CME Slides Forum - D.J. Goldsmith

ANTIBIOTIC RESISTANT STAPHYLOCOCCAL AUREUS IN DIALYSIS PATIENTS

David Goldsmith, London, United Kingdom

Chair: Antonio Santoro, Bologna, Italy

Ali Basci, Izmir, Turkey

Dr D.J. Goldsmith
Renal Unit
Guy's Hospital
London, United Kingdom

Slide 1

Dr Goldsmith: Chairman, Ladies and Gentlemen, thank you very much indeed, thank you also to the organising committee of the ERA-EDTA for the opportunity to give the lecture today. I'm going to talk to you today about staphylococcal infections, I think this is a very important area that deserves a lot more study and attention.

Slide 2

I bring you greetings from London having been out last night in Istanbul, not quite on the town but nearly, I think Istanbul just about gets the edge over London.

Slide 3

What I'm going to talk to you about is a perpetual battle, a battle between good and evil, we're engaged in a sort of microbiological war of attrition, I won't say who's who at the moment but we are fighting microbiological battles all the time with our patients to try and improve their outcomes because if we lose those battles, our patients will lose their outcomes.

Slide 4

Our problem is that over the years we have a new adversary Lord MRSA who is arising and causing us increasing problems.

Slide 5

Now, I think I saw David Kerr in the audience, I hope I did and I didn't do any of that but here we are back again because in 1964 one of the very early papers presented to the congress was from Newcastle on staphylococcal problems and you can see here right at the very beginning of the dialysis story, staphylococcal issues were a problem. Don't read the whole abstract but 40% of patients had staphylococcal infection on admission when they were undergoing dialysis.

Slide 6

We can see here just for sort of old times sake some of the pictures that were put in the abstract.

Slide 7

Those were the days when you could do that sort of thing I imagine, put pictures in abstracts of patients and what they were basically showing is that taking a lot of precautions, trying to reduce infection reduced the infection rate, apologies for the old style graphs here, from around 55% in 1962 to around 20% in 1964. So all I'm saying there is that about 40 years ago at the beginning of the dialysis era, staphylococcal infections were a problem and measures were taken and there was an improvement even then but have we done better than that in the next 40 years and the answer is no because we've had new adversaries to fight. What we're now dealing with of course, are the consequences of infections.

Slide 8

Here for example is an infected exit site in a PD patient with associated tunnel infection.

Slide 9

As you'll know we have terrible problems with endocarditis in some of our patients, these are pictures of two of my patients, sadly both of whom succumbed to complications of endocarditis following on from staphylococcal infections.

Slide 10

Here's the link, at last, we have some osteomyelitis and discitis associated with a staphylococcal infection spread through the blood and causing a problem which eventually lead to some problems with this patient's mobility.

Slide 11

So, MRSA, as we are talking about resistance, the first thing to point out is that methicillin as we all learned it has now been replaced by the term meticillin because a lot of antibiotic names and other drug names have been harmonised, which for me makes it much more difficult to remember actually what they're called, let alone how to spell them, that just reflects my age probably but methicillin was first used in 1960 and it's because we've used this antibiotic that we have MRSA. It follows as night follows day. It's a semi-synthetic penicillinase-resistant beta-lactam and it responded to the altered penicillin-binding protein 2 A that caused a resistance. The first outbreak of MRSA was in 1963 and in those days, this is the important fact, the incidence of MRSA strains, as a proportion of the total staphylococcal strains, was just 0.4% and in the next four decades what we've seen in many parts of Europe but not all as we will see in a moment, is an increase in the proportion of strains that are MRSA related from that tiny proportion at the beginning of the outbreak era to the present situation where in the UK we have 43% of staphylococcal strains are MRSA. We've also got two new problems, we've got glycopeptide-intermediate Staph. aureus developing frist in Japan in 1997 and we have truly vancomycin resistant staphylococcus aureus as well and as you'll see, all of these are as a consequence of what we're doing. Pictorially this shows very nicely how MRSA has spread relentlessly and this is an old graft and you'll see that we're at 35% about a decade ago but in many parts of Europe we're now up to 45% or 50 %, as you'll see in a moment.

Slide 12

I'm also showing you here for completeness vancomycin resistant enterococci as well and here is vancomycin resistant Staph. Aureus, so all of these things are following on one after the other with an inevitable feel about them unfortunately.

Slide 13

Now, why am I talking to you about this, what's my credibility? I come from England and why's that important? I'll show you a bit of Shakespeare, I'm from England, I've got to show you a bit of Shakespeare. The important of this particular slide from Richard II is his "royal throne of kings this sceptred isle", just remember the phrase "sceptred isle" not the rest of the quote.

