Scanning electron microscope image of Vibrio cholerae bacteria, which infect the digestive system. Zeiss DSM 962 SEM T.J. Kirn, M.J. Lafferty, C.M.P Sandoe and R.K. Taylor, 2000, “Delineation of pilin domains required for bacterial association into microcolonies and intestinal colonization”, Molecular Microbiology, Vol. 35(4):896-910 Copyright: Darthmouth College Electron Microscope Facility / These images are in the public domain
The natural ability of bacteria to adapt to various environmental stimuli can also make them resistant to drugs that would kill or slow their growth. In an article published in PLoS Genetics, microbiologist Dr Salvador Almagro-Moreno uncovers the evolutionary origins of antimicrobial resistance (AMR) in bacteria. His studies on the cholera-causing bacterium Vibrio cholerae show that mutations in a bacterial membrane protein, OmpU, are linked to developing antimicrobial resistance.
These findings provide insight into deciphering what conditions must occur for infectious agents to become resistant.
Dr Almagro-Moreno studied genetic variants of a protein found in bacterial membranes called OmpU. Using computational and molecular approaches, his team found that several OmpU mutations in the cholera bacteria led to resistance to numerous antimicrobial agents. This resistance included antimicrobial peptides that act as defences in the human gut. The researchers found that other OmpU variants did not provide these properties, making the protein an ideal system for deciphering the specific processes that occur to make some bacteria resistant to antimicrobials.
By comparing resistant and antibiotic sensitive variants, the researchers were able to identify specific parts of OmpU associated with the emergence of antibiotic resistance. They also discovered that the genetic material encoding these variants, along with associated traits, can be passed between bacterial cells, increasing therisk of spreading AMR in populations under antibiotic pressure.
By understanding how mutations occur, researchers can better understand and develop therapeutics to combat resistant infections. Dr Almagro-Moreno is also looking at environmental factors such as pollution and warming of the oceans, as possible causes of resistant bacteria. “We are studying the genetic diversity of environmental populations, including coastal Florida isolates, to develop a new approach to understanding how antimicrobial resistance evolves,” he explained.
Understanding the bacteria that causes cholera, an acute diarrhoeal illness linked to infected water and foods, has global implications. The disease sickens up to 4 million people worldwide and severe cases can cause death within hours.
A new test revealed that commonly available antibiotics can effectively treat antibiotic-resistant bacteria. They are not prescribed, however, because the gold-standard test predicts they will not work. The new test may improve the way antibiotics are developed, tested and prescribed – and it is openly available to all.
Published in Cell Reports Medicine, the research has significant implications in the fight against bacterial resistance by optimising the prescription and use of currently available antibiotics and enhancing the efforts to discover new ones.
Performed by UC Santa Barbara scientists, the research addressed a fundamental flaw in the healthcare paradigm for determining antibiotic resistance. It does not account for environmental conditions in the body that impact drug potency.
By simulating conditions in the body, the new test identified several effective antibiotics rejected by standard testing. Further, when the new and standard tests agreed — a nearly perfect prediction of treatment success or failure was observed.
The study required a tour de force screening of more than 500 antibiotic-bacteria combinations. The findings suggest that the standard test is incorrect ~15% of the time. And since physicians rely on this test for treatment decisions – it may lead to prescription of the wrong antibiotic.
‘People are not Petri plates’
The project was led by professor Michael Mahan and his UC Santa Barbara research team of Douglas Heithoff, Lucien Barnes and Scott Mahan, along with Santa Barbara Cottage Hospital physicians Lynn Fitzgibbons, M.D. and Jeffrey Fried, M.D., and professor John House of University of Sydney, Australia.
“People are not Petri plates – that is why antibiotics fail,” said Mahan. “Testing under conditions that mimic the body improves the accuracy by which lab tests predict drug potency.”
Physicians are aware of the flaws in the gold-standard test. When recommended antibiotics do not work, they must rely on their experience to decide on the appropriate antibiotic(s) for their patients.
This study provides a potential solution to address the disparity between antibiotics indicated by standard testing and actual patient outcomes.
