The employment of antimicrobials to fight previously devastating microbial diseases, such as tuberculosis, meningitis and pneumonia, has been credited as one of the most transformative medical achievements of the 20th century.
However, the efficacy of antimicrobials has waned as some microbes evolved 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 escalated into a public health crisis, the incentive to develop new antimicrobials has declined. The reasons are twofold: an antimicrobial’s long-term efficacy is increasingly threatened by AMR, and the upfront cost of development is very high — $1.5 billion for a new antibiotic in 2017.1 However, without new diagnostics and treatments for microbial infection, the cost in human life will continue to rise. Already, drug-resistant diseases are estimated to cause at least 700,000 deaths worldwide each year.2 The upfront investment in emerging diagnostics and treatments to combat AMR may be expensive, but we cannot afford further delay.
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.
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, where identification might take weeks, especially for slow-growing pathogens such as the tuberculosis-causing bacteria Mycobacterium tuberculosis. Rapid diagnosis through PCR permits the timely use of targeted therapeutics, and continued testing makes it possible to monitor the effectiveness of a treatment on the patient over time. However, like culturing, PCR techniques require expertise and equipment that limit its use to laboratory settings.
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.
NGS and AI
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, these tools 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.
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.
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 health-care or veterinary options are limited, or a susceptible population is very large.
Vaccines are promising tools for disease prevention. But they are not able to treat active infections. Recently, bacteriophage therapy has emerged as an alternative to antibiotics, the traditional antimicrobial used for active bacterial infections. In fact, its efficacy may prove substantially more enduring than antibiotics.
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.
Like vaccines, bacteriophages may also be better at targeting infectious bacteria than antibiotics, which are more indiscriminate. 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.
Alongside the risk of antimicrobial resistance, antimicrobials can disrupt the balance of preexisting microbiomes that carry out essential physiological functions. In addition, there is emerging recognition that microbiomes, especially the gut microbiome, may contribute to the strength of an immune response against disease-causing microbes. Treatments, such as probiotics, that help to maintain and restore healthy microbes are indirect but powerful supplements to traditional antimicrobials, and may also prove essential in preventative care.
A pivotal moment
An improved understanding of microbes and microbial ecology will continue to foster the development of improved diagnostics and antimicrobial treatments that balance short-term and long-term efficacy. However, it will 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.
Recent investments aimed to combat the ongoing COVID-19 pandemic may facilitate the necessary public awareness and research developments needed to fight AMR. For example, with the rapid development of COVID-19 vaccines, it is now conceivable that novel microbial vaccines could be developed within months, or years, instead of decades.
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: Antimicrobial resistance and combating a global crisis.
1. Plackett B. Why big pharma has abandoned antibiotics. Nature. 2020;586(7830):S50-S52. doi:10.1038/d41586-020-02884-3
2. No Time to Wait: Securing the Future from Drug-Resistant Infections. United Nations Interagency Coordination Group on Antimicrobial Resistance 2019. https://www.who.int/publications/i/item/no-time-to-wait-securing-the-future-from-drug-resistant-infections.