Slide 14

This is a pictorial representation of invasive islets of MRSA in 2002 in Europe and here red is for danger because these are the countries, England, France, Belgium, Italy, other countries, these are the countries that have very high islet rates, 25-50%. Other countries either don't report and therefore the figures will of course look good or seemingly do not have the same degree of problem, as the other countries in other colours, for example Scandinavian countries.

Slide 15

So what's that to do with a sceptred isle, well unfortunately in England we're not so much a sceptred isle but a septic isle because we're full of MRSA and this is a big problem and politically with a big P it certainly had a lot of attention in the UK but it matters a great deal, infection. Because it's one of those things that of course, is a tremendous problem for mortality for our patients.

Slide 16

Traditionally, when I and others have given talks about cardiovascular mortality, we've always focused on the top line but if you look here from the Renal Registry from the UK incident patients' first 90 days, you'll see whether over or under 65 years of age, infection carries a very heavy toll, particularly in the early stages after dialysis has just started.

Slide 17

Causes of death in the general population compared with end-stage renal failure patients, well there is more cardiovascular mortality less malignancy, more infection. So infection is one of those things we're all are familiar with but if we can take measures to reduce infection, we should expect to see reduction in patient mortality.

Slide 18

That's not just true of the UK, here we have data from the ERA-EDTA itself and we have the death due to infection here between 1980 and 2000. And you'll see steadily there's no real trend there I would suggest, it's still a problem just as it was in David Kerr's day, who I do see in the audience, it's nice to see him looking well.

Slide 19

It's also true of USRDS, it's true of America, here infection rates down at the bottom yes, not as important as cardiovascular disease in one sense but you'll note that there hasn't been much impact in cardiovascular disease perhaps in PD in the States possibly, it's debatable what that's due to but infection is jogging along very much at the same sort of levels and it's perhaps a mark of failure that after 40 years we're still dealing with these self-same problems.

Slide 20

If you look at adjusted rates of hospitalisation with septicaemia in the first year after haemodialysis therapy again from America, what you'll find in fact is the trend is not so helpful because you'll see over the decade 1990-2000, there's a steady increase of septicaemia in the first year of haemodialysis comprised of all the different areas but as you'll see in a moment the biggest problem by far is staphylococcal.

Slide 21

Mortality due to bacteraemia again in the States over the same time period around 1992-2002, these are dialysis patients and you'll see that deaths per 1000 patient years at risk has risen over that decade significantly, not so in transplant patients but particularly for dialysis patients over three years of duration and like cardiovascular disease, infection is going to effect increasingly those patients who survive on dialysis and perhaps never get the chance to be transplanted.

Slide 22

The incidence of bacteraemia in haemodialysis patients is very high indeed, as we know, this is the incidence of bacteraemia per hundred patient years from a variety of different sources and what you see here is around 7-15 episodes per hundred patient years. The percentage of bacteraemia due to vascular access, as will come of no surprise to you, is very high. This is mainly American data and it's between 48-89% and the percentage of bacteraemia due to Gram-positive cocci is either 100% in some series or no lower than 50%, as we'll see again in a moment.

Slide 23

Now, I'm going to present briefly a study, a very nice study done by Catherine Sterling and Colin Geddes, very kindly allowed me to show this slide today from the Glasgow Royal Infirmary and it just gives you a flavour of the sort of the infections burdened that a typical dialysis unit in the UK would see.

Slide 24

So this is a period of time of 12 months between January and December 2003 and they collected information on all bacteremic episodes in renal patients and what they found was, they had about 500 dialysis patients in their unit, they had 503 positive blood cultures and if they restricted their analysis just to the chronic haemodialysis patients, there were 418 positive blood cultures with a confirmed bacteremic episode as opposed to contamination in 288. Now, about three quarters were related to dialysis lines and most of those were actually true line infections. So, you can see a sort of hierarchy here from the total number of positive cultures to line infections, which dominates the whole slide.

Slide 25

In terms of line sepsis we have our 167 here and it's 58% of patients where you could trace an aetiology at all, that aetiology was due to line. Now, if we look at the organisms here, we've got a combination of coagulase negative staphs, Staph. aureus and MRSA.

Slide 26

These 3 together are over 70%, 77% is what we're dealing with, so when I'm talking to you about resistant staphylococci of course, I will deal with those, but it's important to take all staphylococci together and try to reduce the overall burden of staphylococcal infection and by doing that you will also reduce the amount of MRSA.

Slide 27

This is a slide here that shows basically that Gram-positive bacteria are responsible for two thirds of the total blood infections in hospitals in Europe. So, it's not just renal patients actually, you must remember that cardiothoracic patients and orthopaedic patients also get these self-same sort of problems.

Slide 28

Microbiological flora, you can see here broken down in more detail but the important point is that Staph. aureus is the majority, Staph epidermidis is there too and some other gram positives too and of course, in dialysis patients we wouldn't forget the importance of some gram-negative organisms.

