28th April 2021

To celebrate our 50th anniversary, we’re inviting a select number of experts to share what they see as being the 21st-century solutions to one of the biggest and most complex challenges of our generation: antimicrobial resistance. In this post, Prof Gail Hayward and Dr Philip Turner explore the future of diagnostic testing...

Where are we now?

Approximately 80% of all antibiotics prescribed in the UK are prescribed by GP surgeries and other community settings. Optimising antibiotic prescribing in this setting should therefore be a priority to reduce AMR.

As a GP, our goal should be to only prescribe antibiotics to patients with bacterial infections where they are necessary either to shorten the duration of unmanageable symptoms or to avoid complications. It might seem from the outside that this could easily be driven by establishing and following guidelines. But the decision to prescribe antibiotics is complex. It includes the expectations of both the patient and clinician, as well as the challenge of predicting the risk that a patient might get worse without antibiotics, and how confident a GP is that a patient will be able to get help if they do feel worse.

Diagnostic technology already plays a role in this decision-making, and has been hailed as a critical component of Antimicrobial Stewardship (AMS) by leaders in the field (O’Neill 2016), but has limitations. The tests currently available are limited in their scope, speed and accuracy. For example in urinary tract infection (UTI), I could use a dipstick which will tell me within 2 minutes whether some biomarkers are present in the urine which suggest an infection, but it has poor accuracy: in up to 4 out of 10 infections, there will be no biomarkers.  The other test I can perform for urine infection will take 3 days to come back from the laboratory, too late to influence my decision to prescribe.

Available rapid tests cannot inform decisions about which antibiotic to prescribe. Good stewardship includes both avoiding unnecessary antibiotics and using the best antibiotic where they are needed.  For example many urine infections would be successfully treated by amoxicillin, a penicillin antibiotic with few side effects which is safe in pregnancy, but the chances of the infection being resistant to amoxicillin (up to 60%) are too high for GPs to prescribe it without proof that it will work. Knowing which antibiotics will work would open up prescribing options meaning newer antibiotics can be preserved for the future.

Available rapid tests cannot inform decisions about which are present but not causing illness. We know that up to 30% of older adults can carry bacteria in their bladder without any symptoms at all. Similarly up to 15% of children carry bacteria also known to cause throat infections harmlessly in their throat. Therefore tests which simply tell us about the presence of bacteria without additional information could actually increase antibiotic prescribing in certain populations.

Tests are focussed on distinguishing between bacterial and viral causes of infections. There is an inherent assumption here that bacterial infections need antibiotics to get better. However this is not the case. Randomised trials comparing antibiotics to placebo show up to 60% of UTIs will get better without antibiotics, although they may take longer to do so, and patients may find this unacceptable. It follows that even an excellent test for bacterial infection could result in unnecessary antibiotics for infections that could get better almost as quickly without.

Finally, the way in which tests are paid for in the NHS does not favour implementation of novel diagnostics. GPs currently do not get additional funding to purchase or maintain easy, quick, point of care tests which could inform prescribing decisions. Test equipment, consumables and quality assurance procedures can often cost as much as paying a doctor to work for half a day a week for a year. In times of unprecedented demand for healthcare it is not surprising that man-power is prioritised over equipment in GP budgets.

 

Where do we need to be within a generation?

We need to develop diagnostics which are cheap enough to roll out across over 7000 primary care sites, and are rapid enough to mean the results are back in time to influence prescribing behaviour for acute conditions.  They need to distinguish between friendly bacteria and those causing disease and be well evidenced enough to give clinicians confidence that they can detect patients where antibiotics are required to avoid longer durations of severe symptoms or complications. They need to be embedded in practice, including within healthcare records and in patient flow, in a way that will encourage change in prescribing behaviour, and be accompanied by appropriate funding for the costs of purchasing test equipment and maintaining it.

 

How do we go from here to there?

Technology development is certainly part of the answer. In our work as the Community Healthcare MedTech and IVD Co-operative, we support a wide range of companies aiming to develop better diagnostics to guide appropriate prescribing. The Longitude Prize has fostered innovation in this field, and particularly in UTI diagnostics, which are a focus as they are the commonest bacterial infection seen in primary care. There is now a high probability that we will have tests available in the coming years which can tell us whether bacteria are present, what kind they are AND which antibiotics will successfully treat the infection before we need to make a prescribing decision. Technology development is most successful when it is done in partnership with clinicians and researchers who are expert in the field, so that from early stages of development the product evolves to be truly fit for purpose. Initiatives encouraging partnerships between research and industry are invaluable in this regard.

Technology development however needs encouragement, and a big stumbling block at present is how diagnostics are paid for. Researchers, including those at the Health Protection Research Unit (HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at Oxford are working on ways to quantify the costs of antibiotic resistance so that we can use this as a basis for funding needed now: in effect, how much is it worth to us to preserve antibiotics for the future?

