The journey so far
Almost a decade ago the O’Neill Review on Antimicrobial Resistance (AMR) set in motion a process aimed at raising the profile of antimicrobial resistance and how best to manage it. The subsequent series of reports published between 2014 and 2016 during the life of this Review clearly laid out the enormous anticipated global impacts and costs of what is now being called both the the “next pandemic” and the “silent pandemic”.
Image credit: Shutterstock.com/Mikhail Grachikov
Progress has been made on some fronts in the battle against AMR since the Review’s final report (O’Neill, 2016) was released. AMR and the forces driving it are now recognised more broadly across the globe. Programmes are being set up to track antibiotic use and development of resistance, and the impact of antibiotics on the environment and in agriculture is increasingly being recognised in a One Health Approach (WHO, 2017).
Action on other recommendations aimed at reducing the demand for use of antimicrobials, however, continues to lag. Availability of rapid diagnostics that can steer antibiotic selection and prescription is one such example.
A role for rapid diagnostics
Streamlining antibiotic prescription by reducing the inappropriate and excessive prescription of these precariously placed drugs was one of the recommendations of the final O’Neill report on how best to tackle an imminent AMR crisis.
The development of new, rapid diagnostic measures was recommended as one of the key ways to do this by providing clinicians with new, accurate, accessible, acceptable, and affordable ways to quickly identify whether an infectious agent was bacterial or viral in nature and to prescribe an appropriate treatment.
Five years later, a need still remains for improved diagnostic tools that can guide appropriate antibiotic prescribing (Davies, 2019). Initiatives such as the Longitude Prize go some way towards meeting this need. Commercialisation gaps are beyond the scope of such R&D-focused initiatives and it is these gaps that are currently one of the bigger barriers to uptake of rapid diagnostics to counter AMR.
Practical realities of antibiotic prescribing in primary care
Whilst a broader awareness now exists of how antibiotic prescription influences AMR across the globe, practical implementation of only prescribing the right antibiotic to the right patient at the right time for the right length of time remains a challenge to implement in practice. The O’Neill (2016) report recommendations remain aspirational in this regard, even though an official UK AMR strategy has set a target to have a diagnostic test or decision support tool available for use by clinicians by 2024 (Featherstone, 2021).
Despite AMR now being globally addressed through national strategies to improve diagnostics, develop new antimicrobials and promote improved antimicrobial stewardship, patients who attend general practice with symptoms of respiratory tract infections (RTIs) are still normally assessed by a form of clinical decision rule (CDR) without a diagnostics test.
Antibiotic prescribing patterns – a UK case study
In the UK approximately 80% of antibiotics are currently prescribed in community settings (Hayward and Turner, 2021). RTIs are among the most common acute conditions where antibiotics are prescribed by general practitioners (GP), even though 70% of cases are viral, and many others are minor self-limiting bacterial infections (Drug.Ther.Bull, 2016; Zumla, et al, 2014).
Around 50% of all GP consultations in the UK for RTIs result in an antibiotic prescription, but actual prescribing rates vary dramatically across practices, ranging from 20% to 80% (Guildford, et al, 2014). In contrast, in the Netherlands only 22.5% of RTI episodes in 2010 were treated with antibiotics (van den Broek, et al, 2014). It is well-established that, in the absence of rapid diagnostics, prescribing is often done empirically, contributing to AMR development.
Availability of rapid diagnostics
Few rapid diagnostic tests are available for use at POC and in community settings (Zumla, et al, 2014). Those that are available require invasive sampling, expensive equipment, and personnel with specialist training for operation and test interpretation.
More accessible options are, however, beginning to emerge. Point-of-care (POC) tests are increasingly recognised as an important tool that can bring an accurate diagnosis quickly, enabling the opportunity for faster diagnosis and therefore approporiate treatment. Timely and reliable results empower physicians to employ antibiotic stewardship principles and prescribe more judiciously where they can have a notable impact.
C-Reactive Protein as an indicator of RTI
C-Reactive Protein (CRP) is widely used as a biomarker for systemic inflammation and tissue injury in such things as heart attacks, cancers, and infections. These feature in an ever-growing number of studies showing that fewer antibacterials are prescribed to patients presenting with RTI symptoms when CRP tests are used. Publications show that GPs and patients both report good acceptability for these tests. CRP-POC tests have been adopted by Public Health England (PHE) (Public Health England, 2017) and the National Institute for Health and Clinical Excellence (NICE) (NICE, 2019). However, in clinical practice, there has been little adoption of the recommendations.
