Could the antibiotic emergency mean the end of modern medicine?

by Sally Blundell / 21 April, 2017

As common bacteria develop new strains resistant to our antibiotic arsenal, we face a future in which more people will die from previously treatable illnesses – and operations will be riskier. Main photo by Getty Images.

It was a rogue branch of a rose bush, brushed away by Christchurch artist Simon Ogden while he was painting his house. He felt an initial sting where a thorn pierced his middle finger. “Then over a number of weeks it became a bit hard on the knuckle, nothing hurting but it restricted movement.” His GP’s initial attempt to remove the suspected thorn failed. Ogden was admitted to hospital, but after five operations and heavy doses of antibiotics, the infection persisted.

“It was a tough four months; the hospital was fantastic, but I was exhausted. In the end, the doctor said, ‘We don’t know what it is, we will give it one more go, but we might have to take that part of your finger off.’” That one more go worked – eight years later, his finger is still fine.

Ogden was lucky. Antibiotics saved his finger and perhaps his life. Had the accidental prick happened in his grandfather’s day, the infection could have spread, most likely necessitating amputation, perhaps causing death.

Should it happen in the not-too-distant future, the outlook could be just as dire, as common bacteria develop new strains resistant to our antibiotic arsenal.

“There are already people living in the post-antibiotic era,” says Siouxsie Wiles, University of Auckland microbiologist and author of the new book Antibiotic Resistance: The End of Modern Medicine? “There are people now having trouble with untreatable organisms. They are not hugely prevalent, but the further in time we go, the more prevalent they will become.”

UK economist and chairman of the Review on Antimicrobial Resistance Jim O’Neill goes further. In a report on antimicrobial resistance – not just antibiotic resistance – published last year, he said that without urgent action, such resistance will kill 10 million people a year by 2050. “Already, at least 700,000 die each year of drug resistance in illnesses such as bacterial infections, malaria, HIV/Aids or tuberculosis.”

The stakes are high.

Common surgical procedures such as appendectomies, caesarean sections and hip or knee replacements rely on antibiotics to prevent infection. Antibiotics are vital for those with compromised immunity as a result of organ transplants and chemotherapy; they also clobber a range of common diseases, including gonorrhoea, tuberculosis and pneumonia. As Wiles writes, “Brace yourself.”

Microbiologist  and author Siouxsie Wiles. Photo/Rebekah Robinson

Reducing the death toll

When Scottish scientist Alexander Fleming returned from holiday in 1928 to find a mould, a rare form of Penicillium notatum, had killed off his cultures of staphylococci, it seemed the path was clear to a new form of drug that would – and largely did – reduce the death toll from infectious disease.

But those bacteria were quick to fight back, acquiring mutations or stealing genes that confer resistance to antibiotics from other bacteria. By the 1950s, penicillin-resistant Staphylococcus aureus, responsible for a variety of illnesses ranging from boils and food poisoning to pneumonia, meningitis, blood poisoning and, in the case of the rare toxic shock syndrome, multiple organ failure, was causing outbreaks of disease in hospitals around the world.

In 1959, British pharmaceutical company Beecham developed a new beta-lactam antibiotic called methicillin – but strains of methicillin-resistant S aureus, or MRSA, were reported as early as 1961.

Enterobacteriaceae, a family of opportunistic bugs that live in the gut, including Escherichia coli and Klebsiella pneumoniae, learnt to live another day by producing a penicillin-resistant enzyme called a beta-lactamase. In the 1960s, US pharmaceutical company Eli Lilly and Co introduced antibiotics called cephalosporins, which are impervious to beta-lactamase enzymes. But this favoured new mutant strains of the bacteria that produced enzymes called extended-spectrum beta-lactamases (ESBLs), able to destroy these antibiotics, too.

Each year, ESBL-producing strains of E coli and K pneumoniae are identified in thousands of New Zealanders. They can be treated with another class of antibiotics called carbapenems, but carbapenem-resistant bacteria are now on the rise.

