Data from Alex Keen - Curated by EPG Health - Last updated 19 April 2018

This year’s ECCMID is being held in Madrid, Spain, from 21‒24 April 2018. The Congress is hosting a large number of abstract sessions, educational workshops, keynote lectures and symposia that discuss antibiotic resistance. This immediate and pressing issue has been described as ‘one of the biggest threats to global health, food security, and development today’ by the WHO, with a recent study forecasting 10 million extra deaths annually worldwide from drug-resistant infections by 2050 if no action is taken, outpacing cancer mortality.

The first antibiotic, penicillin, was accidentally discovered in 1928 by Alexander Fleming after he noticed that one of his bacterial cultures contained areas that were devoid of growth. Further investigation revealed that fungal contamination had occurred, killing the bacteria and leading to the discovery and development of Penicillin, introduced in 1942 as the world’s first antibiotic and earning Fleming a Nobel Prize. This ushered forward a new era in medicine where bacterial infections could be effectively treated, turning a potential death sentence into a minor inconvenience. However, we are now at risk of descending back into the pre-antibiotic era, where even minor surgery could carry a significant risk of infection, sepsis and death, potentially rendering surgical intervention and chemotherapy useless.

Testing for antibiotic resistance.

Testing for antibiotic resistance. Each of the white discs is infused with a different antibiotic, with the left-hand dish showing that the bacterial cultures are susceptible to all 7 of the antibiotics, however, only 3 of the antibiotics are effective in the right-hand dish. Fleming would have seen similar areas devoid of growth when he first stumbled upon his contaminated culture. Credit: Dr Graham Beards.

When an antibiotic is used to treat a bacterial infection, it kills the bacteria, clearing the infection and curing the illness. However, certain bacteria in the population can exhibit resistance to the antibiotic, meaning they are more likely to survive and pass on their resistant genes to the next generation through the process of natural selection. This generates a population of bacteria that have acquired more resistance genes and are therefore better able to survive antibiotic action. Bacteria can also exchange genetic material with one another through a mechanism called horizontal gene transfer, where resistance genes are swapped and incorporated into the genome, conferring resistance. These mechanisms work over generations and generations, gradually increasing the occurrence of resistant genes in a bacterial population.

This is exacerbated when patients don’t take their full course, a situation which is especially apparent in low- and middle-income countries, where antibiotics are often available over the counter without proper indication. This can often mean that as soon as the patient feels better they stop taking the medication before the full course is up, increasing the likelihood that resistant bacteria can survive and proliferate to create a new, more resistant population, although this argument is frequently disputed.

The mechanism of antibiotic resistance.

The mechanism of antibiotic resistance.

In recent years, concern over the use of antibiotics in farming has grown due to their link to resistant infections in humans. When used properly antibiotics are important for the treatment of sick and injured animals, preventing the spread of infection that has the potential to wipe out large numbers of livestock. However, many farms use antibiotics as a form of prophylaxis to keep their animals healthy in crowded and often unsanitary conditions. For decades they were also used as growth promotors as they alter the gut microbiome leading to more efficient digestion and greater nutrient uptake, being banned only in 2006 in the EU and as recently as 2017 in the US.

This resistance can be passed on to humans from livestock through direct contact with the animals, meaning farmers are particularly at risk; through the preparation and consumption of meat; and via animal excretion into the environment, a problem that is exacerbated with the use of animal waste as crop fertiliser. The resistant bacteria live in the meat and on the crops, with some surviving to be consumed by humans, colonising the host and passing into the environment. This issue is worsened through the use of clinically important antibiotics in animals as the resistance acquired by the bacteria increases the ineffectiveness of antibiotics important for human health.

The process by which antibiotic resistance spreads via food consumption and human-to-human transmission.

The process by which antibiotic resistance spreads via food consumption and human-to-human transmission.

An independent report commissioned by the British Government found that 72% of the peer-reviewed academic papers that addressed antibiotic use in agriculture provided evidence of a link between their use in livestock and resistance in humans, with only 5% arguing against, citing figures from the US that animals consume more than twice as many medically important antibiotics as humans, although these statistics may have changed since the FDA introduced the recent ban on the use of antibiotics as growth promotors.