“Reevaluation of FDA-approved antibiotics may be of far greater benefit than the time and cost of developing new drugs to combat antimicrobial resistance,” explained Santa Barbara Cottage Hospital physician Lynn Fitzgibbons, MD, an infectious disease physician, “potentially leading to significant life-savings and cost-savings.”
“Sepsis treatments are expensive and require long hospital stays,” explained Heithoff, “and testing and re-testing is not only time- and labour-intensive, but also leads to antibiotic resistance.”
The new test will lead to reduced costs for the healthcare industry in their efforts to identify new drugs to fight antimicrobial resistant infections.
“More accurate testing reduces the costs of drug discovery by streamlining detection of lead candidates long before expensive human clinical trials,” said professor John House of University of Sydney, a clinical veterinarian.
Jeffrey Fried, MD, a critical care physician, added: “Human clinical safety and efficacy studies will need to be conducted to assure these findings are applicable to patients with various infections and sepsis.”
Methicillin-resistant Staphylococcus aureus (MRSA). Image by CDC on Unsplash
Researchers reported in Cell Host & Microbe that early tests of a bioengineered drug candidate were successful in countering Staphylococcus aureus, a bacteria particularly dangerous to hospitalised patients.
Experiments demonstrated that SM1B74, an antibacterial biologic agent, was superior to a standard antibiotic drug at treating mice infected with S. aureus, including its treatment-resistant form known as MRSA.
The researchers tested mAbtyrins, a combination molecule based on an engineered version of a human monoclonal antibody (mAb), a protein that clings to and marks S. aureus for uptake and destruction by immune cells. Attached to the mAb are centyrins, small proteins that prevent these bacteria from boring holes into the human immune cells in which they hide. As the invaders multiply, these cells die and burst, eliminating their threat to the bacteria.
Together, the experimental treatment targets ten disease-causing mechanisms employed by S. aureus, but without killing it, say the study authors. This approach promises to address antibiotic resistance, say the researchers, where antibiotics kill vulnerable strains first, only to make more space for others that happen to be less vulnerable until the drugs no longer work.
“To our knowledge, this is the first report showing that mAbtyrins can drastically reduce the populations of this pathogen in cell studies, and in live mice infected with drug-resistant strains so common in hospitals,” said lead study author Victor Torres, PhD, the C.V. Starr Professor of Microbiology and director of the NYU Langone Health Antimicrobial-Resistant Pathogen Program.”Our goal was to design a biologic that works against S. aureus inside and outside of cells, while also taking away the weapons it uses to evade the immune system.”
Inside Out
The new study is the culmination of a five-year research partnership between scientists at NYU Grossman School of Medicine and Janssen to address the unique nature of S. aureus.
The NYU Langone team together with Janssen researchers, published in 2019 a study that found that centyrins interfere with the action of potent toxins used by S. aureus to bore into immune cells. They used a molecular biology technique to make changes in a single parental centyrin, instantly creating a trillion slightly different versions of it via automation. Out of this “library,” careful screening revealed a small set of centyrins that cling more tightly to the toxins blocking their function.
Building on this work, the team fused the centyrins to a mAb originally taken from a patient recovering from S. aureus infection. Already primed by its encounter with the bacteria, the mAb could label the bacterial cells such that they are pulled into bacteria-destroying pockets inside of roving immune cells called phagocytes. That is unless the same toxins that enable S. aureus to drill into immune cells from the outside let it drill out of the pockets to invade from the inside.
In a “marvel of bioengineering,” part of the team’s mAbtyrin serves as the passport recognised by immune cells, which then engulf the entire, attached mAbtyrin, along with its centyrins, and fold it into the pockets along with bacteria. Once inside, the centyrins block the bacterial toxins there. This, say the authors, sets their effort apart from antibody combinations that target the toxins only outside of cells.
The team made several additional changes to their mAbtyrin that defeat S. aureus by, for instance, activating chain reactions that amplify the immune response, as well by preventing certain bacterial enzymes from cutting up antibodies and others from gumming up their action.
