Podcasts

Vancomycin: Old Drug, New Tricks

This podcast is a back to basics for an antibiotic that a lot of clinicians, doctors, pharmacists and nurses struggle with, namely vancomycin. My name is Samuel Ford, I'm a Clinical Pharmacist based in Brisbane. And with me is Amy Legg, previous infectious diseases and antimicrobial stewardship pharmacist, and currently the pharmacist research fellow at the Hurston Institute for infectious diseases in Brisbane. Importantly, Amy is a self described proud Vancofile and is here to talk all about it. So welcome, Amy. Thanks, Sam. Great to be here. Let's start with a bit of background on vancomycin, can you just tell us its story and why despite people predicting its demise and removal from clinical care for the last decade, it remains an important weapon in our antimicrobial arsenal.

Yeah, thanks, Sam. And as you're saying a lot of people find vancomycin a bit intimidating. So I thought if we could get to know it a bit better, we might find it less terrifying. vancomycin is a really interesting story. It was initially discovered in the 1950s when scientists from Eli Lilly went out looking for different components of soil that might have antibacterial properties. And they were in the forests of Borneo, and they found a really interesting compound. When they brought it back to their labs in the States, they found that it was incredibly active against Staph species. And in fact, one scientist looked under the Microsoft under the microscope and said, ‘God, it's just vanquishing them’, and that's actually how it got its name to be vancomycin. Vancomycin, the vanquisher of Staph. In the 1950s, however, another drug came into circulation, which was methicillin, and so it largely replaced vancomycin as an anti-staphylococcal agent, well up until the 70s, and it is when MRSA methicillin resistant staph aureus, came into being and thus vancomycin found its way back into the market then after having about 20 years where it was off the shelf, while anti staphylococcal penicillins really did the hard work against Staph aureus. In those early days in the 1950s. Vancomycin vials were very impure and in fact, it was nicknamed Mississippi mud because it had a really brown and impure appearance and so when it was first licenced, there was a lot of toxicities that we thought we'd eradicated with purification of the product. But as we'll talk about, there are still a few toxicities that we need to watch out for even today. Vancomycin itself is a large molecule. It's got a molecular mass of 14 050 Dalton's which can become an interesting fact when thinking about penetration and clearance. But certainly, it's cheap, readily available, and still one of only a few drugs on the market with very good activity against Methicillin Resistant Staph Aureus that MRSA and that's why it's still got a role to play even today.

So in 2022, what are we currently using vancomycin for?

Yeah, so just to summarise, I guess, there's two situations as there always is with infectious diseases. So in the empirical setting, we do use it for severe sepsis. That's really because the drugs that we often pair it with, you know, ceftriaxone, pip-tazo, meropenem, none of those have activity against MRSA in the setting of sepsis. With death rates high and quick, you really can't afford to be missing bacteria. So it certainly gets used empirically in the setting of severe infections. We may also use it in the setting of high risk of MRSA and that can be related to the type of infection. So being a staphylococci it's normally a skin based infection. So if someone had a skin infection, or people who've got intravenous access devices where you've broken that normal barrier being the skin between the outside and the inside, they're the two situations where we worry about stuff and then epidemiologically we think about what's this patient's risk factors for MRSA specifically, so they come from a region with high rates of MRSA have they had a prolonged stay in a hospital or an aged care facility that's known to have a high prevalence of MRSA and even residents in a correctional facility puts people at higher risk of MRSA. So they're the two empirical settings where we use it in the situation whereby we can't miss anything or the situation where we think MRSA is likely and then separately to that it does still get used for directed therapy of resistant Staphs and enterococcus even when there's no alternatives and that there's no alternatives normally because of resistance to beta-lactams.

And what makes it more difficult to use than other antibiotics,

I think because it doesn't have a standard dose per se. So for each patient to get the right dose of vancomycin, you really need to know two things, their weight and their renal function. It's important to get vancomycin dose right both for efficacy and for toxicity. And particularly for critically ill patients important to give a loading dose so that we get to a therapeutic trough level at the end of the first dosing interval, so you know, as quickly as possible. And then we do have to do ongoing monitoring, which I think people do find quite tricky as well.