Slide 29

The importance really is again, I'll come back to this at the end of my talk, survival because these infections do carry a toll, not just at the time when a patient gets this infection, you may be able to get this patient better by antibiotic use but there is definitely a price to pay for that as you'll see because survival is poor after infections and I've got data to show you later where it suggests that in the year or so after a serious bacteremic episode there is a price to pay probably due to cardiovascular complications and there may well be a link between those two types of mortality.

Slide 30

The predisposition to infection, what causes these infections and what's responsible in the host to predispose the patient to these infections there are many, many different things, age, gender, obesity, race, diabetes, nasal carriage of Staph. Aureus, dialysis through lines to name but six or seven, there are many different potential factors. Now, not many of those of course, are directly treatable, so we have to accept that with the exception perhaps of that and that, which I will deal with as I go through the talk.

Slide 31

Vascular access in infection rates, vascular access really is an Achilles' heel, if it goes wrong. What you can see here are the different infection rates for different types of vascular access, so untunnelled central venous catheters, 5 episodes per thousand catheter days compare that with a primary AVF, it's actually 2 orders of magnitude different, 0.05 and a graft is about midway. All lines are bad and as you'd expect femoral lines are worse than subclavian or internal jugular lines. We know this anyway, this is obvious but an important point to try and avoid lines where we can.

Slide 32

The pathogenesis of infection is either intraluminal or extra-luminal. The source can be catheter handling or bacterial migration from the skin. Either way you get a contaminated catheter whether it's the hub or the exit site and then we get catheter tip colonisation and then we get a bacteremic episode. It's actually not an instant process, it's a process that accumulates probably over weeks, sometimes months until the bacterial load is sufficient to seed the bloodstream and cause a distant infectious problem and that does give us, as you'll see in a moment, potential possibilities to intervene to reduce infectious burden by stopping this progression of bacterial accumulation.

Slide 33

The sequelae and infection, I dealt with some of those at the beginning of my talk, the sepsis syndrome, endocarditis between 5 or 10% and the mortality in the series of dialysis endocarditis is around 50%, osteomyelitis and septic arthritis if they're not fatal, they'll certainly keep the patient in hospital for many months often. Spinal epidural abscess and death in around 12-25% of cases with a serious staphylococcal bacteremic episode that brings a patient into hospital.

Slide 34

So, I have taken a long time to show that, perhaps you've already been convinced about this, that staphylococcus is a very significant medical problem, we've got a growing incidence of Staph. Aureus, aging population using immuno-modulatory drugs and of course we classically use implantation of synthetic devices and at the same time as our host is changing we've got a change in our attacking organism because the antibiotic, the organism itself is acquiring progressively a variety of different sorts of antibiotic resistance so that now we're having almost universal resistance to penicillin and ampicillin and the methicillin resistance is rising as well and here I'm afraid the reason for all of this and I'm as guilty as anybody else, is the wide spread use of antibiotics in a slightly inappropriate way.

Slide 35

Why are end-stage renal failure patients so at risk of staphylococcal bacteraemia? They're generally immunocompromised, we'll see in a moment when I talk about one of the therapies of opsonophagocytosis as an important defence mechanism and that's impaired in end-stage renal failure, compliment is disregulated, hypogamma-globulinemia, malnutrition, hypo albuminemia. So this is a very vulnerable patient, there's bacterial access to the vascular system and in certain parts of the world, in certain hospitals there's a Staph rich environment, not staff but Staph. And that leads to particular problems.

Slide 36

The key indicators of staphylococcal event rates in end-stage renal failure are access with catheters versus fistulae and nasal carriage, nasal carriage definitely predisposes to staphylococcal infection and we'll deal with that in a moment when I come to the therapies.

Slide 37

So having taken a long time to build the picture what can we do? And I'm going to break this down into prevention, early diagnosis and prompt therapy, judicious use of antimicrobials and reduction of the risk of transmission, so we'll go through those one after the other.

Slide 38

Prevention.

Slide 39

Now there are various parts to prevention. Where prevention is by far the most important part of this talk. I will start with vaccination, we'll then talk briefly about staphylococcal nasal Staph. aureus, measures to reduce exit site infections, dialysis cannula use and reducing HD and PD related infections. A lot of this overlaps but taken as a whole this is perhaps an attractive strategy.

Slide 40

So vaccination, well hang on you're going to say we haven't got a vaccine yet, well in fact there is a vaccine, it's not absolutely available, I'll come to that in the end but what you need to have the opsonophagocytosis is antibodies, you need to have antibodies. If you have antibodies, you have excellent opsonophagocytosis, and with low levels or low titres you have poor function. And all of us have been exposed to staphylococcal infections ourselves and have low levels but dialysis patients don't seem to have a proper response to a staphylococcal infection though they may get very many of them and don't have very high levels at all. But that can be changed.

