PETER COLLIGNON: The difference with antibiotics to every other drug is that they're the only group that not only gives a side effect to the individual patient, but gives a side effect to the community. And therefore it needs different controls, a different philosophy—a different culture.
CAMILLE MERCEP: Welcome to Pomegranate, a CPD podcast from the Royal Australasian College of Physicians.
This month's episode is presented in partnership with the Internal Medicine Journal, the official peer-reviewed publication of the College's Adult Medicine Division.
“One Health” is a contemporary movement based on a long held observation: that the health of humans, animals, and the environment are inextricably linked. Zoonotic diseases are often cited as prime examples of the One Health concept, but its subtler connections are gaining prominence. One such issue is antibiotic resistance.
In the November issue of IMJ, Professor Peter Collignon has written a One Health-informed perspective: “Antibiotic Resistance – Are We All Doomed?” But paradoxically, he says he's optimistic about the future. Professor Collignon, a Canberra ID physician who also teaches at ANU Medical School, argues that the tools to lower antibiotic resistance already exist—from prescribing patterns to infection control practices, local decisions about antibiotics can have a far reaching global impact.
Professor Collignon is joined in a review of his article by colleague Dr David Looke, of Brisbane's Princess Alexandra Hospital. Together they discuss the sobering trends in global and Australasian resistance rates, mechanisms in driving the spread of resistance genes, and practical steps doctors can take for better antibiotic stewardship.
PETER COLLIGNON: Hi, I'm Professor Peter Collignon; I'm an infectious diseases physician and microbiologist. I'm at the Canberra Hospital, and I'm also a professor at the Australia National University Medical School.
The major trends I've seen in my career over the last few decades is increasing levels of antibiotic resistance—particularly internationally. We now have the situation where probably half of the common bacteria such as E. coli in places like India are for practical purposes untreatable. And we're seeing similar tends in many developing countries, but we're seeing those same bugs now in Australia. Luckily still in small proportions of people but increasing numbers—and that makes it difficult to treat, and in some of them impossible to treat.
DAVID LOOKE: My name is David Looke; I'm an infectious diseases physician and clinical microbiologist at the Princess Alexandra Hospital in Brisbane.
I think that there's a number of messages that can be taken away from Dr Collignon's article. The first one is that we really do have a serious problem, and that we can see what the outcome of resistance is in the countries where resistance is a major problem—examples of what could happen across the whole world.
The majority of practicing clinicians haven't really seen the impact of resistance in large scale at all yet. A few of them may have had one or two patients that have got a resistant bug and then they can call up a microbiologist or an ID physician and get some help with it. So they see that as part of the routine of day-to-day practice. But as yet none of the sub-specialty groups or general practitioners effectively actually have had to face up to making a decision whether or not they're going to be able to do the things that they've been doing up till now.
PETER COLLIGNON: I think it is commonly thought that antibiotic resistance is due to a mutation—that's actually not true. It's usually the acquisition of large complex genetic codes, either De Novo if you're an E. coli you pick it up from a Klebsiella or something like that, because they're interchanging with each other or another E. coli. But much more likely is once a strain has acquired this genetic code, that you then spread these organisms in larger numbers. As you can imagine if you give an antibiotic to somebody with a urinary tract infection, but they’ve got an E. coli that's resistant, the sensitive organisms are eliminated, but what's left is the resistant ones and they are in quite high numbers. So then if your waste material or your E. coli gets into waterways, you get into a positive feedback loop where you get more resistant bacteria, more antibiotic exposure, even more resistant bacterias and really high numbers. And in hospitals that happens as well.
DAVID LOOKE: So I was just teaching my students the other day and showing them the graph—in about 1999 when we had Staph aureus coming into the hospital, it was very rare for an MRSA to come from outside. But by 2010, 25% of all the Staph aureus infections coming into this hospital were MRSA, resistant to all forms of beta-lactam drugs, which are the penicillins. And we have to use drugs such as vancomycin. So you can see that this progression has been quite rapid, and the mechanism of resistance has been the acquisition of a gene—the mecA gene—which came across from another organism.
PETER COLLIGNON: The term that's increasingly used now is "post-antibiotic era," and I guess the question is what does that mean. To put it in context, in the 1920s and 30s we didn’t have antibiotics, so that if people got seriously ill they either survived because of their immunity or they died. And we call that the "pre-antibiotic era.”
