How to fight antibiotic resistance

“A box of amoxicillin, please,” I asked the shop assistant. I’d had a tip-off you could buy antibiotics without a prescription in this grocery store serving the Polish community in a market town in the rural west of England.

Sure enough, no questions asked, the store employee reached into a glass cabinet next to the checkout and pulled out a packet of penicillin from a variety of drugs on display. I paid £15.29, thanked her and left with 24 tablets. Neither she nor I had any idea whether they were the appropriate treatment. It is illegal in all EU countries—the UK and Poland included—to dispense antibiotics without a prescription from a medical professional. But my purchase wasn’t just against the law, it was also contributing to what Dominique Monnet of the European Centre for Disease Prevention and Control (ECDC) calls “a major public health threat”—the increasing resistance of bacteria to antibiotics.

The discovery of penicillin 90 years ago revolutionised medicine. “Before antibiotics, thousands died from bacterial diseases, such as pneumonia, or infection following surgery,” explains Monnet, who is head of the ECDC’s disease programme on antibiotic resistance. Antibiotics now prevent women dying after childbirth, pre-term babies succumbing to bugs they’re too weak to fight off and elderly people perishing from urinary tract infections. They zap bacteria responsible for infections ranging from acne to tuberculosis and are used to treat and prevent illness in livestock as well as humans.

But these miracle drugs are losing their power because of overuse and misuse. As a result, we're in danger of entering what the World Health Organisation (WHO) has called “a post-antibiotic era in which common infections and minor injuries can once again kill.” In this scenario, Monnet says, “organ transplants, cancer chemotherapy, intensive care, and other medical procedures would no longer be possible. Bacterial diseases would spread and could no longer be treated.” As a result, 10 million people a year could die worldwide by 2050, according to a 2016 report funded by the Wellcome Trust and the UK government.

“Antibiotic resistance is not a future threat,” points out Andreas Sandgren, deputy head of ReAct Europe, an independent organisation that urges action on antibiotic resistance. “It is profoundly affecting us and causing many deaths now.” The ECDC estimates that 33,000 people die every year in Europe as a direct result of an antibiotic-resistant infection, costing 1 billion euros annually.

“We need to protect antibiotics by reducing exposure to them and develop new agents to replace the ones we’ve got,“ says Dr Nicholas Brown, a medical microbiologist at Cambridge University Hospital in the UK and head of Antibiotic Action.

So how did we get here? “Resistance is inevitable and is a natural phenomenon that has always occurred following exposure to antibiotics,” says Dr Brown. “The more we use antibiotics, the more resistance will emerge and the less effective they become.”

Bacteria, rather than people, become resistant to antibiotics. The germs mutate in response to these medicines, with the strongest capable of surviving. This is more likely to happen if the treatment is unnecessary, too short or too long, at too weak a dose, or not targeted at a specific bug.

Resistance means that doctors have to use ever more potent antibiotics to combat some infections. Some last-line antibiotics—treatments of last resort—are beginning to fail. Bacteria that are now resistant to many antibiotics include those that cause pneumonia, meningitis, urinary tract infections (UTIs), gonorrhea, surgical site infections like MRSA, diarrhea, bloodstream infections such as sepsis, malaria, skin infections including impetigo, and TB.

New antibiotics aren’t being developed fast enough to keep pace with resistance. “A lot of big pharmaceutical companies have withdrawn from antibiotic development, because it is high risk,” explains Dr Brown. “It costs between £400–800 million to take a drug to market and get regulatory approval for it to be used. The fallout rate is high—only about one in 25 drugs actually make it to market. In that situation the drug companies never get any reimbursement for the money they put in.”

Promising new antibiotics in the pipeline include the soil-derived teixobactin and cefiderocol. But in 2017 the WHO warned that only eight of the 51 therapies in development to treat antibiotic-resistant pathogens were innovative treatments that could add value to existing drugs.

“There is a large variation in the level of consumption of antibiotics among European countries,” says ReAct’s Andreas Sandgren. According to the ECDC, people in Cyprus, Spain, France, Romania, and Poland are the biggest consumers. Meanwhile, the Dutch, Estonians, and Swedes use them very little. In the Netherlands and Sweden, there's a continuing downward trend, with Finland, Germany, Italy, Luxembourg, Norway and the UK also showing decreasing use.

At least 80 per cent of antibiotics are prescribed in the community, mostly by family doctors. But people can also get them on the internet, directly from pharmacies, and even—as I found—in other shops. Sometimes people pass unused tablets to friends or family members. A 2017 EU report found that seven per cent of antibiotics were taken without prescription. One in five Europeans took antibiotics for colds or flu in 2018, even though antibiotics don’t kill viruses, according to a Eurobarometer survey from the European Union.

Spain is now having to tackle high rates of antibiotic consumption and—as a result—antibiotic-resistant infections. Its residents take three times as many antibiotics as people in the Netherlands, which has the lowest rate of antibiolic consumption in Europe. Much research has been devoted to investigating the extent of the problem. Results have varied from an eye-popping 64 per cent of pharmacists admitting to dispensing antibiotics without a prescription in a 2014 survey in northern Spain to 19 per cent in a 2017 study in northwestern Spain.

But the tide could be turning, thanks to the Spanish government’s determination to address what it has described as “excessive and frequently inappropriate” antibiotic use. “The demand for over-the-counter antibiotics is a situation that we experience every day in pharmacies, although in the last two years I have appreciated a fundamental difference,” says Virtudes Roig, a pharmacist from Valencia. “The patient is aware of the legislation and when refused does not insist, which means that the information campaigns have worked.”

