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The O’Neill report¹ suggested that up to 10 million people will die from antibiotic resistant infections by 2050. This figure has been adopted by health authorities, researchers and the general public to suggest the potential of a gloomy outcome if we do not discover new antibiotics; unfortunately, however, we have been dismally ineffective at discovering ‘game-changers’, antibiotics with the potential to make major differences in treating persistent bacterial infections. A new article has served to emphasize that the future envisaged in the O’Neill report is already here and it depends to some extent on how we define resistance^2,3. This major paper, published in the Lancet by Rudd et al.⁴, in January 2020, indicated that 19.7% of all global deaths in 2017 (i.e. ~11 million deaths) were caused by sepsis, a syndrome most commonly linked to bacterial infection, and for which antibiotics are the front-line treatment.

Antibiotic failure and its relationship to resistance

The fundamental issue lies in how we define resistance and whether this should encompass treatment failure, since the net effect is similar. If resistance is defined as a genetic mechanism (intrinsic or acquired) that causes bacteria to survive antibiotic treatment, then the current concept of antibiotic resistance is adequate. However, the issue becomes more complex when considering that resistance leads to bacteria surviving antibiotic treatment, which equates to antibiotic failure^2,3. The reasons for therapeutic failure are manifold but include, for example, other resistance mechanisms such as adaptive resistance (see below), which are not genetic but just as meaningful. For example, many of the 22% of sepsis cases that are fatal⁴ reflect antibiotic failure.

“We need to rethink the antibiotic discovery paradigm. Killing bacteria directly is one strategy with which we are very familiar, but it is not the only way forward.”

Sepsis can be broadly defined as a dysregulated host response to infection causing life-threatening organ dysfunction⁵. Opinions as to the origins and nature of this dysregulated host response vary, but sepsis includes such aspects as an initial cytokine storm (hyperinflammatory response) followed by immunosuppression (hypoinflammatory), for which the root cause has been suggested to include endotoxin tolerance (macrophage reprogramming), immune cellular exhaustion and/or apoptosis, and T-cell anergy^6-8. Sepsis can be triggered by microbial infections and/or major trauma; however, current evidence suggests that at least 65-80% of cases are associated with (and likely caused by) bacterial infections⁹. Thus the major initial treatment for sepsis is the use of potent antibiotics, and usually combinations thereof. For this reason I conclude that the high death rate from sepsis (e.g. 250,000 deaths annually in the USA where sepsis is present in 30% to 50% of hospitalizations that culminate in death¹⁰) is most likely substantially due to antibiotic failure. The basis for antibiotic failure is not well understood but could involve the immune dysfunction in sepsis, which might prevent the body’s natural defences from supporting antibiotic effectiveness¹¹.

Antibiotic failure is common and underestimated

This is not the only situation in which we have vastly underestimated the importance of antibiotic failure. Bacterial biofilms cause 65-80% of all infections, according to the US Centers for Disease Control and Prevention (CDC), being associated with most chronic and device-associated infections¹². Such biofilms are difficult or impossible to treat since organisms growing in the biofilm state are 10- to 1000- fold more resistant to almost all conventional antibiotics. Multidrug resistance in a biofilm is adaptive and multigenic in nature, rather than mutational, since it depends on the growth state and environmental conditions of the biofilm which leads to altered gene expression of multiple resistance genes, and reverts when bacteria are isolated and grown planktonically (e.g. in the broth dilution conditions of a conventional MIC assay). Biofilm infections are a circumstance where antibiotics often fail and include chronic infections such as device-related infections and chronic wound infections, which in the United States alone annually affect 1 and 6.5 million patients, respectively^13,14. Furthermore it is rather staggering to realize that despite the commonness of such infections, not a single therapy has been introduced into the clinic that was specifically designed for treating biofilm infections. For example rhinosinusitis/sinusitis, is one of the most common medical complaints in North America, affecting 12.5-16% of the population and costing $8 billion in the USA annually^15,16. However, antibiotic therapy does not appear to be effective for chronic rhinosinusitis, which is particularly concerning since 10-20% of all antibiotics are applied to this condition¹⁵. Bacterial abscesses are another area in which antibiotics rarely work, despite the 3.2 million emergency ward visits for abscesses in USA every year, and in organs, such as the brain, they can be deadly¹⁷. For abscesses and chronic rhinosinusitis, treatment usually involves surgical debridement. In addition to adaptive resistance^12,20 mentioned above, the well described phenomena of tolerance^18,19 and persistence¹⁹, are associated with such chronic infections and frequent antibiotic failure.

“The high death rate from sepsis (…..) is most likely substantially due to antibiotic failure.”

Rethinking the treatment of bacterial infections

So the issue is not when we will reach the antibiotic apocalypse, it is really a question of just how much worse things can get, when we are already in a situation where antibiotics are failing frequently. From my personal perspective, current drives to develop new antibiotics are using old-world thinking, where in this case the old world represents the glory years of antibiotic development, namely the 1950s give or take a decade. We need to rethink the antibiotic discovery paradigm². Killing bacteria directly is one strategy with which we are very familiar, but it is not the only way forward. For example, when the underlying patient condition is important, perhaps we should start to think about combining antibiotics with host-directed therapeutic strategies to address the factors in patients that are causing antibiotics to fail. Thus reversing the basic immune dysregulation in sepsis might provide a strategy that will enable antibiotic success in this deadly syndrome. In this regard, we recently published a screening strategy using a CRISPR mutagenesis approach for identifying host directed therapeutic targets for Chlamydia²¹ and Salmonella²².

