By James McCormack
It’s the coughing. It won’t stop. You’re meeting clients for lunch in Sydney’s Rocks district and the coughing will not stop. At first it’s just annoying. But as it goes on, it becomes embarrassing. In the end, you’ve just got to excuse yourself and head to the bathroom.
Except that’s not the end. It’s the beginning. Because you’ve been so busy stifling the coughing, you haven’t noticed the hand you’ve covered your mouth with is wet. With blood. By the time you make it to the bathroom you’re spitting blood everywhere. With your free hand you reach for your mobile and call an ambulance.
After a chest x-ray in hospital, doctors find you’ve got a cavity – a cavity – in your right lung. And when you explain to them you’ve recently been in South America, that you’ve lost a bit of weight, that you’ve had a persistent cough for weeks and, oh, that’s right, you’ve been getting night sweats, too, you can see they’re beginning to worry. You’re a 27-year-old guy, you look after yourself, exercise and watch what you eat. You’re not perfect. But still, healthy enough. How bad can it be?
In the end, as unusual as it is for a young Aussie male, the doctors say you’ve got tuberculosis. Except that’s not the end.
Now you’re in quarantine: three weeks on your own, three weeks in a three-metre by four-metre hospital room, all the time googling around to see what you can find out about TB. Wikipedia. Fricken Wikipedia. And you’re holed up in this damn sterile, white-walled closet with Wikipedia’s facts and figures and worst-case scenarios churning through your head.
At least there’s one comforting thought: TB might kill millions worldwide, but in Australia, with our First World medical system, you’ll be safe. In the end, after taking your courses of streptomycin, isoniazid, rifampicin, ethambutol and pyrodixine, antibiotics will save you.
Except once you get home, you begin hacking up blood again. Back at the hospital you tell them something’s wrong – the drugs don’t seem to be working. They say not to worry . . . you’re being overly anxious . . . you need to give it time. But you are worried, because when you were googling, you’d read about drug-resistant TB and how its incidence is rising. That it kills 85 per cent of those who get it. And although the docs tell you not to worry about it, that it’s rare, nonetheless, you know of it. So when, two weeks after leaving hospital, you get the phone call – the one telling you what you already felt, the one telling you four out of the five antibiotics aren’t working, the one you know means you’re heading back into quarantine for who knows how long – well, now you’re shitting yourself.
“Consider the difference in size,” wrote former New Scientist editor Dr Bernard Dixon in Power Unseen: How Microbes Rule the World, “between some of the very tiniest and the largest creatures on Earth. A small bacterium weighs as little as 0.000000000001 grams. A blue whale weighs about 100,000,000 grams. Yet a bacterium can kill a whale.
“Such is the adaptability and versatility of micro-organisms, as compared with humans and other so-called ‘higher’ organisms, that they will doubtless continue to colonise and alter the face of the Earth long after we and the rest of our cohabitants have left the stage forever. Microbes, not macrobes, rule the world.”
And yet we humans possess a formidable weapon to challenge this world order: antibiotics. As the name anti + bio suggests, they are inimical to life, destroying the cell walls of micro-organisms, inhibiting their protein synthesis, disrupting their ability to reproduce. Antibiotics are killers of the first order. But, for humans at least, they have also become lifesavers. Widely regarded as the most important medicine ever made, penicillin alone is estimated to have saved hundreds of millions of lives since its discovery by Alexander Fleming in 1928. “Without penicillin, 75 per cent of the people now alive would not be, because their parents or grandparents would have succumbed to infections,” estimates Dr Trevor Stone, professor of pharmacology at the University of Glasgow.
Antibiotics are, in effect, miracle drugs, says Dr David Looke, an infectious diseases specialist at Brisbane’s Princess Alexandra Hospital. “Relatively, they have been with us for a very short time, but it’s long enough for people to forget what it was like to not have any antibiotics,” he says. “You can have a person come in to see you, who would normally die, who can walk out the next day.”
But the era of relying on antibiotics – commonly called anti-microbials by the medical profession – is coming to a close.
