Antimicrobial resistance is a major challenge facing healthcare globally, with both the WHO (2019) and the National Institute for Health and Care Excellence (NICE) (2023) having issued a quality standard. The WHO has declared antimicrobial resistance as a global public health threat and it is listed on the UK Government's Risk Register. The most commonly resisted antibiotics are: methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), multi-drug-resistant Mycobacterium tuberculosis (MDR-TB), and carbapenem-resistant Enterobacteriaceae (CRE) gut bacteria (Mancuso et al, 2021).
Prior to the era of antibiotics, the only treatments were arsenicals and sulphonamides, strict hygiene with disinfectants, which included metal ions, a wholesome diet and good nursing care. Indeed, many soldiers in World War I died of battle wound infections rather than a catastrophic injury, although there were plenty of those. In the 1930s, chemists searched for biocidal compounds to combat infections and developed sulphonamides. Landecker (2019) has argued that the development of resistant bacteria has its origins in the early 20th century when arsenicals and sulphonamides were treatments, and ammonium compounds formed the base of disinfectants and were produced and used on a large scale. Their widespread use helped drive resistance because they caused environmental selection and triggered genetic change in the existing bacteria, thereby conferring a resistance phenotype. Landecker (2019) tested her hypothesis using two case studies from the US, namely, World War II troop mobilisation and the change to intensive poultry farming between 1940–1950, during which there was widespread use of disinfectants and sub-therapeutic levels of sulphonamides for prophylaxis. The existence of sulphonamides and disinfectants in the environment provided the background for the bacterial landscape prior to the introduction of the first antibiotics, including penicillin during World War II. Therefore, penicillin did not supplant previous chemical therapies but rather, it joined the increasingly complex chemical environment in which microbes existed. Landecker's (2019) thesis challenges the assumption that microbial resistance is solely a clinical phenomenon by highlighting the early role of other chemical agents and their use in agriculture and the food chain, military health and general hygiene practices.
‘…the Antimicrobial Resistance Collaborators (2022) estimated that 4.95 million deaths were associated with bacterial antimicrobial resistance in 2019, with 1.27 million deaths attributable to bacterial antimicrobial resistance.’
Using statistical modelling, the Antimicrobial Resistance Collaborators (2022) estimated that 4.95 million deaths were associated with bacterial antimicrobial resistance in 2019, with 1.27 million deaths attributable to bacterial antimicrobial resistance. There were regional differences, with the highest death rate in western sub-Saharan Africa (27.3 deaths per 100 000) and the lowest in Australia (6.5 deaths per 100 000). The global data suggested that low resource settings bear the highest burden and have the highest vulnerability to antibiotic resistance. While the data indicated that antimicrobial resistance poses the largest threat to human health in sub-Saharan Africa and south Asia, the data were clear that it is an important threat throughout the world. Lower respiratory infections accounted for the most deaths globally (more than 1.5 million deaths) associated with resistance in 2019. MRSA caused more than 100 000 deaths attributable to antimicrobial resistance, while six more pathogens each caused 50 000–100 000 deaths.
There is some evidence that the COVID-19 pandemic increased antimicrobial use, including MRSA antibiotics, especially in hospitals admitting patients with COVID-19 (Winders et al, 2021). Afshinnekoo et al (2021) also noted how hospitals stretched beyond normal capacity, with many immunocompromised patients with high risk of co-infections during the pandemic, increased antimicrobial prescribing to prevent secondary infections and these prescribing practices may have further increased antimicrobial resistance. In Taiwan, Lai et al (2021) observed an increase in antimicrobial resistance during the pandemic due, in part, to increased antibiotic prescribing in COVID-19 patients with low rates of co- and secondary infections. A further complication may be the extensive use of disinfectants/sanitizers as they contain genotoxic chemicals (like phenol and hydrogen peroxide) that damage microbial DNA and activate error-prone DNA repair enzymes (Lobie et al, 2021). This process may lead to mutations that induce antimicrobial resistance; time will tell the extent to which pandemic precautions may contribute to antimicrobial resistance development over time.