Slide 41

Nobody will probably remember now but in 2002 there was a study published in the New England Journal of Medicine and it derived from 1804 hemodialysis patients from the Kaiser Permanente Group and these patients were given a bivalent vaccine against staphylococcus type 5 and type 8, which is responsible for about 85% of all staphylococcal infections. So, these patients were vaccinated, they were stratified by nasal culture and dialysis access into grafts and fistulae and the study was performed and the primary end-point of this study was first time Staph aureus bacteraemia with other secondary end-points to do with how the vaccine worked. The answer is that it did work.

Slide 42

A single injection of this vaccine, Staph. Vac reduced staphylococcal infections by 2/3 over a ten-month period. The reduction was most evident in nasal carriage positive patients, in other words those in fact at the highest risk, as we will see in the placebo group. The vaccine was well tolerated and was profoundly immunogenic and that's quite surprising to all of us if you use vaccines in dialysis patients and have not been very impressed with for example, how hepatitis B vaccines go but this vaccine was immunogenic and there was an estimate from the paper of a protective antibody level of around 100 micrograms/ml and the next slide will show that in context because here we have the concentration of the antibody here, here are patients T5 and T8 are the different strains and here's the reduction of infectious episodes between these two groups.

Slide 43

Now of course, there's more than just staphylococcal infections these patients are prone to and clearly a staphylococcal vaccine can't influence Gram-negative organisms, for example. What you see here is over the first 40 weeks or so a significant reduction in staphylococcal infections. That effect wore off by a year. So the antibody levels declined and as they declined the protective effect of the vaccine disappeared clearly indicating the need for re-vaccination but at least as a proof of principle there is a potential way to reduce staphylococcal infections by vaccination.

Slide 44

Elimination of nasal Staph. aureus carriage.

Slide 45

We can attempt to do that. Nasal Staph. aureus or carriage of Staph. aureus appears to play a key role in the epidemiology and the pathogenesis of infection and the aetiological niche for Staph. aureus is the anterior nares. We all know from healthy and disease subjects that there are 3 patterns of carriage. 20% of patients or people are persistent carriers, 60% have intermittent carriage and 20% seemingly never carry Staph. aureus in the anterior nares.

Slide 46

In patients who repeatedly punctured the skin and obviously our patients are classic examples of that but there are others with HIV and intravenous drug addicts increased carriage rates are found so unfortunately up to 50-60% of our patients are Staph. aureus carriers.

Slide 47

Carriage has been identified as an important risk factor infection for patients undergoing surgery, hemodialysis or CAPD.

Slide 48

Now, staphylococcal nasal carriage does that produce infections? Yes, it does. Here's a paper from 12 years ago now in Kidney International. 167 patients with a long follow-up were followed-up for a mean of 16 months. There were 28 patients in that study with MRSA nasal carriage, carrier status was unrelated to age, sex and presence of diabetes but it was associated, MRSA carriage with the significant increase in the rate of peritonitis and exit site infections, catheter losses and CAPD patient drop out. As we all know that's a significant burden for these patients who may have to go to hemodialysis as a result of these serious infections.

Slide 49

So elimination of Staph in MRSA carriage has been found to reduce infection rates in surgical patients, in hemodialysis patients and in CAPD. We can do that with mupirocin for example, so elimination of carriage appears to be an attractive preventive strategy but unfortunately eradication is often incomplete and often temporary and as we'll see in a moment when I deal with another aspect of using prophylactic antibiotics there is also the potential for the resistance.

Slide 50

Now, mupirocin has been used as a topic antibiotic in this context. There's a variable success rate for many different studies, there are issues about how long you can eradicate for and whether you should repeat courses of mupirocin to maintain eradication of Staph. aureus carriage and patients who are prone to relapse and most patients are prone to relapse. There is an increasing incidence of resistance especially to coagulase-negative staphs at low and high level resistance and this is plasmid-born and I'll show you some data in a second that'll tell us how that actually goes.

Slide 51

Now, measures to reduce exit site infections are perhaps more attractive and we've got perhaps more to say about that in the renal community.

Slide 52

And again I come back to mupirocin, we've seen this slide before, it's a topical antibacterial that we all know and are familiar with but is there resistance out there because if we're going to use this indiscriminately or in a widespread way for all of our patients all of our time, what can we expect to see?

