestricted use, distribution, and
reproduction in any medium, provided the original ing the patient to finalise treatment. Treatment decisions are made as per usual care in con-
author and source are credited. trol group patients. The primary outcome is whether an antibiotic is prescribed at this point.
Data Availability Statement: No data have been All swab samples are sent to the central laboratory for further testing. Patients are asked to
generated or analysed at the time of publication. A complete a diary to record the severity and duration of symptoms until resolution or day 28,
PLOS ONE | https://doi.org/10.1371/journal.pone.0302302 May 20, 2024 1 / 18

PLOS ONE Impact of respiratory microbiological point-of-care-testing on antibiotic prescribing in primary care
data availability statement will be made available and questionnaires at 2 months about their beliefs and intention to consult for similar future
after study completion. illnesses. Primary care medical records are also reviewed at 6-months to collect further
Funding: The trial was funded by the NIHR Efficacy infection consultations, antibiotic prescribing and hospital admissions. The trial aims to
and Mechanism Evaluation Programme recruit 514 patients to achieve 90% power with 5% significance to detect a 15% absolute
(NIHR131758) that was awarded to Prof Alastair D
Hay. LY is also funded by NIHR as a Senior
reduction in antibiotic prescribing.
Investigator and some of her time on this project Qualitative interviews are being conducted with approximately 20 clinicians and 30 partic-
may have been supported by the funding she ipants to understand any changes in beliefs and behaviour resulting from the point-of-care-
received from the NIHR Applied Research
test and generate attributes for clinician and patient discrete choice experiments.
Collaboration West and NIHR Health Protection
Research Unit.
Discussion
Competing interests: The authors have declared
that no competing interests exist. This trial will provide evidence of efficacy, acceptability and mechanisms of action of a rapid
Abbreviations: AE, Adverse Event; AMR, microbiological point-of-care test on antibiotic prescribing and patient symptoms in primary
Antimicrobial resistance; DCE, Discrete Choice care.
Experiment; GP, General practitioner; MCID,
Minimally clinically important difference; PCMR,
Primary care medical record; POCT, Point-of-care-
Trial registration
test; PPI, Patient and public involvement; RCT, ISRCTN16039192, prospectively registered on 08/11/2022.
Randomised Controlled Trial; RSV, Respiratory
Syncytial virus; RTI, Respiratory Tract Infection;
SAE, Serious Adverse Event; SUSAR, Suspected
Unexpected Serious Adverse Reaction; VTM, Viral
Transport Medium.
Introduction
Respiratory tract infections (RTIs) are the most common problem managed by health services
worldwide [1]. In the UK, antibiotics are prescribed for over 50% of RTIs by general practi-
tioners (GP) and primary care nurses [2, 3], with 50% of these prescriptions considered inap-
propriate [4, 5], and despite strong evidence that the majority of patients do not benefit [6–9].
The overprescribing of antibiotics results in unnecessary side effects [10], depletion of normal
flora [11], increased healthcare costs [12], and fuels antimicrobial resistance (AMR) [13, 14],
which is regarded as a significant public health threat [15]. High antibiotic treatment rates are
attributed to clinician uncertainty regarding patients’ microbiological diagnosis and clinical
prognosis [16, 17], leading to ‘just-in-case’ defensive prescribing [17].
One potential solution to address this issue is point-of care-testing (POCT) in primary care
settings. Rapid microbiological POCTs (POCTRMs) use nucleic acid or antigen-based tests to
detect viruses and bacteria from respiratory tract samples in as little as 15 minutes [18]. While
multiplex POCTRMs have shown promising results in reducing hospital admission times and
length of antibiotic courses in secondary care [19–22], more research is needed to evaluate
their impact on antibiotic use and clinical outcomes in primary care.
Observational studies [23, 24] have reported on the effects of POCTRMs testing for Influenza
A and B, and/or respiratory syncytial virus (RSV) in primary care. However, none of these
studies evaluated the use of multiplex POCTRMs on antibiotic prescribing or clinical outcomes.
We conducted a mixed-methods, observational feasibility study [25] which suggested a multi-
plex POCTRM was acceptable in primary care, and helped improve diagnostic certainty. How-
ever, none of these studies used randomised controlled trial methods, and none assessed the
short- and long-term effects of POCTRM testing on clinician and patient beliefs and behaviour.
To address this evidence gap, the RAPID-TEST study will conduct a RCT with the aim of
comparing decision making, antibiotic prescribing and patient outcomes between individuals
allocated to a POCT group and those allocated to a usual care group, at approximately 16 pri-
mary care practices in the south west of England.

