Clinical briefing: Antimicrobial resistance

In May 1845, Sir John Franklin set off on an expedition to find the North–West Passage. Before the expedition went missing, Franklin buried some crewmen on Beechey Island in the Canadian Arctic.

When researchers exhumated two crew members in the mid-1980s, they discovered live Clostridium bacteria in the frozen bodies, which were resistant to some antibiotics.¹

Antimicrobial resistance (AMR) a century before the first antibiotic reached the clinic isn’t as surprising as it may seem. Soil bacteria probably evolved antibiotics 2 billion to 40 million years ago.2 Indeed, a group of soil bacteria called Actinomycetes produce about 70 per cent of antibiotics used clinically, including beta-lactams, tetracyclines, macrolides and aminoglycosides.^3,4 

In response, other bacteria evolved counter-measures. Bacteria in permafrost deposited tens of thousands of years ago show several AMR mechanisms against modern antibiotics.² In other words, AMR lurked in the environment long before the introduction of sulphonamides, the first effective antimicrobials, in 1937.⁵ 

Clinical challenges

Antimicrobial resistance continues to pose big clinical challenges. According to the UK Health Security Agency, the overall AMR burden in England (based on blood stream infections [BSI] caused by certain pathogens), fell by just 4.2 per cent between 2017 and 2021. 

A decline in BSIs caused by Escherichia coli accounted for most of the fall. Resistant BSIs were most common in London (55.5 per 100,000 population), with the lowest prevalence in the East Midlands (32.1 per 100,000).⁶

Rates also differ by ethnic minority. Among Asian and Asian British people, 32.8 per cent of BSIs were resistant to at least one antibiotic. Among Black, African, Caribbean or Black British people, 31.8 per cent of BSIs were resistant. These rates are markedly higher than among white people: 20.9 per cent.⁶

Meanwhile, total antibiotic consumption decreased by only 4.3 per cent between 2017 and 2019. During the Covid-19 pandemic (2019-20) consumption declined by 10.9 per cent. In 2020-21, consumption fell by a further 0.5 per cent (to 15.9 defined daily doses per 1,000 inhabitants). General practice accounts for 72.1 per cent of antibiotic prescribing.⁶ 

Stemming the tide

Improved antimicrobial stewardship remains vital to stem the tide of resistance but we still need new antibiotics – and here, at least, there’s some good news. As of December 2022, clinical studies were assessing 62 potential antibiotics.  

Ten were new combinations of beta-lactams and beta-lactamase inhibitors. Thirty-four had structures not used previously as human antibiotics, a marked increase on previous years: 11 in 2011 and 19 in 2019, for example.⁷ 

New structures are important. “The resulting medication will be less likely to have existing resistance in the bacteria and potentially it will take longer for resistance to develop,” says study author Professor Mark Blaskovich from the Centre for Superbug Solutions at the University of Queensland, Australia.

Five potential antibiotics are ‘non-traditional’ targeting virulence, resistance and patient inflammation rather than bacterial survival. Combination treatments further expand the options, while new targets continue to emerge, including for some of the deadliest infections facing humanity. 

Vibrio bacteria

Despite antibiotics, safer water, better sanitation and vaccination, cholera, for instance, remains deadly. Vibrio cholerae causes 1.3-4.0 million cases a year. Between 21,000 and 143,000 people die from cholera annually.   

A recent paper investigated a related bacterium called Vibrio alginolyticus. Vibrio bacteria swim by rotating their tail-like flagella powered by a protein motor, called PomAB.⁸   

“The Vibrio bacteria use the energy of the sodium ion gradient across their inner cell membrane to move around,” says study author Nicholas Taylor, associate professor at the Novo Nordisk Foundation Centre for Protein Research, University of Copenhagen. “It is an accessible target, because it is somewhere where in principle drugs can go quite easily.” 

Researchers are also exploring non-antibiotic approaches. “There is renewed interest in vaccines, particularly with mRNA technologies, which have been incredibly effective – and unlike antibiotics, can be lucrative products for pharmaceutical companies,” Professor Blaskovich says. However, 62 antibiotics in development is still very low compared to almost 2,000 molecules in the cancer drug pipeline, he says. “We are still not where we need to be given the urgency of the situation.”

References

1. Beattie O and Geiger J Frozen in Time. Bloomsbury

2. Microorganisms 2021; 9: DOI: 10.3390/microorganisms9010116

3. Frontiers in Microbiology 2017; 7: DOI: 10.3389/fmicb.2016.02149

4. Antibiotics (Basel) 2019;8:

5. Microbiology and Molecular Biology Reviews 2010; 74:417-33

6. ESPAUR Report 2021-22

7. Journal of Antibiotics 2023; 76:431-473

8. Nature Communications 2023; 14:4411