The ongoing AMR challenge

The development of antimicrobial agents has saved many lives worldwide since the discovery of penicillin in 1928. ^[1] However, the spread of antimicrobial resistance (AMR), which occurs when bacteria, viruses, fungi or parasites no longer respond to existing treatments, has limited their use. According to the World Health Organization (WHO), there are 4.95 million deaths every year attributed to AMR. The organization regards AMR as one of the top ten global threats to public life. ^{[2, 3]} This piece will focus on antimicrobial resistance in bacterial infections. 

AMR in bacteria is a natural survival mechanism. Its spread has been accelerated by the misuse and overuse of antibiotics and antimicrobials in hospitals, the community, particularly in countries where antibiotics are available without prescriptions, and in farming. Beating AMR will need a variety of different approaches, including the development of new antibiotics, the use of monoclonal antibodies, greater use of diagnostics to allow precision prescribing, and vaccinations to prevent the incidence and spread of bacterial infections. ^[3]

Using diagnostic tools to reduce AMR 

According to a review in 2017, up to half of antibiotics used in Western countries are unnecessary. Using patient-centred, cost-effective diagnostics could reduce this figure drastically; the challenge, however, is ensuring that the diagnostics are rapid enough to make a difference, and that they can be integrated into the clinical pathway. [4] Diagnostics also can be used to monitor the epidemiology of AMR, improving treatment guidelines and patient management. [5]

The impact of new antibiotics and antimicrobials

Antibiotics can be classified under the WHO AWaRe framework into three groups - Access, Watch and Reserve - based on their impact on AMR and their activity against multidrug-resistant organisms (MDRO). The Access group are the first or second choice for common infections, and the Watch group contains antibiotics that have a greater resistance potential, so should be stewarded carefully. Reserve antibiotics are restricted for use against MDRO infections. ^[6] 

Many companies have moved out of antibiotic and antimicrobial development because of the challenges of the science, the rapid development of resistance, the clinical and regulatory hurdles, and the low return on investment. ^[3] The latter is two-pronged; it is as a result of generic competition diving antibiotic prices down to very low levels, and the need to keep new antibiotics as a treatment of last resort (Reserve group), meaning that prescribing levels are low. Because of this, the R&D pipeline for new antibiotics isn't as robust as it needs to be.

There are a variety of programs designed to boost R&D in AMR around the world, including the AMR Accelerator (Europe), INCATE (Incubator for Antibacterial Therapies in Europe), CARB-X (Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator; global), Joint Programming Initiative on Antimicrobial Resistance (JPIAMR; global) and the AMR National Action Plan (UK), amongst others.

According to a 2023 review, the number of candidates in early-stage clinical development is increasing, and includes antibiotics and antimicrobials with new mechanisms of action and new targets. However, the late-stage pipeline is still sparse, with a decline in Phase III candidates. ^[7] Recent antibiotic approvals have been rare and include Zevtera (ceftobiprole medocaril) for Staphylococcus aureus bloodstream infections, acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. ^[8] No new antibiotics for gram-negative infections have been approved in 50 years. 

Antimicrobials and antibiotics in development include:

● Roche's zosurabalpin, a tethered macrocyclic peptide in Phase I development against Carbapenem-resistant Acinetobacter baumanni (CRAB) ^{[9, 10]}

● Glox Therapeutics' bacteriocins, engineered proteins in preclinical development against drug-resistant pathogenic gram-negative bacteria such as Pseudomonas aeruginosa and Klebsiella pneumoniae ^[9]

● Pylum Biosciences' Av-CD291.2, an Avidocin in preclinical development that specifically targets C difficile and acts by physically disrupting the cell wall (so has a low risk of resistance development). ^[11]

Monoclonal and patient-derived antibodies

Monoclonal antibody (MAb) technology dates back to 1975, and there have been huge advances since then, with MAbs launched for allergies, autoimmune diseases, neurodegenerative disorders, cancer, and infectious diseases. [12] A handful of MAbs have been launched for the treatment of infectious diseases, including anthrax, rabies and RSV infection, but they also have potential in targeting resistant pathogens. The challenge has been to increase the half-life of the antibodies and improve the targeting, and recent technologies, including reverse vaccinology, and machine and deep learning for protein structure prediction, have helped to move the area forward. ^[13]

Monoclonal antibody research projects include: 

● Moderna is researching monoclonal antibody-antimicrobial peptide conjugates against bacterial infections, including resistant bacteria infections ^[14]

● The German Center for Infection Research is working on potential monoclonal antibody treatments for acute and chronic infections with Pseudomonas aeruginosa ^[15]

● The University of Cologne is carrying out preclinical studies of neutralising antibodies derived from patients with cystic fibrosis, with potential against multi-drug resistant Pseudomonas aeruginosa. ^[9]

