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Antimicrobial Resistance – the Rise of Global Superbugs
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Antimicrobial Resistance – the Rise of Global Superbugs

Antimicrobial Resistance – the Rise of Global Superbugs
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Antimicrobial Resistance – the Rise of Global Superbugs

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Until the early 19th century one in two people used to die from infectious diseases before the age of 20 years.1 The global life expectancy has now increased to 72 years and the discovery of antimicrobials was one of the major drivers of this improvement in human health.

Antimicrobials kill or inhibit the growth of bacteria (these are also called “antibiotics”), parasites, viruses, and fungi.1 In 1928, Alexander Fleming famously isolated the first antibiotic from the mold Penicillium notatum. Beginning in 1942 during World War II, the mass production of penicillin officially ushered in the era of antibiotics. 


Antibiotics have since revolutionized medicine by enabling treatments that would once have proven fatal, e.g., critical care medicine (such as the use of ventilators and catheters), cancer treatments, orthopedic surgery, organ transplantation, the care of premature babies, and the treatment of autoimmune diseases. 2–4 Indeed, most surgical procedures rely on antibiotics to prevent life-threatening postoperative infections. Antimicrobials are now not only extensively used in human healthcare, but also in toiletries, cleaning products for household and industrial use, and agriculture.


However, antimicrobials have since proven to be a double-edged sword. 


What is antimicrobial resistance?


Antimicrobial resistance (AMR) refers to the inheritable genetic changes that microbes accumulate to reduce or eliminate the efficacy of antimicrobials.2,3,5 


Over the past 60 years, millions of metric tons of antimicrobials have been distributed worldwide in various products.2 This extensive exposure has led to the emergence of multidrug-resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR) organisms such as the Klebsiella and Acinetobacter species.6 Resistant pathogenic strains can develop within only a year of antimicrobial exposure,7 and the death rate from infections with these strains can approach 50%.6


Despite antibiotics only being in extensive use for several decades, certain bacterial infections are now on the verge of becoming untreatable.5


Some common resistant microbes 


In 2017, the World Health Organization (WHO) released a list of AMR pathogens posing the greatest threat.8 The medium and high threat categories include Staphylococcus aureus (S. aureus); cause of pneumonia, as well as bloodstream, skin and soft tissue infections), Vibrio cholerae, Streptococcus pneumoniae (cause of pneumonia and bacterial meningitis among others), and bacteria that cause common diseases such as food poisoning (Salmonella) and gonorrhea (Neisseria gonorrhoeae). The critical category includes bacteria that cause severe (and sometimes deadly) bloodstream, urinary, and respiratory tract infections in hospitals and nursing homes. These include Acinetobacter, Pseudomonas aeruginosa, Serratia, Proteus, Klebsiella, and Escherichia coli


Because there are already extensive efforts underway to combat tuberculosis, Mycobacterium tuberculosis is not on this priority list. However, several MDR and XDR strains of tuberculosis have emerged.9 


How do microbes acquire resistance? 


AMR arises spontaneously through random genetic mutations, and the prevalence of these mutations increases in response to selection pressure from competing microbes, invading pathogens, and human antimicrobial use.2,10 Other microbes then inherit these genes by descent. Only one bacterium in a population needs to be resistant to an antibiotic for drug resistance to emerge.


Particularly worrying, is that certain microbes can also receive AMR genes from non-relatives, even from other species.1,5 AMR is especially a concern for the Gram-negative bacteria on the WHO priority list, as over and above their inherent, physical barriers to antibiotic treatment, these species readily transfer resistant genetic material to other bacteria. 


Why are “superbugs” a global threat? 


The term “superbugs” describes microbes with enhanced morbidity and mortality due to high levels of antibiotic resistance.These microbes have fewer treatment options and are associated with extended and costlier periods of hospital care. In some cases, these superbugs have also acquired increased virulence and enhanced transmissibility. 


