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Tuesday 6 January 2009, 9.00-9.30pm
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CASE NOTES Programme no.2 - Antibiotics and Probiotics








Hello. Today's programme is about antibiotics and probiotics.

The dangers of overuse of antibiotics - particularly resistance and the emergence of "superbugs" like MRSA - are well documented. But what about probiotics - supplements of so called friendly bacteria - can you overdo these too? We'll be talking to a team of Dutch researchers who believe probiotics can do more harm than good in some situations.

But first antibiotics. GPs issue 35 million prescriptions for them every year, a figure that is falling, but one that is still regarded as far too high and now NICE - the National Institute for Health and Clinical Excellence - has stepped in to try and do something about it.

Colds, flu and nearly all the hacking coughs filling GP waiting rooms over the last couple of weeks are caused by viruses, and antibiotics don't help. And you are even more likely to be turned away empty handed this winter thanks to new guidance from NICE advising that antibiotics should not be offered to the vast majority of adults and children with other upper respiratory infections, including tonsillitis, sinusitis, sore throats and ear infections.

Professor Paul Little is a GP and chair of the group that came up with the new guidance.

Antibiotic use in general practice probably peaked in the late '90s, mid to late '90s, and then was falling until sort of the early 2000s and now has been static for a few years now, so we seemed to have reached a plateau.

And how's the new guidance from NICE going to change that do you think?

Well I think we have to be realistic about what guidance can and can't do but I think it's important, if you like, to put down some markers to give GPs some idea of what they can be doing. We know that actually most people come to see their doctor with a respiratory infection - that's coughs, colds, ear infections, sinusitis - still getting antibiotic, in the case of sinusitis it's about 100% or near on 100%, most people with bronchitis or chest infections it's probably well above 50% and even for sore throat and other respiratory infections it's still over 50%. And we know that most of those people just aren't benefiting. So the NICE guidance, I think, give GPs access to the evidence that most people aren't benefiting and provide some suggestions about alternative strategies that they can use.

When you say that there's evidence that most people aren't benefiting, does that mean that some are?

Yes and therein lies the problem. We know that on average the vast majority of people that come and see us aren't going to benefit symptomatically from antibiotics, there are people who probably will benefit from our knowledge at the moment and those will be people like the very elderly with multiple other problems like bad heart failure or bad lung disease who are more likely to benefit from antibiotics and possibly also the very young and also those who are very, very unwell when they see the doctor, probably less than 5% of the people who come to see the doctor who are that unwell. But apart from those groups the studies that have been done, which often actually have excluded those groups, show that on average most people don't seem to benefit.

So to put those benefits or the lack of those benefits into context - if Joe Bloggs comes in with sinusitis and is given antibiotics there's absolutely no benefit over a similar group who aren't given anything at all, is that what you're saying?

That's exactly right.

So what if you are prone to tonsillitis say and have always been given antibiotics in the past? It's GPs like Dr Fred Kavalier - at his practice in North London - who are going to have to explain the apparent U turn.

Well tonsillitis is terribly common, I mean I'm sure millions of prescriptions are issued every year for things like tonsillitis. What is tonsillitis? Well it's a sore throat and it particularly affects the tonsils and it can be very unpleasant - you can get a high fever, you can get a headache, you can be pretty unwell with tonsillitis. Most cases of tonsillitis are caused by viruses. We know this by doing studies - taking swabs - we know that most of them are caused by viruses and we know that viruses do not respond to antibiotics. So the argument against using antibiotics is strong because most of the time they're unnecessary.

I mean it sounds like a sudden change for many patients but of course if you've been in general practice there's been a lot of pressure on antibiotic prescribing for some time, particularly with things like ear infections we've been told that we shouldn't be doing that. One of the problems that we have is when looking at the patient we can't tell whether it's a bacterial infection just by looking.

No if you look down someone's throat, no matter what anyone tells you, it's very, very difficult to know whether it's a bacterial infection or a virus infection, you just can't tell by looking. So you have to sort of use your judgement - how ill is this patient, do they have any complicating factors? But for the great, great majority of them they'll get better without antibiotics.

And how have your patients taken that message?

I think some patients come into the room knowing that antibiotics aren't the right thing and they leave the room feeling happy that you've reassured them about that. But there are many patients still who believe that the only way to get better from a sore throat or from an ear infection is to take antibiotics and sometimes they believe this on the basis of their own experience - they've taken it and they've got better - so that makes them think this is the way to do it.