Material and methods

Design and setting
This is a multi-centre, individually randomised controlled trial with a mixed-methods investi-
gation of microbial, behavioural and antibiotic mechanisms, conducted in UK primary care.
The trial is using eight POCT RM machines and recruiting from 16 GP (family doctor) prac-
tices across the South West of England, with eight sites recruiting participants per Winter.
Sites with previous research experience and those who were confident they could deliver the
relatively complex trial design were prioritised during site selection.
Population
The trial is aiming to recruit 514 patients aged �12 months presenting to primary care with a
suspected RTI where the Study Clinician and/or patient believes antibiotic treatment is, or
may be, necessary. Patients can present to their GP practice face-to-face, via telephone or via
online appointment. Study Clinicians can be any member of staff at the practice that is usually
responsible for the care of patients with RTIs (GPs, nurses, paramedics and pharmacists) and
who have been trained in study procedures.
Patients must meet all the following criteria to be eligible to take part:
1. Aged �12 months on the day of presentation
2. Presenting to primary care for the first time in this episode, and within 21 days of illness
onset, with a Study Clinician suspected acute RTI. Symptoms may include one or more of:
a. Sore throat
b. Runny nose
c. Earache
d. Cough
e. Sputum
f. Wheeze
g. Shortness of breath
3. Study Clinician diagnoses of an upper or lower RTI such as:
a. Acute otitis media

b. Acute sinusitis
c. Acute pharyngitis or tonsillitis
d. Sore throat
e. Acute laryngitis
f. Acute cough
g. Acute bronchitis
h. Chest infection
i. Acute lower RTI

j. Infective exacerbation of chronic lung disease e.g. asthma, chronic obstructive pulmonary
disease (COPD), emphysema or bronchiectasis
4. Study Clinician or patient/parent/carer believes antibiotic treatment is, or may be,
necessary
5. Patient/parent/carer willing and able to give informed consent
6. Patient/parent/carer willing for patient to have a nasal and throat swab taken, or willing
and able to collect, self-take and promptly return the swab to the site
7. Study Clinician and patient/parent/carer willing to wait for the POCTRM result before an
antibiotic prescribing decision is made
8. Laboratory transport pick up for samples expected <24 hours e.g. sample is expected to be
ready prior to final sample collection on a Friday
9. Patient/parent/carer willing to complete Trial Diary and for outcome data to be collected
from medical record
Patients with any of the following criteria are excluded:
1. Known to have cystic fibrosis
2. Require hospital admission
3. Previously taken part in the RAPID-TEST RCT
4. Currently taking part in another conflicting RTI study.
Patients already being treated with antibiotics or antivirals (for any indication) are
eligible as long as the Study Clinician suspects a new (or ongoing) RTI, and the Study Cli-
nician and/or patient/ parent/ carer believe further antibiotic treatment is, or may be,
necessary.
Co-enrolment to other research studies are considered on a case-by-case basis.
Objectives
Clinical objectives. The primary clinical objective is to investigate whether the use of a
rapid POCTRM can reduce same-day antibiotic prescribing for children and adults presenting
to primary care with RTIs where the Study Clinician and/or patient believes antibiotic treat-
ment is, or may be, necessary.
The key secondary clinical objective is to investigate whether the use of a rapid POCTRM
changes participant reported symptom severity on days 2 to 4.
Other clinical secondary objectives include:
a) To investigate whether the use of a rapid POCTRM changes participant reported severity
and duration of symptoms over 28 days including any hospital admissions for respiratory
symptoms, antibiotic consumption, and time to return to normal activities.
b) To investigate whether the use of a rapid POCTRM changes participant (or parent/carer if
the participant is <16 years) confidence in the clinical management of the infection, and
their intention to consult for future similar illnesses
c) To investigate whether the use of a rapid POCTRM changes subsequent healthcare resource
use in the following six months

