In yet another grim report about rising levels of resistance to bacteria, experts warn that by 2050 an estimated 10m people will die annually of drug-resistant infections, with sub-Saharan Africa expected to be the worst-hit region, writes Medical Brief.
A World Health Organisation report warns that patients with infections could run out of treatment options if injudicious antibiotic use does not end soon, with inappropriate prescribing being blamed for the situation in SA too.
South Africa's struggle with increasing resistance, was not just related to bacteria, but fungi and viruses as well, a local expert said, adding that major areas of concern were in the bacteria causing hospital infections, where there was increasing resistance to the antibiotics available and an increasing need to use last-resort antibiotics.
Gram negative bacteria that caused pneumonia, meningitis and septicaemia (blood infections) were among those that were a problem.
A WHO report, based on data from 87 countries, notes the escalating levels of resistance in bacteria are causing life-threatening bloodstream infections and increasing resistance to treatment in several bacteria that cause more common infections.
At the same time, leading global public health experts are also calling for urgent action to develop antibiotics for newborn babies, a population that is particularly vulnerable to antibiotic resistance, with about 2.3m newborns dying from severe bacterial infections annually.
The vital need to prioritise the development of antibiotics specifically for these babies through a global antibiotic development and access network has been outlined in a paper co-authored by international experts in the field of antimicrobial resistance (AMR). They include healthcare specialists from the Global Antibiotic Research & Development Partnership (GARDP), Penta – Child Health Research and St George’s University of London (SGUL), as well as neonatologists in South Africa and India. It was published in the December 2022 Bulletin of the World Health Organisation.
“AMR undermines modern medicine and puts millions of lives at risk,” said WHO director-general Tedros Adhanom Ghebreyesus. “To understand the extent of the global threat and mount an effective public health response to AMR, we must scale up microbiology testing and provide quality-assured data across all countries, not just wealthier ones.”
The WHO said that its Global Antimicrobial Resistance and Use Surveillance System (Glass) report provided analyses for AMR rates in the context of national testing coverage, AMR trends since 2017, and data on antimicrobial consumption in humans in 27 countries, reports The Independent on Saturday.
The Glass report shows that high levels (above 50%) of resistance were reported in bacteria, frequently causing bloodstream infections in hospitals, like Klebsiella pneumoniae and Acinetobacter spp.
While these life-threatening infections required treatment with last-resort antibiotics, like carbapenems, 8% of bloodstream infections caused by Klebsiella pneumoniae were resistant to the drugs, increasing the risk of death.
The WHO report said common bacterial infections were becoming increasingly resistant to treatments, for instance with more than 60% of Neisseria gonorrhoea isolates, a common sexually transmitted disease, showing resistance to one of the most used oral antibacterials, ciprofloxacin.
At least 20% of E.coli isolates – the most common pathogen in urinary tract infections – were resistant to first-line drugs (ampicillin and co-trimoxazole) and second-line treatments (fluoroquinolones).
Senior lecturer of pharmacology at the University of KwaZulu-Natal Andy Gray said increasing resistance to antibiotics was an issue “across all of our private and public sector hospitals, and the direct result of inappropriate use of antibiotics, inappropriate prescribing but also inappropriate prevention of infections, infection control measures and in some cases vaccination”.
He said the second area of concern for South Africa was tuberculosis because of the high burden and as one of the countries heavily affected by drug-resistant TB.
While South Africa had reported on the Glass antimicrobial data, there was a big hole in the antimicrobial stewardship programme.
“We should be using antibiotics when we have to – they’re absolutely crucial to dealing with established infection – but we’ve got to use the right antibiotic for the right reason at the right dose for the right duration of time. Inappropriate prescribing is what drives increasing resistance,” said Gray.
He said some patients were able to access antibiotics without a prescription and there was definitely overuse of the medication, for instance where there was a viral infection and an antibiotic was prescribed even when it was “going to do absolutely nothing”.