Resistance is reaching alarming levels. The World Health Organisation has declared it one of the three greatest threats to human health. It’s not that resistance is new – Fleming himself raised the issue back in the Forties. Although no antibiotic yet has proven immune to resistance development, in the past the effect has been countered by the release of new antibiotics.
But over the past few decades, the development of new antibiotics has virtually dried up and the use of so-called last-line antibiotics is steadily increasing. Beyond this last line we have nowhere else to go. Some experts are even likening it to the medical equivalent of peak oil.
Imagine you’re running a marathon. But at the 38-kilometre mark, with only four kays to go, they tell you it’s a 55km race.
Near the end of that, they tell you it’s a 60km race. Then 80km. And so on. And so on. Not knowing how or when it’s going to end was the hardest thing for Christiaan Van Vuuren, the advertising sales guy who began hacking up blood at that Sydney lunch, who went back into quarantine for a second time on January 18, 2010 and was still there 187 days later. To wile away the time, he began recording hip-hop videos and in the process became a YouTube phenomenon self-styled as The Fully Sick Rapper.
“When I first got in there, we thought it would be one month and I’d be out,” he recalls when we meet at a Sydney cafe.
“Then, when the finish line kept moving, I thought I might be a bubble boy for the rest of my life. Some mornings I’d look at myself in the mirror and say, ‘You’re a bloke who can beat this’. Other mornings I’d look in the mirror and just see a crazy patient with messy hair and a big beard, and think, ‘Oh no, I live in a hospital!’.”
The not-knowing, the loss of certainty – that’s what antibiotic resistance represents on a grander scale. All these sicknesses that were treatable, that we thought we could beat – now that certitude is dwindling. And that’s what galls Professor Peter Collignon, Canberra Hospital’s director of infectious diseases and microbiology: situations “where I can’t cure someone I could cure 10 years ago”.
Worryingly, large elements of this future picture are with us already. Globally, as a consequence of overprescription, overuse, incomplete courses (yeah, bacteria love that), a rogues’ gallery of illnesses have already developed resistance: typhoid fever, pneumonia, salmonella, dysentery, gonorrhoea. Half a million new cases of multi-drug-resistant (MDR) TB alone are now diagnosed annually, including increasing numbers in our near-neighbour, Papua New Guinea.
And if MDR TB’s not scary enough, worse yet are the new strains of XDR-TB, which are more resistant still. Then there’s NDM-1, a gene recently discovered in India that’s resistant to almost all antibiotics, including the last-line variety.
And it’s not just developing countries that are affected. In the US, about 99,000 people die yearly from hospital-acquired infections, the vast majority a result of resistance. A 2009 European Union report found 25,000 European deaths annually were directly attributable to antibiotic resistance. And in Australia, results published in 2009 of the first extensive nationwide study of staph deaths – of the 6000 annual cases, 20 per cent died within a month – found that a quarter of the infections were MRSA (methicillin-resistant Staphyloccus aureus).
But there is good news. Rates of hospital-acquired MRSA have recently stabilised or even declined, and if you’re young, your risk of death is low. The bad news is that MRSA is becoming increasingly resistant to vancomycin, the antibiotic most commonly used to treat it.
And it gets worse. “Up until 10 years ago, we could say [in Australia] that resistance was largely acquired in hospitals,” says Looke. “But now we’re getting it in our communities. Common infections like boils, urinary tract infections and pneumonia are being caused by resistant bacteria. So in some cases now, we’re needing to use antibiotics of last resort straight up.”
Resistance isn’t just problematic in terms of tackling diseases or sick patients – surgery itself becomes a game of Russian roulette, in everything from organ transplants to knee clean-ups. “We may not be able to do procedures in the future,” says Collignon. “If you don’t have the antibiotics to treat the almost inevitable infections, it would just become too dangerous.”
Of concern for men, prostate biopsies will become far riskier. The probe goes through the bowel, where many nasty organisms live, and these can be transported into the bloodstream. With antibiotics, the procedure is safe. But if in future they aren’t effective, well, you don’t need a medical degree to understand the implications.