The researchers tracked the growth of S. aureus strains commonly occurring in US communities in the presence of primary human immune cells (phagocytes). Bacterial populations grew almost normally in the presence of the parental antibody, slightly less well in the presence of the team’s engineered mAb, and half as fast when the mAbtyrin was used.
In another test, 98% of mice treated with a control mAb (no centyrins) developed bacteria-filled sores on their kidneys when infected with a deadly strain of S. aureus, while only 38% of mice did so when treated with the mAbtyrin. Further, when these tissues were removed and colonies of bacteria in them counted, the mice treated with the mAbtyrin had one hundred times (two logs) fewer bacterial cells than those treated with a control mAb.
Finally, the combination of small doses of the antibiotic vancomycin with the mAbtyrin in mice significantly improved the efficacy of the mAbtyrin, resulting in maximum reduction of bacterial loads in the kidneys and greater than 70% protection from kidney lesions.
“It is incredibly important,” said Torres, “that we find new ways to boost the action of vancomycin, a last line of defence against MRSA.”
Research in animal models published in Nature Communications shows that an approved antibiotic regimen for multidrug-resistant (MDR) tuberculosis (TB) may not work for TB meningitis. Limited human studies also provide evidence that a new combination of drugs is needed to develop effective treatments for TB meningitis due to MDR strains.
In the study from Johns Hopkins Children’s Center, the investigators showed that the Food and Drug Administration (FDA)-approved regimen of three antibiotics – bedaquiline, pretomanid and linezolid (BPaL) – used for treating TB of the lungs due to MDR strains, is not effective in treating TB meningitis because bedaquiline and linezolid struggle to cross the blood-brain barrier.
Tuberculosis, caused by the bacteria Mycobacterium tuberculosis, is a global public health threat. About 1%–2% of TB cases progress into TB meningitis, the worst form of TB, which leads to an infection in the brain that causes increased fluid and inflammation.
“Most treatments for TB meningitis are based on studies of treatments for pulmonary TB, so we don’t have good treatment options for TB meningitis,” explains Sanjay Jain, M.D., senior author of the study and director of the Johns Hopkins Medicine Center for Infection and Inflammation Imaging Research.
In 2019, the FDA approved the BPaL regimen to treat MDR strains of TB, specifically those that lead to pulmonary TB. However, there are limited data on how well these antibiotics cross the blood-brain barrier.
In an effort to learn more, the research team synthesised a chemically identical and imageable version of the antibiotic pretomanid. They conducted experiments in mouse and rabbit models of TB meningitis using positron emission tomography (PET) imaging to noninvasively measure pretomanid penetration into the central nervous system as well as using direct drug measurements in mouse brains. In both models, researchers say PET imaging demonstrated excellent penetration of pretomanid into the brain or the central nervous system. However, the pretomanid levels in the cerebrospinal fluid (CSF) that bathes the brain were many times lower than in the brains of mice.
“When we have measured drug concentrations in the spinal fluid, we have found that many times they have no relation to what’s happening in the brain,” says Elizabeth Tucker, MD, a study first author and an assistant professor of anaesthesiology and critical care medicine. “This finding will change how we interpret data from clinical trials and, ultimately, treat infections in the brain.”
Next, researchers measured the efficacy of the BPaL regimen compared with the standard TB treatment for drug-susceptible strains, a combination of the antibiotics rifampin, isoniazid and pyrazinamide. Results showed that the antibacterial effect in the brain using the BPaL regimen in the mouse model was about 50 times lower than the standard TB regimen after six weeks of treatment, likely due to restricted penetration of bedaquiline and linezolid into the brain. The bottom line, says Jain, is that the “regimen that we think works really well for MDR-TB in the lung does not work in the brain.”
In another experiment involving healthy participants, three male and three female aged 20–53 years, first-in-human PET imaging was used to show pretomanid distribution to major organs, according to researchers.
Similar to the work with mice, this study revealed high penetration of pretomanid into the brain or central nervous system with CSF levels lower than those seen in the brain. “Our findings suggest pretomanid-based regimens, in combination with other antibiotics active against MDR strains with high brain penetration, should be tested for treating MDR-TB meningitis,” says study author Xueyi Chen, MD, a paediatric infectious diseases fellow, who is now studying combinations of such therapies.