Slide 53

Well a recent study published in Peritoneal Dialysis International in 2001 from Toronto looked at a 4-year experience of prescribing and using mupirocin in everybody on peritoneal dialysis. 149 patients between May and July 2001 and these patients were then swabbed. MRSA Staph. aureus was isolated from 17% of the patients from the nares etc and the groin and one from the exit site and high-level mupirocin resistance Staph aureus was isolated from 4 patients. Now that's a small proportion of the total number but 15% of total Staph aureus isolates were actually mupirocin resistant after 4 years, so there's no question that mupirocin resistance does happen, if you apply mupirocin to everybody and continue it for long enough. The outcome was not too bad though, as you'll see because one patient only with high-level mupirocin resistance had peritonitis due to Staph. aureus and that lead to treatment failure. Now you may say that's a perfectly acceptable price to pay, one catheter loss for a lot of prevented infections but the point I'm making here is that mupirocin resistance will appear, if we use mupirocin to everybody and how far that will go over the next 5 or 10 or 15 years remains to be seen but if the future is like the past, mupirocin resistance will become a problem.

Slide 54

Is mupirocin the answer? It depends on the question of course, but there is another player. This study has just been reported in JASN and this is about the use of Medihoney.

Slide 55

Medihoney is cheaper and certainly sweeter than mupirocin and this particular study looked at the application of Medihoney and you can't go down to the supermarket and just buy the honey to save money because the bees have to use a particular flower, Leptospermums which is from Australia and New Zealand but if you apply Medihoney to hemodialysis exit site and compare that with mupirocin, you might be quite surprised at the outcome. Honey itself has been used for centuries, in fact millennia as a topical antibacterial although obviously not knowing that's what it was doing in the ancient times and does have quite specific antibacterial, antiseptic properties despite you'd think it would be a good culture medium but it isn't. One figure from this particular study shows basically that Medihoney was at least as effective, at least as effective at reducing exit site infections in hemodialysis patients as mupirocin and significantly cheaper. So mupirocin is not the only thing that you could use potentially to reduce staphylococcal infections. If we go to peritoneal dialysis, we've got another option again comparing mupirocin, which is sort of the standard therapy to gentamicin cream, so you can use either mupirocin or gentamicin.

Slide 56

If you look here in this paper again published I JASN in February 2005 from Pennsylvania, what you can see here is that gentamicin cream applied to the exit site is very significantly better than mupirocin. Now, of course, there's a risk of resistance eventually. The reason for this improved result, as you can see here in terms of episodes free from infection, is because gentamicin naturally will attack or reduce the incidence of Gram-negative infections, which are very important for peritoneal dialysis patients and interestingly has just as much effect on Gram-positive organisms as the mupirocin did. So yet again there's another potential agent here beyond mupirocin.

Slide 57

Reducing dialysis cannulas.

Slide 58

That's almost self-evident, it's just worth saying again that the type of vascular access, has a huge impact on the incidence of Staphylococcus Aureus bacteraemia, as we've seen before.

Slide 59

Basically if we have one of these for too long, we're going to get this and a problem, so we have to break this vicious cycle where possible. This is particularly a problem for late presenting patients as we know, hence the increased mortality in the first 90 days as I showed you earlier with data from the UK Renal Registry but breaking this cycle of lines.

Slide 60

And infections is the single biggest thing that we can do to reduce subsequent problems as we all know.

Slide 61

Reducing hemodialysis and PD related infections. Here I'm going to talk about antimicrobial locks and briefly about biofilm eradication.

Slide 62

Now, there are a lot of issues to do with prevention. We don't have to read the whole of this but basically if we wash the area carefully with chlorhexidine or alcohol or povidone-iodine, we can reduce the transmission of infection at this stage, this is for an arteriovenous fistula or a graft. So careful preparation of the skin is mandatory. And units under pressure for time may sometimes not have the opportunity or the practices to do that really well.

Slide 63

Similarly for hemodialysis catheter infection, a lot of different things to do, evidence base is not particularly strong, it's all, I wouldn't say self-evidence for example, soaking the caps and catheter connectors in povidone-iodine and allowing to dry before separation.

Slide 64

All of which takes a lot of time, effort and energy to do really well in a standard operating procedure approach to dialysis. Peritoneal dialysis similarly, as I think it's easier there, we train our patients as best as we can to be as careful as possible about making connections.

Slide 65

Now antibiotic heparin or citrate locks, I would describe these as novel strategies to the evolution, they're certainly very interesting and they hold some promise. So if we deal with these as gentamicin citrate, gentamicin heparin or cefotaxime these have been put into lines of all sorts to try and reduce subsequent infection. They may have an effect to reduce blockage, they may have an effect to reduce biofilm, and they hopefully have an effect to reduce the amount of bacterial load in the line, so it doesn't get a chance to accumulate and then cause an infection. There are also antimicrobial or antiseptic coded catheters. I think people who tried to put chlorhexidine on a catheter, silver, which is definitely strongly antibacterial minocycline and vancomycin. These lines, well do they work? Well, they're certainly expensive, they don't have a long history of whether they work for a long period and there's some evidence that their antibacterial qualities don't last all that long. So, you have it for a while but then it wears off. The line characteristics are not established, in other words what's a line there for in the first place? It's to dialyse the patient, get a good blood flow and you have to make sure that in changing the characteristics of your line to give it antibacterial properties you won't in some way reduce its effectiveness for its primary purpose which is dialysis. So there are some questions about that.