Of course one of the problems with this evidence based practice is it's based on large groups of patients and we know that antibiotics make little difference, for instance, to recovery rates from ear infections but you and I know, looking at the coal face, that it transforms the recovery rates in some people and has no effect in the majority. So how can you tell, as a GP sitting there looking, whether you're doing this for the greater good of the patient or society in general?

Well I feel this is one of the new doctors' dilemmas really because you know we're faced with the dilemma - are we doing our best for the patient who's sitting in the chair across from us or are we doing best for the greater population in trying to reduce antibiotic prescribing and reduce antibiotic resistance? And sometimes it is a genuine conflict of interest because there are some patients - it's hard to identify them - but there's some patients who will do better if you give them antibiotics.

So what is the main driver behind the new NICE guidance - public health and the growing threat of antibiotic resistance or the wasting of precious NHS resources on treatments that are unlikely to work? Paul Little again.

Well I can only speak for myself as chair of that particular guideline that actually the emphasis is on trying to do the right thing. We do have a long term issue about antibiotic resistance in that everybody's heard about the story about these resistant superbugs. We don't have anymore antibiotics that are going to be coming online for us to use in general practice and we do need to keep antibiotics for those people who are desperately unwell who really need them. So we have a problem - we don't have anything in the pipeline, we have a public health problem that is likely to be getting worse if we go on using antibiotics inappropriately. So I think that's a major driver. The other issue is that actually it isn't a sensible use of resources because we know what happens that if you prescribe antibiotics for somebody they will get better, they will attribute that to the antibiotics, they will then - the next time they have similar symptoms of course because they've had antibiotics and they thought that they got better because of antibiotics want to go and see the doctor again and expect antibiotics. So you get into, if you like, a medicalising vicious circle. And we know from the research that we've done that that's exactly what happens and it's quite a powerful effect, for example, compared to people who haven't had an antibiotic people who have had an antibiotic are about 40% more likely to come back again the next time they have something similar. So it's really quite a big effect. So I think it's a message that goes out to society that keeps going round, if you like, it creates its own vicious circle and it's not sensible if we're not actually therefore doing terribly much for people, it is wasting resources and people are just getting the disadvantages of antibiotics, it's not just antibiotic resistance, it's the fact that they're - 10, 20% of people will get a side effect from a broad spectrum antibiotics like amoxycillin, they'll get diarrhoea, women will get thrush, there's allergies and so forth. So antibiotics aren't without their problems either, it's not just that you're wasting NHS resources, which is probably true, but that's not the main driver.

One compromise is to use what we call delayed prescribing and that's where we educate the patient about what's going on, it's probably a viral illness antibiotics probably aren't going to help, but we can give them a prescription to take with them that they can filled at a later date if certain criteria are met, could you explain how the system works?

Yes well the way the research has worked is that we wanted to know whether obviously the antibiotics were being used or not, so a delayed prescription was offered to the patient and the deal was that people were offered the antibiotics prescription at the front desk of the surgery to be collected if symptoms weren't settling around the sort of time you'd expect for the natural history of that illness, so the patient would then come back and say that I was told that I had an antibiotic prescription, collect the antibiotics prescription and use it. So the conditions were if it's not starting to settle in that expected timeframe or getting significantly worse. So the advantage is it allows people access to antibiotics fairly rapidly without having to make a new appointment. As it happens the antibiotic use, if you use that strategy as a doctor, is actually rather low, it's not that much more than if you say no antibiotics for you because a certain number of people will come back anyway and we know from the research on delayed prescribing so far that in fact you seem to sort of empower people in their use of antibiotics and very few of them will come back for the prescription - between 20 and 30% - and over the subsequent year or so when you follow people up they'll come back even less often then the people who you said no offer of antibiotics to, if you like.

Patient Rory Reilly has been on the other end of the NICE guidance after being struck down by one of the viruses doing the rounds over the festive season.