Limitations included the small quantities of the imageable version of pretomanid per subject (micrograms) used. However, current evidence suggests that studies with small quantities of a drug are a reliable predictor of the drug biodistribution.
A clinic trial published in The Lancet Microbe found that a promising approach to that ‘decolonised’ Staphylococcus aureus by using a probiotic instead of antibiotics. The probiotic Bacillus subtilis markedly reduced S. aureus colonisation in trial participants without harming the gut microbiota.
Staphylococcus aureus are colonising bacteria that often live in the nose, on the body and in the gut but if the skin barrier is broken or the immune system weakened, they can cause serious disease.
Preventing S. aureus infections by “decolonising” the body has gained increased attention as antibiotic resistance has spread, but large amounts of antibiotics are needed, damaging other microbiota and promoting more antibiotic resistance. So far, it appears that only nasal S. aureus colonisation can be targeted with topical antibiotics without doing too much harm, but bacteria quickly can recolonise in the nose from the gut.
Probiotics may be a way to complement or replace antibiotics, of which Bacillus is especially promising because it is administered orally as spores that can survive passage through the stomach and then temporarily grow in the intestine. In prior studies, Dr Otto’s group discovered an S. aureus sensing system needed for S. aureus to grow in the gut. They also found that fengycins, Bacillus lipopeptides that are part peptide and part lipid, stop the S. aureus sensing system from functioning, eliminating the bacteria.
In the clinical trial, conducted in Thailand, the research team tested whether this approach works in people. They enrolled 115 healthy participants, all of whom were colonised naturally with S. aureus. A group of 55 people received B. subtilis probiotic once daily for four weeks; a control group of 60 people received a placebo. After four weeks researchers evaluated the participants’ S. aureus levels in the gut and nose. They found no changes in the control group, but in the probiotic group they observed a 96.8% S. aureus reduction in the stool and a 65.4% reduction in the nose.
“The probiotic we use does not ‘kill’ S. aureus, but it specifically and strongly diminishes its capacity to colonise,” Dr. Otto said. “We think we can target the ‘bad’ S. aureus while leaving the composition of the microbiota intact.”
The researchers also found that levels of S. aureus bacteria in the gut far exceeded S. aureus in the nose, which for decades has been the focus of staph infection prevention research. This finding adds to the potential importance of S. aureus reduction in the gut.
“Intestinal S. aureus colonisation has been evident for decades, but mostly neglected by researchers because it was not a viable target for antibiotics,” Dr Otto said. “Our results suggest a way to safely and effectively reduce the total number of colonising S. aureus and also call for a categorical rethinking of what we learned in textbooks about S. aureus colonisation of the human body.”
The researchers plan to continue their work by testing the probiotic in a larger and longer trial. They note that their approach probably does not work as quickly as antibiotics, but can be used for long periods because the probiotic as used in the clinical trial does not cause harm.
Despite stringent infection-control efforts around the world, hospital-acquired infections (HAIs)keep on popping up from new strains of bacteria. In Science Translational Medicine, researchers report evidence pointing to an unexpected source of such bacteria: the hospitalised patients themselves.
From experiments with mice, researchers at Washington University School of Medicine in St. Louis discovered that urinary tract infections (UTIs) can arise after sterile tubes, called catheters, are inserted into the urinary tract, even when no bacteria are detectable in the bladder beforehand. Such tubes are commonly used in hospitals to empty the bladders of people undergoing surgery. In the mice, inserting the tubes activated dormant Acinetobacter baumannii bacteria hidden in bladder cells, triggering them to emerge, multiply and cause UTIs, the researchers said.
The findings suggest that screening patients for hidden reservoirs of dangerous bacteria could supplement infection-control efforts and help prevent deadly HAIs.
“You could sterilise the whole hospital, and you would still have new strains of A. baumannii popping up,” said co-senior author Mario Feldman, PhD, a professor of molecular microbiology. “Cleaning is just not enough, and nobody really knows why. This study shows that patients may be unwittingly carrying the bacteria into the hospital themselves, and that has implications for infection control. If someone has a planned surgery and is going to be catheterised, we could try to determine whether the patient is carrying the bacteria and cure that person of it before the surgery. Ideally, that would reduce the chances of developing one of these life-threatening infections.”