There is increasing evidence that antibiotic residues are interacting with pathogens in various environments and are promoting the development and spread of antimicrobial resistance in the global aquatic environment. Booth et al (2020) found that 7.9% of all antibiotic residues in environmental matrices globally exceeded Predicted No Effect Environmental Concentration (PNEC) levels, with hospital wastewater and industrial wastewater having the highest burden of antibiotic residues exceeding PNEC levels. Ciprofloxacin and clarithromycin had the greatest proportion (>30%) of residues exceeding PNEC; however, no antibiotics exceeded PNEC levels in the drinking water. Yet, currently, there is a lack of on-site treatment systems in hospitals that aim to destroy or remove antibiotics prior to discharging wastewater to surface waters.
‘The global data suggested that low resource settings bear the highest burden and have the highest vulnerability to antibiotic resistance.’
Antibiotic pollution in the environment and its contribution to antimicrobial resistance is set out by Larsson and Flach (2022), who have noted how the low production costs of China and India have enabled them to become the largest producers of antibiotics. but this has been accompanied by insufficient waste management and excessive emissions of antibiotic residues from manufacturing. The selection pressure as part of evolution has promoted the transfer of antibiotic resistance genes (ARGs) to many bacterial species, including those which cause disease, between humans, domestic animals and microbiota in the wider environment. Not surprisingly, there is growing concern that the environment acts as an antimicrobial resistance reservoir and a key source of ARGs through antimicrobial use in healthcare and agricultural livestock management. Thus, antibiotic residues enter the environment via the soil, air and water via various routes including hospital waste water, agricultural waste and run-offs, and sewage/waste water treatment plants.
In 2019, the UK Government published the antimicrobial resistance National Action Plan (2019-2024) with three foci, namely: reducing need for, and unintentional exposure to, antimicrobials; optimising use of antimicrobials; and investing in innovation, supply and access (UK Government, 2019). The Action Plan set several targets, which included: reducing healthcare associated gram-negative blood stream infections by 50%; reducing specific drug-resistant infections by 10% by 2025; reducing antimicrobial use in humans by 15% by 2024; and reducing UK antibiotic use in food-producing animals by 25% between 2016 and 2020. If the global data are an indicator, it is likely that some, if not all, of the targets will be missed and increased antimicrobial resistance will be another collateral effect of the COVID-19 pandemic in the UK. In the meantime, all healthcare professionals need to reflect on their clinical practices and consider how they are contributing to efforts to reduce antimicrobial resistance in the UK.
Since 2020, when the SARS-CoV-2 virus caused a global pandemic and untold disruption to everyone's lives, viruses (including ebola, human immunodeficiency virus, influenza, among others) have been considered dangerous, should be killed and vaccinated against. However, bacteriophages (or phages) are viruses that infect and kill bacteria, that is, they are biological predators and are harmless to humans. They are present everywhere including in rivers, the soil, and form part of human commensal microbiota. There is now an increased interest in the potential of phages with the House of Commons Science and Technology Committee (UK Parliament, 2023), which is currently undertaking an inquiry, having completed both the written and oral evidence phases. Jones et al (2023) have described how 12 UK patients (10 of whom had diabetic foot) during the last 2 years with difficult to treat infections, have received unlicensed phage therapy. They have set out how phage therapy might form part of the treatment for infections in the future, drawing upon NHS microbiology services, clinical phage libraries and a National Phage Library based in the newly established Centre for Phage Research at the University of Leicester, as part of the infrastructure for this initiative.
Therefore, while many antibiotics are increasingly less useful in treating infections, it is incumbent upon all healthcare professionals to practice antibiotic stewardship. There is hope that gene editing or plant toxins may enable the development of new antibiotics and that phages may offer an alternative to antibiotics in the future.