Over time, resistance has spread and more and more untreatable bacterial strains are emerging, adding further pressure to health services worldwide. MRSA is a well known example of a 'superbug'. They pose a particular problem to hospitals due to the densely packed nature and susceptibility of ill and injured patients and a highly mobile and hands on workforce, creating the perfect conditions for the rapid spread of infection. As many penicillins can no longer treat MRSA, other antibiotics must be used depending on the severity, location and individual resistance of the infection. New strains with greater resistance are constantly emerging, such as GISA, which displays partial resistance to vancomycin, one of the last available antibiotics able to treat this strain of S. aureus.

Super gonorrhoea is another emerging ‘superbug’. A man in the UK recently contracted what was described as the ‘world’s worst’ gonorrhoea after a trip to South-East Asia. The standard antibiotic treatment of azithromycin and ceftriaxone failed to treat the infection, so the doctors were forced to use ertapenem as a last resort. The treatment appears to have worked, however, scientists warn that ‘superbugs’ are becoming more and more common, with gonorrhoea and many other diseases becoming unmanageable unless new treatments are developed.

The consequences of inaction have the potential to severely damage economic and social progression, incentivising governments and organisations to slow the growth of resistance and encourage drug development. In 2016 the UN General Assembly called a high-level meeting on the issue, only the 4th time in the UN’s history that this has occurred, highlighting the seriousness of the situation.

In England, the NHS has introduced an incentive scheme designed to reduce the inappropriate use of antibiotics in order to slow the growth of resistance. Around 10% of antibiotic prescriptions in the UK are thought to be unnecessary helping to fuel resistance and wasting millions annually in unnecessary prescriptions. This involves extra funding that is rewarded to hospitals and GP surgeries if they reduce the amount of antibiotics prescribed and share data on their use. So far the results have been promising, with a 5.3% reduction in overall prescriptions in 2015 and a 16% reduction in the use of broad-spectrum antibiotics, the drugs reserved for the treatment of the most serious infections.

Greater funding has also been made available for new antibiotics and other antimicrobial agents. Antibiotic research spending currently lags well behind other drug areas, such as cancer medicines, as the risk-reward ratio is much less favourable. This has created a fairly hollow drug pipeline that is not sufficient to replace the increasingly ineffective drugs currently on the market. Critics argue that a new business model is needed to create a more attractive commercial environment that encourages long-term pharma investment through the use of push- and pull-funding. Funding is provided as a government grant to help kick off research and development, the push, with further money promised after development, such as a lump-sum awarded to the pharma company upon bringing a successful antibiotic to market, the pull, with the aim of removing the economic barriers that currently discourage development.

As antibiotics become less and less effective, other treatments avenues are being explored. Bacteriophages are viruses that can infect bacteria, having been used in medicine for many decades, however, since the advent of antibiotic therapy, clinical research into bacteriophages largely dried up. They show a lot of promise as antibacterial agents, the most notable being the comparative ease to produce new bacteriophages that are able to overcome resistance, a process that currently takes several years for antibiotics, but could be reduced to just a few weeks for bacteriophages. There are challenges with this approach, such as potential immune responses, their extremely narrow host range that limits the broad treatment of infection, and their relative unfamiliarity to western science that impedes research.

It's now more important than ever that worldwide strategies are implemented to prevent a global health crisis costing millions of lives and trillions of dollars. There is optimism though, with a rapidly growing awareness of the issue, regulations are catching up to scientific understanding and the general public are more aware of the danger of antibiotic misuse. Hopefully this isn’t too little too late.

Resources & further reading

The Guardian ‒ England’s chief medical officer warns of ‘antibiotic apocalypse’

The Telegraph ‒ New thinking is required to create desperately needed new antibiotics. We must act now

DRIVE-AB Report ‒ Revitalizing the antibiotic pipeline

Antimicrobials in agriculture and the environment ‒ Reducing unnecessary use and waste

Kesselheim AS, Outterson K. Fighting Antibiotic Resistance: Marrying New Financial Incentives To Meeting Public Health Goals. Health affairs (Project Hope). 2010;29(9):689‒96

Llewelyn MJ, et al. The antibiotic course has had its day. BMJ. 2017;358:j3418

Loc-Carrillo C, Abedon ST. Pros and cons of phage therapy. Bacteriophage. 2011;1(2):111–114

Matsuzaki S, et al. Perspective: The age of the phage. Nature. 2014;509:S9.

Munita JM, Arias CA. Mechanisms of Antibiotic Resistance. Microbiol Spectr. 2016;4(2)

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