What has actually happened is then we got a lot of antibiotics—particularly in the 50s, but also 60s, 70s, 80s, so much so that a U.S. secretary of health, or surgeon general, said that the era of infections was over because we have all these drugs to cure all these things. Well, what has actually happened is we have gone into a post-antibiotic era with some bacteria. For a lot of people with very common infections, we're back into the 1920s because we don’t have effective antibiotics that work.
DAVID LOOKE: The generation that was alive back then of course remember the cases of brothers and sisters that died of infections now that nobody would die of—you know, meningitis and ear infections. Appendicitis was a very feared disease because people died after even having their appendix removed, because the infections that occurred with a ruptured appendix were unable to be treated.
Of course the era that’s coming, if it is that way, is going to be quite different from the era that was then because we've got a lot more intense understanding of infection and how we can prevent it, and what might be done to manage people with various types of infections. But the changes that have occurred only in 50 years are enormous in terms of the development of new agents, and those agents becoming redundant. All happening within a very, very short period of time. And when you consider that the bugs have been around for billions of years, this is just a blink of eye.
It’s getting harder to find new antibiotics—all the low hanging fruit were discovered early and lots of the antimicrobials, as Peter says in his paper, were developed from natural products. But the coals have been raked over well and truly in terms of the easy to find antimicrobials.
The second thing is it's actually harder to test them because the regulations for human testing are way more stringent nowadays. We all say quite often that penicillin, of course, would never get up now if it was put on the market under the current regulations, because a certain proportion of people, five percent of people, are allergic to penicillin. And some of them die after they get it. So you’d never get penicillin up, you'd never get gentamicin up, you'd never get sulpha drugs up now—because they would be regarded to be too dangerous.
The regulation and testing requires almost 100% guarantee of safety. The pharmaceutical industry has lost a lot of interest in antimicrobials—they would much prefer to develop an agent that someone is going to be on for life, or for a long time, to give them a good income stream. And so most of the new drug development now is being done in universities and academic centres.
PETER COLLIGNON: The prevailing view of a lot in the profession is: “Well, unless we get new antibiotics we're all doomed—we're all going to inevitably die from untreatable infections.” I don’t actually share that same pessimistic view because my view is that if we can do the two fundamental things that drive antibiotic resistance—which is the volumes of antibiotics we use, and then stopping the spread—and we really do that meaningfully, we can make a difference with what we've got now.
If we give an antibiotic for anything we should be saying, "Do we really think this is going to make a difference to the outcome of the person?” Now that's really easy if you've got bacterial pneumonia, or meningitis, or a bloodstream infection—if you don’t give antibiotics, these people are going to come to grief. They're going to die more often, they're going to have more morbidity. But if you’ve got a sore throat, for instance, we know that 95% of those are due to viruses, so antibiotics are going to do nothing except give the patient side effects like a rash and diarrhoea.
One survey I saw suggested doctors had a perception that all the patients wanted antibiotics, but that's not what the patients actually thought. So there may be more two-way communication that's needed.
The other practical thing is we can all make efforts to prevent infections. That can be basic things like hand hygiene, taking good infection control precautions with people with respiratory infections. So now only don’t we get it, but it doesn’t spread to others. Making sure people are immunised appropriately with vaccines that work—if lots of people do that locally it makes a difference globally, in our country and internationally globally.
DAVID LOOKE: Most of the people reading this article will be prescribers, and people that prescribe antibiotics need to look at the way they prescribe antibiotics to make sure that they prescribe in a way that is going to have a minimum impact on the environment while still treating their patients adequately. You can't just treat human health in isolation from animal health and plant health—we all live in the same biosphere and effects on one group are seen in the others.
It's now been genetically shown that MRSA travelled from humans to the pig herds in Europe, and then mutated and became a new strain that affected all the pig herds, which then affected back the pig farmers and their families, and then started to spread in the villages where they live. And so we can't just live with our bugs in isolation, they and the genetic material are shared across the environment in different hosts.
PETER COLLIGNON: Australia has a relatively low rate of resistance—in fact I suspect it's one of the lowest countries in the world. It's as low as Scandinavia, which is a surprise when you look at the way we dish out antibiotics to people—we're using twice as much. And this is why it's important to actually in my view take a One Health approach, because what we simplistically think is the answer can't be right. It doesn’t explain what's happening here.
We’re very fortunate in Australia, our geography is an advantage for us. But I think a really big factor also is we don’t import any fresh meats. There is no chicken that's imported into Australia unless it's canned and cooked, there is no pork unless it is cooked, and there's very little beef or cattle imported as well. And if you look at figures, even from Europe, if you look at chicken meat in particular it has huge levels of multi-resistant E. coli, to fluoroquinolones, to third generation cephalosporins—50% plus resistance.