The notoriously multidrug-resistant A. baumannii is a major threat to patients, causing many cases of UTIs in people with urinary catheters, pneumonia in people on ventilators, and bloodstream infections in people with central-line catheters into their veins.
The researchers set out to investigate why so many A. baumannii UTIs develop after people receive catheters.
Most UTIs among otherwise healthy people are caused by the bacterium Escherichia coli. Research has shown that E. coli can hide out in bladder cells for months after a UTI seems to have been cured, and then re-emerge to cause another infection.
The researchers investigated whether A. baumannii can hide inside cells like E. coli can. They studied mice with UTIs caused by A. baumannii. They used mice with weakened immune systems because, like people, healthy mice can fight off A. baumannii.
Once the infections had resolved and no bacteria were detected in the mice’s urine for two months, the researchers inserted catheters into the mice’s urinary tracts with a sterile technique. Within 24 hours, about half of the mice developed UTIs caused by the same strain of A. baumannii as the initial infection.
“The bacteria must have been there all along, hiding inside bladder cells until the catheter was introduced,” said co-senior author Scott J. Hultgren, PhD, a professor and expert on UTIs. “Catheterisation induces inflammation, and inflammation causes the reservoir to activate, and the infection blooms.”
Since A. baumannii rarely causes symptoms in otherwise healthy people, many people who carry the bacteria may never know they’re infected, the researchers said. According to the researchers’ literature search, 2% of healthy people carry A. baumannii in their urine.
“I wouldn’t put much weight on the precise percentage, but I think we can say with certainty that some percentage of the population is walking around with A. baumannii,” Feldman said. “As long as they’re basically healthy, it doesn’t cause any problems, but once they’re hospitalised, it’s a different matter. This changes how we think about infection control. We can start considering how to check if patients already have Acinetobacter before they receive certain types of treatment; how we can get rid of it; and if other bacteria that cause deadly outbreaks in hospitals, such as Klebsiella, hide in the body in the same way. That’s what we’re working on figuring out now.”
In APL Bioengineering, researchers report on an injectable hydrogel that treats infections around hip and knee replacement prosthetics without the problems caused by current treatments. Testing showed that the gel inhibits common bacteria and promotes tissue regrowth.
After hip and knee replacement surgeries, pathogenic bacteria can adhere to the surface of the joint prosthesis and form a dangerous biofilm. Gold standard clinical methods use potent antibiotics and further surgery, including removal of infected tissue and transplantation of new tissue, to treat these infections. However, these strategies run into problems with hyper-resistant bacteria caused by the abuse of antibiotics, persistent damage caused by tissue removal, difficulties in obtaining tissue donors, and toxicity and immune system complications.
A team from Shanghai Jiao Tong University School of Medicine created ablack phosphorus-enhanced antibacterial injectable hydrogel to re-establish biological barriers in soft tissue and suppress persistent infections. The gel has a porous structure, excellent injectability, and rapid self-healing properties.
“It is important to explore a new strategy for treatment of infected soft tissue wounds because it is directly related to prognosis,” said author Ruixin Lin. “We aspire to develop a simpler, safer method to help more patients avoid suffering and help more doctors make the right choices.”
In vitro tests showed the hydrogel had good stability and low toxicity to tissue cells. Irradiating the gel with near infrared light causes it to release silver ions. This process was highly efficient at inhibiting the common bacteria S. aureus.
“Furthermore, an in vivo infected wound model showed that the hydrogel could not only inhibit the persistent infection of the wound, but also accelerate the deposition of collagen fibres and angiogenesis, thereby realizing the repair of the natural barrier of soft tissue,” said Lin.
The novel hydrogel provides a safe and feasible synergistic antibacterial strategy for infected soft tissue healing. The team believes that it solves current clinical problems, such as stubborn infections caused by antibiotic resistance, and provides new ideas for minimally invasive treatment. They hope to see it used in the clinic after conducting sufficient studies on its underlying mechanisms.