One of the most notorious superbugs is S. aureus.3 This multidrug-resistant pathogen has been a major source of hospital-acquired infections; recently, however, MDR strains have also moved into the community. Another superbug is Salmonella enterica, with some strains resistant to five antibiotics.7 Most concerning, however, is the emergence of pathogens resistant to nearly all (and in rare cases, all) antimicrobials, such as carbapenem-resistant Klebsiella pneumoniae.11,12


Approximately 700,000 deaths per year are attributed to AMR, but with the emergence of more and more “superbugs”, this number is projected to rise to 10 million by 2050 at a cost of $100 trillion.13 The rise of AMR is therefore considered by experts to be one of the most critical issues in modern healthcare. 


How do we best prevent the rise of “superbugs”? 


Experts suggest two major approaches to slow the spread of AMR: (1) reduce the number of infections, and (2) reduce antibiotic use.


Prevention


Whenever an infection is prevented, one less person needs to be prescribed drugs. According to Prof. Willem van Schaik of the Institute of Microbiology and Infection at the University of Birmingham, one of the leading EU institutes researching AMR, “The most important technology for combatting drug resistance is to prevent infections. This can be done by technologically simple solutions (e.g., handwashing by healthcare workers, and isolation of patients colonized by multidrug-resistant bacteria), but novel approaches (e.g., disinfection of air by UV) are promising too. As prevention is always better than treating infections, vaccine-based approaches to combat AMR are of considerable interest as well.”


Indeed, many experts agree that improved vaccine design, production, and delivery methods may eventually comprise the main strategy for combating AMR.1 Other than vaccines, isolation, and proper hygiene, surveillance is also key. Next-generation sequencing technologies, which can sequence the entire genomes of microbes, are increasingly being used to track AMR genes across the food chain.14,15 However, such surveillance has not yet been implemented worldwide, and most countries still rely on older, less informative techniques to characterize specimens. In fact, many parts of the world currently lack adequate (if any) surveillance methods.9 AMR surveillance, therefore, requires global strengthening and harmonization, with the adoption of agreed methods and standards. 


Reduction


Every administered dose of antibiotic drugs selects for resistance.2 Antibiotic stewardship is critical to ensure that antibiotics are taken in the right amounts for the full course and only when necessary.


Antibiotics were, until recently, freely available in most parts of the world. However, even when not provided over the counter, misuse is rampant. In the US alone, healthcare providers prescribed 258 million courses of antibiotics (833 prescriptions per 1000 persons) in 2010.9 At least 50% of all these antibiotic prescriptions are deemed unnecessary. 


More information campaigns (such as Get Smart) targeted at both the consumer and healthcare professional are needed.9 Many people take antibiotics to treat the common cold and flu, even though antibiotics are ineffective against both. Prescription audits should, therefore, become routine. Improved diagnostics that allow rapid, point-of-care identification of the pathogen down to strain level would also help healthcare providers improve their antibiotic treatment decisions. 


Interventions are also required to prevent the ongoing misuse of antimicrobials in cleaning products, agriculture, and other industries.9 In certain countries, up to 75% of all antibiotics are used for veterinary applications.2,16 Antibiotics are used in livestock and poultry to treat diseases and in sub-therapeutic doses as growth promotants or prophylactics to compensate for stressful and unsanitary conditions. In the US, around 8 billion animals are treated by as many as 10 different antibiotics. Worryingly, many of the same antimicrobial classes are also used in human health. 


A further concern is that an estimated 75% of all antibiotics given to animals are not fully digested.16 Vast quantities of manure are routinely sprayed onto fields and these antibiotics leech into the water supply. The AMR bacteria that arise can be spread by animals, birds, and insects.17–19 Large amounts of antibiotics are also released into municipal wastewater because of incomplete metabolism in humans and the disposal of unused antibiotics.9 Plant products can also be affected through irrigation with contaminated water.10 Regulations governing the non-human use of antimicrobials, therefore, need to be put in place and/or more strictly enforced, and consumers should rally for improved animal husbandry to reduce the need for antimicrobials. 