In Lorne, on Victoria’s Great Ocean Road, the summer tourist season has finished. As midnight approaches the streets are largely quiet, save the gentle lapping of waves and the thin sound of music drifting down from the town’s edge. There, at the Grand Pacific Hotel, a seven-piece band blasts away in front of a dance floor crowd more notable for its enthusiasm than its rhythm. To be fair, the dancers aren’t here for the nightlife: the Australasian Society of Infectious Diseases (ASID) is in Lorne for its Annual Scientific Convention, and the agenda tomorrow is that of resistance. For tonight, though, there is dancing.
But if anyone has forgotten they’re here for work, not fun, and if anyone has cobwebs from the previous night, then at nine o’clock the next morning, visiting US professor Dr Robyn Patel blasts them away. The Mayo Clinic professor/freight-train slams the jam-packed conference hall with a wall of sound, spitting out tongue twisters – depsipeptide D-alanyl-D-lactate incorporated into a pentapeptide peptidoglycan cell wall precursor! – with an auctioneer’s no-breath-drawn, mile-a-minute, motor-drive mouth. As a non-medical professional I find her, frankly, intimidating. But not nearly as intimidating as some of the slides she shows – especially a series illustrating the spread of VRE (vancomycin-resistant enterococcus) around a hospital ward. Despite the original patient being quarantined, new outbreaks popped up like lights turning on around the city at dusk.Up next is the reason I’m here: the University of Queensland’s world-renowned infectious disease expert, Professor David Paterson. What I want to know is why this is happening. Why now? And what causes resistance in the first place?
After his lecture, we meet. Paterson – an angular man in his forties who still gets his best ideas out on three-hour runs – is an expressive individual, using hands to amplify or illustrate points, fingers in the air to create diagrams or display triangulations of influence. And when describing his favourite resistant micro-organism – klebsiella, every young man’s idol, he says – the upturned fist pump to demonstrate the universal symbol of virility.
The root cause of resistance turns out to be, in a word, evolution. If you’ve ever doubted the theory, antibiotic resistance may well offer the proof you need. While the relative longevity of humans, and most animals around us, means evolution occurs so slowly we see little change, bacteria are different. With their shorter lifespans, we can observe the transformations.
And what we’re seeing, Paterson tells me, is that they’re evolving to “outsmart” antibiotics.
There are many types of bacteria, he says, and they’re competing. Some bacteria have “learnt” to destroy their competitors by naturally producing antibiotics – bacteria, in fact, were the original source of antibiotics. But in the most common mechanism of antibiotic resistance, some bacteria have retaliated by producing enzymes known as beta-lactamases that destroy antibiotics by disrupting their chemical ring and bonds. And while these mutations happen by chance, once one of them can do that, they’ve got a competitive advantage. So they proliferate.
Assisting this is the fact that bacteria are out and out sluts. “They’ve got no morals,” says Paterson. “In our intestinal tracts, it’s bacterial group sex with no regard to species barriers. It’s shocking.” As a result, resistance genes can pass from one species to another. In response to the enzymes produced by resistant bacteria, pharmaceutical companies historically have developed new drugs beta-lactamases couldn’t break down. “But it’s like a nukes race,” says Paterson. “We do something, they do something back. And what’s frightening is that now we’re at this stage where we’ve got beta-lactamases that will knock out top-of-the-line antibiotics like carbapenems. It’s a process that has long been occurring naturally, but it’s ramped up now we’ve started using antibiotics.”
And that’s one of the key issues. Because not only have we been using antibiotics, we’ve been using loads of them.
“We’ve become used to using antibiotics not just for treating defined infections, but as a what if?, a just-in-case,” says Sydney University associate professor Dr Tom Gottlieb, president of the Australasian Society for Infectious Diseases. It might not sound like the most grievous of crimes, but the consequences are grim. First, antibiotics are the only drugs that affect someone else. “Take a medicine for heart disease, or say for lipid control,” says the softly spoken Gottlieb, now communicating with rapid-fire purpose, “and it’s just between you and the medication. It may make you healthier. It may make you sicker if you have a reaction to it. But nobody else is affected. When you take antibiotics, you’re not the only one affected by it. If your bacterial flora, in your nose or your gut . . . becomes resistant then everyone around becomes exposed to these more resistant organisms.”