On Boxing Day I really began to feel lousy, I felt I was getting a temperature, I was certainly getting much, much shorter in breath and began to just feel pretty low. Had some friends around, once they left went to bed, I didn't get out for about six days. I think after about four days I decided that I would give the doctor a call. And rather than go down and see the doctor in the surgery, which is about a mile and a half away, I decided that I would just talk to the doctor on the phone. I outlined my symptoms to her and she said to me that it sounded, yes, as though I had this flu and it would take time for me to get over it but that I should come and see her if it got worse. Which I did, approximately two days later. My temperature was going up a bit, but not very much, but I really wanted to check that I didn't have a chest infection, as my daughter Emily had developed a chest infection from very similar symptoms. Well I thought that if I had a chest infection then I would be put on antibiotics but I knew that if I didn't have a chest infection that I wouldn't. Well the result was she checked my breathing on my chest, on my back, very thoroughly and decided that my lungs were clear. I think since then I have been getting slowly better but it seems to be a very slow process, frustratingly slow.

And that frustration often drives patients back in to see their GP believing that their persisting symptoms indicate they do need antibiotics after all. Patients - and many GPs - often seriously underestimate how long it can take to recover from a viral infection. So how long should people expect to be under the weather? Paul Little

So for somebody with an ear infection they've normally had about a day of illness, it's quite an acute painful illness, and they're going to have about three days after that. For sore throat they'll normally have had about three days of illness prior and will have, on average, about five days after that. For sinusitis about a week to 10 days before and then usually about 10 days after. And for cough often 10 days before and about 10 days to two weeks after. So you have to give people very realistic information about the natural history and that's one of the things, I think, GPs could get from the NICE guidance - just some simple guidelines, if you like, about giving information about the natural history so that expectations about rapid resolution aren't reinforced.

And antibiotic use of course will continue for other conditions, I mean I'm thinking of long term treatment of acne and things, we haven't changed our thoughts on that?

Yes, I mean that's not part of this guidance because the guidance was specifically for respiratory infections. So yes antibiotics seem to work for acne and we don't quite know why they work for acne but they certainly seem to and there's a role there and obviously NICE will be producing guidance about other conditions, this is particularly about the commonest use of antibiotics which is respiratory infections.

Do we know what proportion of antibiotics prescribed in general practice are given for these so-called respiratory tract infections?

It's - it's the vast majority. So the remainder is for some skin - so that would be acne and cellulitis, that's a very important infection in the skin that does need antibiotics. And the other common infection that we prescribe for is acute urinary infection or cystitis. And again those conditions probably do benefit from antibiotics, although it's not mandatory. So they are outside this guidance.

Paul Little talking to me earlier. And as he indicated there, antibiotics still have a very important role to play particularly in the very young, the elderly and the very sick.

Professor Raj Kumar, is professor of geriatrics and stroke medicine at the Brighton and Sussex Medical School and has a special interest in the use of probiotics to reduce some of the unwanted side effects of antibiotics in his elderly patients.

Raj, firstly perhaps we should start by explaining what a probiotic is?

Well probiotics in simple terms are friendly bacteria, which live in our gut. They're found in all sorts of drinks, particularly in yoghurt drinks, and people have consumed it for hundreds of years, so it's not something which has just been discovered, it's been there for a long time.

Now I said you had a special interest in it, you've got patients who are in hospital and on antibiotics who are at risk of diarrhoea, people may have heard of the term C.Diff, it's one of those problems that we have in hospital. You had a problem with it, explain how you got your initial interest.

Initially when I was a registrar, more than 10 years ago, I found that our wards were getting closed or bays or parts of our ward were closed purely because people had diarrhoea. Some of it was obviously viral outbreaks of diarrhoea but other times it was because of the same bug, which you mentioned, called C. Difficile. And it is a dangerous organism and in fact it can result in deaths as well. So that's what got me interested.

So what did you do about it?

After looking at the literature, over 150 papers, we found out that probiotics are in fact effective. We published that data in the British Medical Journal over seven years ago. And the next step was to actually do a placebo controlled trial. So half the patients received the active ingredient and half the patients received a placebo - a look alike.

And the active ingredient was what - what were you giving your patients?

The active ingredient was Actimel, which has L Casei in it, which is a probiotic, and has got a couple of other organisms in it. And...

And why particularly that one?