Why don’t we just discover more new antibiotics?


Despite the issue of AMR, the search for new antimicrobials remains a priority for treating severe infections. However, new antibiotic development has slowed to a standstill because of financial and regulatory disincentives.4,11 FDA approvals declined by 94% between the mid-1980s and 2010, with only two approvals between 2008 and 2013. With over 140 antibiotics developed over the past century, the “easy” discoveries have already been made.


Antibiotics are also not as profitable as drugs used for long-term conditions, and this is particularly true where proper antibiotic stewardship is in place. Indeed, the cost of developing a new antibiotic is now likely to outstrip the return.11 As Prof. Willem van Schaik says, “The economy of antibiotic R&D in large pharmaceutical companies is challenging as new antibiotics are unlikely to become important profit generators in the short-term and so are unlikely to be prioritized by large, shareholder-driven companies.”   


Some economic and regulatory incentives have, therefore, been provided by the FDA (through the GAIN Act) and through public-private funding bodies such as the CARB-X collaboration between the US and UK, and the “New Drugs for Bad Bugs” program in the EU.4,20 An alternative public-private partnership, the Global Antibiotic Research and Development Partnership (GARDP), sources funds to not only develop antibiotics but also to ensure their sustainable access. However, more resources are likely needed.


Another avenue is the repurposing of “old” antibiotics. As Prof. Laura Piddock, Head of Scientific Affairs at GARDP says, “In addition to identifying new drug candidates, we are recovering the knowledge, data, and assets of forgotten or undeveloped antibiotics that can be candidates for pre-clinical or clinical development.”


It is, of course, crucial that any new antibiotics be scrupulously guarded against misuse to prevent the rapid rise of AMR yet again. 


Are there any alternatives to antibiotics?


There are several emerging technologies that may provide alternatives to antibiotics. Other technologies include CRISPR, antimicrobial peptides, and phage therapy, although these all face significant challenges to clinical implementation.6, 7,16 Pathogens could potentially be targeted for neutralization rather than destruction, thus exerting less selection pressure to drive resistance.4 Alternatively, the host, rather than the microbe, could be targeted to modulate the immune response and the host environment to minimize the effects of infection without resorting to antibiotics.


In summary


For a while, the discovery of antibiotics mostly eliminated the threat of infectious diseases. But now, some scientists believe we are approaching a post-antibiotic age.1,2 We face a future in which people again die of common infections and medical interventions begin to pose unacceptable risks. 


In the words of Alexander Fleming: “…the thoughtless person playing with penicillin is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organism.”4


We must actively encourage the return of susceptible microbes into the clinical and overall environment.


References


1) Tagliabue A., Rappuoli R. Changing priorities in vaccinology: Antibiotic resistance moving to the top. Frontiers in Immunology. 2018, 9, article 1068. doi: 10.3389/fimmu.2018.01068.


2) Smith R.A., M’ikanatha N.M., Read A.F. Antibiotic Resistance: A Primer and Call to Action. Health Communication. 2015;30(3):309–314. doi:10.1080/10410236.2014.943634.


3) Davies J., Davies D. Origins and Evolution of Antibiotic Resistance. Microbiology and Molecular Biology Reviews 2010;74(3):417–433. doi:10.1128/MMBR.00016-10.


4) Spellberg B. The future of antibiotics. Critical Care. 2014;18(3):228. doi:10.1186/cc13948.

5) Perry J., Waglechner N., Wright G. The Prehistory of Antibiotic Resistance. Cold Spring Harbor Perspectives in Medicine. 2016;6(6):a025197. doi:10.1101/cshperspect.a025197.