Qualitative objectives.
d) To explore participants’ (or parents’/carers’ if the participant is <16 years) understanding
of the test and the result they were given, and their views of the implications for treatment
and future consultations
e) To explore the trade-offs participants (or parents/carers if the participant is <16 years)
make in choosing to visit the GP with respiratory infection symptoms and the extent
POCTRMs might increase or decrease help seeking behaviour
f) To describe the situations in which clinicians most and least value the new microbial knowl-
edge, and how it may influence clinical reasoning and participant management
g) To explore the trade-offs clinicians make about whether and when to use the POCTRM
Mechanistic objectives
h) To determine whether there are overall (intervention vs. control) and differential (virus
detected vs. not detected) effects with respect to reducing the number of participants for
whom the Study Clinician believes antibiotics are necessary
i) To describe the effect of POCTRM results on Study Clinician and participant (or parent/
carer if the participant is <16 years) beliefs in the necessity, and benefits, of prescribing
antibiotics for the respiratory infection, and confidence in the value of the POCTRM to
guide the prescribing decision and explore relationships of Study Clinician and participant
(or parent/carer if the participant is <16 years) beliefs, attitudes and intentions with antibi-
otic prescribing and consumption.
Patient identification, ‘Appointment one’ and consent

Fig 1 represents how participants progress throughout the trial and the different activities that
take place at each stage.
Potentially eligible patients, identified from appointment request lists by a member of the
GP practice, are offered a Participant Information Sheet, on paper or electronically. The ‘Study
Champion’ (e.g. receptionist, healthcare assistant, medical student, pharmacist, paramedic,
practice nurse or manager) explains the trial to the patient and answers any questions. Patients
are asked to answer three questions regarding their views on their need for antibiotics (see
Table 1. Participant and Study Clinician views). These are asked before the patient sees the
Study Clinician at ‘Appointment One’ since this interaction could change their views.
At Appointment One, the Study Clinician assesses the patient as per usual care. They con-
firm eligibility and completes their ‘Study Clinician Views’ (see Table 1. Participant and
Study Clinician views) on whether they consider the patient requires antibiotics.
If eligible and willing to take part, the patient completes a consent form, either electroni-
cally, on paper or verbally (in the presence of an independent witness). For patients aged
under 16 years, the consent form is completed by their parent/carer. Patients aged 12–15 years
old can also complete an assent form.
Once consent has been provided, the participant is asked to complete a second set of ‘Par-
ticipant Views’ and baseline questions about their symptoms and an EQ-5D-5L questionnaire.
All participants are asked to provide a combined nose and throat swab using MWE Sigma
S-VIROCULT1 swab kits provided by the central trial team. Where possible, these swabs will
be collected by a member of staff at the GP practice, but self-swabbing is permitted if

Fig 1. Participant flow diagram.

https://doi.org/10.1371/journal.pone.0302302.g001

Table 1. Participant and study clinician views.

Mediating variable Measures to be used (steps according to Fig 2) Response options
Participant Views (or parent/carer if the participant is <16 years)
Expectation that antibiotics 1. I believe an antibiotic is needed to treat my/my Strongly disagree; Disagree;
are needed child’s illness [Steps 1, 3 and 7] Neither agree nor disagree;
2. I believe my/my child’s illness will get better Agree; Strongly agree
faster if I/they take an antibiotic [Steps 1, 3 and 7]
3. I believe my/my child’s illness will be less
severe if I/they am/are given an antibiotic [Steps
1, 3 and 7]
Confidence to manage illness 4. A point-of-care test would help in making the Strongly disagree; Disagree;
without antibiotics (self- right decision about whether I/my child need/ Neither agree nor disagree;
efficacy) needs antibiotics [Step 3] Agree; Strongly agree
5. A point-of-care test would have helped/has
helped in making the right decision about
whether I/my child need/needs antibiotics [Step
7]
6. I am confident that I/my child will get/am
getting/is getting the right treatment [Steps 3 and
7]
Confidence to manage 7. If I/my child have/has an infection in future Strongly disagree; Disagree;
similar infection without that is like the one I/they had when I/they joined Neither agree nor disagree;
antibiotics in the future this trial then I/we will see my/our doctor to Agree; Strongly agree
check if antibiotics are needed [2 Month
Questionnaire]
8. If I/my child have/has an infection in future
that is like the one I/they had when I/they joined
this trial then I/we would like to have a point-of-
care test to check if antibiotics are needed [2
Month Questionnaire]
Study Clinician Views
Expectation that antibiotics 1. I believe an antibiotic is needed to treat the Strongly disagree; Disagree;
are needed patient’s illness [Steps 2 and 5] Neither agree nor disagree;
2. I believe the patient’s illness will improve faster Agree; Strongly agree
if I prescribe an antibiotic [Steps 2 and 5]
3. I believe the patient’s illness will be less severe
if I prescribe an antibiotic [Steps 2 and 5]
Confidence to manage 4. The point-of-care test would help in making Strongly disagree; Disagree;
patient without antibiotics the right decision about whether the patient Neither agree nor disagree;
(self-efficacy) needs antibiotics [Step 2] Agree; Strongly agree
5. The point-of-care test would have helped/has
helped in making the right decision about
whether the patient needs antibiotics [Step 5]
6. I am confident that the patient will believe they
are getting the right treatment [Steps 2 and 5]
Confidence to manage 7. If a patient has a similar infection in future I Strongly disagree; Disagree;
similar infection without am likely to prescribe them antibiotics [Step 5] Neither agree nor disagree;
antibiotics in the future 8. If a patient has a similar illness in future I Agree; Strongly agree
would like to use the POCTRM [Step 5]
https://doi.org/10.1371/journal.pone.0302302.t001
necessary. Swabs are placed in a tube with viral transport medium (VTM) before being tested
at the practice, if randomised to the intervention, and sent to the central laboratory.
Randomisation
Once a swab has been provided, participants are individually randomised 1:1 to intervention
(GP POCTRM test) or control (No GP POCTRM test) using an internet-based randomisation
system developed and maintained by Sealed Envelope™ to ensure concealment. Randomisation