Well this is based on the [indistinct word] as I said before. We came up with two organisms which were active and one of this was this one. We looked around to see how we could get a matching placebo and Danone, the company which makes Actimel, was kind enough to provide us, in the initial stages, about 40 samples of look alike - or placebo as you'd call it - with active ingredient. And then we went on to then expand it into a larger pilot trial, as you can call it, with 150 patients. But unfortunately when we were at that stage we couldn't get the placebo, so we had to go and find another look alike agent from the supermarket and that's how we did the trial.

So you were buying off the shelves?

Yes, in fact it was delivered by a supermarket.

And what sort of results did you get?

We found fantastic results. The antibiotic associated diarrhoea was significantly reduced in the population which got the active ingredient. C. Diffile was zero, there was no one got C. Diffile infection in the group which was receiving the active ingredient. So that's what prompted us. And then the next stage of that is I actually tried to implement that in my own hospital now in Brighton where we use the left side of the hospital where there are elderly care wards, we give them the active ingredient, on the right side of the hospital which is also has elderly care patients in there we didn't give them any active ingredient and we found that on the left side C. Diff rates were reduced quite significantly from the same period last year to the other side. So we actually applied it in real life as well and we find it works.

So Raj what do we think that lactobacilli are actually doing in the gut to protect the patients?

What happens is when you take antibiotics the good and the bad bacteria are killed. When you give them probiotics it actually helps to colonise them in the gut. Some of them will be killed obviously but the trick in our paper, as you would have seen, is at the end of your antibiotic course we continued to give them probiotics, the good bacteria, for at least seven days. So that's when they'll be getting a foothold into the gut and establishing themselves and preventing C. Diffile infection coming on and that's what I think maybe. Apart from that there are a whole lot of other mechanisms which probiotics do, including changes to the immune system. There are again small papers published on this and again this area needs to be investigated further.

So where you do you go next with your research?

We need to have large multi-centre trials, we need to do this in probably 10, 20 hospitals round the country. We need to have placebo controlled trial, which means real versus a look alike but exactly similar ones.

So no one can tell the difference?

That's right. And when you do that I think you'll get the right answer and the other important thing in all of this is you should look at cost effectiveness - how much does it cost to have one patient in a hospital bed, anyone would say oh it's a lot of money but realistically if you work it out and if you do a trial like this you can work that out and that would help.

Well let's pre-empt those research findings. Based on what you know now what do you think the practical applications might be, I mean do you see a day where your patients are routinely put on these things when they come into hospital?

I think not only that - I agree with you, I see a day when patients would routinely be given probiotic drinks when they are admitted to hospital, probably the staff may also be taking probiotic drinks when they come - when they work in a hospital environment but I also think there will be a day when the general practitioner - such as yourself - when you're prescribing antibiotics to any of your patients you would probably recommend that they continue to take this good bacteria at least for a period of seven days after they've finished antibiotics and that would then prevent the chances of them coming in with C. Diffile infection because some of these people probably have had a course of antibiotics with the GP, have already at the verge of developing C. Diffile infection, they're then coming into the hospital and then another course of antibiotics tips them over the balance. So I think the day will come when it'll be out in the community, the GPs will be prescribing it and then from there they'll be going on to the hospital where there's less likelihood of developing the infection.

Well over in Holland, another team of researchers have been investigating the benefits of probiotics. This time in a very sick group of patients with inflammation of the pancreas or pancreatitis. But their results - published last year in the Lancet - were not quite what they had anticipated. As Marnie Chesterton discovered.

St. Antonia's teaching hospital just outside Utrecht in Holland. It was here that nearly 300 patients with severe acute pancreatitis took part in a probiotics trial between 2004 and 2007. When the results were published, earlier this year, they showed shockingly that patients given the probiotics were more likely to die than those on the placebo. Dr Marc Besselink is the lead author of the study, he explains more.

Our interest was to prevent infections, caused in patients with pancreatitis. In the Netherlands 3,500 patients get it each year and of the patients that die that's about 4-5% of these patients, 80%, 80 or over percent, has got an infection. So if you could prevent the infections you could prevent the mortality. What we did we selected the high risk patients, patients who were about a 30% risk of getting infections in pancreatitis, these patients are acutely ill and yet we randomised 300 patients between either probiotics or placebo. And they used it for four weeks and then what we found was that the patients using probiotics had almost over a doubled rate of mortality - 16% versus 6% - 24 patients versus nine patients. So more patients died in the probiotics group and it was a total surprise to everybody.

So what went wrong?