Second, and most crucially, resistance is related to the volume of antibiotic use. The equation is simple: the more antibiotics we use, the more resistance develops. And the more resistance develops, the more antibiotics we need to use.It’s a vicious circle. Especially when that means that as doctors feel they can’t trust standard antibiotics, they’ll
turn more quickly to last-line versions, which in turn breeds resistance to those drugs as well. In essence, over-prescription speeds up the rate of evolution.
In Australia, at least, you need a prescription to get antibiotics. But that’s not the case in many developing countries. After contracting amoebic dysentery in India, I simply approached a hole-in-the-wall “medical shop” and told the pharmacist what I wanted – and got it, no questions asked. I use the term “pharmacist” loosely, though, because who knew his qualifications? Many have none. “Business rather than science is their occupation,” complains the Indian Journal of Medical Ethics.
“One of the problems,” says Gottlieb, “is that antibiotics came after World War II and it was an optimistic era. They assumed antibiotics could save lives. And obviously they can. But they just assumed they could be used everywhere.”
The use of antibiotics hasn’t just been restricted to humans or pills, either. Especially if you add antibacterials – which similarly cause resistance – to the mix. We use them in dishwashing detergents, sponges, chopping boards, plastic bin liners, cosmetics. “Some argue [some of these antibacterials] are not an issue, because humans don’t use them [medically],” says Collignon, “but I argue they feed into the whole culture of overuse.”Then there’s agriculture, perhaps the most contentious area of antibiotic use. Antibiotics are used therapeutically to treat sick animals, to prevent infection and, widely, as growth promoters. As a result, more antibiotics are used in agriculture than on humans. They’re added to feed. Injected into chickens before they hatch. Sprayed on fruit. And while not all antibiotics used in agriculture are the same as those used to treat humans, many are. Confusing the issue is that many antibiotics undergo name changes when they’re used for animals. “Oh no,” farmers might say, “that’s not an antibiotic, that’s a growth promoter.” Or perhaps, “No, the tylosin we use isn’t used for humans.” But tylosin is a macrolide, the same class as clarithromycin that is used in people. And once you’re resistant to one drug in a class, you’re usually resistant to all drugs in that class.
“The tragedy is that most of these antibiotics are a complete waste,” says an indignant Collignon. He may not be shouting and raging, but the long, hard looks he’s giving me – at odds with his mild-mannered bow tie and rimless spectacles – are almost unnerving in their intensity. “It’s obscene,” he says. “Farmers . . . are made to believe if they don’t use them lots of their animals will die. But in Denmark, they convincingly showed that stopping the routine use of antibiotics made no difference to production.”
Resistant bacteria in animals transfer to humans by several means. It can be animal effluent in the water supply, or using manure as fertiliser for vegetables. But most commonly in Australia it involves the slaughtering process.
Originally, these bugs were in the bowels of animals. But when they’re slaughtered, faecal matter gets on the outside of meat. And chickens usually go through a warm-water bath, which transports the resistant organisms. But I only buy organic meat, you might say. Doesn’t matter. Remember, antibiotics affect not just the person consuming them, but the entire community. You might know where your produce comes from, and that it’s antibiotic-free, but if Joseph Bloggs next door picks up a resistant infectious bug, then you can catch it from him.
Collignon stresses the Australian situation needs to be put into perspective. We do use too many antibiotics in agriculture, he argues, and should cut our use by 50 per cent, minimum. But we don’t feedlot our beef. “And although we use more antibiotics in agriculture than the EU, our social conscience on this is much better than the US and Canada. And compared to India and China, we’re almost saintly.”
Of course, India and China aren’t alone in lax pharmaceutical regulation. Nor is the globalised food chain the only way Australians are affected by other countries’ overuse of antibiotics. Instead of importing the resistance to us, we can export ourselves to it, just as The Fully Sick Rapper did. The explosive growth in overseas travel is a key factor driving multi-drug resistance in Australia. Studies show that when travellers return from certain countries, their resistant bacteria may have increased by as much as 30-40 per cent. And in 2004, the British Medical Journal, after noting that “over the last four decades, [Australia’s] resident population has doubled, whereas the movement of people across its international boundaries has increased nearly 100-fold”, singled Australia out as a “striking example” of the influence of travel on infection.