Bacteriophages

Bacteriophages are viruses that infect specific types of bacteria. Phage therapies, therefore, have potential to target bacterial infections, including antibiotic-resistant strains. Research is ongoing to refine their efficacy and safety, but challenges include developing manufacturing methods that are scalable and standardised, and ensuring that the preparations can be transported and stored without losing efficacy. Bacteria can also become phage-resistant. ^[16]

The PrIMAVeRA project (Predicting the Impact of Monoclonal Antibodies & Vaccines on Antimicrobial Resistance), a European project with collaborators from more than 19 academic and industry partners across 10 the UK, EU and Russia, aims to clarify the potential role of MAbs and vaccines against AMR. ^[17]

In 2016, the University of Chicago carried out the first known successful clinical use of intravenous bacteriophage therapy in the US, against a severe multi-antibiotic-resistant Acinetobacter baumannii infection. ^[18]

BiomX is developing customised phage therapies against bacteria in chronic diseases, and Phase II trials are under way in chronic pulmonary infections caused by Pseudomonas aeruginosa in cystic fibrosis (BX004) and Staphylococcus aureus infections in diabetic foot osteomyelitis (BX211). ^[19]

Avoiding AMR though vaccination

By preventing bacterial infections, vaccines reduce the levels of circulating bacterial pathogens (both antibiotic-sensitive and antibiotic-resistant). This lowers the likelihood that the mutations that cause resistance will emerge and spread. Vaccines against viruses such as influenza can also reduce the incidence of secondary bacterial infections, as well as lowering the use of unnecessary antibiotics by up to 64%. The likelihood of resistance against vaccines is very low. ^{[1, 3, 20]} Over half a million deaths associated with AMR could be prevented using vaccines. ^[1]

There are a number of vaccines on the market that target bacterial infections, including vaccines against meningococcal and pneumococcal diseases, typhoid, cholera, tetanus, tuberculosis, plague, haemophilus B infections and anthrax. 

Academic and industry researchers are developing vaccines against a range of bacteria, including resistant strains. Examples include:

● ReNewVax's RVX 001, a potentially universal protein vaccine against invasive pneumococcal disease, in preclinical development ^[21]

● Syntiron's E. coli/Klebsiella protein vaccine against urinary tract infections (UTIs), in preclinical development ^[22]

● Glyprovac's GPV02, a glycated protein vaccine for pregnant people to prevent neonatal sepsis, in preclinical development ^[23]

● LimmaTech Biologic's vaccine against Neisseria gonorrhoeae, in preclinical development. ^[24]

The University of Birmingham-hosted Bacterial Vaccines Network (BactiVac) has been granted ?1.4 million by the UK government's Global AMR Innovation Fund (GAMRIF) funding programme to accelerate research into bacterial vaccines. The money will support development of a pipeline of vaccines, and increase collaborations between researchers in low- and middle-income countries (LMICs) and the UK. ^[25] 

References

1. Kim, C., et al., Global and regional burden of attributable and associated bacterial antimicrobial resistance avertable by vaccination: modelling study. BMJ Glob Health, 2023. 8(7).

2. Thompson, K., Vaccines could avert half a million deaths associated with anti-microbial resistance a year. World Health Organization. 28 July 2023. Available from: https://www.who.int/news/item/28-07-2023-vaccines-could-avert-half-a-million-deaths-associated-with-anti-microbial-resistance-a-year.

3. Micoli, F., et al., The role of vaccines in combatting antimicrobial resistance. Nat Rev Microbiol, 2021. 19(5): p. 287-302.

4. Elvidge, S., AMR and diagnostics: pointing the way to better infection control. The Pharmaceutical Journal, 2017. Available from: https://pharmaceutical-journal.com/article/feature/amr-and-diagnostics-pointing-the-way-to-better-infection-control.

5. Peeling, R.W., D.L. Heymann, and D. Boeras, The value of diagnostics in the fight against antimicrobial resistance - by GARDP Antimicrobial Viewpoints, 25 January 2024.

6. Huttner, B., L. Moja, and M. Sharland, The end of the pipeline is dry: major gaps in the clinical evidence required to inform clinical and country-level appraisal and use of newly approved antibiotics. GARDP Antimicrobial Viewpoints, 13 December 2023. Available from: https://revive.gardp.org/the-end-of-the-pipeline-is-dry-major-gaps-in-the-clinical-evidence-required-to-inform-clinical-and-country-level-appraisal-and-use-of-newly-approved-antibiotics/.

7. Butler, M.S., et al., Antibiotics in the clinical pipeline as of December 2022. The Journal of Antibiotics, 2023. 76: p. 431-473.

8. Staff writer, FDA Approves New Antibiotic for Three Different Uses. FDA. 3 April 2024. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-new-antibiotic-three-different-uses.