So let's jump into a hypothetical case. Say we have a patient who's 35 years old and has an MRSA bacteremia. Let's say he has normal renal function and weighs about 120 kilos. How can we go about creating a dosing regimen?

Yeah, great case. So I think the first thing to say is that vancomycin is very appropriate and important in this clinical scenario. So even in developed countries, we have a mortality rate with MRSA bacteremia of around 20%. So noting here that about one in five patients with this deadly complication does pass away. If it's a Staph that's susceptible to a penicillin like flucloxacillin or Cephalosporin, like cefazolin, then actually those drugs are superior to vancomycin for a Methicillin-Sensitive Staphylococcus. aureus, but this patient has an MRSA, so those drugs will not be useful and vancomycin is our go to here. It's very important in this situation with a bacteremia that we get to therapeutic drug levels from the start. So I would be interested in giving this patient a loading dose. Outside of the ICU the loading doses are normally about 20 to 25 mg per kg, and on, although we recommend dosing on total body weight, we do have a cap at around three grammes. So for this patient weighing 120 kilos, his dose loading dose would be around 2.5 g, if you went to the higher end of 25 mg per kg, you'd be up around that cap of 3 gs. Then after the loading dose, we take the dosing frequency which is driven by the patient's renal function. And for this guy with normal renal function, it will be 12 hourly, so 12 hours after that we start the maintenance dose, which is 15 mg per kg twice a day. It's important with these doses that we do make it so that the nurse can draw it up, and so we round to the nearest 250 mg, so for this patient, he would get the 2.5 g to 3 g loading dose with a maintenance dose of around 1.75 g 12 hourly, daily creatinines, and they're a predictor of concentrations as dictated by the hospital guidelines. In general, with our maintenance doses, we don't go above 2 g BD, so even in patients with big body weights, at the 15 mg per kg dosing, we initially give 2 gs BD until we can get to the first level. And then if it's still sub therapeutic at that point, definitely important to find infectious diseases or one of the experts in your local area, because we'll often switch that patient to eight hourly dosing as opposed to continue to push up with the BD dosing.

Right, so call a friend at that point. That sounds good. So after we've chosen a dose, and we've started therapy, the next step will be to check that we've got the dose, right, that is a dose that's safe and efficacious. How can we go about this?

Yeah, there's a few ways there's the normal ways in terms of monitoring the patient's clinical status. So we always do like to see that the blood cultures become negative, we like to see the fever defervesce, white cells trending down all of those things that makes us so happy when the patients do that for us. And then there's two ways to really monitoring. Well, I mean, there's quite a few ways, actually to monitor toxicity. But what we tend to think about first and foremost in our minds is nephrotoxicity. And there's really two ways to monitor for that, which is certainly the serum creatinine and the therapeutic drug monitoring of vancomycin, so checking vancomycin concentrations, and really we check vancomycin concentrations for two reasons, not just for the safety, but also to make sure it's at the right level. In general, we like to have a vancomycin concentration checked every two days, it does depend a little bit on the dosing frequency, which is related to the renal function. So when we have patients who started on vancomycin, normally their weight drives the dose that they get, and their renal function drives how frequently we give it. So if we have a patient with a high weight, but poor kidneys, you'll be looking at a big dose given relatively infrequently, as opposed to a patient with a small bodyweight who has really good kidneys, where you might be giving a small dose but giving it more frequently. However, in cross both of those settings, we like to be getting a level or a drug concentration checked roughly every two days. It is also a little bit tricky about what the target ranges are. So we get a trough level about 30 minutes before the dose. And if the patient is stable with a non serious infection, the majority of guidelines actually say that 10 to 15 is appropriate provided they're clinically improving, with levels of 15 to 20 recommended for patients who aren't clinically improving, or who have more serious infections, and then even higher target concentrations can be used in the setting of a CNS infection

is that lower target Amy new in recent years, I feel like when I was initially taught, it was always that 15 to 20 for most people unless it was a CNS infection is that a new thing that's come about,