Slide 66

A good study appeared in Kidney International 2004 from Derby. Locking tunnelled hemodialysis catheters with gentamicin and heparin and this is a randomised controlled study and what they were able to show was that using gentamicin and heparin compared to heparin alone led to a significant prolongation of catheter usefulness either by infection or by blockage.

Slide 67

So, this is the routine application of a lock with gentamicin and heparin. So again gentamicin comes out quite well. There are plenty of other studies that have looked at this, most of them are short-term, most of them are quite small scale and we don't have a good strong body of evidence in a randomised controlled study but this is one of the best that's currently available and you'll see that in Kidney International August 2004.

Slide 68

Don't forget also that during an infection, I was talking there about putting antibiotic locks in between infections as it were to prevent infections but in lots of other situations where you have an infection you could use an antibiotic lock to reduce the duration of a current infection. And that has been done in dialysis patients, AIDS patients, cancer patients. Now, next. So that's prevention, I think that's the key personally.

Slide 69

Early diagnosis and prompt therapy.

Slide 70

Well, early diagnosis and prompt therapy come down to careful blood culture, PD fluid culture, avoiding inappropriate antimicrobials, a prompt start of the definitive antibiotic and where you have an infected line we all know this, many of us in the room will have not practised this, try to remove it within 24 hours. Now of course, we've all got patients with such pressures and difficult vascular access but we try and we struggle and we leave that line in for longer than we should. But there's good evidence that that approach, however difficult it may be in terms of vascular access, is one of the key things that leads to the long-term sequelae in terms of peripheral seeding of infection and prolongation of antibiotic use. Also with the correct duration of antibiotic, there is often a war between microbiologists and nephrologists on many subjects and one of them is how to treat their patients for and increasing evidence and good practise suggests 10 or 14 days of therapy whether it's with flucoxacinnin or vancomycin. Inadequately short periods of treatment will lead to complications and rapid relapse.

Slide 71

Judicious use of antimicrobials is important.

Slide 72

Where should we use vancomycin? Because as I've told you vancomycin intermediate Staph. aureus is now around and it's because we have been so liberal with our use of vancomycin over the years. I'll deal briefly with alternatives to vancomycin.

Slide 73

Well, it's a lot to read, don't worry about it, the important point is we should not be using vancomycin for routine surgical prophylaxis in patients who don't have a beta-lactam allergy. Life threatening allergy beta lactam antibiotics. Inappropriate prophylactic use of vancomycin will be the single biggest reason why VRSA will take off and have an opportunity to thrive. So we should really reserve vancomycin for serious infections caused by beta lactam resistant Gram-positive microorganisms like MRSA.

Slide 74

Are there alternatives to glycopeptides for MRSA? Yes, there are. Just to bear in mind that all of the ones I've listed here from mithramycin to clindamycin these antibiotics do have some action against MRSA, they're certainly not very strong. You would never use them in monotherapy but typically you can use rifampacin to synergize with vancomycin or one of the glycopeptides to improve its antibacterial characteristics and efficacy.

Slide 75

Let's go through those in a bit more detail. The new antibiotics but I don't want to show you these and to have everybody think, well this is the answer, new antibiotics because for 40 years we've hoped that we can pull out from up our sleeve another Ace of spades because we've got a new trick to play but it's redundant, it will not work. No sooner have we got a new antibiotic then we have the resistance and I'll show you good evidence for that. Streptogramin combination of quinupristin and dalfopristin or Synercid is a useful drug it certainly has anti MRSA activity but its problem is it comes in large volumes of an IV solution and you have to give it slowly, so that's not exactly tailor-made for dialysis patients. Perhaps more, very much more promising is Zyvox, a linezolid and that's active against MRSA and also glycopeptide resistant enterococci. You'll know its oral and IV bioavailability are excellent and equal, there's no problem in patients with hepatical, renal impairment. It has excellent tissue penetration but hey presto! No sooner has it been introduced to the market then there are increasing incidents in the literature of resistant organisms and treatment failures. It was produced a couple of years ago and there are plenty of reports now of linezolid resistance developing and why should that be? Because it's getting widely used and inappropriately used. But it is a powerful antibiotic.

