With pharma companies pulling out of antibacterial research, are resistance horror stories about to become reality?
“I have this horror story, this idea in the back of my mind that in 20 years I get cancer and I go to my doctor and he says, ‘Well Sally, I can cure your cancer, but you’ve sure as hell got some nasty infection, and I don’t know whether I can cure that.’”
“We all thought molecular biology was very sexy, and genetics would sort it out. Wrong,” Professor Dame Sally Davies, the UK government’s Chief Medical Advisor, said.
Speaking to a group of health professionals at a roundtable at Bond University in Queensland, Professor Davis warned the global community was not making the inroads needed on antibiotic resistance in primary care.
The discovery of penicillin, the first antibiotic, in 1928 was a revolution. Suddenly a course of pills might be all that was needed to treat previously life threatening infections such as meningitis, pneumonia, gonorrhoea and syphilis.
But thanks to the overuse and misuse of antibiotics, microbes have been evolving and gradually improving their ability to survive treatment. And as of 2015, the last antibiotic in our arsenal has fallen. Resistance to the antibiotic, colistin, the last line of defence for significant E. coli and Klebsiella infections, has now spread across the world.
In total, around 700,000 people a year die as a result of antimicrobial resistance, according to a UK review. The authors estimate that by 2050, this death toll would rise to 10 million.
In response to the growing danger, the World Health Organisation labelled antibiotic resistance, “one of the greatest threats to human health”.
World-wide almost half a million people develop drug-resistant TB each year, and in India, 60,000 newborns die of drug-resistant infections every year.
To put it into context, Professor Davis likened Europe’s annual 25,000 deaths from antibiotic resistance to a Boeing 747 plane crashing each week. A conservative estimate for the US is similar.
Not a single new class of antibiotics has been brought to the market since the 1980s … this situation is unlikely to change any time soon.
Discovery void
Not a single new class of antibiotics has been brought to the market since the 1980s, and with pharmaceutical companies pulling out of the development field, this situation is unlikely to change any time soon. Simply put, there’s not enough money in antibiotics. They are expensive to develop as all the cheap, readily accessible sources of these drugs – the low-hanging fruit as it were – have already been taken.
Instead, the search for new antimicrobials has people hunting through the soils of the Amazon jungle and other exotic locations in the hopes of finding a new and effective weapon against our bacteria here at home.
And then there’s the matter of recouping the cost of the drug once it’s been discovered and developed. Antibiotics are used only on an occasional basis. Financially speaking, this is far less appealing to a pharma company than a drug for diabetes that patients take regularly for the rest of their lives.
This was an example of market failure, Professor Davies said.
General practice
If the search for new antibiotics appeared to heading for a dead end, we must make serious efforts to preserve the ones we had, GP Paul Glasziou, professor of evidence-based medicine at Bond University, said.
Australia has one of the highest rates of antibiotic use in the world, and most of that occurs in general practice.
To put it into perspective, patients in Australia were prescribed 87 units per capita, per year, which was more than in New Zealand at 70, and way more than the 7.5 units per capita in India, Professor Davies said.
And looking at countries’ efforts in addressing antibiotic overuse, Scandinavian countries in particular appear to have had success in reining in antibiotic prescribing, with Sweden standing out as a high achiever.
According to Professor Glasziou, the Swedish experience has significant implications for general practitioners.
Data from Sweden following the reduction in antibiotic prescribing showed no apparent increase in the rates of complications from underuse of antibiotics, such as mastoiditis or quinsy, and, in fact, some decrease.
To get an understanding of where antibiotics were being most unnecessarily prescribed, Professor Chris Del Mar, a GP and expert in evidence-based medicine, analysed BEACH data of new cases managed by antibiotics in general practice.
He and his colleagues found that acute respiratory infections had the biggest disparity between guideline-recommended prescribing and real-world prescribing, with current levels five times what would be expected under the guidelines.
The researchers estimated that just adhering to guidelines would reduce antibiotic prescribing to 10% to 15% of what it currently was.
Professor Del Mar also agreed that restricting antibiotic prescribing appeared to be safe.