We used to be quite nervous about the levels of 10 to 15. So one thing that we do know is levels below 10, do drive resistance. So levels below 10 are a problem. And we know that that exposure can drive what we call H visa. Ten to 15 is a newer thing, we used to have a recommendation of 15 plus or minus three in some of the earlier, some of the previous therapeutic guidelines. So that was really looking at levels around 12, to 18. But all of the trough levels that we use are a surrogate for AUC or area under the curve. And we want an area under the curve of at least 400. And if you're in the range of 15 to 20, you're almost guaranteed an AUC of above 400. However, you're probably far exceeding that, because we've made it so that you're so likely to get it, you're probably likely to get more than that. Whereas a 10 to 15, you're less definitely achieving that AUC. But you're probably achieving that AUC. So that's why we also marry that 10 to 15, up with clinical improvement, where we think well, if the patient's clinically improving, and they're less assured of an AUC, but it's not completely out of the question. And we know that that 15 to 20, also was when the rates of nephrotoxicity start to increase. So it's all a bit of a washing machine of risk versus benefit within that 10 to 20 range, where, if you're getting better, you can probably facilitate 10 to 15. Knowing that the patient is getting better, you may be achieving the AUC you need and the risk of nephrotoxicity is less. But if you absolutely want to make sure you're achieving the right AUC, and you don't think nephrotoxicity is going to be a problem. That's where the 15 to 20 comes from.

Something I've heard a lot about, I feel like maybe for a few years now is that there is this shift in international recommendations to move towards AUC for vancomycin TDM. Australia hasn't gone there yet. We're still using troughs, to monitor that. Can you expand on that? And tell us why we haven't gone that way yet?

Yeah, I think the AUC wave is happening definitely happening. As you say, in other countries, what the AUC based monitoring allows us to do is give lower doses. And that's why we see decreased rates of nephrotoxicity in patients because as opposed to using a surrogate, where, if you're just trying to guess what sort of a AUC you might get from a trough, you have to aim higher, because you have to think, or at what minimal risk of missing it. But if you're checking an AUC, you know, you're getting the right AUC, you can get the dose that that patient actually needs. And when they've gone back and done retrospective reviews on people with AUC based dosing, the average trough is about 11 to 12. It's not actually as high as, as we have been using in clinical practice to sort of assure us of that AUC attainment, in terms of what hasn't rolled out here, it is actually quite difficult to do. So to do it on the based on the patient's whole context, in terms of doses they've previously had largely requires the use of dosing software, which is both expensive and time consuming. And to do it without dosing software. Often it means more than one level. So I think until we've got a process whereby it's easy to do an AUC, we are going to struggle to transition to AUC based on trend, even though it has been shown to to reduce rates of nephrotoxicity.

For those of us that practice in more tertiary or quaternary sites, we know that we're pretty spoiled, we get pathology results reasonably quickly. What about our friends in more rural or remote locations? Obviously, these things can take up to a couple of days to be reported their vancomycin trough levels. What can we do with these sites?

Yeah, and it's particularly difficult because we ask people to take a level 30 minutes before the dose, and there's no way they're going to get it back before the dose is due. So I will say in general, if a patient's going along really well, in the vast majority of cases, you don't need to withhold a dose wait waiting for the level to come back. But in the situation where it can take a few days for the concentrations to come back, it's really important that we have used guideline based dosing, and that we're likely to be in a safe and effective range. And also, you can use serum creatinine to at least double check on the patient's renal function. Knowing that if the creatinine starts increasing, that's an nephrotoxicity is a known complication of vancomycin. And again, use their clinical parameters to think about are they improving, but certainly at that, in that situation, it's not a bad idea to also phone a friend, because a lot of us have quite a bit of experience now with vancomycin and based on the patient's comorbidities and their age, we can really help with trying to tailor a vancomycin dose that we think will be safe and then yeah, in the meantime, just keeping an eye on that creatinine that as a surrogate for nephrotoxicity.

And if we are using creatinine then can we approach it in a pretty linear manner if we see that the creatinine and then has gone up by 25%? Should we be thinking about reducing the vancomycin dose by 25%?