is stratified by age (<16 years vs. �16 years) and chronic lung disease, defined as asthma,
chronic obstructive pulmonary disease (COPD), emphysema or bronchiectasis (present vs.
absent). It is not possible to blind allocation since subsequent trial processes differ by group.
Immediately following randomisation, the Study Clinician is informed of the allocation so that
clinical management of control group patients can proceed (management of intervention
group participants should wait for POCTRM results).
Intervention
A portion of the VTM from the swab sample from participants in the GP POCTRM test group
is analysed as soon as possible using the BioFire1 FilmArray1 Torch 1 in conjunction with
BioFire1 RP2.1 plus reagent pouches (Biomerieux) according to the manufacturer’s instruc-
tions at the GP practice. The time for processing one swab to results being available is approxi-
mately 1 hour, assuming the Torch 1 machine is not already in use. The results indicate
presence or absence of 23 upper respiratory microbes: 19 viruses (Influenza A (no subtype
detected, H1, H1-2009, H3), Influenza B, Adenovirus, Coronaviruses (HKU1, NL63, 229E,
OC43, Mers-CoV, SARS-CoV-2), Human Metapneumovirus, Human Rhinovirus/ Enterovi-
rus (not possible to distinguish due to genetic similarity), Parainfluenza (types 1, 2, 3, 4) and
RSV and four atypical bacteria: Bordetella pertussis, Bordetella parapertussis, Chlamydia pneu-
moniae and Mycoplasma pneumonia.
Study Clinicians are advised during trial set up and training that the POCTRM result should
be used as a guide to clinical decision making, with final responsibility for antibiotic prescrib-
ing residing with the Study Clinician. To help with results interpretation, Study Clinicians are
provided with information describing the typical presentation of illnesses caused by the
microbes tested (S1 Appendix).
If the POCTRM results are reported as ‘failed’, ‘invalid’ or ‘equivocal’, the original swab sam-
ple is retested as per the manufacturer’s instructions. If it is not possible to obtain POCTRM
results after following the manufacturer’s instructions the participant continues in the trial
and the Study Clinician makes an antibiotic prescribing decision based on the clinical evidence
available at that time.
‘Appointment two’
Appointment two takes place on the same day as randomisation.
For participants randomised to the GP POCTRM group, the Study Clinician waits to receive
the POCTRM test results, and then completes a second set of ‘Study Clinician Views’ (Table 1)
and then contacts the participant to inform them of the randomisation outcome and discuss
treatment.
If the participant has been randomised to the No GP POCTRM group, the Study Clinician
can proceed to complete their second set of ‘Study Clinician Views’, contact the participant,
inform them of the randomisation outcome and discuss treatment.
Control and central laboratory testing

The remaining swab sample from all (intervention and control) participants is stored at ambi-
ent temperature at the GP practice prior to transfer to the central research laboratory (UKHSA
South West Regional Laboratory, Southmead Hospital, Bristo) within 24 hours of collection.
Samples not sent on the same day of collection are stored in the GP practice fridge (2 to 8˚C)
overnight. At the central laboratory, these samples are tested for the presence of respiratory
viral and bacterial pathogens using a Taqman Low Density polymerase chain reaction array
card assay [26] as well as the same BioFire1 RP2.1 plus reagent pouches run on the Biofire1