Although the state of resistance overseas is sobering – stats such as E. coli resistance in India and China being as high as 60 per cent, compared with three per cent here – it’s important not to scaremonger, says Paterson. “Ninety-five per cent of people travelling to those areas who get a resistant organism in their system are not going to notice any difference. We have millions of bacteria in our guts – a few resistant ones won’t necessarily make us sick.” The thing to be aware of, he says, is that every now and again, some do make us sick. And it can occur in the general healthy population – just ask Christiaan Van Vuuren.
But if there’s one single factor bringing the resistance issue to a head, it’s the lack of new antibiotics. Paterson recalls a surgeon once telling him he didn’t care about resistance, because there was always something he could use. “Well, now we’re at the stage [where] that’s not the case,” he says. “We’ve come to this perfect storm where we have this resistance, but there are no new drugs in the pipeline.”
US Food and Drug Agency approvals of new antibiotics have dwindled. Actually, “dwindled” doesn’t quite do justice to the drop-off (see graph on page 89). The issue is simple economics. Antibiotics might be used for five or six days at a time; drugs for cholesterol or heart disease 10 or 20 years. That’s after jumping through all the developmental and regulatory hoops, the lab testing, the animal testing, the clinical testing – as well as the drugs that don’t go anywhere – all of which makes the cost of bringing a new antibiotic to market as much as $800 million.
“But from our point of view,” says Looke, “we say, Yes, we know we can use it for everything, but what we’d like to do is hold it in reserve until we really need to use it. And some of the more recent antibiotics, from 15 years ago, we’re still holding in reserve effectively. Meanwhile, the patent runs out. Now other manufacturers can make it, and they [the original researching pharmaceutical company] don’t make any money out of it.”
It’s hard enough expecting pharmaceutical companies to take half-billion-dollar-plus losses on the chin. But there’s another, non-economic factor: technical difficulty. Many experts fear that most of the “easy” antibiotics have already been found. Currently, antibiotics are discovered by screening compounds. Problem is, we’re running out of compounds to screen.
Which is what leads me to leave my Sydney home at 5am, fly to Melbourne and creep across town during peak-hour to Monash University’s Microbiology Department. This is where I find researcher Dr Anton Peleg, who I’d met at the ASID conference. Back then, I’d been struggling with the microscopic nature of resistance – I wanted to see something. So when Peleg offered to show me his C. elegans, well, this was an opportunity too good to pass up.
Now I’m looking through a microscope at . . . pubes. At least that’s what the millimetre-long worms I’d come to see look like: little curly grey hairs on a lighter grey background. But am I disappointed? Not one bit. It’s not only the youthful exuberance of Peleg – a man barely able to contain himself as he demonstrates mutant bacteria and the knocking out of genes by the waving of arms, clasping of palms, slicing of air and twisting of fingers – but the potential secrets these little worms can unlock.
“We need to think more laterally about how we attack bacteria,” he says. “Not necessarily to kill them off, but what if we can attenuate their virulence? Or prevent them from being persistent in the human body? Or prevent them from attaching to medical instruments to prevent biofilm? What if we just turn everything off so that the bacteria are still there, but they can’t make us sicker?”
One approach involves mutating prototype bacteria by inserting genetic elements called transposons into their genomes.
“We don’t know what the outcome will be,” says Peleg, “but the more random the better.” Because who knows what the effect of each mutation might be? Say, for example, they find a mutant unable to attach to plastic (an important consideration, as it could stop bacterial biofilm attaching to surgical equipment like catheters). Since the transposon has been marked, and since they know the parents can attach to plastic, they can figure out which gene has been knocked out and is therefore important for attaching to plastic. The same can be done for growth in human serum or whatever other virulence screen you want to do.
But, while interesting, Peleg’s lab isn’t alone in doing this kind of thing. What’s unique is another approach, one he says the pharma companies aren’t exploring. It harks back to Paterson’s comments about competing bacteria.
