When Alexander Fleming delivered his Nobel lecture, in 1945, the man who discovered penicillin presented his audience with a whodunnit. “Mr X has a sore throat,” he began. “He buys some penicillin and gives himself not enough to kill the streptococci but enough to educate them to resist penicillin. He then infects his wife. Mrs X gets pneumonia and is treated with penicillin. As the streptococci are now resistant the treatment fails. Mrs X dies. Who is primarily responsible for Mrs X’s death?”
Fleming presented his story as a hypothetical illustration of the dangers of misusing his discovery by underdosing. Six decades later there is nothing hypothetical about the carnage being inflicted worldwide by the inappropriate use of antibiotics.
Back then the culprit, for Fleming, was Mr X, the “ignorant man” who failed to take his penicillin properly. Today the rising death toll from antibiotic resistance can be laid at the door of doctors and entire health systems as much as it can be blamed on individual patients.
Already the problem is costing 700,000 lives a year, including 200,000 children. A report last year forecast 10 million deaths a year by 2050 – more than from cancer – unless action is taken. In some areas, such as the treatment of gonorrhoea, doctors are down to their “last line of defence” because of increasing drug resistance.
The reason is the overuse and inappropriate use of antibiotics across the world. Fleming’s wonder drug, and others developed over the past 60 years, are widely used when they aren’t needed and where they won’t work. They are widely used in human medicine but even more so in agriculture.
Forty million Americans are prescribed antibiotics each year for respiratory issues, 27 million of them unnecessarily. In Ireland at least half of antibiotic use in hospitals is inappropriate, according to the Health Service Executive’s health-protection surveillance centre.
Yet although antibiotic resistance has been ranked as big a problem as global warming and terrorism, the issues involved struggle to be heard. As with climate change, there is the “tragedy of the commons”, whereby we use antibiotics copiously for perceived personal benefit and ignore the community gain that would accrue from using them less often or more wisely.
Spread of superbugs
That insouciance may soon change. Drug resistance is turning into multidrug resistance, and doctors’ options are narrowing. So-called superbugs are spreading internationally, often aided by medical tourism.
Some of them have a firm foothold in the Irish health system. A decade ago MRSA wreaked havoc as it spread through hospitals. Its advance was finally checked by stringent rules about hand-washing, among other measures.
Today a new army of superbugs, more resistant and even more difficult to eradicate, is on the way. Ireland has the highest rate of life-threatening vancomycin-resistant enterococci in Europe.
In the midwest region, carbapenem- resistant Enterobacteriaceae, a family of bacteria that kill up to 40 per cent of the people they infect, has become entrenched in some hospitals and nursing homes.
The potentially deadly impact of this outbreak was brought home recently with the revelation, through a whistle-blower, that up to 30 patients in Limerick had died with the superbug in their system over a two-year period. In recent months Tallaght Hospital has suffered a similar outbreak, with dozens of patients infected.
Whereas MRSA – methicillin-resistant Staphylococcus aureus – lives on the skin, from which it can be eradicated with an antibacterial agent, these new threats live in the body. "Once in the bowel they sit in place, and you can't get rid of them without knocking out other bugs that we need," says Dr Nuala O'Connor, of the Irish College of General Practitioners.
They may not pose a threat to healthy people, but that can change if the immune system becomes suppressed. They can also be passed on to more vulnerable patients, as has happened in the Limerick and Tallaght outbreaks.
The HSE found in 2012 that one in 20 patients had a hospital-acquired infection. The rate in public tertiary hospitals, which is to say large hospitals that offer a full range of services, was three times higher than in private hospitals, and patients who had had surgery or procedures involving invasive devices – probes, say, that had been used before and could, in some circumstances, introduce bacteria – were more likely to have been infected.
Yet public awareness remains low, and death certificates seldom record the role played by infection in a patient’s demise.