Filmarray1 Torch 1 system used at the GP practices. At the end of the study any residual sam-
ple will be destroyed. All samples are handled according to the Human Tissue Act.
Follow up
All participants (or parent/carer if the participant is <16 years) are asked to complete a vali-
dated Trial Diary [27] until symptoms resolve (defined as all symptoms being rated zero for
two consecutive days) or up to day 28, whichever comes first. The central trial team contacts
participants via email, text or phone to support completion of the Trial Diary.
Participants (or parent/carer if the participant is <16 years) are sent a follow-up question-
naire at 2 months to collect beliefs and intention to consult for similar future illnesses (see S1
Appendix). Up to two reminders are sent where questionnaires are not returned.
In addition to Trial Diaries and questionnaires, data on any further GP consultations for
RTIs are collected from participants’ primary care medical records (PCMR) at 2 and 6 months
by site staff.
Optional qualitative interviews and Discrete Choice Experiment (DCE)

surveys
During the consent process, participants (or parents/carers if the participant is <16 years) are
asked whether they are interested in being contacted about taking part in an optional Partici-
pant Interview and receiving a separate optional Participant Discrete Choice Experiment
(DCE) survey. Participants (or parents/carers if the participant is <16 years) can choose to be
contacted about the interview and the DCE survey, just one, or neither. This does not affect
their ability to take part in the main trial.
Clinicians from each site are asked whether they are interested in being contacted about
taking part in an optional Clinician Interview. In addition, Study Clinicians involved in the
trial and other clinicians recruited through the West of England Clinical Research Network
will be invited to complete a Clinician DCE survey.
A DCE is a method commonly used in health economics to elicit stated preferences from
health care stakeholders.[28] Participant and Clinician DCE surveys will be developed based
on the qualitative interview findings with participants and clinicians, respectively.
Outcome measures
The primary clinical efficacy outcome is antibiotic prescribing for a RTI at Appointment Two,
as reported by Study Clinicians and/or collected from participants’ medical records.
The key secondary clinical outcome is symptom severity on days 2 to 4, as reported on Trial
Diary.
Other clinical secondary outcomes include:
1. Symptom severity and duration, length of time to return to usual activities, and antibiotic
and antiviral consumption within 28 days as reported by patient on Trial Diary.
2. Health-related quality of life measured by the EQ-5D-5L (age >16 years) or EQ-5D-Y (age
1–15 years)
3. Participant and clinician views (see Table 1)
4. Hospital admissions within 28 days
5. Consultations for respiratory infections within 6 months
6. Name and dose of antibiotics and antivirals prescribed within 28 days

Data collection and management

The data collection schedule is outlined in Fig 2. Data is directly entered onto a bespoke RED-
Cap database and stored on a secure server, only accessible to authorised staff. Patient reported
Trial Diary and questionnaire data are also recorded and stored on the trial database All study
documentation will be retained in a secure location during the study and for at least 5 years
after the end of the study. For children under the age of 16 at recruitment, research data will be
kept until their 25th birthday.
Fig 2. Schedule of enrolment, interventions and assessments.


Safety reporting
Site staff are responsible for recording appropriate adverse events (AEs) for the participants
during the trial. Only non-serious AEs that are assessed as being possibly, probably or defi-
nitely related to the intervention or trial procedures will be recorded in the relevant trial docu-
mentation. They should also be recorded in the participant’s medical notes by site team and
the participant should be followed up until the event resolves. Non-serious AEs that are unre-
lated to the intervention do not need to be recorded. The reporting framework for non-serious
AEs is shown in Fig 3.
Sites are also required to record all serious AEs (SAE) on the trial database. These should
also be recorded in the participant’s medical notes and should be followed up by the site until
the event resolves. Any SAEs which are assessed by the local Principal Investigator (PI) as
being related to the trial procedures and unexpected for the procedure are classed as Suspected
Unexpected Serious Adverse Reactions (SUSAR) and must be documented on the full SAE
report form and submitted within 24 hours of staff becoming aware of the event. As is propor-
tionate to the nature of the trial, only SUSARs will require expediting reporting to the Sponsor.
The reporting framework for SAEs is shown in Fig 4.
All SAEs will be further reported to the DMC as part of their oversight meetings.
Fig 3. Recording framework for AEs assessed as non-serious.


Fig 4. Recording framework for serious adverse events (SAEs).