One country that has long embraced good antibiotic stewardship is Sweden. The rapid spread of penicillin-resistant ear infections among children in the early 1990s acted as a wake-up call. It led to the creation in 1995 of Strama, a strategic program tackling antibiotic resistance at local, regional, and national levels. “Worried colleagues from different fields­—clinical microbiologists, infectious disease experts, GPs, pharmacists, nurses and vets—came together and said, ‘We must do something,’” says Dr Stephan Stenmark, chairman of the Strama Program Council and county medical officer for communicable disease control for Västerbotten.

Today, local multi-professional groups work with GPs, while the government funds a national executive group. There is rigorous monitoring both of antibiotic prescribing and resistance, and a national target of no more than 250 prescriptions a year per 1,000 inhabitants.

Keeping prescribers up to date is crucial. “There are constantly new studies being done and today we know that there are few, relatively small sub-groups of respiratory tract infections that fare better with antibiotics than without,” says Lars Blad, chairman of the Strama Network and WHO consultant on containing antibiotic resistance. “These studies are continuously taken into modern and updated treatment guidelines.” Now doctors can often advise patients to wait two to three days to see if an upper respiratory tract infection will go of its own accord.

It has worked. Outpatient antibiotic prescriptions dropped 43 per cent over 24 years, 73 per cent among children. There has also been a shift away from broad spectrum to narrow spectrum antibiotics, which target specific bugs and reduce the development of resistance. At the same time, levels of resistant bacteria—always low—have remained stable.

The secret of Strama’s success? “Feedback,” says Stenmark. “You must work with clinicians and show them your data, not as the antibiotic police but as a colleague. GPs were involved all the way in the development of national guidelines.”

He also cites the importance of the media in winning over the public. “Without the media, we wouldn’t have been able to afford big information campaigns.”

Awareness is now high: 2018 Eurobarometer data shows that 74 per cent of Swedes know antibiotics don’t cure viruses. In 1991, parents and the authorities alike would have been unhappy if he had not prescribed antibiotics for a child with an ear infection that would probably have cleared up on its own, Stenmark says. “Now, when children really do need antibiotics, I have to persuade the parents they’re necessary.”

Lisa Österlund, 50, from Stockholm is proof of the change in attitudes. The music librarian and mother of three children aged between 13 and 18 can only remember one occasion anyone in her family used antibiotics: when her eldest daughter had pneumonia at the age of nine.

“My husband Jon and I have had no antibiotics since the mid-1990s,” she says. When a family member is ill, Lisa’s first port of call is the Swedish e-health system. She goes to the 1177 website where she can get information, send a secure message to a doctor, and have an online consultation. “Jon and I get sinus problems after a cold, but there’s no point in asking the doctor for antibiotics. We’re always told that it will pass in time.”

The fight against antibiotic resistance is taking place elsewhere in Europe. Marc Bonten, professor of molecular epidemiology of infectious diseases at the University Medical Center Utrecht, calls the Netherlands’ efforts “very successful.”

“With the Scandinavian countries, we have the lowest antibiotic consumption and lowest resistance rates in Europe,” he says. Good surveillance of antibiotic use and resistance in hospitals, nursing homes, and the community, as well as among farm animals, has been key. There was a 63 per cent reduction in antibiotic use in food animals between 2009 and 2017, and a ten per cent drop in human prescriptions in the community between 2016 and 2017.

Meanwhile, the UK government has pledged to cut prescriptions by 15 per cent by 2024. There have been big public information campaigns. A catchy song in a television ad urges people to “keep antibiotics working” by not taking them for viruses and by following your doctor’s advice. Initiatives seem to be working; between 2014/15 and 2017/18, community pharmacies in England dispensed more than 3.7 million fewer antibiotic prescriptions.

The EU’s ambitious One Health action plan is battling the problem on several fronts—human, animal and environmental. Measures include reliable Europe-wide surveillance data, guidelines for prudent drug use and funding for research into new antibiotics and other treatments.

Given that all antibiotics will eventually develop resistance, there is heightened interest in finding alternative weapons in the fight against superbugs. One possible solution is bacteriophages. These naturally occurring viruses attack bacteria and have been popular in eastern and central European countries, including Poland and Russia, for many years. An EU-funded project in the French city of Nantes hopes to develop phages for more widespread use.

Recently there have been some promising results. Thanks to a cocktail of three viruses, British teenager Isabelle Carnell-Holdaway, who has cystic fibrosis, fought off an antibiotic-resistant infection she picked up after a lung transplant. Doctors had put her chances of survival at one per cent. However, large-scale clinical trials of phages are needed and, as Dr Brown points out, at present “it’s difficult to pinpoint which bacteriophage you need and when you would use it.”

“Antibody therapy specifically targeting a certain bacterium could be useful,” suggests Utrecht’s Professor Bonten. Scientists from the German Cancer Research Centre in Heidelberg, Germany, recently succeeded in using antibodies from healthy people to attach to sugar structures on Klebsiella pneumoniae bacteria to protect against common antibiotic-resistant hospital infections such as pneumonia, UTIs and septicaemia.

Also in Heidelberg, at the European Molecular Biology Laboratory, scientists have been looking at combining existing antibiotics and combining antibiotics with other types of drugs, and even food additives, to make them more effective. They found that vanillin, which gives vanilla its flavor, helped the antibiotic spectinomycin to enter bacterial cells and inhibit their growth. Spectinomycin had been used to treat gonorrhoea, but has fallen out of circulation due to antibiotic resistance.

Until these twinkles in scientists’ eyes become a treatment reality, we all need to join the battle to cut unnecessary use of antibiotics.

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