Molecular- and antigen-based tests
Medical diagnostics companies are playing their part in the fight against AMR related to RTIs. POC diagnostic devices using molecular-based polymerase chain reaction (PCR) tests to test for viral or bacterial pathogens are starting to be available for POC use rather than only in a traditional molecular laboratory. This trend has grown as the COVID-19 pandemic has progressed. These PCR tests can identify a specific bacterium or DNA virus. Multiplexed PCR testing can differentiate between respiratory viruses.
SME companies are also breaking into the health and life sciences sector with novel technologies that have the potential diagnostics power to identify and differentiate between bacterial and viral infections rapidly at POC. Portable, real-time PCR-based DNA sequencing capabilities are being transformed from laboratory-based research use only devices to devices with regulatory-certified diagnostic functionality.
Academic institutions are adding know-how across diagnostic device development with a view to reducing antibiotic prescribing in primary care through the use of rapid microbiological POC testing to diagnose respiratory infections. Rapid antigen testing to identify Streptococcus A throat infection is also under consideration in commercial pharmacy settings.
Breath analysis as an emerging alternative
Image credit: Shutterstock.com/Mikhail Grachikov
An emerging alternative approach being applied by many researchers and SMEs is to undertake diagnostics via breath analysis. This approach meets stipulated criteria for rapid RTI diagnostics (Zumla, 2014).
This analysis is of the volatile organic compounds (VOCs) in the breath, which contain metabolites of disease or infection and reflects the metabolomic state of the body. Some research is still in its fundamental stages and analysis is laboratory-based only. A few companies are starting to move towards carrying out breath analysis at POC, with results delivered within minutes. Many of these use sensor arrays for the detection of VOCs, but currently, none of these technologies have CE marking for RTI diagnostics.
Imspex Medical, a division of Imspex Diagnostics Ltd, brings a different approach to rapid diagnostics in the form of its proprietary VOC breath analysis platform technology.
Breathspec®, its proprietary breath analyser, is based on combined gas chromatography – ion mobility spectrometry (GC-IMS). Its ultrahigh sensitivity means that it can detect even trace amounts of chemicals in breath and it can be used at POC with results in less than 15 minutes.
The Breathspec® device has been developed as a new, rapid diagnostic measure for RTI to provide clinicians with rapid, accurate, accessible, acceptable, and affordable diagnostics to quickly identify whether an infectious agent is bacterial or viral in nature and to prescribe the appropriate treatment. It has already been trialed successfully in primary and secondary care settings, emergency departments, and within communities across Europe, the US, and the far East for respiratory infection. It is in the final phases of CE marking preparations.
BreathSpec® is a growing platform, with proven capability to accommodate new disease applications as its VOC database expands.
Taking rapid RTI diagnostics to market
No new rapid diagnostics have been brought to market since the O’Neill report recommendations were made in 2016. This is due to a combination of high development costs, high regulatory hurdles, severely constrained reimbursement possibilities, and convoluted market access possibilities.
Adoption and uptake of new diagnostics into clinical practice in public health services such as the NHS remains challenging. Expectation gaps both on the supply side and on the demand side (Featherstone, 2021) often scupper effective communication between diagnostic developers and purchasers. Sufficient cost-effectiveness detail needs to be provided by innovators to comply with NICE’s Diagnostics Assessment Programme. Insufficient detail translates into limited support by clinical commissioners for a given new technology. From the demand side, a lack of clarity about the correct point of contact within the health service, health service procurement policies, and technology adoption requirements also prevents new and effective diagnostic technologies from being adopted.
For new RTI diagnostics, tests need to be quick, accurate, and well-evidenced to ensure clinicians are confident to use them. Results should guide antibiotic selection and be easy to integrate with other patient data, and procurement and maintenance arrangements should be acceptable to clinicians and end-users (Hayward and Turner, 2021). From a national health service perspective, new rapid diagnostics tests need to show clear patient benefit, market value and be cost-effective.
In particular, this combination of requirements can become a significant barrier in funding systems that have different budget holders for therapeutics and diagnostics. A diagnostics-focused approach could potentially reduce the levels of inappropriate prescribing, but who pays – and therefore whose budget impact is improved - is an ongoing question. POC diagnostics are used routinely in other fields, but there is no disguising the fact that antibiotics are a very cheap generic drug whereas a rapid diagnostic test tends to be much more expensive. The UK is a case in point where existing antibiotic therapies are funded centrally whilst any diagnostic tests, their consumables, and maintenance costs are borne by individual general practice surgeries.
