Penicillin to Peril

As our arsenal of antibiotics faces the relentless evolution of resistant microbes, the urgency to fortify our defenses intensifies. 
In this narrative, we unravel the intricate tapestry of AMR and technological ingenuity flourishing to safeguard the foundations of modern medicine. 

What is Antimicrobial resistance (AMR)?

AMR is a natural process that occurs when microbes (bacteria, viruses, etc) evolve mechanisms that protect them from the effects of antimicrobials (antibiotics, antivirals, etc).
Widespread antibiotic resistance is a significant component of AMR.

Rise of AMR

In 1928, the lucky accident of Penicillin discovery in Alexander Fleming's London laboratory changed the course of medicine.

Ten years after its discovery - in 1939, extensive research began on Penicillin. It led to the establishment of “The Penicillin Project” - a collaboration that brought 15 pharmaceutical companies in the USA and the UK together to produce Penicillin.

The first trials of Penicillin were conducted in military hospitals in North Africa in 1942. Within the year, there was evidence of penicillin-resistant infection found in hospitalized patients.

By early 1945, Fleming predicted that the high public demand for antibiotics would determine an “era of abuse”; this eventually became a reality.

By the 1970s, the term “Superbugs” was popularly seen in news media to refer to drug-resistant bacteria and infection.

Present situation

Today, The World Health Organization has ranked Antimicrobial Resistance (AMR) as a global health threat.

A 2019 WHO report, disclosed bacterial AMR responsible for 6.22 million global deaths (Primary cause of death in 1.27 million patients and secondary cause of death in 4.95 million patients).

The World Bank estimates that AMR could result in US $1 trillion in additional healthcare costs by 2050. Shortly by 2030, losses of US $1 trillion to US $3.4 trillion in gross domestic product (GDP) are expected per year.

The resolution to the problem is not as straightforward as the pharmaceutical industry developing new antibiotics as microbes rapidly adapt to introduced antibiotics.

Over the past 80 years, more than 140 antibiotics have been developed for use in humans. Using existing methodologies provides the same old results. This has increased the scientific complexity of discovery methods which in turn has resulted in the discovery programs being riskier, more time-consuming, and expensive.
Thus, there is a considerable scientific barrier to discovering the next generation of antibiotics.

Developing Solutions

Various companies are making efforts to create innovative solutions to address the challenges around AMR.

Real-time AMR Data

The one important step in addressing antibiotic resistance would be establishing a systematic, real-time data collection and reporting mechanism for monitoring antibiotic resistance rates among various pathogens. This would help in swiftly identifying and responding to emerging threats related to antimicrobial resistance.

Solu (a Finnish biotech company) is taking up this challenge by establishing the world's most extensive pathogen DNA library and building proprietary software to analyze this data. The company has collaborated with international universities (including Stanford University & the University of Hamburg) that use Solu's product in their research on antibiotic resistance. The software offers the advantage of real-time monitoring, facilitating the rapid identification of potentially dangerous mutations. Furthermore, they can model the evolutionary trajectories of these pathogens, pinpointing emerging health-threatening variants.

The product and approach is in trials at universities. We did not find any comparable offering or advancement in this field thus far.

Preventing Over-prescription of Antibiotics

A behavioral change is required in how antibiotics are prescribed and utilized - without it, the persistence of antibiotic resistance would continue with new drugs.

An NCBI study in 2020 showed that the rate of inappropriately used antibiotics across health facilities in developing countries (and in India) was as high as 50%.

One of the most common causes of inappropriate prescriptions is the long turnaround time for diagnostic tests. Presently, clinical diagnostic tests for microbial infections typically necessitate a minimum of 18 hours. Further, it often takes up to 72 hours for results, during which time the risk of mortality associated with resistant infections escalates at a rate of 7% per hour. This results in a high amount of prophylactic and broad-spectrum antibiotics being prescribed.

Inflammatix and MeMed are companies making Point-of-care testing devices that will help reduce the turnaround time of diagnostic tests for microbial infection. 