In Asia, researchers found that antibiotic residues in wastewater and wastewater treatment plants risk contributing to antibiotic resistance, and the drinking water may pose a threat to human health. Published in The Lancet Planetary Health, their comprehensive analysis also determined the relative contribution of various sources of antibiotic contamination in waterways, such as hospitals, municipals, livestock, and pharmaceutical manufacturing.
“Our results can help decision-makers to target risk reduction measures against environmental residues of priority antibiotics and in high-risk sites, to protect human health and the environment,” says first author Nada Hanna, researcher at the Department of Global Public Health at Karolinska Institutet. “Allocating these resources efficiently is especially vital for resource-poor countries that produce large amounts of antibiotics.”
Antibiotics can enter the environment during their production, consumption and disposal. Antibiotic residues in the environment, such as in wastewater and drinking water, can contribute to the emergence and spread of resistance.
Major antibiotics producers and users
The researchers looked for levels of antibiotic residues that are likely to contribute to antibiotic resistance from different aquatic sources in the Western Pacific Region (WPR) and the South-East Asia Region (SEAR), regions as defined by the World Health Organization. China and India, among the world’s largest producers and consumers of antibiotics, fall within these regions.
To find the data, researchers made a systematic review of the literature published between 2006 and 2019, including 218 relevant reports from the WPR and 22 from the SEAR. They also employed a method called Probabilistic Environmental Hazard Assessment to determine where the concentration of antibiotics is high enough to likely contribute to antibiotic resistance.
Ninety-two antibiotics were detected in the WPR, and forty five in the SEAR. Antibiotic concentrations exceeding the level considered safe for resistance development (Predicted No Effect Concentrations, PNECs) were observed in wastewater, influents and effluents of wastewater treatment plants and in receiving aquatic environments. Wastewater and influent of wastewater treatment plants had the highest risks. The relative impact of various contributors, such as hospital, municipal, livestock, and pharmaceutical manufacturing was also determined.
Potential threat to human health
In receiving aquatic environments, the highest likelihood of levels exceeding the threshold considered safe for resistance development was observed for the antibiotic ciprofloxacin in drinking water in China and the WPR.
“Antibiotic residues in wastewater and wastewater treatment plants may serve as hot spots for the development of antibiotic resistance in these regions and pose a potential threat to human health through exposure to different sources of water, including drinking water,” says Nada Hanna.
Limitations to be considered when interpreting the results are the lack of data on the environmental occurrence of antibiotics from many of the countries in the regions and the fact that only studies written in English were included.
Antibiotics play a vital role in the management of bacterial infections, reducing morbidity, and preventing mortality. A 2011 report from the United Kingdom estimated that they have increased life expectancy by 20 years. However, the extensive use of antibiotics has resulted in drug resistance that threatens to reverse their life-saving power and if the situation is not reversed, it has been estimated that by 2050, 10 million people will die annually of drug-resistant infections.
Such estimates of future deaths are obviously uncertain, but there is strong evidence the problem is already very serious. A major study published earlier this year in the Lancet estimated that globally around 1.27 million deaths in 2019 were directly due to antibiotic resistance. The study identified sub-Saharan Africa as the hardest-hit region.
What is AMR?
Sham Moodley, a community pharmacist from Durban and the vice chairperson of the Independent Community Pharmacy Association (ICPA) explains that antimicrobial resistance (AMR) is the ability of microorganisms (bacteria, viruses, fungi, and protozoa) to withstand treatment with antimicrobial drugs. “It is vitally important as it directly impacts our ability to treat and cure common infectious diseases, including pneumonia, urinary tract infections, gonorrhoea and tuberculosis,” he says.
According to Professor Olga Perovic, Principal Pathologist at the National Institute of Communicable Diseases’ Centre for Healthcare-associated Infections, Antimicrobial Resistance and Mycoses (CHARM), there are six factors fuelling the AMR crisis. These are over-prescribing and dispensing of antibiotics by health workers, patients not finishing their full treatment course of antibiotics, poor infection control in hospitals and clinics, lack of hygiene and poor sanitisation in the community, lack of new antibiotics being developed, and the overuse of antibiotics in livestock and fish farming.