9. Deswal, P., Early AMR pipeline looks beyond traditional antibiotics. Pharmaceutical Technology, 21 March 2024. Available from: https://www.pharmaceutical-technology.com/news/early-amr-pipeline-looks-beyond-traditional-antibiotics.

10. GlobalData Healthcare, Zosurabalpin shows promise in the fight against antibacterial resistance. 16 January 2024. Available from: https://www.clinicaltrialsarena.com/analyst-comment/zosurabalpin-promise-antibacterial-resistance/.

11. Gebhart, D., et al., A modified R-type bacteriocin specifically targeting Clostridium difficile prevents colonization of mice without affecting gut microbiota diversity. mBio, 2015. 6(2).

12. Chung, C., et al., Expanding the Reach of Monoclonal Antibodies: A Review of Synthetic Nucleic Acid Delivery in Immunotherapy. Antibodies (Basel), 2023. 12(3).

13. Troisi, M., et al., A new dawn for monoclonal antibodies against antimicrobial resistant bacteria. Front Microbiol, 2022. 13: p. 1080059.

14. Johnson, K., et al., Development of an antibody fused with an antimicrobial peptide targeting Pseudomonas aeruginosa: A new approach to prevent and treat bacterial infections. PLoS Pathogens, 2023. 19(9): p. e1011612.

15. Simonis, A., et al., Discovery of highly neutralizing human antibodies targeting Pseudomonas aeruginosa. Cell, 2023. 186(23): p. 5098-5113.

16. Carson, C. and L. Furfaro, 'Phage therapy' could treat some drug-resistant superbug infections, but comes with unique challenges. The Conversation, 15 November 2023. Available from: https://theconversation.com/phage-therapy-could-treat-some-drug-resistant-superbug-infections-but-comes-with-unique-challenges-207025.

17. Marzo, R.D. and I. Meln, PrIMAVeRa, an ambitious project to demonstrate how vaccines can combat AMR. European Vaccine Initiative. 9 November 2021. Available from: https://www.primavera-amr.eu/post/primavera-how-vaccines-can-combat-antimicrobial-resistance.

18. Hitchcock, N.M., et al., Current Clinical Landscape and Global Potential of Bacteriophage Therapy. Viruses, 2023. 15(4).

19. Waldron, J., BiomX acquires fellow bacteria-killing virus company Adaptive Phage to accelerate phase 2 plans. FierceBiotech, 6 March 2024. Available from: https://www.fiercebiotech.com/biotech/biomx-acquires-fellow-bacteria-killing-virus-company-apt-accelerate-phase-2-plans.

20. Staff writer. Vaccines for Antimicrobial Resistance (AMR). World Health Organization. 29 April 2024. Available from: https://www.who.int/teams/immunization-vaccines-and-biologicals/product-and-delivery-research/anti-microbial-resistance.

21. Murray, N., Accelerating AMR vaccine development. European Pharmaceutical Review, 1 November 2023. Available from: https://www.europeanpharmaceuticalreview.com/article/187174/accelerating-amr-vaccine-development/.

22. Dall, C., Vaccine makers seek a role in the fight against antibiotic resistance. 7 February 2024. Available from: https://www.cidrap.umn.edu/antimicrobial-stewardship/vaccine-makers-seek-role-fight-against-antibiotic-resistance.

23. Staff writer, CARB-X FUNDS GLYPROVAC TO DEVELOP A NOVEL VACCINE TO PREVENT SEPSIS IN NEWBORNS. CARB-X. 29 February 2024. Available from: https://carb-x.org/carb-x-news/carb-x-funds-glyprovac/.

24. Staff writer, CARB-X FUNDS LIMMATECH BIOLOGICS AG TO DEVELOP A VACCINE THAT PREVENTS GONORRHEA INFECTIONS. CARB-X. 27 February 2024. Available from: https://carb-x.org/carb-x-news/carb-x-funds-limmatech/.

25. Stewart, L., BactiVac funded to develop bacterial vaccines in global fight against AMR. The Microbiologist, 28 September 2023. Available from: https://www.the-microbiologist.com/news/bactivac-funded-to-develop-bacterial-vaccines-in-global-fight-against-amr/1646.article.

About the Author:

Suzanne Elvidge

Based in the north of England, Suzanne Elvidge is a freelance medical writer with a 30-year experience in journalism, feature writing, publishing, communications and PR. She has written features and news for a range of publications, including BioPharma Dive, Pharmaceutical Journal, Nature Biotechnology, Nature BioPharma Dealmakers, Nature InsideView and other Nature publications, to name just a few. She has also written in-depth reports and ebooks on a range of industry and disease topics for FirstWord, PharmaSources, and FierceMarkets. Suzanne became a freelancer in 2006, and she writes about pharmaceuticals, consumer healthcare and medicine, and the healthcare, pharmaceutical and biotechnology industries, for industry, science, healthcare professional and patient audiences.