An audit of UK general practices found that low antibiotic-prescribing practices had no increased rates of mastoiditis, empyema, bacterial meningitis, intracranial abscess, or Lemierre’s syndrome compared to practices that had higher prescribing rates.
Indeed, if a practice of 7000 patients reduced their antibiotic prescribing for respiratory tract infections by 10%, only one extra patient would develop pneumonia in a year, and one extra patient would develop quinsy over a decade, the study authors estimated. While GPs are the largest prescribers of antibiotics, patients requesting antibiotics are cited as a major driver of prescribing behaviour.
According to Professor Tammy Hoffman, a clinical epidemiologist at Bond University, patients “grossly overestimated” the benefits antibiotics would bring.
Her newly published research, conducted with Professor Del Mar et al, found that parents believed antibiotics could reduce the duration of an acute respiratory infections such as acute otitis media, sore throat, and acute bronchitis at a level five to 10 times greater than the reality.
And patients weren’t the only ones getting it wrong. Paediatricians also overestimated the benefits, and underestimated the harms of antibiotics, Professor Hoffman told the audience. Still, simply telling patients “you don’t need antibiotics” would not work, she said. Because there was nothing stopping patients from walking down the street to another GP who would prescribe them.
To the public, antibiotic resistance seems like an abstract, societal problem.
However, what they do care about was passing antibiotic resistance onto their family or making their future selves more vulnerable, so it was important to bring the discussion back to the individual level, Professor Hoffman said.
Research has showed that patients are more satisfied when they are given the opportunity to be involved in the decision-making process.
Findings from a trial into the use of decision aids in general practice, showed that parents of sick children who used the aids were significantly more likely to make an informed choice with regard antibiotics compared with those given a standard NPS information booklet, Professor Mieke van Driel, Chair in General Practice at the University of Queensland said.
Use of the aid reduced the number of antibiotics prescribed, and did not result in patients returning later for a script or feeling unhappy with their consult, she added.
Another promising, though controversial, strategy had been delayed prescribing, where the evidence for antibiotics was discussed, and the patients asked to have the script filled only if their symptoms persisted or worsened, Professor Hoffman said.
This also worked as a behavioural experiment for patients, allowing them to see for themselves that the illness was self-limiting.
In another Australian study, the General Practitioners Antimicrobial Stewardship Program Study (GAPs), doctors were given a sticker to put at the top of the prescription to label it as a “delayed prescription”. This also helped bring the pharmacist into the discussion process.
Uncertainty drove health-seeking behaviour, Dame Davies said. So the GAPS stickers and having all the team on the same page, with no conflicting information, was a huge factor in managing the problem.
Doctors in the GAPs study could choose from a range of techniques, including delayed prescribing and a delayed prescribing sticker, a waiting room poster on antibiotic prescribing policy, a patient information leaflet, a GP online communication training package, patient decision aids and C-Reactive Protein testing.
Over the six-month study, researchers found a significant 7% overall reduction in antibiotic prescribing, equivalent to almost four fewer scripts per GP per month.
According to Professor Glasziou, the interventions with the most evidence so far were delayed prescribing, shared decision-making and procalcitonin testing.
Procalcitonin is an inflammatory marker in blood that helps distinguish between bacterial and non-bacterial cause of infection as it rises more dramatically in bacterial sepsis.
Evidence does suggest procalcitonin testing is of value as part of an antibiotic stewardship program but the test is not, as yet, Medicare rebateable, which has limited its uptake.
But the question was how to encourage people to use these interventions, he said.
In the UK last year, GPs were able to reduce the level of antibiotic prescribing by 7.3%, far exceeding the 1% target.
But reaching the Swedish rates of antibiotic prescribing would require a 49% reduction compared with current prescribing, Professor Glasziou said.
This would require hard work, sustained over decades, he said. But if we did manage to achieve a 50% reduction, this could at least halve the level of resistance and double the life of new antibiotics.
Of course, reducing antibiotic prescribing alone won’t solve the entire problem.
