How Can Novel Antibiotics Help Combat Antimicrobial Resistance?

Ricardo L Chaves, MD, PhD- Executive Medical Director, Debiopharm, Switzerland.

In the last 100 years, antibiotics have drastically changed modern medicine, helping to drive a phenomenal decrease in mortality rates due to infectious diseases¹ and extending the average human lifespan by more than 20 years.² In addition to treating bacterial diseases, antibiotics have made many modern medical procedures possible, including cancer treatment, organ transplants, and open-heart surgery.² It is, therefore, vitally important to ensure that the effectiveness of antibiotics remains stable for as long as possible.

Infectious diseases represent a pervasive threat to society, capable of causing widespread illness, economic instability, and overwhelming healthcare resources, as recently demonstrated by the COVID-19 pandemic.³ Since the emergence of COVID-19, there has been a heightened recognition of the critical need to advance innovation in the field of antimicrobials and to enhance preparedness for potential future pandemics.

The Threat and Burden of Antimicrobial Resistance (AMR)

It may be surprising for many to learn that nearly all classes of antibiotics are becoming increasingly ineffective against the bacterial pathogens they were developed to treat.² This is a result of the ability of these pathogens to constantly evolve and survive by developing or acquiring resistance to current antibacterial treatments.

What is now considered to be an AMR crisis has the potential to undermine the positive developments from the last century in the treatment of bacterial diseases.² AMR has become a leading cause of mortality globally, with bacterial AMR associated with an estimated 4.95 million deaths in 2019, of which 1.27 million are directly attributable to bacterial AMR.⁴ Alarmingly, the number of deaths due to AMR has been projected to increase further over the next three decades.⁵ It would seem that the successes achieved with antibiotics in the last century may have had too high of a price, with a significant amount of collateral damage to our normal bacterial flora and disruption of the beneficial microbiome, the consequences of which we are now beginning to understand.^6,7

The Impact of Antibiotics on the Microbiome

Until recently, there was limited knowledge and awareness about the effects of current antibiotics on an individual’s health via the collateral damage of the drug on the bacteria that normally live on or in healthy humans (i.e., our microbiota). These organisms - their genes, metabolites, and interactions with one another as well as with their host collectively - represent our microbiome.⁸ Current antibiotics, which kill not only the bacteria causing the infection but also a variety of other bacteria in the host, lead to disruption of the fine balance that underpins our beneficial gut microbiome.⁹ This disruption of the healthy composition, including species abundance and diversity, as well as the functionality of the microbiome is known as dysbiosis.⁸

The gut microbiome has an important role in human health. In addition to its structural and metabolic functions, it protects the host against colonization by many external pathogens.⁸ It is also a known reservoir for a wide variety of antibiotic resistance genes, from the resident “friendly” non-pathogenic bacteria and gut-dwelling opportunistic pathogens, as well as transient bacteria that pass through the gut when swallowed.¹⁰

The impact that current antibiotics can have on the gut microbiome is profound and far-reaching:

• Antibiotic-induced dysbiosis expands and sustains AMR by selecting antibiotic-resistant bacteria, which enriches the presence of resistance genes in the gut microbiome and promotes their dissemination.⁹

• The protection provided by the gut microbiome against colonization is diminished, predisposing the host to the overgrowth of resistant organisms, including multidrug-resistant pathogens.⁸ This also predisposes the host to develop antibiotic-induced infections such as colitis and candidiasis.^11,12

• The risk of subsequent infection by multidrug-resistant pathogens, and the risk of infection by any cause, is increased.^13,14  Multidrug-resistant pathogens are then transmitted to other people, especially in the hospital setting, keeping the healthcare system in a vicious cycle of AMR.