Yeah, that's a great question and vancomycin pharmacokinetics are incredibly linear, the problem is, our patients don't always stay the same. So normally, we can use the vancomycin levels in a very linear approach. And if the creatinine is also going off, it can make a double sort of linear situation where you don't know how much they're feeding into each other. So certainly, vancomycin is about 70%, renally cleared. So at any time, creatinine increases, and we think that's telling us that there's a decrease in renal function, you're gonna see an increase in your vancomycin level. So the vancomycin will start accumulating as soon as renal function starts decreasing. And you don't know necessarily where it's whether it's the cause or an innocent bystander. But I would say it's one of the biggest issues that we have clinically when a creatinine starts to increase in a patient's on vancomycin, it can be very hard to know what to do. If I was to give my advice here, I would follow a clear set of steps. In the first instance, I would be checking if the patient still needed to be on vancomycin. I think as pharmacists, we always tend to think it's the vancomycin causing the nephrotoxicity. And if it is, then obviously removing it's going to be best for the patient. As I say, we often use vancomycin and in the setting of empirical therapy, and so if cultures have come back negative if Staph has grown, but it's turned out to be susceptible to flucloxacillin, you know, at that point, just getting the patient off the vancomycin and onto another therapy, great. However, that's easy, we can all sort of do that. If that's not the case and the patient needs to be on vancomycin, I would still just talk to the team about whether or not the vancomycin is likely to be the cause. Because there are other options for the treatment of MRSA, they're more expensive, they have their own drawbacks, but certainly, if we think that vancomycin is the cause we can be switching. If the vancomycin is not likely to be the cause. Maybe they've had an hypertensive episode, they've been back to theatre, they've had contrast and they actually think it's something else. And they want to keep them on the vancomycin, but the creatinine is going up, I would recalculate a creatinine clearance and check whether that dose is still appropriate and I would dose adjust based on current guidelines. I would really think about moving a concentration vancomycin level to earlier. And this is the only situation whereby I would often withhold the dose until the level is back. As pharmacists, we often say don't do a level until you're at steady state. And that is very true, particularly if you want to know whether your dose is effective. So if you want to know whether you're at 15 to 20, 20 to 25, if it's CNS, 10 to 15. You want to be at steady state, because you know, you don't want a dose increase before you've gotten to your final level. However, in the setting of toxicity, if you're doing a level to really check that there's no toxicity, if it's high, it's high. And you'll be glad you did it, because you can withhold the dose and decrease it for ongoing doses if you need it. So that can be a very tricky thing to explain to people. But when we do a level of vancomycin, we are normally checking two things, efficacy and safety. And if we're not a steady state, we can't check efficacy, but I do think we can still check for safety.

And is it fair to say then that if there's no other obvious insult, and we do think it's the vancomycin causing the injury, is there any scenario where you would continue the vancomycin or will we always swap to another agent?

Yeah, that's a really good question. I definitely think people would like to often push on with the vancomycin. So if we just quickly talk about the other MRSA therapies, we've got linezolid and in the setting of haematology, they're often very reluctant to use it because it has myelosuppressive effects. We have daptomycin, which is inactivated by pulmonary surfactant and can cause rhabdo. So that's the two reasons that people might not want to use daptomycin. And if the patient is on high dose statin which can't be stopped that might be an issue due to myopathy and rhabdomyolysis. And then one other drug that's very expensive and not totally readily available. It's ceftaroline, which we can use for MRSA. It doesn't have anaerobic or gram negative cover, but it is a nice option except that it's, I think, roughly 10 times the cost of vancomycin. And as I mentioned, I'm not sure that it's readily available in Australia. So there are situations where people can drop the dose, keep it at a low level, then I might be able to push on and minimise the toxicity for this patient, but it needs to be done really carefully. You're going to be taking a lot of levels you're gonna be doing once or twice daily creatinines in that setting. And if the creatinine keeps going off, particularly to a doubling or tripling, we know that that's associated with seriously bad outcomes for our patients. And at that point, I think we would strongly advocate for change.