Under overuse, she stresses the misuse of antibiotics to treat upper respiratory tract infections, which are typically viral rather than bacterial. Antibiotics are powerless against viruses. Another driver of inappropriate or overprescribing of antibiotics, she says, may be the lack of testing of specimens for the presence of bacteria and their susceptibility to treatment.
How can we prevent AMR?
Dr Marc Mendelson, Professor of Infectious Diseases and Head of the Division of Infectious Diseases and HIV Medicine at Groote Schuur Hospital, the University of Cape Town as well as chairperson of the Ministerial Advisory Committee on Antimicrobial Resistance, says reducing the use of antibiotics is about preventing the need for prescription in the first place. (Mendelson’s recent SAMJ article provides excellent further reading on AMR in South Africa.)
“So, reducing the burden of infections through the provision of clean water and safe sanitation (reduces diarrhoeal diseases) and vaccination programmes (reduces diarrhoea and pneumonia for instance),” he says. “Education and awareness raising of the public and (sadly) healthcare professionals as to the correct use of antibiotics is also critical.”
Broadly speaking, all the experts we interviewed agreed that we should use far fewer antibiotics and only use them when they are absolutely necessary. But actually making this happen is surprisingly complex.
Part of the complexity, for example, is that resistance profiles and disease profiles are different in different places. Geraldine Turner, a pharmacist at Knysna Hospital in the Western Cape, says there is a need for guidelines tailored to the South African context or linked to the local epidemiology. This, she says, can play an important role in determining the correct antibiotics to be used.
It is also not just an issue of what antibiotics are prescribed for humans.
“A big driver of antimicrobial resistance is overuse in agriculture and collaboration with stakeholders in this regard is required,” says Turner. She says we need policies that facilitate improved integration among environmental, animal, and human sector interventions.
Moodley agrees that a multidisciplinary, One Health approach is needed at every level of care and in both human and animal health sectors.
“It is important we reinforce the principle that antimicrobial medicines for human use are only supplied on the authority of a healthcare professional and that antimicrobial medicines for either human or animal use are only supplied in accordance with country legislation and regulations,” he says.
The role of stewardship programmes
One response to the AMR crisis is antimicrobial stewardship programmes or ASPs. Moodley describes ASPs as a systematic approach used “to optimise appropriate use of all antimicrobials to improve patient outcome and limit the emergence of resistant pathogens whilst ensuring patient safety.”
Perovic says, “In healthcare institutions, resistant bacteria can spread easily within and from patient to patient. That is why there are guidelines, which we call ASPs in the medical and veterinary fields, on how and when antibiotics are prescribed as well as how to implement infection prevention and control measures, particularly for patients with health risks such as diabetes, high blood pressure, and cancer.”
“In hospitals,” explains Mendelson, “ASPs will consist of a governance body such as an AS Committee that directs a work programme of stewardship, often with AS teams as the implementers of policy. AS teams can involve anything from single pharmacists or physicians, through one to two dedicated individuals, through to all-singing all-dancing multi-disciplinary teams in academic teaching hospitals, comprising infectious diseases specialists, microbiologists, pharmacists, [and] infection prevention and control nurses.”
ASPs are not only important at institutional levels, adds Moodley, but imperative for every individual prescriber/practitioner to implement to reduce AMR in our population.
Critical role for pharmacists
Mendelson stresses that pharmacists are integral to antibiotic stewardship in South Africa and globally. “Community pharmacists give advice to patients seeking symptomatic relief and reduce doctors’ visits, which can result in antibiotic prescriptions when not needed,” he says. In hospitals, dispensing pharmacists help optimise the antibiotics prescribed to patients by checking indication for the antibiotic, dose, dosing frequency, and duration. “Some hospitals have pharmacists on the wards, again, checking and helping to optimise the use of antibiotics,” he says.
“Pharmacists play an important role in recommending symptomatic treatments for non-specific symptoms and particularly, the common cold, which is a major cause of inappropriate antibiotic prescribing, requiring simple paracetamol with or without decongestants. Unfortunately, a recent pilot study suggests that a small number of community pharmacies are dispensing antibiotics without a prescription, which is not allowed in South Africa,” says Mendelson.
