Continuing the fight against AMR with new tools for diagnosis and treatment
The employment of antimicrobials to fight previously devastating microbial diseases, such as tuberculosis, meningitis and pneumonia, has been credited as being one of the most transformative medical achievements of the 20th century. However, the efficacy of antimicrobials has waned, as some microbes have developed antimicrobial resistance (AMR). Increased selective pressure on microbes to acquire AMR has been driven by an accelerated application of antimicrobials in everything from medicine and agriculture to household cleaning products.
While the problem of AMR has snowballed into a public health crisis, the incentive to develop new antimicrobials has declined. The reasons are twofold: 1 an antimicrobial’s long-term efficacy is increasingly threatened by AMR, and 2 the upfront antimicrobial development costs are very high — $1.5 billion for a new antibiotic in 2017.1 New financial models — such as establishing a blended capital fund aimed at providing flexible capital in later stages of clinical trials, or pooling drug assets into a bond structure to attract risk-averse investors — have been proposed to help alleviate some of this financial stress and drive new capital into antibiotic development.2 However, these models would require the federal government to guarantee its involvement in addressing antimicrobial resistance.
As the situation stands, without new diagnostics and treatments for microbial infection, the cost in terms of human lives will continue to rise. In 2019, alone, 1.27 million deaths were directly attributable to antimicrobial resistant pathogens.3 Fortunately, advancements in diagnostics, prevention, and treatments are providing new options for continuing the fight against AMR.
Diagnostics
Diagnostics help identify the cause of infection, guide appropriate treatments and monitor treatment response. However, many traditional diagnostic methods, such as microbial cultures, have limited utility because they are slow, require substantial expertise or expensive equipment, or are unable to identify treatment resistance in pathogens. Therefore, the development of rapid, accessible, accurate diagnostics is key to reducing antimicrobial misuse and overuse, especially in clinical settings.
Rapid PCR techniques
Polymerase chain reaction (PCR) diagnostics identify disease-causing bacteria, viruses and fungi through DNA identification. This method is a rapid alternative to traditional culturing techniques, and permits the timely use of targeted therapeutics. Adaptations of PCR technology, such as PCR loop mediated isothermal amplification (PCR LAMP), improve the practical utility of PCR-based diagnostics by making the already rapid diagnostic cheaper, accessible and transportable. The limited equipment required for LAMP, paired with its speed, made it an ideal tool for COVID-19 testing during the pandemic.
Next-generation sequencing and artificial intelligence
Next-generation sequencing (NGS) and artificial intelligence (AI) also have great potential in the development of accurate, cheap and accessible diagnostics for AMR. Although these novel methods are in the early development stages for AMR diagnostics, they have the potential to expand the source and complexity of disease characteristic markers that can be used in diagnosis. For example, the company Inflammatix combines NGS and AI to characterise host response to discern bacterial and viral infections, and score sepsis severity.
Improvements in the speed and accessibility of NGS may also facilitate the development of diagnostics that can identify known antimicrobial-resistant genotypes, and predict whether newly sequenced strains are likely to have a resistant phenotype. Diagnostics that identify signatures of AMR resistance may also enable community surveillance of AMR infections through broad screening of environmental samples, such as water, soil and sewage.
Treatments
Novel diagnostics can help identify which antimicrobial therapies will be effective to treat a specific infection in the short term. However, controlling the emergence and spread of AMR disease will rely on the development of accessible treatments that retain their efficacy over time.
Targeted prevention
Vaccines, which prime an immune response against a specific pathogen, provide a promising alternative to traditional antimicrobials. Vaccines facilitate an immune response that is early, targeted, and varied between individuals, making vaccine resistance much less likely to develop than resistance to antimicrobials that directly target microorganisms. In addition to their long-term efficacy for a population, the extensive treatment window and lasting protection of vaccines make them an accessible and practical treatment option, especially when healthcare or veterinary options are limited, or a susceptible population is very large.
Targeted treatment
Vaccines are promising tools for disease prevention, but they are not able to treat active infections. Yet, there is hope: Recently, bacteriophage therapy has emerged as an alternative to antibiotics for active bacterial infections. Phage therapy relies on bacteria-killing viruses to treat disease. While antibiotics have a fixed method of attack — to which bacteria can evolve permanent resistance — phages are able to coevolve with bacteria, so that any emerging resistance is temporary. However, development of infection-specific bacteriophages will require substantial investment, and the utility of treatments will be limited by the accuracy and availability of diagnostics.
Another possible alternative is the use of monoclonal antibodies (mAbs), which mimic natural antibodies to recognise and mark specific pathogenic targets for the immune system to attack. Because they often target the proteins that impact a pathogen’s virulence rather than its survival, mAbs provide less evolutionary imperative for a bacteria to develop resistance. While many have proven successful in the treatment of viruses, development of mAbs for bacterial infection has been limited by several challenges: Bacteria may present hundreds of potential surface targets, making it difficult to determine which one is optimal. Further, difficult-to-penetrate biofilms, or locations in the body difficult for antibodies to access, can impede mAbs in accessing target proteins. Nevertheless, advances in mAb capabilities are empowering the development of potential future treatments.
Utilising advanced tools for treatment and prevention
Exploring the use of relatively new technology, such as AI, is also enabling the discovery and development of new approaches to AMR. AI algorithms are helping to uncover new antibiotics that are effective against multidrug resistant bacteria, such as Acinetobacter baumannii. By using machine learning to identify patterns in antimicrobial agents, the time and difficulty of drug discovery can be significantly reduced.
Gene editing tools, namely CRISPR, are facilitating the possibility of removing AMR genes from pathogens, or preventing these genes from being passed between bacteria. This system allows the targeting and cutting of a specific DNA sequence — such as one linked to resistance to a particular drug — which either causes cell death if the sequence is in the chromosome, or destroys the plasmid (a circular strand of DNA) that allows resistance to spread. AMR gene editing is still largely under research, but has the potential to one day be deployed in areas where AMR is known to propagate, such as sewage treatment plants.
A pivotal moment
Recent initiatives — such as the Antimicrobial Resistance Multi-Stakeholder Partnership Platform, launched by the Food and Agriculture Organisation of the United Nations, the UN Environment Programme, the World Health Organisation and the World Organisation for Animal Health — show that global organisations are prioritising the threat of AMR. And it will certainly take global awareness and substantial public and private investment to undercut our reliance on traditional antimicrobials, and adopt more effective strategies against treatment-resistant infectious disease.
While existing tools show promise, no single diagnostic or treatment will solve the problem of AMR. Enduring success against infectious disease will demand the ongoing investment into the research and development of adaptive diagnostics and treatments. Pathogenic microbes will continue to evolve. Hopefully, our response will too.
Learn more about innovations and improvements seen in this important field in our whitepaper:
1. Plackett B. Why big pharma has abandoned antibiotics. Nature. 2020;586(7830):S50-S52. doi:10.1038/d41586-020-02884-3
2. Murray, Christopher J. L., et al. “Global Burden of Bacterial Antimicrobial Resistance in 2019: A Systematic Analysis.” The Lancet, vol. 399, no. 10325, 2022, pp. 629–55, https://doi.org/10.1016/S0140-6736(21)02724-0
3. Murray, Christopher J. L., et al. “Global Burden of Bacterial Antimicrobial Resistance in 2019: A Systematic Analysis.” The Lancet, vol. 399, no. 10325, 2022, pp. 629–55,