Most clinicians are probably familiar with this vancomycin renal related injury that we're talking about. Vancomycin has some other toxicities and other side effects. What can you tell us about that?

I do this all the time where I just talk about vancomycin nephrotoxicity, but there are others. So one of the first things one of the first ones is Redman syndrome, so called historically, although it's really is a big push to change that naming to either vancomycin flushing syndrome or vancomycin infusion syndrome. And that's really related to a non immunologic histamine release. That happens with the administration of vancomycin. Just a couple of really quick points here. It's not a true allergy. If it occurs while the infusion is running and disappears, within an hour of the infusion being stopped. I'd be very keen not to put that down as a formal allergy, that the patient can receive vancomycin in the future. And the management of that vancomycin flushing syndrome, which is really a redness and flushing an itch from the chest upwards that can also just be managed by slowing the infusion rate down.

Because you do you see that a lot don't do on charts, you'll see it listed as you know, allergies to vancomycin, and they've got red man syndrome listed as the description, which obviously does limit care for a lot of people.

Totally and it makes it very difficult for the next practitioner to feel comfortable charting it because they think what was it was it more than that bronchospasm and hypotension are not normally related to red flushing syndrome or vancomycin flushing syndrome. But it does make it very hard. I think once it's documented as an allergy for someone to feel safe charting it but, you know, as we've mentioned, there's there's really only three drugs on the market that treat MRSA, I think it can be life saving in many situations, so accurately documenting true allergies. So there are some skin reactions that are very serious, that should preclude the ongoing use of vancomycin. And that's really related to DRESS which stands for drug reaction with eosinophilia and systemic symptoms. But even some of the other severe cutaneous reactions can occur with vancomycin TEN, SJS. So those are true allergies and patients who get those should be should avoid vancomycin and they should be counselled. But the vast majority of patients have an infusion syndrome that's mediated by histamine not immunologically and can safely have vancomycin, you know, either with pretreatment with anti histamine if absolutely necessary, but the vast majority can have it just with a slower rate. And also we, vancomycin has traditionally been thought of as ototoxic. It's very rare. Again, in the early days of vancomycin use, there was reports of tinnitus and deafness, but very minimal now, outside concurrent use with other ototoxic drugs like aminoglycosides, or macrolides. It does cause a bit of irritation, so phlebitis, and we do have strict rules about concentrations. Although for patients with fluid restrictions, actually, you can get quite, you can go up to 10 mg/ml for your continuous for your infusions. And the other one is the haematological complications of vancomycin. So rarely, vancomycin can be a cause of neutropenia almost always happens in the setting of prolonged use so longer than 14 days. And it resolves quite rapidly on cessation of vancomycin, normally in a couple of days.

And in general, is there anything that we can do to reduce the chance of vancomycin related toxicity?

So I think all of the things that, you know, we've been talking about, but really keeping a close eye on our patients, some of the things related to vancomycin infusion are very interesting. So in terms of vancomycin nephrotoxicity, we know that you do there is this sort of overlap between the risk of nephrotoxicity being in the same range as the effectiveness so that 15 to 20. What we've seen with continuous infusions is that actually, you don't get nephrotoxicity until your vancomycin concentrations are much higher, like even over 25. So it might be something about the way that we give the vancomycin and how the kidneys have to deal with it. That makes it safer to give it as a slow drip feed as opposed to these big bolus doses twice a day. One of the other things, just to get a little bit nerdy, that we have seen particularly in rat models, is the peak vancomycin level often correlates with the release of a urinary biomarker that we know is related to tubular toxicity. So it might be that these high peaks that you get with bolus dosing, are actually what's pushing the vancomycin nephrotoxicity. And if we can move to continuous infusions or decreased dosing intervals with lower peaks and high troughs, we may see that our rates of nephrotoxicity fall from at the moment what is commonly about 20% to less than 5%.

Where do we most commonly go wrong with using vancomycin in clinical practice?