6) Steckbeck J.D., Deslouches B., Montelaro R.C. Antimicrobial peptides: new drugs for bad bugs? Expert Opinion on Biological Therapy. 2014;14(1):11–14. doi:10.1517/14712598.2013.844227.

7) Ali J., Rafiq, Q.A., Ratcliffe E. Antimicrobial resistance mechanisms and potential synthetic treatments. Future Science OA. 2018;4(4):FSO290. doi: 10.4155/fsoa-2017-0109.


8) WHO publishes list of bacteria for which new antibiotics are urgently needed. World Health Organization. 27 February 2017. (http://www.who.int/news-room/detail/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed)


9) Prestinaci F., Pezzotti P., Pantosti A. Antimicrobial resistance: a global multifaceted phenomenon. Pathogens and Global Health. 2015;109(7):309–318. doi:10.1179/2047773215Y.0000000030.


10) Meredith H.R., Srimani J.K., Lee A.J., Lopatkin A.J., You L. Collective antibiotic tolerance: Mechanisms, dynamics, and intervention. Nature Chemical Biology. 2015;11(3):182–188. doi:10.1038/nchembio.1754.


11) Toner E., Adalja A., Gronvall G.K., Cicero A., Inglesby T.V. Antimicrobial resistance is a global health emergency. Health Security. 2015;13(3):153–155. doi:10.1089/hs.2014.0088.


12) Doorduijn D.J., Rooijakkers, S.H., van Schaik W., Bardoel B.W. Complement resistance mechanisms of Klebsiella pneumoniae. Immunobiology. 2016;221(10):1102–1109. doi: 10.1016/j.imbio.2016.06.014.


13) O'Neill J. Antimicrobial resistance: tackling a crisis for the health and wealth of nations. 2014. (http://amr-review.org/sites/default/files/AMR%20Review%20Paper%20-%20Tackling%20a%20crisis%20for%20the%20health%20and%20wealth%20of%20nations_1.pdf) 


14) Oniciuc E.A., Likotrafiti E., Alvarez-Molina A., Prieto M., Santos J.A., Alvarez-Ordóñez, A. The present and future of whole genome sequencing (WGS) and whole metagenome sequencing (WMS) for surveillance of antimicrobial resistant microorganisms and antimicrobial resistance genes across the food chain. Genes. 2018;9(5):268. doi:10.3390/genes9050268.


15) Köser C.U., Ellington M.J., Peacock S.J. Whole-genome sequencing to control antimicrobial resistance. Trends in Genetics. 2014;30(9):401–407. doi:10.1016/j.tig.2014.07.003. 


16) Jassim S.A.A., Limoges R.G. Natural solution to antibiotic resistance: bacteriophages “The Living Drugs.” World Journal of Microbiology & Biotechnology. 2014;30(8):2153–2170. doi:10.1007/s11274-014-1655-7. 


17) Zurek L., Ghosh A. Insects represent a link between food animal farms and the urban environment for antibiotic resistance traits. Müller V, ed. Applied and Environmental Microbiology. 2014;80(12):3562–3567. doi:10.1128/AEM.00600-14.


18) Vaz-Moreira I., Nunes O.C., Manaia C.M. Bacterial diversity and antibiotic resistance in water habitats: searching the links with the human microbiome. FEMS Microbiology Reviews. 2014;38(4):761–78. doi: 10.1111/1574-6976.12062. 


19) Verraes C., Van Boxstael S., Van Meervenne E., et al. Antimicrobial Resistance in the Food Chain: A Review. International Journal of Environmental Research and Public Health. 2013;10(7):2643–2669. doi:10.3390/ijerph10072643. 


20) Carlet, J., Pulcini C., Piddock, L.J.V. Antibiotic resistance: a geopolitical issue. Clinical Microbiology and Infection. 2014;20(10):949–953. doi.org/10.1111/1469-0691.12767.

Meet The Author
Natasha Beeton-Kempen, PhD
Natasha Beeton-Kempen, PhD
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