MICA: Accelerating Development of Infection Diagnostics for Patient Management and Reduction of Antibiotic Misuse

The discovery of antibiotics early in the 20th century revolutionised healthcare provision and antibiotics and other antimicrobials have become an integral part of modern healthcare. However, in recent decades, the use of antibiotics has increased massively, not only in healthcare provision but also in veterinary and agricultural (live stock) applications. This has led to an enormous rise in antimicrobial resistance (AMR), which is forming an ever-growing problem in modern healthcare, proving a serious threat to society. The number of instances where infections are resistant against common antibiotics is increasing rapidly, and bacterial infections with strains that are resistant to almost all known antibiotics (e.g. meticillin-resistant staphylococcus aureusis, MRSA) have contributed to a significant number of death (almost 300 in 2012, source: Office for National Statistics) and caused significant problems for affected patients and healthcare providers.

The solution seems simple: drastically reduce the prescriptions of antimicrobials. However, where antimicrobials are required for medical treatment, withholding prescription is dangerous for the patient and unethical, and could furthermore negatively impact on the general public through increased spreading rates.

There are two major types of infections: viral and bacterial. Only bacterial infections can be treated with antibiotics, but certain symptoms are common to both types of infections. A typical example is throat pain, which could be caused by a bacterial infection (e.g. Streptococcus pneumonia) or viral (e.g. influenza), or in fact could be caused by non-infection causes such as heart failure. More critical examples include meningitis, which, when caused by a bacterial infection (meningococcal disease) needs immediate medical attention, while viral meningitis tends to take a milder course requiring rest and observation for encephalitis.

We argue that antimicrobial prescriptions can be reduced safely and ethically if better infection diagnosis is available. Many infections are viral in origin (and hence do not benefit from antibiotics), but often antibiotics are prescribed as a precaution as without suitable diagnostics the doctor cannot be sure what the origin of the infection is. Although some laboratory-based tests are currently available, these can take several days to give a clear answer, and hence precautionary antibiotic treatments are started before the test results are available.

In this research programme we will develop rapid diagnostic tests that can be performed by the doctor her/himself, i.e. a GP in a primary care clinic or a consultant in a hospital, which will give an answer in less than 15 minutes, quick enough to inform treatment before it is prescribed.

The first diagnostic test that this programme will develop will thus be to distinguish between viral and bacterial infections. Once a bacterial infection is diagnosed, or if symptoms are encountered which indicate bacterial infections, it is important to identify the bacterial strain that causes the infection, as different strains require different antibiotic treatments. The second diagnostic test that this project aims to develop is thus to test for pathogen that causes the infections and we have chosen the example of C. difficile infections, a common infection that causes severe diarrhoea. Finally, many bacteria are now resistant to common antibiotics and if the type of resistance is known, the antibiotic treatment can be tailored to be effective. The third diagnostic test that will be developed is thus to diagnose a common subtype of Carbapenem Resistant Enterobacteriaceae (CRE), which is common type of infection with antibiotic resistance. These quick and accurate tests will reduce the prescription of the wrong antibiotics, which will not only reduce to the total amount of antibiotics used (thus reducing AMR), but will also lead to a more effective patient management.

The lack of instant and accurate diagnostic tools for infectious diseases leads to inappropriate or unnecessary antibiotic prescribing. In primary care and hospital settings, this contributes directly and significantly to antimicrobial resistance (AMR). The aim of this programme is to address this challenge by developing innovative approaches for the next generation biosensors.

This programme aims to develop three biosensors that (a) distinguish between viral and bacterial infections and (b) specifically diagnose Clostridium difficile infection (CDI) and (c) detect common subtypes carbapenemases which cause the most problematic forms of Carbapenem Resistant Enterobacteriaceae (CRE) infections. Diagnostic biomarkers have been previously established to for these infection diagnosis applications and in this programme synthetic antibody mimetics (Adhirons) will be raised/selected against these biomarkers. Using the Adhirons as 'recognition elements', multiplexed, impedimetric and fluormetric biosensors will be constructed based on established and novel technologies, respectively.

Furthermore, this programme aims to develop novel biosensor platforms with improved accuracy and sensitivity. The majority of biosensors use passive capture molecules, such as antibodies or antibody mimetics, as 'recognition elements'. However, while antibody-biomarker binding is generally highly specific, changes in dielectric upon binding of biomarkers can be small, limiting the sensitivity and reproducibility of the sensor. Furthermore, non-specific binding of other molecules onto the sensor can lead to false-positive signals. Here, these bottlenecks will be targeted by designing new classes of antibody mimetics that generate an active electrochemical signal upon binding of the biomarkers.

This proposal describes the development, analytical and clinical validation of point-of-care biosensors for the rapid and reliable diagnosis of infection for the reduction of antibiotic misuse and improved patient management. This programme will impact on a range of stakeholders, including: patients; healthcare providers; clinicians/clinical scientists; manufacturers of in vitro diagnostics.

1 Patients: Our technology will provide tools for healthcare providers to determine accurately and rapidly the origin of an infection, thus benefitting patients directly. For example, if a GP or emergency physician could use a rapid point-of-care test to distinguish bacterial from viral respiratory tract infection, it would allow them to target antibiotic prescriptions to patients most likely to benefit. A similar argument applies to C. difficile infection (CDI), where rapid and accurate diagnosis of CDI is important to enable use of a broader set of antibiotics as well as quarantining patients quickly to avoid spread of the infection. Furthermore, our programme will reduce AMR, which will indirectly benefit all patients as well as the general population.

2 Clinicians and healthcare providers: This programme will lead to a reduction in AMR and therefore reducing the number of patients infected by anti-microbial resistant pathogens. This leads to significant cost savings for healthcare-service providers (reduced treatment costs, fewer quarantining of patients, etc) as well as reduced risk for their staff. Additional cost savings will result from the availability of low-cost tests which replace more expensive traditional tests.

3 Manufacturers of in vitro diagnostics (IVD): The outputs of this programme will provide manufacturers of IVD instrumentation with new technologies that have the potential to monitor biomarkers more accurately, sensitively, and reliably, and hence enable new modalities of operation (such as rapid point-of-care analysis). This will increase their capabilities and competitiveness. Our generic technology will not only find application in clinical diagnostics, but has the potential to produce an analytical technology that can be used in over-the-counter diagnostic tests (e.g. well-being testing), environmental monitoring (e.g. water pollution), veterinary practice (e.g. animal screening), and security (e.g. detection of biological/chemical agents).

4 Academics across a broad range of scientific disciplines: Research and results from this programme will find widespread use, interest, and generate impact, across the wider academic community beyond clinical science, notably in biosensors, clinical microbiology, microfluidics, AMR, and bionanotechnology (see 'Academic Beneficiaries for more details).

5 The PDRAs on the programme will benefit from the training and development opportunities offered through this challenging interdisciplinary programme. The project will bring together scientists from a wide range of backgrounds with industry and clinical end-users, therefore benefitting the PDRAs through networking opportunities, and significantly increasing employability in academia, industry, and regulatory bodies, inter alia (see 'Academic Beneficiaries for more details).

IP arising from this research will be exploited fully through, e.g., direct licensing, or through University spin-out companies, as appropriate. The investigators have extensive experience in both approaches, e.g. the spin-out companies Relitect Ltd (co-founder Wälti) and Elisha Ltd (co-founder Millner) (both manufacturers of biosensor technologies), or the Adhiron license to Avacta Plc for commercial exploitation of Leeds' antibody mimetics (co-inventors McPherson, Tomlinson).