Health Department spokesperson Foster Mohale said South Africa had submitted data to the WHO Glass system since its induction.
This year, he added, SA was applying to submit national antimicrobial procurement to the Glass system as well, although these data was not yet available on the WHO website.
However, Mohale said in the Surveillance for AMR and Consumption of Antimicrobials in South Africa, 2021, there were data on the resistance patterns in human and animal health-care sectors as well as the procurement of antimicrobials in both sectors.
“Unless humans can ensure the prudent use of antimicrobials in humans and animals, and protect the environment from antibiotic by-product, antimicrobial resistance will, and should, increasingly be of the utmost concern to all,” he added.
Gray said there was a “real problem” in private hospitals where the doctors were not employed by the hospital. Instead they were solo practitioners and had the right to admit patients to the hospital. Because of this, private hospitals struggled to intervene to improve the quality of the use of antibiotics.
“In our public sectors we have large numbers of prescribers, including primary health-care nurses … who suspect something, they do not do a culture and on the basis of the patient presentation, decide to use an antibiotic … we see over-usage of those.
“Many of them are becoming increasingly useless as resistance increases across the country.”
Sham Moodley, a community pharmacist from Durban and the vice chairperson of the Independent Community Pharmacy Association (ICPA) said AMR is the ability of microorganisms (bacteria, viruses, fungi, and protozoa) to withstand treatment with antimicrobial drugs, and “is vitally important as it directly affects our ability to treat and cure common infectious diseases, including pneumonia, urinary tract infections, gonorrhoea and tuberculosis”, he says.
Professor Olga Perovic, principal pathologist at the National Institute of Communicable Diseases’ Centre for Healthcare-associated Infections, Antimicrobial Resistance and Mycoses (CHARM), said six factors were fuelling the AMR crisis. These are over-prescribing and dispensing of antibiotics by health workers, patients not finishing their full treatment course, 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 highlighted 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 said, might be the lack of testing of specimens for the presence of bacteria and their susceptibility to treatment.
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, said reducing antibiotic use is about preventing the need for prescription in the first place.
“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 said. “Education and awareness raising of the public and (sadly) healthcare professionals as to the correct use of antibiotics is also critical.”
Geraldine Turner, a pharmacist at Knysna Hospital in the Western Cape, said there is a need for guidelines tailored to the South African context or linked to the local epidemiology. This 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, writes Tiyese Jeranji in Spotlight.
“A big driver of antimicrobial resistance is overuse in agriculture and collaboration with stakeholders in this regard is required,” said Turner, adding that “we need policies that facilitate improved integration among environmental, animal, and human sector interventions”.
Moodley agreed that a multidisciplinary, One Health approach was 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.”
The role of stewardship programmes
One response to the AMR crisis is antimicrobial stewardship programmes or ASPs. Moodley described ASPs as a systematic approach used “to optimise appropriate use of all antimicrobials to improve patient outcome and limit the emergence of resistant pathogens while ensuring patient safety”.
Perovic said: “In healthcare institutions, resistant bacteria can spread easily within and from patient to patient. That is why there are guidelines, or 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,” said 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 said 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.” 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 said.
“Pharmacists play an important role in recommending symptomatic treatments for non-specific symptoms and particularly, the common cold, a major cause of inappropriate antibiotic prescribing, requiring simple paracetamol with or without decongestants.”
Turner concurred that pharmacists play a crucial role in ensuring the correct antibiotics are used appropriately and only if indicated, and that they are also in a good position to 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. This 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 challenges remain in promoting prescribing behaviour change among the health workforce in SA and the expectations and social position that antibiotics hold in society, he added.
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,” said Mendelson.
Meanwhile, on the issue of newborns and AMR, an increasing number of babies under the age of 28 days are becoming resistant to currently used antibiotics. Over the past decade, AMR has worsened to the point that around 50%-70% of common pathogens exhibit a high degree of resistance to available first- and second-line antibiotics.