So I think there's lots of things we can do, not just looking at people and prevention but by looking at the environment: what we dump in the environment, what we take out of the environment. How we spread both drugs and bugs can do a lot to decrease both the development of antibiotic resistant bacteria, but more importantly the spread. Because it's the spread that is actually the major factor in having a lot of these bacteria present and causing infection.
DAVID LOOKE: We saw at one of our conferences that some Dutch microbiologists were driving their car along the highway following a truck full of chickens. And they noticed that their windscreen was splattered with chicken poo. So when they got back to their lab they took some swabs and went and cultured them and found they were full of multi-drug resistant E. coli. That really started the movement in Europe to get rid of antibiotics out of farm production.
Australia has been a place that has not used antibiotics in large amounts in food and farm production, because it hasn't had intensive farming like they do in Europe and the United States. But still many many more tonnes of antibiotics are used in animal production in Australia compared with used in humans. And so to try to take away that environmental pressure towards resistance development we need to do what we're doing in humans—which is trying to do good antibiotic stewardship to reduce antibiotic use down to where it's absolutely necessary—we need to do the same in the farming fields and the veterinary fields.
PETER COLLIGNON: In my view there is ample evidence from Denmark, a lot of Europe, the Netherlands, that you can have huge decreases in antibiotic usage without detrimental economic welfare. And in the U.S. recently their major chicken producers—there's a producer called Perdue, for instance—they've gone completely antibiotic-free in their production. And Tyson's, which produces billions of chickens a year, have said they're going to do the same from 2017.
So this can be done without going bankrupt. There's a belief system out there rather than reality and fact, but the trouble is beliefs drive behaviours.
Underlying all of this is if we can prevent infections we need to do that. Because if you don’t have an infection then antibiotic resistance isn't an issue because there's nothing to treat. There's quite good studies in Australia that show practical and particularly nationwide approaches make a difference for infections and preventing infections. And a good example where Australia is fairly unique in the world—over the last decade more and more places are collecting all the data to do with staph aureus bacteraemia. Now, the figures have only really been out for three to four years, but this practice has been happening in lots of places for the last 10 years or more, and it has involved infection control practices—everything from hand hygiene to better bundles for intravenous lines.
And the difference in Australia, compared to everywhere else in the world, is not only did we get the resistant MRSA rates down, but the MSSA, or methicillin sensitive staph aureus, rates are down. And in a study that I did with a few others where we looked at Western Australia, South Australia, Tasmania, and the ACT—mainly because that's where we could get the data—we have had a 68% drop in the number of staph aureus bacteraemias due to healthcare-associated infections over the last 10-12 years.
Now that's many hundreds of people who aren't dying a year because of these many infection control practices. And it does mean for them there's less antibiotics to have to be used, so you have less driving of these numbers of bacteria up. And also you'll have less spread because you're not using antibiotics as much, and you haven't got people with the same high numbers of organisms in the same numbers.
DAVID LOOKE: New technology has been absolutely critical to reducing infections, and one good example is laparoscopic surgery. Back before laparoscopic surgery occurred we used to have people have their gallbladders taken out with a standard cholecystectomy procedure where they'd have the coccyx incision—a large incision underneath the ribcage—and probably five to ten percent of those patients would get postoperative wound infection, and a significant number would get postoperative pneumonia. And so they ended up getting lots and lots of antibiotics.
What laparoscopic surgery has done is it has basically got rid of that operation. We never see, except in very isolated circumstances, people with gallbladders having them taken out through a standard gallbladder operation. It's taken out through keyhole surgery. These people go home the same day—they don’t get wound infections and they don't get pneumonia.
PETER COLLIGNON: One of the examples that I think is very clear for how preventative measures can make a lot of difference is haemophilus influenzae, Hib meningitis. 20 years ago this was a major problem, with increasing levels of resistance in Hib. The answer to that wasn't a new special wonder antibiotic, it was finally coming up with a vaccine that worked, a conjugated vaccine rather than an unconjugated one. The numbers of meningitis in children has dropped 95% or more with Hib, because the vaccine works and it stops the disease. So you don’t have to have a special antibiotic.