Earlier this year, the US reported a woman had died after being infected with a strain of K pneumoniae resistant to 26 different antibiotics.

Similarly with tuberculosis. Since the discovery of antibiotics capable of killing Mycobacterium tuberculosis in the 1950s, new multi-drug-resistant TB (MDR-TB) and now extremely drug-resistant TB (XDR-TB) have developed. With every new “super bug”, treatment options diminish.

“Every time a new type of antibiotic was taken up, resistant microorganisms emerged and spread like a wave,” writes Wiles. “But there was always another antibiotic on the shelf, so we’d start using that one, and the cycle would repeat itself. The waves of resistance have now become a tsunami, and for some resistant microorganisms, we’ve no treatments left.”

Scottish scientist Sir Alexander Fleming. Photo/Alamy

Increased use

The more we use antibiotics, the more chance there is for bacteria to develop antibiotic-resistant strains. The global Center for Disease Dynamics, Economics and Policy (CDDEP) reports that between 2000 and 2010, the world’s intake of antibiotics increased from 50 billion to 70 billion standard units (the smallest dose given to a patient, so one pill or capsule).

New Zealand has played its part, with antibiotic use here increasing by almost half between 2006 and 2014. Of OECD and some other European countries, we now rank in the top third, beaten only by Romania, France, Italy, South Korea, Belgium and Luxembourg.

Recent research from the University of Auckland’s longitudinal study of child development, Growing Up in New Zealand, shows more than nine out of 10 children are exposed to antibiotics by the age of three. Almost all children (97%) have had antibiotics by the time they are five.

Why? For a start, they work – as a first line of attack against infectious diseases they generally do the job. And antibiotics, particularly off-patent ones, are cheap – cheaper than improving hygiene and infection control in hospitals, cheaper than sanitation, cheaper than ensuring access to clean water or warm homes and cheaper than rolling out vaccine programmes.

Sometimes, they are prescribed as a precautionary measure, when the actual cause of an illness is unknown. This is understandable as symptoms of many infections are indistinguishable – a rash could be a mild viral infection or a sign of the potentially fatal meningococcal bacteria. That chesty cough could be a sign of bacterial pneumonia or viral bronchitis. More worrying is the use of non-prescribed antibiotics, shared between family and friends and often taken for conditions they can’t treat – such as flu viruses – or conditions that will clear up unaided, such as some forms of food poisoning.

The use of broad-spectrum antibiotics, rather than the more bacteria-specific narrow spectrum, is convenient – they often have fewer side effects, children usually prefer them because they taste better and you don’t always have to take them with food.

Ground-breaking Penicillium notatum discovery.

But broad-spectrum antibiotics, writes Wiles, can be “the equivalent of burning down a forest to get rid of one tree. They’ve wiped out many beneficial bacteria and given antibiotic-resistant strains the opportunity to evolve and dominate. In cases like these, the antibiotic-resistant bacteria don’t make you ill. They just live on or inside you and spread to others in your community.”

The more antibiotics we use, the more opportunity we give to these diseases to develop and favour mutant antibiotic-resistant strains. But not taking the full course of antibiotics is also risky. If bacteria are exposed to an inadequate dose, instead of quickly killing them, the antibiotic puts them under stress, so they make more mutations, boosting the chance of their becoming resistant. As Fleming warned in his 1945 Nobel Prize lecture, in making penicillin too widely available, “The ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug, make them resistant.”

We need to take note. As countries become more developed, they tend to have lower rates of infectious diseases, but New Zealand is heading in the opposite direction.

In 2013, more than two-thirds of our infectious-disease hospitalisations were for bacterial infections, most commonly S aureus, Streptococcus pyogenes and food- and waterborne infections caused by various organisms.

We are topping the charts for many of them. Our rates of S aureus, or “staph”, are the highest in the developed world – and rising. Similarly, S pyogenes, or Group A strep – a common cause of sore throats and tonsillitis. This virulent bacterium can also cause a variety of illnesses, including skin and soft-tissue infections, scarlet fever, toxic shock syndrome, childbed fever and the infamous “flesh-eating bug” Post-streptococcal glomerulonephritis. This “truly terrifying disease”, as Wiles  describes it, often requires surgery and sometimes amputation to stop its spread.