Despite substantial progress in medical research and a steep decline in the number of children under five who die of preventable diseases, many problems related to child health remain to be tackled. Severe bacterial infections are one of them.
“There is an urgent need to identify high priority antibiotics to understand which ones work best and safely in children, and then make them available where they are needed,” said Mike Sharland from St George’s, University of London, and member of the Antimicrobial Resistance Programme at Penta – Child Health Research.
Working collaboratively could speed up both development and access to urgently needed antibiotics for newborns.
“By achieving global consensus, we can streamline the process of antibiotic development, allow for faster access to antibiotics, and reduce the burden of AMR on the vulnerable neonatal population,” said Manica Balasegaram, executive director of GARDP.
The article published in the WHO Bulletin conveys how a collaborative global antibiotic development and access network specifically targeting newborns could also prove valuable compared to single independent studies.
“By bringing together academic clinical trial networks, international research networks, regulators, donors, government and industry sponsors, these public-private partnerships can leverage their multi-disciplinary expertise and funding to speed up access to antibiotics and facilitate the update and routine implementation of global treatment guidelines,” said Carlo Giaquinto, president of the Penta Foundation.
A successful example has been the collaboration between GARDP, Penta – Child Health Research, SGUL, and other key partners on their recent global observational study of 3 200 babies with neonatal sepsis across 19 hospitals in 11 countries.
They are also partnering on an upcoming clinical trial, which will start in South Africa within the next few months before being expanded to other countries. It is evaluating potentially more effective neonatal treatment regimens to overcome resistance to current treatments, especially in low- and middle-income countries, where multidrug-resistant organisms are more prevalent.
The paper highlights an opportunity for more flexible and efficient approaches to the development of paediatric antibiotics within a changing research and development landscape. However, there are still numerous challenges facing the development of new antibiotics for newborns.
Despite a rising number of these deaths caused by AMR, very few effective antibiotics have been adequately studied to treat serious bacterial infections, such as neonatal sepsis. Furthermore, of 40 antibiotics approved for use in adults since 2000, only four have included dosing information for newborns in their labels.
Ethical concerns, logistical issues and regulatory requirements have made it difficult to conduct clinical research in newborns. There is a long delay in completing paediatric regulatory studies and they are also not harmonised globally to demonstrate clinical utility in newborns.
The paper outlines how a stakeholder group could work together to define which antibacterials to prioritise for accelerated development as well as to standardise regulatory criteria and close the gap in study designs to address both regulatory evidence and clinical utility.
“We need to move fast to develop guidelines and protocols on the use of antibiotics, as well as develop new antibiotics,” said Sithembiso Velaphi, head of Paediatrics at the Chris Hani Baragwanath Academic Hospital in Soweto.
“We have the opportunity to prevent more unnecessary deaths of babies from these severe and preventable infections by intervening, quickly, equitably, and safely. It is also critical that all efforts must be made to prevent these infections through ensuring that all healthcare facilities and providers adhere to infection prevention and control protocols.”
Antibiotics play a vital role in the management of bacterial infections, reducing morbidity, and preventing mortality, and according to a 2011 report from the UK, have increased life expectancy by 20 years.
However, their extensive use, resulting in AMR, threatens to reverse their life-saving power. If the situation is not reversed, it has been estimated that by 2050, 10m people will die annually of drug-resistant infections,
Estimates earlier this year were that globally, around 1.27m deaths in 2019 were directly due to antibiotic resistance. Sub-Saharan Africa is the hardest-hit region, and if there is not a turnaround soon, millions more deaths can be expected.
global AMR report
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Independent on Saturday PressReader article – Patients could run out of options (Open access)
WHO article – Antibiotics needed to treat multidrug-resistant infections in neonates (Open access)
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East African medical graduates ‘lack antibiotics knowledge’ — Research report
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Urgent need for more funds to fight AMR drug resistance
Rising antibiotic-resistant infections prompt global study with SA hospitals