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, developing 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, pharmaceuticals have slowed their development of new antimicrobials. The incentive to develop new antibiotics is especially low because their efficacy declines over time, and the upfront cost of drug development has risen to $1.5bn. As a result, combating the problem of AMR requires new, innovative and durable tools to diagnose and treat microbial infections.

Novel diagnostics help monitor for AMR outbreaks and reduce the overuse and misuse of antimicrobials. Meanwhile, innovative treatments provide alternative and more sustainable methods of treating microbial infection. Developing and implementing these technologies will be pivotal in addressing the larger, multifaceted problem of AMR. However, achieving the potential of novel diagnostics and treatments is unlikely without international coordinated support for research, development and distribution. New antibiotics may be an unreliable investment, but the development of new tools to combat microbial infection is promising and necessary.

Affordable, accurate and rapid diagnostics for infectious disease will be crucial for the appropriate use of antimicrobials to treat patients, and for the containment and monitoring of AMR outbreaks. In cases where a disease-causing pathogen – virus, bacterium, fungus, or parasite – is not clear from symptomatology, diagnostics can identify the cause of infection and direct appropriate treatment.

Diagnostics that are sensitive to an identified pathogen’s characteristics – for example, whether it is resistant to traditional treatments – can further inform patient care. Additionally, diagnostics can help to monitor a patient’s response to treatment and may help prevent antimicrobial overuse. Accurate, rapid and accessible diagnostics are, therefore, key to preventing misuse of antimicrobials. However, on the whole, traditional diagnostic methods, such as microbial cultures, struggle to determine the cause and characteristics of infection quickly and reliably.

Polymerase chain reaction (PCR) diagnostics overcome the difficulty of pathogen identification by using genetic fingerprints to facilitate the rapid identification of bacteria, viruses and fungi, and diagnose disease. For example, a PCR diagnostic enables clinicians to diagnose tuberculosis within hours instead of weeks following the collection of a clinical sample. Rapid diagnosis through PCR permits timely use of targeted therapeutics, and continued testing makes it possible to monitor the effectiveness of a treatment on the patient over time. However, PCR techniques require specific conditions and equipment that limit the technique 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 them cheaper and transportable. For example, the limited equipment required for LAMP, paired with its speed, made it an ideal tool for rapid COVID-19 testing.

Technologies, such as next-generation sequencing (NGS) and artificial intelligence (AI), also have great potential in the development of accurate, cheap and accessible diagnostics for AMR. Although the use of these novel methods is in the early stages for AMR diagnostics, bioinformatics 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.

Diagnostics can help identify which antimicrobial therapies will be effective in treating a specific infection in the short term. However, an understanding of how antimicrobial treatments influence microbial evolution is key to developing novel treatments that will retain their efficacy over generations of microbial adaptation.
  
The likelihood that microbes will evolve resistance to a treatment depends, in part, on a treatment’s mechanism of action, timing and duration of use. If an antimicrobial treatment places strong, direct, continuous stress on a large population, resistance is much more likely to evolve than with a treatment that places multiple indirect stressors on a small number of microbes.

Antimicrobial treatments can be subdivided into three methods that differ in their mechanism, timing of use and their influence on microbial evolution:

1. Targeted treatments directly attack bacteria during an active infection and have a strong influence on microbial evolution.
2. Treatments that bolster a healthy gut microbiome, which can be taken continuously because their protection against pathogenic microbes is less direct.
3. Treatments that prime a targeted immune response, which are also indirect and administered pre-emptively, so that they target pathogenic microbes in the earliest stages of infection.

‘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’