Other approaches with promise are alternatives to antibiotics²³ and novel combination therapies²⁴. While these strategies are just starting to be tested clinically, it is worth mentioning that probiotics are having an enormous impact on infant sepsis²⁵. I believe in human ingenuity and only by thinking out of the box can we solve our current and future problems.

References:

1. Review on Antimicrobial Resistance. Tackling Drug Resistant Infections Globally: Final Report and Recommendations. 2016. 
2. Hancock, REW. Rethinking the antibiotic discovery paradigm (commentary). eBiomedicine 2015;2:627-628.
3. Bassetti M, JG Montero and JA Paiva. When antibiotic treatment fails. Intensive Care Med. 2018;44:73–75.
4. Rudd KE, Johnson SC, Agese KM, Schackelford KA, Tsoi D, Kievlan DR et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: Analysis for the global burden of disease study. The Lancet 2020;395:200-211.
5. Singer M, Deutschman CS, Seymour W, Shank-Hari M, Annane D, Bauer M et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). J. Amer. Med. Assoc. 2014;315:801–810.
6. Hotchkiss RS, Monneret G, and Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect. Dis. 2013;13:260-268.
7. Pena OM, Hancock DG, Lyle NH, Russell JA, Xia J, Fjell CD et al. An endotoxin tolerance signature predicts sepsis and organ dysfunction at initial clinical presentation. eBiomedicine 2014;1:64-71.
8. Cao C, Yu M, Chai Y. Pathological alteration and therapeutic implications of sepsis-induced immune cell apoptosis. Cell Death & Disease. 2019;10:1-4.
9. Mayr FB, Yende S and Angus DC. Epidemiology of severe sepsis. Virulence 2014;5:4–11.
10. Rhee C, Dantes R, Epstein L, Murphy DJ, Seymour CW, Iwashyna TJ et al. Incidence and trends of sepsis in US hospitals using clinical vs. claims data, 2009-2014. JAMA 2017;318:1241-1249.
11. Ankomah P, and Levin BR. Exploring the collaboration between antibiotics and the immune response in the treatment of acute, self-limiting infections. Proc. Natl. Acad. Sci. 2014;111:8331-8338.
12. Fuente-Núñez C, Reffuveille F, Fernández L and Hancock REW. Bacterial biofilm development as a multicellular adaptation: Antibiotic resistance and new therapeutic strategies. Curr. Opinion Microbiol. 2013;16:580–589.
13. VanEpps JS, and Younger JG. Implantable Device-Related Infection. Shock. 2016;46(6):597-608.
14. Sen CK, Gordillo GM, Roy S, Kirsner R, Lambert L, Hunt TK et al. Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen. 2009;17(6):763-71.
15. Meltzer EO and Hamilos DL. Rhinosinusitis diagnosis and management for the clinician: a synopsis of recent consensus guidelines. Mayo Clin Proc. 2011;86: 427–443.
16. Schleimer RP. Immunopathogenesis of Chronic Rhinosinusitis and Nasal Polyposis. Annu Rev Pathol. 2017;12: 331–357.
17. Taira BR, Singer AJ, Thode HC and Lee CC. National epidemiology of cutaneous abscesses: 1996 to 2005.  J. Emerg. Med. 2009;27: 289–92. 
18. Carvalho G, Forestier C and Mathias JD. Antibiotic resilience: a necessary concept to complement antibiotic resistance? Proc. Royal Soc. B: Biolog. Sci. 2019;286(1916):20192408. https://doi.org/10.1098/rspb.2019.2408
19. Levin-Reisman I, Brauner A, Ronin I, and Balaban NQ. Epistasis between antibiotic tolerance, persistence, and resistance mutations. Proc. Natl. Acad. Sci. USA 2019;116:14734-14739.
20. Fernández L and Hancock REW. Adaptive and mutational resistance: Role of porins and efflux pumps in drug resistance. Clin. Microbiol. Rev. 2012;25:661-681.
21. Yeung ATY, Hale C, Lee AH, Gill EE, Bushell W, Parry-Smith D et al. Exploiting induced pluripotent stem cell-derived macrophages to unravel key host factors influencing Chlamydia trachomatis. Nature Communications 2017;8:15013.
22. Yeung ATY, Choi YH, Lee AHY, Hale C, Ponstingl H, Pickard D et al. A genome-wide knockout screen in human macrophages identified host factors modulating Salmonella. mBio 2019;10(5):e02169-19.
23. Czaplewski L, Bax R, Clokie M, Dawson M, Fairhead H, Fischetti VA et al. Alternatives to antibiotics – a pipeline portfolio review. Lancet Infect. Dis. 2016;16:239-251.
24. Schneider EK, Reyes-Ortega F, Velkov T and Li J. Antibiotic–non-antibiotic combinations for combating extremely drug-resistant Gram-negative ‘superbugs’. Essays in biochemistry. 2017;61:115-25.
25. Denkel LA, Schwab F, Garten L, Geffers C, Gastmeier P and Peining B. Protective effect of dual-strain probiotics in preterm infants: A multi-center time series analysis. PLoS One 2016;11(6):e0158136.