In nature, micro-organisms are everywhere, and all these different bugs compete for space or nutrients. Bugs attack other bugs, or prepare themselves for attack by other bugs. So Peleg began thinking: where, and how, does acinetobacter – a resistant bug that caused major problems in Australian hospitals a few years back – interact with other bugs? And how does it interact with something more diverse? Not another bacteria, say, but a fungus? What about Candida albicans, one of the most common fungi in ICUs? Wouldn’t it be fascinating to understand the molecular interactions between acinetobacter and candida?
What Peleg found was that as the candida grows, it develops a mechanism for dealing with the acinetobacter. And – here’s where the worms come in – he’s infecting C. elegans with candida and the acinetobacter to understand not just the molecule or compound that candida develops to fight the acinetobacter, but the mechanism. “That’s even more important,” he says. “Because if I can understand that, then maybe I could engineer a compound with the same mechanism.”
Peleg’s isn’t the only left-field approach to tackling resistance. There are others targeting anti-virulence, and beyond that, others looking at vaccines and immunology. Even further out there, some are studying methods to use bacteria to transport lethal genes to the nasty bacteria, or using photodynamic therapy for skin infections. In sum, even if we are running out of compounds to screen, even if the quest for new antibiotics is becoming increasingly difficult, the future is not entirely bleak.
Many solutions don’t even involve discovering anything. What they do require is willpower. The will to clean the dirty hospitals and weed out the lazy doctors, for instance? Well yes . . . and no. Both would be an oversimplification.
First, improving hospital hygiene does work, but it’s easier said than done. Drug-resistant acinetobacter, for example, can exist on dry surfaces such as bed rails for a month. In short, obtaining a perfectly clean hospital, one that’s 100 per cent germ-free, requires massive resources – resources that could be used to treat patients. Unless we’re willing to raise taxes in order to boost staffing levels considerably, there will always be a trade-off.
Second, although there are some lazy doctors who don’t think about – or worse, don’t care about – the ramifications of overprescribing antibiotics, most doctors “want to do the right thing”, insists Looke. But the right thing by an individual patient and the right thing by the entire community may not just differ, but be diametrically opposed.
Although reducing the volume of antibiotics prescribed might be good for the community, you run the risk of, every now and then, a patient getting sick who otherwise might not have. And in these cases, it’s the individual doctor who shoulders the burden of guilt, or lawsuits, or both.
It comes down to a public good that’s shared (and for which they’ll personally never see the results), versus an individual loss borne entirely by the doctor (and their patient). Bear in mind, most doctors aren’t lazy, or in the pocket of drug reps.
What they want to do is make sure each and every one of their patients do not get sick. And the end result, says Looke, “is [your doctor] probably does more than is necessary. More procedures. More drugs. More antibiotics. He wants you to go away saying, ‘This guy’s great, he thought of everything’.”
So the need for willpower extends further out: to helping developing countries secure clean water supplies, which stops people from getting sick and needing antibiotics in the first place; to providing funds for education and research; and to making a few changes ourselves – to not expect antibiotics for every sniffle or minor ailment, or for colds and viruses, against which antibiotics don’t work anyway.
This is the end. The bit where Gottlieb says, “We’re not trying to say ‘don’t use antibiotics’ – we have to use them. But if we can control the amount we use, we can keep our antibiotics longer, by which time science will hopefully have found another way to treat these infections.” To the bit where The Fully Sick Rapper gets angry, in a punk kinda way. “We would be in a far better position if we (in the First World) spent some money on it and actually gave a shit about people in the Third World.” And the bit where Paterson says, “If you remember with HIV, you had celebrities like Magic Johnson contracting the disease. We almost require that now. I hope it never happens, but it’s almost the only way this will get the political pressure it deserves.” And finally the bit where I return to Gottlieb saying, “I think we’ll look back on the antibiotic era and say, ‘Wow, that was a great time. A pity it’s passed’.” Except that it’s not the end. While we continue to dawdle, resistance is growing inexorably.
It’s only the beginning . . .
For more information, head to MedicineWise.com.au