• Dysbiosis in the gut microbiota is now also being linked with several diseases and disorders including obesity, allergic diseases (asthma, atopic dermatitis, and allergic rhinitis), and inflammatory bowel disease,¹⁵ as well as to host resistance to immunotherapies in various cancers.^16,17

Precision Therapy with Novel Antibiotics

As there are patients with serious infections caused by multidrug-resistant bacteria for which there is almost no available therapeutic option, there is an urgent need to develop new antibiotics to fight these immediate threats. However, in the search for public health solutions for the growing AMR problem, it will be key to develop new classes of antibacterials that not only combat current infections but also do not exacerbate the problem or even extend to reducing the risk of resistance development, e.g., by avoiding antibiotic-induced dysbiosis and/or the spread of AMR. This is similarly expressed in a recent article by Rooney et al., where the authors state that “an altered approach during drug discovery is needed to strike a balance between sufficient coverage against the target pathogens and yet minimized microbiome untoward effects (collateral damage).”¹⁸

Considering the consequences of collateral damage with currently available antibiotics, the development of extremely narrow-spectrum antibiotics, ideally pathogen-specific antibiotics, is an obvious option in the fight against AMR.^19,20 Such antibiotics could provide us with a treatment strategy that spares the beneficial gut microbiome while simultaneously targeting the primary bacterial threat. This has the potential not only to combat AMR but to circumvent other consequences of antibiotic-induced dysbiosis, as mentioned above. It is important, however, to acknowledge that a pathogen-specific treatment strategy is only viable when the causative organism is known, and as such, would go hand-in-hand with the development of rapid diagnostics.¹⁹

The concept of using antibiotic regimens with the narrowest spectrum possible is not a new one and is grounded in the principles of antimicrobial stewardship. In fact, the 2019 Guidelines on the Diagnosis and Treatment of Foot Infection in Persons with Diabetes from the International Working Group on the Diabetic Foot (IWGDF) emphasize the importance of selecting an antibiotic regimen with the narrowest spectrum and cite the risk of collateral damage to the commensal flora as a consideration for treatment selection.²¹ These important treatment considerations are highlighted again in the 2023 combined IWGDF/IDSA update.²²

Key Steps in the Development of Microbiome-Sparing Antibiotics

There is hope on the horizon with several antibiotics with microbiome-sparing potential currently in development.¹⁹ However, given that microbiome-sparing antibiotics are a novel treatment strategy, the path forward in their development is currently not well established, and there are potentially a number of regulatory and financial hurdles to overcome. One particular challenge created by the current lack of precedence and defined regulatory framework is how drug developers can both convincingly and realistically demonstrate the microbiome-sparing properties of these antibiotics in clinical trials. We need robust clinical data that links surrogate endpoints (i.e., microbiome-associated biomarkers) for the microbiome-sparing properties of these antibiotics to hard clinical outcomes. These data will be a key piece of the puzzle in the ongoing collaboration between drug developers and regulatory authorities that is aiming to define the pathway to regulatory approval for these drugs.

By their nature, microbiome-sparing antibiotics require us to rethink the value paradigm that we currently apply to antibiotics. Antibiotics in general possess an inherent societal value that extends beyond the individual patient; they not only treat bacterial infections but also help contain the spread of infectious diseases, help protect particularly vulnerable patients from infections, reduce hospitalization rates, and lower healthcare costs associated with complications. However, this broader public health benefit is frequently overlooked in pricing models. Beyond this, a further paradigm shift is warranted: while the usual model of last-line antibiotic utilization is one in which reserved use is justified to reduce the emergence of AMR, microbiome-sparing antibiotics should provide evolutionary favor in the prevention of AMR and their use will need to be widespread for their benefits to be realized. We are, therefore, going to need to consider how to best support access to and use of, these microbiome-sparing antibiotics through innovative models of reimbursement that correspond to this new paradigm and adequately reflect the true societal value of antibiotics.

Lastly, there is a critical and well-recognized need to improve incentivization and funding for pharmaceutical companies to develop novel antibiotics. The 2023 progress report by the Global AMR R&D Hub and WHO highlights the need for policies rewarding R&D programs that successfully bring products to market and ensure access, such as pull incentives or other innovative financing mechanisms, to help support the development of a sustainable pipeline of novel antibacterials and reinvigorate innovation across the life sciences ecosystem.²³ Many AMR stakeholders are hopeful that a different type of business model, such as a subscription model, will bolster enthusiasm for antibiotic development globally.