Sample size
Antibiotic prescribing at the index consultation is the primary outcome measure. The largest
individual patient data meta-analysis to date [3] reported a total of 65% use of antibiotics in
patients in observational and experimental studies, across a wide spectrum of respiratory infec-
tions and patient groups, as we propose in RAPID-TEST.
Previous stewardship trials of POCTs have used varying minimum clinically important dif-
ference (MCID) definitions of absolute prescribing reductions, from 10% [29] to 20% [30],
with actual reductions observed of 15% [29] and 22%[30]. Since POCTRMs are expensive, we
selected a MCID of 15%.
Assuming an antibiotic prescribing rate of 60% in the control group, 244 participants per
group will allow a true reduction to 45% in the GP POCTRM test group to be detected with
90% power at 5% significance. A total randomisation target of 514 will allow for 5% attrition.
We have assumed a relatively large minimum clinically important difference due to the high
cost of POCTRM.

If the POCTRM results in fewer antibiotic prescriptions, we wish to demonstrate non-inferi-

ority of the POCTRM in terms of not increasing mean symptom severity at days 2 to 4 to a clin-
ically significant extent. Assuming 80% completion of Trial Diaries (as previously achieved in
adults [31] and children [32]) we will have data for symptom severity at 2 to 4 days in 206 par-
ticipants per group. Data on 7,000 adults and children managed without POCT indicates a
mean symptom severity at days 2 to 4 of 2.3 (standard deviation 1.5) [3]. We know this mea-
sure’s distribution is positively skewed and have used a calculation that accommodates this
(assuming equal skew in both groups, quantified as a coefficient of variation of 0.7) [33].
Assuming, in truth, no difference between groups, 206 participants in each group will give
90% power for a one-sided 95% confidence interval to exclude increases in the average symp-
tom score of 20% or more.
Statistical analysis
A detailed statistical analysis plan will be finalised and made publicly available ahead of the
completion of recruitment. In outline, the primary analysis will be of observed data and con-
ducted according to the intention to treat principle. A logistic regression equation will estimate
the causal association between the primary outcome of antibiotic prescribing and allocated
intervention group as an odds ratio, presented with 95% confidence interval and p-value. Fur-
ther covariates will include participant age and chronic lung disease (used to stratify randomi-
sation). Variations between participating GPs in prescribing tendency will be accommodated
as dummy variables to distinguish each GP. Sensitivity analyses will gauge the robustness of
the conclusions to different assumptions about any missing data. The above approach will be
adapted e.g. through the choice of a suitable regression model, to the secondary outcome vari-
ables such as symptom severity at 2 to 4 days.
Potential mechanisms of action, linking the intervention with the prescribing of an antibi-
otic will be investigated. A key potential mechanism is the result of the POCTRM test which
will be investigated in a logistic regression models with covariates including allocated group
(results inform the clinical decision or not), result (virus detected or not), and the interaction
between the two. The interaction term will capture any evidence that the test result is influenc-
ing the prescribing decision, rather than a non-specific effect of the POCTRM which is inde-
pendent of the result, and distinguish this effect from any underlying ability of GPs to
prescribe to those participants who will benefit from an antibiotic.
Study management
The study is managed by the Bristol Trials Centre and sponsored by University of Bristol. The
Trial Management Group (TMG) includes members responsible for the day-to-day manage-
ment of the trial, including the chief investigator, co-investigators, trial manager, statistician
and patient representatives. The role of the TMG is to monitor the progress and conduct of the
trial, including adherence to the trial protocol. The Trial Steering Committee (TSC) is made
up of representatives from the RAPID-TEST trial team and independent members approved
by the funder. The Data Monitoring Committee (DMC) consists of an independent medical
statistician and medical experts in the field also approved by the funder. The TSC and DMC
meet as required; at least once a year.
Patient and public involvement (PPI)

Patients and members of the public have been involved in the design and management of this
trial and will also be involved in dissemination activities. Multiple PPI meetings took place at
the grant application stage and provided input into the final design on the trial.