Slide 76

So what about new ideas, well there are some new glycopeptides coming, oritavancin, dalbavancin and the glycolipodepsipeptide, ramoplanin but I'm afraid the glycopeptides and if we have glycopeptides, we're going to get resistance. Daptomycin is not a glycopeptide, it's a lipopeptide, it has a unique mode of action and daptomycin is one thing that we'll probably start to have to use in the next few years against MRSA when we get the vancomycin resistant strains. I'm afraid to say, no sooner has it been introduced, then glycopeptide resistance in MRSA has been also reported to daptomycin in 2005. So again this is not the answer. These are useful tools in desperation but inappropriate use of these newer antibiotics will simply get us where we already are today.

Slide 77

Reducing the risk of transmission, the final part of this talk.

Slide 78

Scrupulous hygiene for patients, carers and staff and proper and appropriate design of human dialysis facilities to reduce infection and one of the points David Kerr made in that paper I showed you from 1964 was how to segregate patients and it's interesting that in the early dialysis era, patients were very much more segregated and isolated and not herded together, next to each other. In terms of infection carriage I think that's one of the key problems. Now, we'll just move on from there.

Slide 79

Slide 80

Now, to finish off, in dialysis patients septicaemia is associated with an increased risk for cardiovascular events and death and I think the septic episodes and septic problems will be one of the obstacles that we face in lowering cardiovascular morbidity and mortality.

Slide 81

Why should the two be related? Well, epidemiologically there's good evidence that in the first six months after a septicemic episode there's a very high price to pay in terms of heart failure and acute myocardial infarction. So you get over your septic episode but the patient then in the next year, typically in the next 6 months will come in and maybe have a death or a serious adverse event due to a cardiovascular problem.

Slide 82

The reason for that is we know that there's a very, very strong link between inflammation and outcome, inflammation, malnutrition and outcome in dialysis patients. One of the ways in which inflammation, well one of the ways we generate or patients have generated inflammation in them as we know lipopolysaccharide, endotoxin, dialysate, vascular access. There's good evidence that long-term vascular access of this line variety for example, produces a low-grade increase in CRP due to low-grade bacteremic episodes. This will lead through to increase CRP and through to death.

Slide 83

In the acute phase you have atherosclerotic plaque stability and that's another constant battle between good and evil and if you have more inflammation systemically, there's evidence that plaques are more active, so what you're really seeing here is chronic inflammation, chronic infection and an up regulation of a whole variety of processes that tend to put the patient in that half of the diagram rather than this half of the diagram and that's the link between infection and cardiovascular disease.

Slide 84

So, to summarise and to conclude, I've shown you that staphylococcal bacteraemia is very common. I don't make any excuse for talking to you about staphylococcal bacteraemia and not just resistant organisms because the incidence of the resistant strains is so high that I think you have to take the two together. It's associated with vascular access, with hygiene, with hospitals and reduced immunity. Staph. aureus bacteraemia is the major issue, there has been a relentless increase in MRSA and glycopeptide intermediate sensitive Staphylococcus Aureus. Tackling the predilection of propensity to these infections is the correct approach, not just focusing on one particular infection but reducing infection in general. Hospitalisation, morbidity, mortality are very high particularly as we know with MRSA.

Slide 85

Reliance on a trump card of antibiotics is futile because as we know microbes can adapt faster than most pharma companies and they don't have shareholders to please, so they can just get on with the job of becoming resistant, nor do they have trials or FDA. Preventive measures are possible, they're practical and they're powerful. Now, what preventive measures would I single out? When vaccination becomes available in the next year or two I think we should look very seriously at this because it does offer an opportunity to reduce infection without provoking resistance. I'd remind you that vaccination is one of the few areas in health, global health that has actually made a dramatic difference to the incidence of different infections such as polio, and small pox, it's very effective. You'll have to be persuaded that the staphylococcal vaccine will work in dialysis patients and more evidence will become available probably this year. There are other things to do, again I would favour the preventive approach, the use of locks, the use of creams. Which lock, which cream? How long for? We don't know the details yet. We need to have a lot more randomised studies to answer these particular and important questions.

Slide 86

But if we do those sorts of things hopefully, we can banish Lord MRSA to history and be Luke Skywalker. Thank you very much indeed for your attention.

Chairman: Are there any questions?

Question: Thank you for a very nice presentation. When you remove an infected catheter, what is your schedule for giving the patient a new catheter? Do you wait some days or do you do it the same day?

Dr Goldsmith: Is that a new line you're saying?

Question: Yes.

Dr Goldsmith: No I would. I think most of us would agree that you would take out the catheter, you would then use a temporary line, you would ideally leave the patient 48 hours line free, insert a temporary line and then come back with a definitive procedure once the CRP is as low as you can get it but I would try and leave the patient plastic free for as long as possible. In practise it's often very difficult, as you know to do that.