Between 2002 and 2012, almost 3000 people – most of them under five or over 70 – were hospitalised with a S pyogenes infection.

Our rates of rheumatic fever, typically developing in reaction to an S pyogenes infection, doubled between 2005 and 2010, most commonly affecting Maori and Pasifika children aged from five to 14. This has prevented us from running education programmes to reduce the spike in GP visits and antibiotics in winter when seasonal respiratory-tract infections, mostly caused by viruses impervious to antibiotics, are at their peak.

“Other countries have tried to solve that misprescribing over  winter months, saying if you have a sore throat it is just a virus, don’t go to the doctor,” says Wiles. “But in New Zealand, it might be strep throat, and with our rates of rheumatic fever, there really is a need to treat it.”

Gonorrhoea on the rise

Our rates of campylobacteriosis are also among the highest in the developed world.

On Friday, August 12, last year, 13 people turned up at Hawke’s Bay Regional Hospital’s emergency department with symptoms of gastrointestinal illness. By Monday, another 68 had gone to the emergency department, and 70% of staff and students were absent from the town’s schools. By the end of the outbreak, an estimated 5530  Havelock North residents had had symptoms of campylobacteriosis, apparently floored by a water supply contaminated with Campylobacter jejuni, a helical-shaped bacterium commonly found in animal faeces. Forty-five people ended up in hospital, and two died.

Cases of the sexually transmitted disease gonorrhoea are also rising. Although not notifiable in New Zealand, best estimates, says Wiles, put our rate at 70 per 100,000 people in 2014, mostly in the 15-29 age group. Already, as new antibiotic-resistant strains emerge, it is a struggle for once commonly used treatments to control the disease. “Once these antibiotics stop working,” says Wiles, “the options are very limited.” According to the World Health Organisation (WHO), 10 countries have confirmed the failure of third-generation cephalosporin, one of the treatments of last resort for gonorrhoea.

Chlamydia trachomatis, transmitted during vaginal, anal and oral sex and able to be passed by an infected mother to her baby during childbirth, is twice as common in this country as it is in Australia and the UK. Without antibiotics, about half of asymptomatic women will go on to develop pelvic inflammatory disease and, for men, painful swelling of the testicles and epididymis as well as reactive arthritis and infertility.

Dr Keiji Fukuda. Photo/Getty Images

The art of prevention

“Without urgent, co-ordinated action,” said Dr Keiji Fukuda, WHO’s assistant director-general for health security, “the world is headed for a post-antibiotic era, in which common infections and minor injuries which have been treatable for decades can once again kill.”

Most of our infectious diseases are treatable. Only about 4% of the 29,636 people who died in 2013 had infectious diseases listed as the cause of death. But as new antibiotic-resistant strains of bacteria emerge, we have to look further. New Zealand has made a commitment to the WHO to have a national strategic antimicrobial resistance action plan in place by next month, and a cross-agency group is working on it.

As those living in cold, damp, overcrowded homes carry the burden of many of these diseases, the need to address poverty and ensure access to affordable, warm, dry housing is becoming even more urgent.

Wiles is also calling for more education on the use and misuse of antibiotics.

In her book, she quotes a survey of people of Samoan descent that found two-thirds thought antibiotics were for pain relief, most thought they were a useful treatment for colds and the flu, and many said they stopped taking them before finishing the course. Similar studies show those from countries where it is easier to get antibiotics without a prescription “are more likely to have misconceptions about what they are useful for”.

Our high rates of chlamydia can be reduced through the use of condoms and dental dams during sex, but in a recent survey, fewer than half of sexually active young people reported using condoms. Sexually transmitted infection is part of sexuality education in the curriculum, says Wiles, “but schools can choose to leave it out, or parents can opt to remove their children from class”.