The RAPID-TEST Trial Management Group and Independent Steering Committee both
include PPI members. PPI members of these groups have provided feedback on Patient Infor-
mation Sheets provided to trial participants, contributed to draft reports to funders and over-
sight committee meetings, and have provided input to develop strategies to improve trial
diversity and inclusivity.
Ethical considerations and dissemination

The trial was approved by the North West—Preston Research Ethics Committee on 11th Octo-
ber 2022 (REC reference 22/NW/0294). Any amendments to the trial protocol will be
approved by the Sponsor and ethics committee before implementing at sites. Written,
informed consent (or verbal consent where written is not possible) to participate will be
obtained from all participants (or the parent/carer if under 16 years old).
A plan to disseminate the trial results will be developed by the TMG. The trial team plan to
present findings at national and international meetings, and in peer-reviewed publications. Inno-
vative methods of dissemination will be explored such as videos and blogs to accompany scien-
tific papers that are accessible to the public, as well as providing a lay summary to participants.
Trial status
The trial opened to recruitment on 28th November 2022 and is currently using protocol v3.0,
06 March 2023. The trial is recruiting well and recruitment is expected to finish within the
original timelines (by 30th September 2024).
Discussion
The ‘holy grail’ of antimicrobial stewardship is to ensure the minority of patients needing anti-
biotics are given the shortest course of the narrowest spectrum treatment possible, while pre-
venting unnecessary exposure among the majority unlikely to benefit. The vast majority of
stewardship interventions currently available aim to reduce overall prescribing [34], with only
a handful of validated tools available to support precision prescribing in primary care [35, 36].
Given that a significant proportion of RTIs managed in primary care are considered viral
[37–39], it is plausible that a POCTRM providing accurate results quickly could improve pre-
scribing. However, there is currently insufficient evidence regarding the safety, efficacy, or
mechanism of action, let alone clinical and cost effectiveness, to recommend use of POCTRMs
in primary care. Efficacy studies are urgently needed to address these issues using randomised
controlled designs, as well as qualitative methods to understand clinician and patients’ percep-
tions of the tests. One of the strengths of the RAPID-TEST trial is its randomised controlled
trial design, which will be delivered in NHS GP practices. This RCT will show whether using
multiplex POCTRMs in primary care could safely reduce the unnecessary use of antibiotics,
and the beliefs that sustain unnecessary use, thereby reducing the public AMR risk. The trial
will also show whether POCTRM use affects clinically relevant patient outcomes, antiviral pre-
scribing, re-consultations and future consultations for RTIs. Although the use of the test in the
intervention group slightly extends the initial consultation time, it is possible that this longer
consultation could reduce re-consultations in the future. Using a mixed-methos approach, the
trial will also provide further insight into behavioural changes, such as how the POCTRM
might influence clinician and patient beliefs and confidence in the treatment decision to
reduce antibiotic prescribing.
The authors acknowledge the trial’s limitations. Participants are unblinded when complet-
ing the Trial Diary, which could lead to bias in patient-reported outcomes, and there is no
cost-effectiveness analysis at this stage. The POCTRM used in the trial does not test for typical

bacteria such as S. pneumoniae, S. pyogenes, H. influenzae or M. catarrhalis, since these can be

commensally carried in the upper respiratory tract, and the test is unable to determine whether
any pathogens that are detected are the cause of the patient’s symptoms.
The authors are also aware of similar ongoing trials, also evaluating the use of POCTs in
RTIs in primary care, such as PRUDENCE (ISRCTN13336322). However, these trials are eval-
uating different types of POCT.
Recruitment to RAPID-TEST opened in November 2022 and the trial has proven to be
acceptable to patients and clinicians so far, with recruitment ahead of target and expected to
be completed within the original budget and timelines.
Supporting information
S1 Appendix. Information provided to clinicians.
(DOCX)
S1 Checklist. SPIRIT checklist.
(DOCX)
S1 File. RAPID-TEST protocol v3.0 06Mar23.
(PDF)
S2 File. RAPID-TEST PIS v2.0 04Oct22.
(PDF)
S3 File. RAPID-TEST ICF v2.0 04Oct22.
(PDF)
S4 File. RAPID-TEST protocol v2.0 04Oct22 (original approved protocol).
(PDF)
Acknowledgments
The RAPID-TEST study is sponsored by the University of Bristol. The sponsor is responsible
for oversight of the RAPID-TEST study and will ensure the study is managed appropriately.
The study was designed and is delivered in collaboration with the Bristol Trials Centre, a
UKCRC-registered clinical trials unit.The authors would like to thank all research and clinical
teams involved in recruitment, coordination and data entry for this study. Particular thanks
are given to Katalin Bagi, Lynne Bradshaw, Emma Bridgeman, Rachel Brierley, Emily Brown,
Joanna Coast and Hayley Dash, Paul Roy, Hannah Thornton and Liang Zhu.
The authors would also like to acknowledge the Trial Steering Committee and Data Moni-
toring Committee members.
Author Contributions
Conceptualization: Kathy Eastwood, Stephen Granier, Athene Lane, Chris Metcalfe, Paul
Mitchell, Peter Muir, Matthew Ridd, Jodi Taylor, Lucy Yardley, Alastair D. Hay.
Funding acquisition: Kathy Eastwood, Stephen Granier, Athene Lane, Chris Metcalfe, Paul
Mitchell, Peter Muir, Matthew Ridd, Jodi Taylor, Lucy Yardley, Alastair D. Hay.
Methodology: Kathy Eastwood, Stephen Granier, Athene Lane, Chris Metcalfe, Paul Mitchell,
Peter Muir, Matthew Ridd, Jodi Taylor, Lucy Yardley, Alastair D. Hay.
Project administration: Samantha Elizabeth Abbs, Lindsay Armstrong-Buisseret.