Two thirds of antibiotics are used for livestock, which demands tougher restrictions on industry.
Preventing the transmission of infection is another important part of the equation, so education and awareness campaigns are needed to teach each new generation the importance of hygiene strategies such
as handwashing.
One of the big areas of concern is residential care, where, in Australia, one in five antibiotics are prescribed.
The more antibiotics were prescribed in aged care homes, the greater the number of adverse events and the greater the antibiotic resistance in the individual, Victorian infectious diseases physician Associate Professor Kirsty Buising said.
The liberal use of antibiotics among the elderly also caused direct harm to all residents in aged care homes, not just the patient taking the antibiotic, the deputy director of the National Centre for Antimicrobial Stewardship said.
Australian research shows that while the prevalence of signs and symptoms of infection is only 4.5% in aged care facilities, 11.3% of individuals are on one or more antimicrobials at any one time.
What’s more, 21.7% of these residents were on antibiotic prophylaxis – with no documented signs or symptoms of infection in the week prior to their initiation. Even when there were documented signs and symptoms, two in three did not meet the internationally established criteria for infection, she said.
In their audit, one in three antibiotics prescribed in aged-care homes were for six months or longer, and most of these were for urinary problems.
One of the big areas of concern is residential care, where, in Australia, one in five antibiotics are prescribed.
This kind of prophylactic approach seriously needed challenging, Professor Buising said.
Other strategies
So what are the other options to combat antibiotic resistance?
Addressing the audience, Chief Medical Officer of Australia Professor Brendan Murphy said he was considering a nudge tactic, such as that enacted by Professor Davies with some success in the UK.
Using this tactic, a letter is sent to doctors in the top portion of prescribers, informing them that they are an outlier. Our innate human desire to be like everybody else does the rest.
But the key intervention put forward by Professor Murphy was to work with the RACGP to establish a Practice Standards guide for GPs around antibiotic prescribing – something he said he hoped would be rolled out by the end of the year. While there was support for the idea, some GPs expressed doubt about the extent to which clear and explicit recommendations could really be made.
Other suggestions included structural change, such as altering prescription software so that the default was not to issue repeats, or to provide a shorter window in which patients could fill their script than the current six-month period.
Or a software notification could be introduced to prompt doctors with an “Are you sure?” message prior to prescribing.
It could also be time to introduce more serious legislation around antibiotics, with some in the audience in favour of establishing a new drug class for antibiotics to allow the government and public health professionals to be more agile and innovative in managing their use.
The fact Australia is more restrictive in the use of quinolones has meant that quinolone resistance is low compared with other nations.
There is another question in all of this, which is whether antibiotic resistance is reversible?
Assistant Professor Anna Scott, at the Centre for Research Excellence in Minimising Antibiotic Resistance from Acute Respiratory Infections, presented convincing evidence that a reduction in antibiotics among livestock correlated to a reduction in resistance in animals.
Resistance among humans also seemed to be associated with this drop, but researchers were unable to precisely determine the magnitude of the effect, she said.
Professor Scott and her team are also attempting to replicate an older 2010 systematic review, which also suggested resistance is reversible in humans.
The study found a week after completing a course of antibiotics, a person was 12 times more likely to have antimicrobial resistance if they were to get another infection, however six months after that initial antibiotic exposure, antimicrobial resistance was only twice as likely compared with a person who had no history of antibiotic use in that period.
For Professor Davies, the economic arguments in favour of a stronger approach on antibiotic resistance speak for themselves.
“When you have a case of antimicrobial resistance in hospitals, it doubles the length of time in hospital, it doubles the mortality rate and it doubles the cost,” she said.
Modelling suggested the growing need for hospital beds could be eliminated if antimicrobial resistance was addressed, Professor Murphy said.
“It demands action, because without it, we are going to lose modern medicine.”
Professor Hoffman and colleagues are inviting general practices to take part in a paid trial of decision aids for acute respiratory infection and its usefulness in antibiotic prescribing. To find out more email cremara@bond.edu.au or call Amanda Murray on 0474 013 381.