Inflammatix is releasing its FDA-approved device in the market next year. The device helps perform tests and support the doctor through their decision making process when confronted with a patient with infectious disease. The system known as “Triverity” will enable doctors to know if the disease is infectious, the agent causing the disease (bacterial or viral), and the severity of the disease. Thus, the product will empower healthcare professionals to make informed decisions regarding antibiotic treatments - benefiting individual patient care and public health.

MeMeds device on the other hand provides rapid diagnostic results all under 15 minutes to inform the user of the type of pathogen causing the disease. The device which is being sold in partnership with Bechman Coulter helps in rapid identification and judicious use of antimicrobials.

These innovations will help nudge a behavioral change in healthcare workers in how they prescribe antimicrobials. Furthermore, the diagnostic reports would also play a pivotal role in steering patients toward a more judicious consumption of antibiotics and reducing their demand for unnecessary prescriptions.

New Treatment Modalities 

Alongside enhancing existing workflows, reinvigorating antimicrobial discovery and development remains paramount. 

Several promising products from companies such as Bioversys, Adaptive Phage Therapeutics, and Vedanta Bioscience have been developed to combat AMR.

Bioversys, a pharmaceutical company based in the USA, is strategically aligned with the World Health Organization (WHO) and Centers for Disease Control and Prevention's (CDC) priority pathogens. Their solution uses ‘Transcriptional Regulator Inhibitory Compounds (TRIC)’ that specifically target carbapenem-resistant Acinetobacter baumannii (CRAB) in lung and bloodstream infections. As CRAB stands among the top three priority pathogens designated by both the WHO and CDC, known for its substantial mortality impact in intensive care units, this breakthrough development holds significant promise.

Adaptive Phage Therapeutics employs bacteriophages to construct resilient antibiotics that dynamically adapt to sustain efficacy against evolving bacterial pathogens. The solution leverages phage strain specificity, thus, exhibiting exceptional effectiveness, particularly against the targeted bacterial strains. The developed treatment is specifically designed to combat prevalent conditions like diabetes and respiratory infections.

Vedanta Bioscience is pioneering the development of an orally administered drug comprising a meticulously designed bacterial consortium. This innovative solution is tailored to effectively decolonize multi-drug resistant organisms (MDROs) residing in the gut, particularly in high-risk patients vulnerable to infections. The primary goal is to prevent the recurrence of infection and colonization by various multi-drug-resistant organisms.

However, it's worth noting that these solutions are in clinical trial and face an extended journey to market availability due to the rigorous FDA guidelines for approval.

Equitable Antimicrobial Medicine Access

Finally, an essential component of the global response to antimicrobial resistance is ensuring equitable and affordable access to antimicrobial agents. Often antibiotics coming out of the antibiotic development pipeline are not making it to patients around the world. This results in a decreased number of treatment options being available to patients and poor patient compliance. 

Initiatives taken by the Global Antibiotic Research & Development Partnership (GARDP) are helping provide access to antibiotics, especially in low- and middle-income countries, which are most affected by antibiotic resistance.

Their efforts also include coordinating between international organizations to ensure constructive global action against this threat to health security. 

Conclusion

Antimicrobial Resistance is a crisis looming ominously.

Medical experts have raised concerns about the growing threat of returning to a healthcare landscape reminiscent of the pre-antibiotic era. Evidence shows that while we can take measures to slow down developmental antibiotic resistance, we cannot entirely halt its progression.
Thus, the challenge at hand is not only to mitigate resistance but also to navigate a future where antibiotics remain effective through responsible and innovative practices in healthcare.

The arsenal against AMR needs to be diverse and dynamic - requiring a collective and concerted effort to safeguard the effectiveness of antibiotics and preserve the foundation of modern medicine. 
For young doctors and researchers – this presents an exciting problem area to hunt for solutions.

References 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369031/#:~:text=The%20first%20sign%20of%20antibiotic,by%20producing%20penicillinase%20%5B20%5D.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2937522/  https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance  https://www.sciencedirect.com/science/article/pii/S1876034121003403 

Organizations

https://www.solu.bio/about  https://inflammatix.com/  https://www.me-med.com/  https://aphage.com/  https://www.bioversys.com/medical-needs/antimicrobial-resistance/  https://www.vedantabio.com/about  https://gardp.org/