Resources: Samantha Elizabeth Abbs, Lindsay Armstrong-Buisseret.

Supervision: Samantha Elizabeth Abbs, Lindsay Armstrong-Buisseret, Kathy Eastwood, Ste-
phen Granier, Athene Lane, Mandy Lui, Chris Metcalfe, Paul Mitchell, Peter Muir, Mat-
thew Ridd, Jodi Taylor, Lucy Yardley, Grace Young, Alastair D. Hay.
Writing – original draft: Samantha Elizabeth Abbs, Lindsay Armstrong-Buisseret, Alastair D.
Hay.
Writing – review & editing: Samantha Elizabeth Abbs, Lindsay Armstrong-Buisseret, Kathy
Eastwood, Stephen Granier, Athene Lane, Mandy Lui, Chris Metcalfe, Paul Mitchell, Peter
Muir, Matthew Ridd, Jodi Taylor, Lucy Yardley, Grace Young, Alastair D. Hay.
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PLOS ONE

Rapid respiratory microbiological point-of-

‡ SEA and LAB are Joint first authors on this work.

Citation: Abbs SE, Armstrong-Buisseret L,

PLOS ONE | https://doi.org/10.1371/journal.pone.0302302 May 20, 2024 1 / 18

PLOS ONE | https://doi.org/10.1371/journal.pone.0302302 May 20, 2024 2 / 18

Material and methods

a. Acute otitis media

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Patient identification, ‘Appointment one’ and consent

PLOS ONE | https://doi.org/10.1371/journal.pone.0302302 May 20, 2024 5 / 18

Fig 1. Participant flow diagram.

PLOS ONE | https://doi.org/10.1371/journal.pone.0302302 May 20, 2024 6 / 18

Table 1. Participant and study clinician views.

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Control and central laboratory testing

PLOS ONE | https://doi.org/10.1371/journal.pone.0302302 May 20, 2024 8 / 18

Optional qualitative interviews and Discrete Choice Experiment (DCE)

PLOS ONE | https://doi.org/10.1371/journal.pone.0302302 May 20, 2024 9 / 18

Data collection and management

Fig 2. Schedule of enrolment, interventions and assessments.

PLOS ONE | https://doi.org/10.1371/journal.pone.0302302 May 20, 2024 10 / 18

Fig 3. Recording framework for AEs assessed as non-serious.

PLOS ONE | https://doi.org/10.1371/journal.pone.0302302 May 20, 2024 11 / 18

Fig 4. Recording framework for serious adverse events (SAEs).

PLOS ONE | https://doi.org/10.1371/journal.pone.0302302 May 20, 2024 12 / 18

If the POCTRM results in fewer antibiotic prescriptions, we wish to demonstrate non-inferi-

Patient and public involvement (PPI)

PLOS ONE | https://doi.org/10.1371/journal.pone.0302302 May 20, 2024 13 / 18

Ethical considerations and dissemination

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bacteria such as S. pneumoniae, S. pyogenes, H. influenzae or M. catarrhalis, since these can be

PLOS ONE | https://doi.org/10.1371/journal.pone.0302302 May 20, 2024 15 / 18

Resources: Samantha Elizabeth Abbs, Lindsay Armstrong-Buisseret.

PLOS ONE | https://doi.org/10.1371/journal.pone.0302302 May 20, 2024 16 / 18

PLOS ONE | https://doi.org/10.1371/journal.pone.0302302 May 20, 2024 17 / 18

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