Question: If you can't use staphylococcus you culture only free bacteria not biofilm. What are your experiences with biofilm infections? Only removing of infected device or anything else?

Dr Goldsmith: No, as you know there is good evidence that if you can selectively culture the tip of lines, you can find flora there well before they've caused systemic infections and there are studies and there are ways as you know to put locks in or indeed to strip the inside of a catheter to try and remove the biofilm. I've not seen good outcome data for those studies yet but it's an interesting approach. I'm a little bit, slightly not in favour of major manipulations of dialysis lines except for dialysis itself, so we've not had wonderful experience ourselves in our hospital with the stripping approaches sometimes led to complications with the line themselves but it's an idea. Yes. Thank you.

Question: You talked about segregation. I think it's very difficult especially in the UK is there any tradition or something like that, I mean we still put the patients in the same room and so on?

Dr Goldsmith: I think it's genuinely very hard isn't it? You've got out patients who are coming in 3 times a week and they're mixing together in the waiting areas and talking and there's a social element to dialysis that we can't forget. If we segregate patients and make them isolated, it's going to be even more miserable for them. So the practicalities are that you can either say to all the patients you will wash your hands and you'll have protection, you'll wear gloves yourself and you'll note that if you have an MRSA positive patient in your hospital, I hope you'll make the relatives all wear protective gowns and masks and wash their hands very scrupulously before they come and visit the patient because they should. In practise it's jolly difficult to do I agree with you. Leaving people just to mill around if they're MRSA positive is a potential problem and it's something we've ignored I think for a long time.

Question: What is your behaviour with nurses and doctors who are positive or who are Staph. aureus carriers? I think this is a big problem because 20% of the normal population is a carrier, a permanent carrier and it's difficult to find nurses for dialysis if you eliminate 20%.

Dr Goldsmith: Thank you for answering the question you posed! You're absolutely right it's a tremendously difficult problem. In our hospital we've banned this on ward rounds. So we've gone to a tieless society in England. You'd think England would be the last place on Earth to do away with ties but we're not allowed to wear ties on ward rounds and in fact we've got to clean our stethoscopes. You're absolutely right about that. That staff also do carry Staph. But we have a big problem as you say in the UK particularly terrible recruitment problem and if we start to segregate people by their MRSA carrier status I think we'll have further difficulties. It's a question of a balance of risks, isn't it? Competing risks. Maybe you can try and eradicate the infection in a healthy person, you maybe lucky and eradicate the MRSA. I have to tell you that we don't screen our staff and we don't know the carriage rate for all of our patients and do you know why we don't know that? Because we daren't find out the answer.

Question: If you have Staph. aureus in a biofilm in a catheter can you eradicate it with an antibiotic?

Dr Goldsmith: If you have Staph. aureus in a biofilm?

Question: In a biofilm is there a special problem?

Dr Goldsmith: I don't know the answer to that question. I mean I would imagine you could, if you knew it was there you could strip the biofilm and/or use the antibiotics, you probably could.

Question: There's a US publication, they say that you have to have a 500 concentration of vancomycin to eradicate it?

Dr Goldsmith: Yes.

Question: You have to go up with the concentration of the antibiotic.

Dr Goldsmith: I've seen that you can put vancomycin and hope to eradicate, if you can strip the biofilm. It may work, it may work and the problem I have with that is it's the use of vancomycin all over again and as much as we use that I think we will find vancomycin resistance but for particular patients and the one thing I didn't touch on is some patients repetitively get staphylococcal infections and for patients with precious vascular access all my sort of preaching about not using vancomycin, not doing this, not doing that, you may have to throw some of that by the wayside because for patients who are literally running out of vascular access, you all know and I know I'd try anything including stripping biofilm, putting antibiotics down because I know that the loss of that line will be followed by a real problem. So yes.

Question: Some doctors use taurolin solution against the infection or prophylaxis. Can you make a comment on this?

Dr Goldsmith: I have no experience of it myself whatsoever but I know it's another solution that's been used. The attraction there is it's not an antibiotic itself, it's got antibacterial action and therefore resistance is not an issue. That's the correct approach is to avoid if you can wide spread use of antibiotics. That's why I'm against mupirocin on a regular basis and would prefer something different.

Question: Is there any difference in bacteraemia frequency in patients with femoral or jugular catheters?

Dr Goldsmith: Yes, 3 times for femoral. In fact, oddly enough as I showed you the data there, subclavian lines have the least propensity to infection but obviously we don't use those. That's true from ITU.

Question: And the carrier state is related to the vascular access of the patient?

Dr Goldsmith: No there's no direct relationship that way round. You can have a double hit as it were, you can be a carrier and of course, you can also have a line and that puts you at double jeopardy of getting infection but the two are not linked.

Chairman: OK, thank you very much.