Yeah, I think the main times that we get vancomycin wrong is almost just forgetting how crucial it is to keep up and check these things. So you can really have, you know, any of these toxicities. You know, some are more common earlier, some are more common later. So really making sure we're not forgetting to check our patients creatinine, not forgetting to make sure we've got a plan for the next level, making sure we are thinking about you know, is we are we giving this in the right concentration? Are we giving it over the right frequency? I think you've you've really got to keep up with those things because they can sneak up on you over time.

Are there any medicines that we should be careful of co-administering with vancomycin?

Oh, great point. It's a nice opportunity, knowing that vancomycin can affect the kidneys, to have a quick look at the Med chart and make sure there's no other nephrotoxins on there, or particularly those that could be stopped. I always look out and try and avoid NSAIDs, non steroidal anti-inflammatory drugs with vancomycin. Aminoglycosides very rare that we need to use a minute glycosides in combination with vancomycin. And the two together does carry an increased risk of nephrotoxicity. Some other nephrotoxins that can sometimes be used, but just monitor the kidneys closely like amphotericin. And we've recently had some interesting evidence that's coming out around concurrent use of flucloxacillin and vancomycin where we do think there's some additive nephrotoxicity. And we try and avoid that combination as much as we can and limit it to a maximum of that 48 hours. Similarly, we're seeing some increased creatinines for people who are using vancomycin and pip-tazo at the same time. And again, we're not really sure what's going on, but we try and absolutely keep that combination to a minimum to a maximum of about 72 hours. And in both those situations with the vancomycin and the flucloxacillin and vancomycin and pip-tazo, they can be used empirically. But normally, once you've got a pathogen, you can really get them off those combinations.

And finally, can you tell us is there anything sort of on the horizon for vancomycin, any new things coming up?

Yeah, I think vancomycin even though people do think it's forever about to fall off the clinical scale scale, it persists. And there are a few things we are looking at urinary biomarkers in humans. So one of our problems with creatinine that I have, again, really highlighted its use. But it's not a perfect biomarker for renal toxicity. And it's slow to rise. So it takes about 48 hours to rise. And it really only rises after about 50% of the nephrons have been damaged. And what we're thinking is that there might be local damage within the kidney that results in the release of these urinary biomarkers into the urine at a much earlier phase. And before there's maybe what would call true nephrotoxicity happening. So what we're hoping to do as a sub study of a major trial that's coming up, is actually test the urine of patients with staph aureus bacteraemia is and see if anyone is weeing anything interesting out. And if that then correlates with AKI as an early biomarker of patients who might not be suitable for vancomycin, or who might need increased monitoring or lower dosing or something to help avoid that, you know, damaging their nephrotoxicity. The next thing that I think is pretty cool is researchers in Brisbane actually have been piloting micro sampling. So can you imagine in the future, a finger prick point of care, vancomycin tests where we go to the bedside like a blood glucose machine, take a finger prick sample, get a level right then and there and then adjust the dose based on that? We're not there yet. We haven't got the point of care tools, but we certainly have got the technology to do micro sampling using like, point two of a microliter of blood and being able to send that off. So that will really facilitate I think, an ongoing problem with vancomycin which is levels being taken at the wrong time waiting for phlebotomy services. This could really help anyone you know, pharmacists, to help with that blood collection effort is just a finger prick type sample,

and help patients to I'm sure they prefer the finger prick test and the full blood draw.

Yeah, that's right, particularly when it's only one every couple of days. You know, we do know that diabetic patients do get sore fingers, but often that's four times a day. So you know if we're talking about one finger prick every couple of days, although once it's so easy, I'm sure that we will be asking them for a fingerprint before every dose but still, yeah, I agree with you. I think patients would prefer that a lot more. And the last thing is really interesting science that's very early stages about sensors that you could put on your arm that have a whole bunch of little needles that go intradermally and that essentially monitor your vancomycin concentrations every second of the day. And so you can have, you know, it can Bluetooth to a computer screen and it can show you the vancomycin in your patient in real time. But I think the problem with that is, you know, we'll never want to go home, because we'll want to sit there and watch our vancomycin time kinetics.

Thank you so much Amy for all the clinical pearls. I know I will be listening to this again.

Amy Legg: 30:30

Thank you