And the conjugated pneumococcal vaccine is interesting too—we give that to children, the same profound drop for the serotype is covered for both meningitis, bacteraemia, and pneumonia. But what's also interesting about that is their grandparents are getting less disease because the children have less pneumococcus in their nasopharynx, they're spreading it less to their grandparents, who then are not getting invasive disease in their 60s and 70s with this as well. And hence protecting them from antibiotic resistant bacteria.
DAVID LOOKE: If people want to look at the large scale sort of what are we doing as a community, the federal government has got its antibiotic resistance plan. If people want to know what the rates of resistance are like—what their local rates are and where is it impacting—you can either ask your own pathology service for statistics on your own area, or very soon we're hoping that the initiative for a national surveillance system that the Australian Commission on Safety and Quality in Health Care is now putting in place, will start producing statistics and data on national resistance patterns.
New Zealand does have similar issues with us, and they have a national taskforce on antibiotic resistance. Their national reference laboratory is the ESR, and has put out data on resistance patterns. New Zealand has had a big problem with MRSA in the community—it actually occurred there before it happened here, in many ways. They're very aware of resistance problems and there are some issues that are unique to their country.
And lastly, the Antibiotic Guidelines was revised to Edition 15 at the end of last year, and this should be the way that people prescribe antibiotics. I'd commend everyone to have that on their desktop, or on their desk.
PETER COLLIGNON: There's a lot of very good references available on antimicrobial resistance. Particularly the Centre for Disease Control in the U.S. has lots of good resources on their website. In Europe there's something called the ECDC, which is the European equivalent, they actually have good websites and good data. To show the importance of this, the G7 meeting that just finished in Berlin—there is a hundred-page booklet that's been put out that's on the website of the German Health Department. That's in English, and is very clear on the basic things one needs to do to help control and manage antibiotic resistance.
DAVID LOOKE: The Infectious Diseases Society of America website, IDSA—part of their website is a series of case studies, either people themselves or people and their families who have suffered the consequences of multi-drug resistant infections. And so I'd point people towards that, if they actually want to see examples of what resistance means in real terms, in human terms.
I think in every hospital and health service around the country the infectious diseases departments and microbiologists, when they have their turn at a grand round, they're putting up cases of this and warning their fellow clinicians that this is an issue. But you know, it's like most things—it doesn't happen to me until it really comes home, does it. Bone marrow transplant experts haven't had to say, “Well, is it still safe to do bone marrow transplants?” Kidney transplant experts haven't had to say, “Well, I'm not sure that we can do kidney transplants anymore, because we can’t treat the infections these patients are getting.”
So that's the sort of scenario that's happening in Asian countries that’s not happened here yet. And I don’t think its really dawned on them that that's a possibility within their practicing lifetimes.
PETER COLLIGNON: We all suffer from the fact that we see people sick and we want to make them better. That's human nature if you're a doctor. But we've got to realise there's some things that we really don't have drugs that work very effectively for, or not at all. And a lot of those are common viral infections, where we have to accept: you get better because of your immune system. We as physicians can actually say, “Do I really need to prescribe this antibiotic? If I do, is a narrow spectrum antibiotic better than a broad spectrum antibiotic?” And also, “How long should I be treating for?” A lot of times antibiotics might be given for 10 days, when 3 days is enough.
Much more we've got to get that message over, and we’ve got to get the community to get that message. I'll believe we're in the right situation when every time we prescribe an antibiotic to a patient they say, "Doctor, do I really need this and why?"
CAMILLE MERCEP: Professor Collignon's full IMJ article, with references to all the studies mentioned on today's episode, is linked on the Pomegranate website: racp.edu.au/pomcast. We've also provided links to his recommended resources for further learning.
Many thanks to Peter Collignon and David Looke for appearing on this episode. The views expressed are their own and may not represent those of the Royal Australasian College of Physicians. A special thank-you also goes to the editors and staff of the Internal Medicine Journal for our first podcast collaboration. If there's an IMJ article you'd like to hear more about, or even discuss on an episode, get in touch by emailing email@example.com.
Pomegranate comes to you from the College's Learning Support Unit. The program is presented by Camille Mercep, and this episode was produced by Anne Fredrickson. We will be taking a break over the holiday season, but you can explore past programs on our website, in iTunes or wherever podcasts are distributed. Fellows of the College are eligible for CPD points for listening to the show.
Pomegranate will return in January with new episodes—including a critical look at supervision.
PETER DAVOREN: I think the biggest misconception is that it doesn’t require a lot of effort or a lot of time to do it properly. That may come from the view of when one was being supervised, and thinking the supervisor wasn't doing very much.
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