Antimicrobial drugs are medicines that fight a range of infections, such as those caused by bacteria (treated with antibiotics), viruses (treated with antivirals), fungi (treated with antifungals) and parasites (treated with antimalarials). Resistance arises when the micro-organisms that cause infection survive exposure to a medicine that could formerly stop their growth. The resistant strains then grow and spread, and become resistant to further treatments, giving rise to so-called superbugs.
Life without antibiotics
To imagine life without antibiotics, just turn the clock back 70 years. The world before penicillin was a dangerous place, where anyone could be struck down at short notice by an infectious disease. Tuberculosis was rampant. A simple strep throat in a child could result in scarlet fever and then organ failure and septicaemia, killing one in five patients. Infectious diseases killed more people than gunshot wounds in the first World War.
At that time “even an infected paper cut in a healthy environment could have a serious outcome”, says Dr Jennifer Westrup, an oncologist at the Beacon Hospital in Dublin. “Patients went through major surgery, childbirth and trauma without antibiotics, and many didn’t survive.”
Antibiotics made possible most of the advances of modern medicine: chemotherapy, open-heart surgery, organ transplants and joint replacements. We lived longer and longer as new drugs were developed to keep bacterial infections in check. Now all this is at risk.
“In the 70 years since we have started buying penicillin at the local chemist, something has changed. The bacteria have changed,” says Westrup.
In an increasingly time-poor society, our need for antibiotics has grown and grown.
“How many of us don’t have time to be sick but don’t take the time to get well? We’re often looking for an immediate remedy, in the form of an antibiotic,” she says.
Scientists have known for decades that bacteria can adapt to protect themselves against antibiotics. Evidence of antibiotic resistance has been found in Egyptian mummies dating back thousands of years. The first resistance to penicillin was detected within a few years of the drug being developed.
This wasn’t too much of a problem for many years. Scientists developed more powerful drugs, and resistance remained at fairly low levels. In recent years, however, levels have soared – and medicine is running out of new options, as few new antibiotics are being developed.
“We always knew this was coming, but the problem has grown significantly in the last 10 to 15 years, to the extent that it is now a significant public-health threat,” says Ramanan Laxminarayan, a Princeton academic who is also director of the Center for Disease Dynamics, Economics & Policy, in Washington, DC.
“We are almost at a postantibiotic era, because we have bacterial infections that are not treatable by any antibiotic available today.”
What started as a local problem has quickly become a global one. It has also spread from hospitals into the community.
“People go on holidays, they get sick, and they end up in hospital, where they get infected with a resistant bug,” says Nuala O’Connor. “Within days they are back in Ireland, and so is the bug.”
One particularly nasty bacteria-altering gene, NDM-1, for example, was first identified in Europe in 2009. Swedish researchers believed it was introduced by people returning home from New Delhi after dental surgery in India. In six years it has spread to more than 110 countries, including Ireland. The World Health Organisation is concerned that it may usher in "the doomsday scenario of a world without antibiotics".
“Much of what we consider modern medicine depends on our ability to keep infections at bay, and in giving up our antibiotics we’re essentially dismantling that foundation,” Laxminarayan says.
Because their options are reduced, doctors are increasingly forced to treat serious illness with toxic drugs, such as colistin, which causes kidney failure and was not used for many years. Yet even this is incurring resistance.
Drugs for pigs
Huge and often uncontrolled use of antibiotics in agriculture is one of the main drivers of resistance. In many countries entire flocks of animals are medicated with antibiotics. Outside the EU their use as growth promoters is common.
Irish farmers give their pigs four times as much antibiotic as Danish farmers do, one report found, while another found evidence of the widespread medication of feed for pigs as a preventive measure. In parts of the country pharmacies have been selling prescription-only drugs to farmers to administer to their animals, without veterinary supervision.
Meanwhile, little is done to ensure that unused supplies aren’t dumped in the ground or into lakes, rivers and seas.
“Studies have shown that antimicrobial-resistant bacteria are very widely disseminated in Ireland, not just in sewers but also in rivers and lakes and in rural drinking-water sources,” says Prof Martin Cormican, a microbiologist at the school of medicine at NUI Galway.