We also need to understand how we can use tests in combination with the holistic assessment of the patient to predict likely prognosis, so that we are able to prescribe to only those patients who really need antibiotics to avoid longer illness or complications. The rapid development of digital health databases will support this move towards a personalised approach to prescribing, which could extend beyond the decision to prescribe to help clinicians understand which antibiotics and for which duration, are optimal for an individual patient.

References

https://doi.org/10.3399/bjgp17X693641

Butler CC, Francis N, Thomas-Jones E, Llor C, Bongard E, Moore M, et al. Variations in presentation, management, and patient outcomes of urinary tract infection: a prospective four-country primary care observational cohort study. British Journal of General Practice. 2017;67(665):e830-e41.

https://doi.org/10.1136/bmj.h6544

Gágyor I, Bleidorn J, Kochen MM, Schmiemann G, Wegscheider K, Hummers-Pradier E. Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial. BMJ. 2015;351:h6544.

https://amr-review.org/sites/default/files/160525_Final%20paper_with%20cover.pdf

O’Neill J. Tackling Drug-Resistant Infections Globally: Final Report and Recommendations. London, UK: The Review on Antimicrobial Resistance; 2016.

https://doi.org/10.1542/peds.2009-2648

Shaikh N, Leonard E, Martin JM. Prevalence of Streptococcal Pharyngitis and Streptococcal Carriage in Children: A Meta-analysis. Pediatrics. 2010;126(3):e557-e64.

https://doi.org/10.1371/journal.pmed.1002569

Vik I, Bollestad M, Grude N, Bærheim A, Damsgaard E, Neumark T, et al. Ibuprofen versus pivmecillinam for uncomplicated urinary tract infection in women—A double-blind, randomized non-inferiority trial. PLOS Medicine. 2018;15(5):e1002569

 

Prof Gail Hayward MBBChir, D.Phil, MRCP, DRCOG, MRCGP

Professor Gail Hayward is the Deputy Director of the NIHR Community Healthcare MedTech and IVD Cooperative. Her research interests lie in diagnosis and management of common infections in primary care and in the generation of evidence for new diagnostic technologies in primary care settings. She is co-PI of the PRINCIPLE study evaluating treatments for COVID-19 in community patients. She is also interested in characterising the work of the primary care Out-of-Hours services and exploring the ways this service could be improved by use of new technologies or different models of care. Professor Hayward is a practicing GP in Oxford city.

 

Dr Philip Turner B.Sc, PhD

Dr Philip Turner is the Manager of the NIHR Community Healthcare MedTech and IVD Co-operative and a Senior Researcher in the Infections and Acute Care Research Group based at the Nuffield Department of Primary Care Health Sciences at the University of Oxford. His research has focussed on the diagnostic needs of clinicians, barriers to implementation, and the identification of evidence gaps which commonly exist in the evidence base for point-of-care diagnostic tests. He has a particular interest in IVDs which could be deployed in resource-limited settings. He is co-Investigator of the CONDOR platform and RAPTOR-C19 study for the field evaluation of SARS-CoV-2 diagnostic tests.l

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Initial response from BSAC

Improving the use of diagnostic tests is a key recommendation of the O’Neill AMR Review. The Review committee was struck by the fact that currently most antibiotic prescriptions are empirical. That is, they are written on a ‘best guess’ basis and the doctor does not know for certain if the patient actually has an infection at the time the prescription is written, or what the cause of that infection is. The final report of the AMR Review included an ambition to make it mandatory that by 2020 the prescription of antibiotics will need to be informed by data and testing technology wherever it is available. Clearly, we are past that date now, but the UK AMR strategy does contain a target to be able to report on the percentage of prescriptions supported by the use of a diagnostic test or decision support tool by 2024, with improvement targets set by 2025.

The issues relating to the use and mis-use of diagnostic tests are explained clearly in the blog and it is written from the perspective of a community practice. This is important, because approximately 75-80% of antibiotics used in human medicine are given by GPs. I like the fact that the potential unintended consequences of misusing or misinterpreting a test result are discussed. The blog also mentions some behavioural aspects hindering implementation of change.

One very interesting feature of this piece is the emphasis on funding models. This is something that is not often discussed. As an example, GPs are often criticised for not implementing the use of C-Reactive Protein (CRP) measurement in their surgeries. These rapid tests can help differentiate between bacterial and viral infections and hence inform a decision about whether-or-not to prescribe an antibiotic. Antibiotic costs are currently funded centrally. Whereas costs of diagnostic tests in GP surgeries are funded by the practices themselves. Therefore, an initiative to implement CRP testing to prevent unnecessary antibiotic prescribing saves on antibiotic costs at the expense of the GP practice unless some form of central procurement is arranged.

 

We want to hear your thoughts on this article. What you say could inform the recommendations we make in the Vanguard Report itself, which will be published at the end of the year.

You can join the conversation by emailing mcorley@bsac.org.uk or tweeting our @BSACandJAC account.

 

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