Nothing went wrong. What happened is that we found out that if you give probiotics to patients who have organ failure, who are on the intensive care and who need support, who can't breathe on their own, who are on a respirator, who need medication to keep their blood pressure on a good level, if you give probiotics to patients who are in that condition that something happens to the bowel, small bowel wall, we're not entirely sure what happens but what we saw in nine patients was that their entire small bowel or parts of it became ischemic, carotid.

Bowel ischemia is that like a heart attack but in the gut?

Exactly. It's a black dead bowel, it's very ugly.

Professor Louis Akkermans, head of experimental surgery at Utrecht Medical Centre in the Netherlands, and has been working with probiotics for 13 years, does he think this clinical trial has shown probiotics to be dangerous?

I'd say for healthy people they are not dangerous and I believe at this moment but has not absolute proof of it when you use them preventive - so before you get a disease - then all the literature till now is very positive. But we have proven that when you have the disease and want to treat the disease it can be completely different situation. So it depends on the timing of applying the probiotics. For instance, in patients who have large operations if you give them probiotics let's say one week every day before the operation then you can reduce significantly the chance for infection. So in that preventive way it's I think still very useful to do.

Back to the trial, what actually caused the bowel ischemia? Marc Besselink's team are looking at two hypotheses.

The first is is that patients who are severely ill there's less blood in the bowel than normal, because if you're very ill the first task of your body is to get blood to your brain and to your heart and not to your bowels. So when you give probiotics to those patients probiotics might produce some compound which might be very bad for the bowel. That's one hypothesis. The second is there's some reaction in this poorly vascularised bowel to the probiotics or that there is a sort of inflammation in the bowel wall as a response to the presence of these high numbers of probiotics and that the inflammation in the bowel wall leads to problems with the supply of oxygen and that leads to the ischemia.

When do you think you'll get an answer?

If we ever find out it's probably going to be two or three years from now. So until that our advice and also in our paper in the Lancet was do not administer probiotics to patients on the intensive care who are at a very high risk for organ failure and if you wish to do so do so in a very controlled setting of a study with specific attention to the bowel function.

There was a theory that you can take too few of these probiotic bacteria for them to have any effect, that the general idea that you can't take too many, they don't do any harm. So your trial has shown that they're not actually harmless.

I think a healthy person it's highly unlikely that they can too many probiotics or probiotics can harm them.

Professor Akkermans is also positive about a future for probiotics in abdominal surgery.

I'm convinced that in the end when we have done a lot of research and studying and see the interaction between the microbes in the gut and let's see the epithelium and the mucosal barrier function and your immune system and your defence when we understand more of this then it gets easier to develop the right combination of the right lactobacilli to treat in certain disease. It would be an illusion to think that you take probiotics and it helps against everything, I think that's complete nonsense, it's still a long way to go.

Louis Akkermans talking to Marnie Chesterton in the Netherlands.

Raj, do those findings surprise you?

No not at all. Look these are very sick people in this trial. Acute pancreatitis is a serious condition. They gave it to people who had organ failure. If your organ's already failed and then you give six different probiotics, which is what they used, they used a combination of six organisms, then certainly that is going to cause problems. It was given not by mouth but is given through an enteral feeding tube, which is a tube which goes from your nose and sits down into your gut. Now that might be different because when we normally take it goes through the stomach and a whole lot of changes happen. So there's a whole lot of reasons why this may have been the case. So all we can say is it is serious but not something we'd be worried about in the way we are planning to use it.

But despite that - the problems that they had they were actually very positive I felt about probiotics, they felt that given appropriately early in patients who are well that they were likely to benefit and that was the argument you were making earlier on.

Yeah, no, I mean I'm all for it, in fact my main area is preventive medicine. I prefer to have prevention than cure. And one of the ways we can prevent, as I told you before, is we should give it earlier in the patients when your general practitioner gives you your first course of antibiotics and you finish that, that's when you should be taking these drinks, so that it doesn't come to the stage when you're sick and then you're developing C. Diff and then people start giving you some probiotics, it's too late, you've lost your battle, you've got to be prepared for the battle rather than lose your battle.

Professor Raj Kumar, thank you very much.

Next week I travel to Bristol to talk to the world's leading authority on cot death to learn more about the research behind the latest advice on how parents can best protect their child. Advice that has already saved 20,000 babies.


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