Most pressingly, we need new antibiotics. Following the antimicrobial gold rush of the 1940s-50s, the hunt for new antibiotics has become a “game of diminishing returns”. Between the 1960s and 80s, just three new antibiotic classes were discovered from microbial sources. New chemically synthesised derivatives of existing antibiotics, the so-called “me-too” antibiotics, and recent advances in microbiology and bacterial genomes have yet to yield major advances.

Universities and institutions throughout the country are researching bacteriophages (viruses that infect specific strains of bacteria), better vaccines and treatments for TB, new antimicrobial surfaces and new antibiotics – Wiles’ team is trying to develop new antibiotics from a collection of fungi held at Landcare Research.

“But no one antibiotic is going to solve this. We need another whole cupboard full as well as more vaccines and potentially different ways of treating infection.”

But competition for research funding is fierce; applications are costly and time-consuming. Of the $365 million allocated for applied medical research to improve human health from the Health Research Council between 2012 and 2016, less than 10% went to infectious diseases research. And although death rates from infectious disease are not much lower than those from cancer, the subject does not attract the same strong charity or philanthropic backing that other illnesses get.

Wiles admits to a vested interest – as a scientist, she makes a living from research. “But I have a family and friends – I really don’t want people dying of this stuff. And we clearly need more money for research, because this is something the private sector is not picking up.”

Professor Kurt Krause. Photo/University of Otago

New ideas needed

In 2006, the University of Otago’s Professor Kurt Krause led a bid to create a Centre for Molecular Biodefence Against Infectious Pathogens, bringing together practitioners, researchers and public-health officials to mount “a comprehensive response to the needs of infectious disease”.

“We need new antibiotics, new vaccines and good surveillance to put New Zealand on the front foot. People have been predicting antibiotic resistance for a decade, but developments over the past five years show the time is now. We have to learn about the antibiotics, we have to husband those very carefully and we have to make some smart decisions about using antibiotics on livestock,” says Krause.

Although the bid failed, there is still a need, Krause says, for a clearer understanding of biology and disease mechanisms in order to develop new treatments. “We can’t do the same old approaches over and over again – we need new ideas.”

Malign bacteria and their ability to develop resistance to whatever we throw at them are here to stay. Recent exploration of caves in New Mexico, isolated from the rest of world for thousands of years, has found organisms that produce antibiotics and organisms that resist those antibiotics.

“So it is clear organisms use these amazing medicines themselves,” says Wiles. “And where they are used, through the natural process of mutation, mutants arise and when it is a chance for them to have an advantage, then those organisms flourish. But we have massively accelerated this by our use of them.”

She likens antibiotic resistance to climate change, a “slow-burning crisis that took a long time before it became less of a fringe issue and something the vast majority of people take an interest in”.

Our understanding of antibiotic resistance now, she says, “is where climate change was 15-20 years ago. People might have heard the phrase but don’t really know what it is. I’m assuming in the next five to 10 years it will become much more prevalent, partly because many more people will be dying or more people’s operations will become more risky.”

ANTIBIOTIC RESISTANCE: THE END OF MODERN MEDICINE?, by Siouxsie Wiles (Bridget Williams Books, $14.99), on sale from April 10.

Staying safe

The infectious microbes plaguing society – Campylobacter and other food- and water-borne micro-organisms, Staphylococcus aureus, Streptococcus pyogenes, Chlamydia trachomatis and Mycobacterium tuberculosis – are very different from each other and spread in very different ways. But by taking precautions, we can reduce our susceptibility.

  • wash and dry hands properly
  • avoid unwashed fruit and vegetables
  • keep raw meat away from fresh vegetables
  • cook meat properly
  • avoid swimming in risky rivers and lakes
  • get vaccinated
  • use condoms and dental dams if sexually active
  • get tested for asymptomatically sexually transmitted infections

This article was first published in the April 8, 2017 issue of the New Zealand Listener. Follow the Listener on Twitter, Facebook and sign up to the weekly newsletter.

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