References

1. Armstrong GL, Conn LA, Pinner RW. Trends in infectious disease mortality in the United States during the 20th century. Jama. 1999;281(1):61-66.
2. Hutchings MI, Truman AW, Wilkinson B. Antibiotics: past, present and future. Curr Opin Microbiol. 2019;51:72-80.
3. Zhang XX, Jin YZ, Lu YH, et al. Infectious disease control: from health security strengthening to health systems improvement at global level. Glob Health Res Policy. 2023;8(1):38.
4. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022;399(10325):629-655.
5. O’Neill J. The Review on Antimicrobial Resistance. May 2016. https://amr-review.org/sites/ default/files/160518_Final%20paper_with%20cover.pdf. Accessed 18 October 2023.
6. Blaser MJ. Antibiotic use and its consequences for the normal microbiome. Science. 2016;352(6285):544-545.
7. de Nies L, Kobras CM, Stracy M. Antibiotic-induced collateral damage to the microbiota and associated infections. Nat Rev Microbiol. 2023.
8. Seekatz AM, Safdar N, Khanna S. The role of the gut microbiome in colonization resistance and recurrent Clostridioides difficile infection. Therap Adv Gastroenterol. 2022;15:17562848221134396.
9. Modi SR, Collins JJ, Relman DA. Antibiotics and the gut microbiota. J Clin Invest. 2014;124(10):4212-4218.
10. Salyers AA, Gupta A, Wang Y. Human intestinal bacteria as reservoirs for antibiotic resistance genes. Trends Microbiol. 2004;12(9):412-416.
11. Abt MC, McKenney PT, Pamer EG. Clostridium difficile colitis: pathogenesis and host defense. Nat Rev Microbiol. 2016;14(10):609-620.
12. Guinan J, Wang S, Hazbun TR, Yadav H, Thangamani S. Antibiotic-induced decreases in the levels of microbial-derived short-chain fatty acids correlate with increased gastrointestinal colonization of Candida albicans. Sci Rep. 2019;9(1):8872.
13. Willems RPJ, van Dijk K, Vehreschild M, et al. Incidence of infection with multidrug-resistant Gram-negative bacteria and vancomycin-resistant enterococci in carriers: a systematic review and meta-regression analysis. Lancet Infect Dis. 2023;23(6):719-731.
14. Dubinsky-Pertzov B, Temkin E, Harbarth S, et al. Carriage of Extended-spectrum Beta-lactamase-producing Enterobacteriaceae and the Risk of Surgical Site Infection After Colorectal Surgery: A Prospective Cohort Study. Clin Infect Dis. 2019;68(10):1699-1704.
15. Keeney KM, Yurist-Doutsch S, Arrieta MC, Finlay BB. Effects of antibiotics on human microbiota and subsequent disease. Annu Rev Microbiol. 2014;68:217-235.
16. Matson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018;359(6371):104-108.
17. Routy B, Le Chatelier E, Derosa L, et al. The gut microbiome influences the efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91-97.
18. Rooney CM, Ahmed S, Wilcox MH. Protecting the Microbiota. J Infect Dis. 2021;223(12 Suppl 2):S290-s295.
19. Avis T, Wilson FX, Khan N, Mason CS, Powell DJ. Targeted microbiome-sparing antibiotics. Drug Discov Today. 2021;26(9):2198-2203.
20. Diamantis S, Retur N, Bertrand B, et al. The Production of Antibiotics Must Be Reoriented: Repositioning Old Narrow-Spectrum Antibiotics and Developing New Microbiome-Sparing Antibiotics. Antibiotics (Basel). 2022;11(7).
21. Lipsky BA, Senneville É, Abbas ZG, et al. Guidelines on the diagnosis and treatment of foot infection in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36 Suppl 1:e3280.
22. Senneville É, Albalawi Z, van Asten SA, et al. IWGDF/IDSA Guidelines on the Diagnosis and Treatment of Diabetes-related Foot Infections (IWGDF/IDSA 2023). Clin Infect Dis. 2023.
23. Incentivising the development of new antibacterial treatments 2023. Progress Report by the Global AMR R&D Hub & WHO. https://globalamrhub.org/incentivising-the[1]development-of-new-antibacterial-treatments-progress-report-by-the-global-amr-rd-hub-and-who/. Accessed 7 October 2023.

Publication Details

This article appeared in Pharmaceutical Outsourcing:
Vol. 4, No. 24
Oct/Nov/Dec 2023
Pages: 14-16

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