Turner concurs that pharmacists play a crucial role in ensuring that the correct antibiotics are used appropriately and only if indicated. She says pharmacistsare also in a good position to counsel and advise patients on the correct use of antibiotics.
Strategy framework
The key policy document setting out South Africa’s response to AMR is the South Africa Antimicrobial Resistance Strategy Framework of 2018-2024. The framework outlines nine strategic objectives – they include improving the appropriate use of diagnostic investigations to identify pathogens, guiding patient and animal management and ensuring good quality laboratory, enhancing infection prevention and control, promoting appropriate use of antimicrobials in humans and animals as well as legislative and policy reform for health systems strengthening.
Mendelson is positive about what has been achieved so far. “There have been major improvements to the surveillance and reporting of antibiotic resistance and antibiotic use in humans and animals, development of a greater one health (human, animal, and environmental health) response. There was a formation of national training centres for antibiotic stewardship and empowerment of under-resourced provinces to train and develop Antimicrobial Stewardship programmes and there have been improvements in governance and delivery of infection prevention and control measures in hospitals and development of education programmes for healthcare workers in South Africa,” he says.
But Mendelson also says that challenges remain in promoting prescribing behaviour change amongst the health workforce in SA and the expectations and social position that antibiotics hold in society.
As with several other health policies, there are questions on whether the plan has been backed up with funding.
“The national strategic framework remains largely unfunded (shared by most low- and middle-income countries) but this does hamper progress in developing programmes of interventions,” says Mendelson. “In food production, reducing [the] use of antibiotics is an important goal but will require investment in reducing drivers of infection in the animals that produce food. Legislation to bring all antibiotic prescribing in food production under veterinarian control will be an important intervention,” says Mendelson.
A major clinical trial found that the risk of gastrointestinal bleeding caused by long-term aspirin use can be reduced with a short course of antibiotics, potentially improving the safety of aspirin when used to prevent heart attacks, strokes and possibly some cancers.
The results of the HEAT (Helicobacter pylori Eradication Aspirin) trial, which was led by Professor Chris Hawkey from the University of Nottingham, are published in The Lancet.
Aspirin in low doses is a very useful preventative drug in people at high risk of strokes or heart attacks. However, on rare occasions, its blood thinning effect can provoke internal ulcer bleeding. These ulcers may be caused by Helicobacter pylori.
The STAR (Simple Trials for Academic Research) team from the University of Nottingham investigated whether a short course of antibiotics to remove these bacteria would reduce the risk of bleeding in aspirin users.
The HEAT trial, conducted in 1208 UK general practices, was a real-life study which used clinical data routinely stored in GP and hospital records, instead of bringing patients back for follow up trial visits.
The researchers recruited 30 166 who were taking aspirin. Those who tested positive for H. pylori were randomised to receive antibiotics or placebos (dummy tablets) and were followed for up to 7 years.
Over the first two and a half years, those who had antibiotic treatment were less likely to be hospitalised for ulcer bleeding than those taking placebo (6 versus 17). Protection occurred rapidly: with the placebo group, the first hospitalisation for ulcer bleeding occurred after 6 days, compared to 525 days following antibiotic treatment.
Over a longer time period, protection appeared to wane. However, the overall rate of hospitalisation for ulcer bleeding was lower than expected and this in line with other evidence that ulcer disease is on the decline. Risks for people already on aspirin are low. Risks are higher when people first start aspirin, when searching for H. pylori and treating it is probably worthwhile.
Aspirin has many benefits in terms of reducing the risk of heart attacks and strokes in people at increased risk. There is also evidence that it is able to slow down certain cancers. The HEAT trial is the largest UK-based study of its kind, and we are pleased that the findings have shown that ulcer bleeding can be significantly reduced following a one-week course of antibiotics. The long-term implications of the results are encouraging in terms of safe prescribing.
Professor Chris Hawkey, University of Nottingham’s School of Medicine and Nottingham Digestive Diseases Centre