He cites the example of ESBL E coli – which is to say extended-spectrum beta-lactamases, enzymes produced by Escherichia coli bacteria – which can cause urinary-tract and bloodstream infections and have often been found in the environment.
“This didn’t exist as a biological entity 50 years ago,” he says. In Ireland, he adds, throwing medication into the toilet or the bin is common practice. “We have put in place a pretty effective system for batteries, so why can we not do something similar for used pharmaceuticals?”
The other way that resistant organisms enter the environment is when antibiotics taken by humans or animals are excreted in faeces or urine. Up to 90 per cent of the substance is excreted unaltered. In India, rivers have been found to contain higher concentrations of antibiotics than are found in a person’s bloodstream. Even in Ireland a major hospital will discharge about 500g of ciproflaxin in sewage each day.
“No one would permit a pharmaceutical company to discharge kilograms of active product in the effluent from their plant, yet we know very little about discharges from hospitals, nursing homes and centres of intensive animal production,” Cormican says.
The individual risk caused by this pollution is low. The real danger is the population exposure, and the risk that the generation of antibiotic resistance could cause what Cormican describes as “an irreversible event of permanent consequence with unquantifiable results”.
Developing countries have relied on antibiotics instead of improving water supply, sanitation and public health or widening vaccine programmes, according to Laxminarayan.
“This is like mopping up the floor when the tap is running. If you want a clean floor you have to turn off the tap first,” he says.
Flu season
The flu season is the biggest driver of antibiotic consumption, even though the medicines are ineffective against influenza. Countries such as Spain and Italy hand out antibiotics without a prescription, while in China 25 per cent of hospital revenue comes from sales of these drugs.
“We’re helping these bugs build a library of how to be resistant. We’re teaching them, and then the resistance is there forever and ever. So if you think we have a problem with drug resistance now, you haven’t seen anything yet,” Laxminarayan says. The problem is behavioural as much as medical. “If a patient expects an antibiotic they get one. If the doctor thinks the patient expects an antibiotic they get one.”
Studies have shown that the more tired doctors are, the more likely they are to prescribe antibiotics. Surgical complications make money for hospitals, and incentives are stacked against good infection control.
There are signs that the world is starting to take the problem seriously. New efforts are being made to invent new antibiotics, or alternatives to them, and to develop rapid diagnostic tests that would allow doctors to make more accurate and timely diagnoses, thereby reducing the need for antibiotics. The wider use of vaccines could help reduce drug usage.
Other proposals being mooted are the labelling of products containing antibiotics and a worldwide ban on their sale over the counter.
In Ireland, the Government set up an interdepartmental committee in 2014, but it has met only four times. Members agreed that it was a forum for “sharing experiences” rather than one for pursuing specific actions or developing legislation. Worries about a lack of resources also feature prominently in the minutes.
Government has yet to devote significant resources to tackling the problem, and Ministers have yet to implement anything that would force a change in behaviour.
“At a political and departmental level Ireland’s response has been woefully inadequate,” Cormican says. “I can see no evidence that the Taoiseach, who put this on his risk register, or the Minister or the department share in any measure the sense of urgency that most professionals in this area feel is required to manage this problem.
“We have already lost control of several antibiotic-resistant bacteria. We are on the verge of losing control of CRE” – carbapenem-resistant Enterobacteriaceae – “and the interdepartmental committee is meeting twice a year, with not much evidence of action in between.”
This may change, as the Government has committed to having a national action plan on antimicrobial resistance in place by May 2017. This will be designed to feed into the World Health Organisation’s global action plan for improving awareness, reducing infection and designing new agents to tackle antimicrobial resistance. Latest figures show a small drop in the consumption of antibiotics.
One way or another life is going to change for all of us: either, as individuals, we restrict our use of antibiotics or they stop working for us.
“We’re not going to get rid of these drug-resistant bugs, but we are going to have to try to contain them,” O’Connor says.
Jennifer Westrup summarises the view of the experts: “We think we have a God-given right to cheap antibiotics forever and ever, and that’s simply not going to happen.”
