Need to fast-track new antimicrobials — Part — 2

Centre for Cellular and Molecular Platforms C-CAMP

7 min readJan 31, 2023

In the first part of this blog, we discussed AMR-centered innovations and the financial models for their promotion.

Understanding Broad and Narrow-spectrum antimicrobials

Antimicrobials are classified as narrow and broad. This classification is based on how diverse the microbes affected by a particular compound could be. For example, is the anti-microbial action of a compound restricted to one genus or species of bacteria, or does it target multiple species? This may be relative. For example, one broad-spectrum antimicrobial could be narrow in comparison to another one that targets a larger number of microbes.

Nonetheless, both narrow and broad-spectrum antimicrobials are equally useful tools in a clinician’s toolbox to deal with infections based on the type, frequency, severity, etc of an infectious event. The pre-requisite for using narrow-spectrum antimicrobials is an accurate diagnosis of the causative microbe. In the absence of accurate and reliable diagnostic tools, broad-spectrum antimicrobials become the first choice of clinicians. Even when accurate diagnostic tools are available, these tests typically need 48 hours for a conclusive result. In cases like pneumonia and sepsis, time is of the greatest essence. In such instances, broad-spectrum antibiotics are useful.

Although guidelines exist for the use of narrow versus broad-spectrum antimicrobials in a clinical setting, its implementation is largely at the behest of the treating physician’s clinical judgment.

“The first rule of antibiotics is to try not to use them, and the second rule is to try not to use too many of them.” — Paul L. Marino, Critical Care Physician, Author of “The ICU Book”

In 2017, a study looked at broad-spectrum and narrow-spectrum antibiotics for treating children with acute respiratory tract infections. The results showed no difference in treatment failure rates between the two antibiotics, but broad-spectrum antibiotics increased adverse events and decreased quality of life.

These adverse events can be limited to a particular individual in the short run or might lead to the emergence of AMR in the long run. Typically, broad-spectrum antimicrobials disrupt the indigenous gut microbiota of an individual. This disruption can persist for up to several weeks or months after the last dose of a broad-spectrum antimicrobial. The emergence of AMR in microbes is due to either genetic mutations, or horizontal gene transfer of AMR genes combined with evolutionary pressures that get amplified with antimicrobial use. AMR can develop for both narrow and broad-spectrum antimicrobials.

Research and Development of antimicrobials

The rate of development of new antimicrobials has decreased since the discovery of the first antimicrobials. The market size of a drug is proportional to the prevalence of a disease or the wide application of that drug across multiple diseases. Due to this, research and development of broad-spectrum antimicrobials has had been favoured by pharmaceutical entities. The counterargument is that the wide use of broad-spectrum antimicrobials will lead to them being rendered ineffective because of the high chances of the emergence of AMR. On the other hand, the commercial ‘shelf-life’ of narrow-spectrum antimicrobials will be more.

The other way of approaching this problem is not resorting to ‘market forces’ but use not-for-profit organizations and government entities to fund research and development of these antimicrobials. Efforts on this line are in place for Neglected diseases, be they rare genetic disorders or tropical diseases that are prevalent in LMICs and hence receive less commercial attention.

Neglected diseases need a research focus

Mobile health workers in Yalikombo, Democratic Republic of the Congo, evaluate communities for sleeping sickness. The location breeds disease-spreading tsetse flies. Credit Neil Brandvold/DNDi

Diseases affecting the poor and underserved have historically received less R&D investment. Malaria, dengue, Hansen’s Disease (leprosy), and sleeping sickness are among such neglected diseases. DNDi, Medicines for Malaria Venture, and the Bill & Melinda Gates Foundation have all announced new programs to address neglected diseases. DNDi, for instance, has developed effective, affordable remedies. Through the HAT (Human African Trypanosomiasis) platform, they are teaching local researchers how to run clinical trials in places that are hard to reach or conflict-affected areas. Even though most NTD deaths can be prevented or treated if caught early, these efforts have not led to a big drop in death rates. While LMICs must prioritize sanitation, hygiene, access to safe water, one health, and vector management as infection preventive measures, funding organizations need to look at ‘pull’ incentives that suit LMIC markets to fully address the neglected disease burden.

Intervention through policy change and stewardship

The global scientific community is trying to keep up with the AMR problem despite advancements in drug discovery, diagnostics, and treatment. Only 6 of the 32 WHO-priority antibiotics in development in 2019 are new. WHO has identified a list of 19 priority fungal infections that need immediate attention based on factors like global occurrence, mortality rate, and persistence in populations. A regulatory framework to speed up drug research and antimicrobial stewardship can change this dismal state of affairs.

India developed a 5-year national action plan, or NAP, in 2017 to enhance its AMR leadership. Through this action plan, WHO’s GLASS (Global antimicrobial resistance and use surveillance system) report on antibiotic use and misuse employs data from an India-wide research initiative. India has taken other key regulatory steps recently, like announcing a proposed strategy in 2021 to prioritize tech-enabled regulatory streamlining to cut clearance delays, research funding, and academic-industry partnerships.

An analysis of the systems for approving drugs in LMICs like Brazil, South Africa, and India found that centralization and technology-driven approaches can improve regulatory processes and help different AMR stakeholders work together. India’s Central Drug Standard Control Organization (CDSCO) now accepts domestic clinical studies within 30 days of an application, compared to six months in the past. International trial approvals take up to 90 days. India, with its wide microbiological lab support, ICU populations, and clinicians with experience in AMR, could also be the world’s next destination for clinical trials.

Developed countries like the USA, Canada, and the UK provide systemic aid and incentives to commercialise speedy and cost-effective drug discovery and distribution solutions. An exemplary lesson for the effectiveness of “push” incentivization is discussed in the first part of this blog.

The slow pace at which new antimicrobials are being developed means that we cannot keep up with the rate at which resistant organisms are developing. The solution to this, are judicious use of current antimicrobials, increasing the efficiency of existing antimicrobials by use of Antibiotic resistance breakers (ARBs), development of new therapeutics using novel technologies, improving the accuracy and reliability of diagnostic tools etc.

C-CAMP and CARB-X are actively involved in the above efforts. CARB-X with its international reach has been supporting innovations addressing AMR. These innovations and companies have products with direct therapeutic uses or products linked to antimicrobial stewardship, like vaccines and rapid diagnostics that help prevent and reduce the spread of antibiotic-resistant infections. C-CAMP on the other hand with its unique position at being instrumental in nurturing India’s biotech innovation ecosystem along with its in-house facilities is addressing the same issues. C-CAMP supported Module Innovations, that was also previously supported by CARB-X is an example in this domain.

Conclusion

AMR disrupts multiple SDGs, particularly SDG 3, “Good health and well-being”. In recent years, global AMR awareness and efforts to address it have expanded. The problem also requires a multipronged solution. Innovative technologies are needed for medicine development, pathogen detection, and systemic infection prevention. Incentives, supportive regulatory frameworks, and a good global antimicrobial stewardship policy can reduce antibiotic use in food, the environment, and medicine. Pathogens will continue to change and spread, no matter how hard we try to stop them. So, how can we keep up? Infection control and appropriate use of antimicrobials are our best bets.

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Disclaimer: The blog is a compilation of information on a given topic that is drawn from credible sources; however, this does not claim to be an exhaustive document on the subject. It is not intended to be prescriptive, nor does it represent the opinion of C-CAMP or its partners. The blog is intended to encourage discussion on an important topic that may be of interest to the larger community and stakeholders in associated domains.

Need to fast-track new antimicrobials — Part — 2

Written by Centre for Cellular and Molecular Platforms C-CAMP

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