There are conflicting arguments around the health economic benefits of RTI POC tests, as this depends on how a country’s health system assesses the cost burden of infectious diseases. Some evidence shows there is significant cost-effectiveness of testing over existing RTI management in primary care, but only when looking at the full patient journey including secondary care admissions. In a standalone general practice scenario, however, where a course of antibiotics can cost less than 50 pence, budget impact models show POC testing to be more expensive than usual care.
Research has shown that confirmed costs and lack of central government funding are as important, if not more so, than physical and operational constraints barriers, even in the presence of advanced training and local AMR champions as enablers. Without systemic changes that avoid penalising local primary care clinicians for using POC tests, there may well be a reluctance to new adopt new practices.
Looking ahead
With the rapid development of AI, patients are expecting greater precision in diagnosing and managing their illnesses. Adopting systems that markedly reduce antibiotic consumption would be a win-win-win solution for governments and health systems that are struggling to address the rise in AMR and for patients. Irrespective of the cost implications, using a POC test optimises antibiotic choice, safeguards our current stores, and reduces the longer-term impacts associated with further antibiotic resistance. A more focused prescribing method will take us towards better patient outcomes, which ultimately saves lives now and will save even more in the future.
Challenge or chasm?
How we navigate the gap between economic models, clinician experience, patient expectations and antimicrobial stewardship requirements for RTIs is an imminent challenge. This could be seen as an insurmountable chasm. It could also be a starting point to achieve a milestone in containing, controlling, and mitigating RTI-related AMR. Taking up the challenge of crossing the chasm is an opportunity not to be missed for those of us with an interest in powering up primary care as an essential resource.
References
Davies, S. (2019) in Holly, E. “UK medical chief: ‘we are in an arms race against microbes’, Nature, www.nature.com/articles/d41586-019-01409-x.
Drug.Ther.Bull (2016) Point-of-care CRP testing in the diagnosis of pneumonia in adults, Drug and Therapeutics Bulletin, 54 (10):117–20.
Featherstone, J. (17 June 2021) Q&A with Jeff Featherstone, Head of AMR at the NHS https://longitudeprize.org/blog/qa-jeff-featherstone-head-of-amr-nhs.
Gulliford MC, Dregan A, Moore MV, et al. Continued high rates of antibiotic prescribing to adults with respiratory tract infection: Survey of 568 UK general practices. BMJ Open 2014;4:e006245.
Hayward, G. and Turner, P. (28 April 2021) Vanguard Report: Antimicrobial resistance and the future of diagnostic testing, British Society for Antimicrobial Chemotherapy, https://bsac.org.uk/vanguard-report-amr-and-the-future-of-diagnostic-testing.
National Institute for Health and Clinical Excellence (NICE) Pneumonia in adults: diagnosis and management, 2019. Available: www.nice.org.uk/guidance/cg191.
O’Neill, J. (May 2016) Tackling drug-resistant infections globally: Final report and recommendations, HM Government, London.
Public Health England. Management and treatment of common infections antibiotic guidance for primary care: for consultation and local adaptation. London: Public Health England, 2017.
Review on Antimicrobial Resistance, https://amr-review.org/Publications.html.
van den Broek, D.J., Verheij, T.J.M., Numans ME, et al. (2014) Antibiotic use in Dutch primary care: relation between diagnosis, consultation and treatment, Journal of Antimicrobial Chemotherapy, 69:1701–7.
WHO One Health (2017), www.who.int/news-room/q-a-detail/one-health.
Zumla, A., Al-Tawfiq, J. A., Enne, V., et al (2014) Rapid point of care diagnostic tests for viral and bacterial respiratory tract infections—needs, advances, and future prospects, https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(14)70827-8/fulltext.
About Imspex Medical
Imspex Medical brings the combined power of gas chromatography and Ion Mobility Spectrometry to bear on volatile organic compound analysis as a non-invasive, ultra-sensitive, rapid and reliable way of detecting and diagnosing a wide range of infectious and inflammatory disease states at point-of-need.
At Imspex Medical, we know the value of identifying disease states early. Our objective is to make regular, non-invasive volatile organic compound screening accessible and affordable to maximise individuals’ health, wellbeing and opportunities for economic prosperity.