Evidence for managing Biofilm
Dr Matthew Malone looks at the available evidence for clinicians to consider when deciding what antimicrobials to use in managing chronic wound biofilm.
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Hello. I'm Ruth Timmins from Smith and Nephew and it's my pleasure to be here today for this really relevant podcast episode with our special guest, Dr Matthew Malone. Matthew will explain what the evidence is available to clinicians when deciding on which antimicrobials to use in wounds for managing chronic biofilm infections. Matthew is a leading global expert in wound biofilm and the current Director of Research for the South West Sydney Limb Preservation and Wound Research academic unit. Welcome Matthew, and thanks for joining us today.
Hi Ruth, it's a pleasure to be here with you in this podcast.
Yeah, I know many clinicians are gonna be interested to hear about the latest evidence to help them decide on the appropriate antimicrobial use.
Yeah, you know, I think I am as well, to be honest. It's a sort of a pet thing of mine is to try and go out there and educate clinicians around the globe around wound biofilms because I just think there's so much confusion out there at the minute.
Yeah so, thanks Matthew. Why is it important for clinicians who treat chronic wounds to understand evidence-based practice and what does this mean?
I think, look, I think the best place to start is just trying to provide a little bit of context for wound care, in general, with regards to levels of evidence. Now, many people may have seen the evidence pyramid with systematic reviews and randomised control trials right at the top, down, as you go down to observational studies and in case series, in case reports, and then retrospective reviews and expert opinion. I think the problem with wound care is for the majority of research that they have a, well, particularly with regards to biofilm and topical antimicrobials, most of the evidence is right down at the bottom and a lot of that sometimes is because medical device companies just don't have, you know, a million dollars to spend on a randomised control trial, they don't have the same budgets as pharmaceutical companies. And so, what that means is that there's a lot of evidence existed out there which is generally of the lower levels and lower grades of recommendations. And I think what that means is that, you know, with regards to clinicians, there is not great information to go from and I think what happened with biofilm is that that's particularly one of the key areas where we see not a great deal of high level evidence because I, from my own recollection, I certainly don't know of any medical device company that has invested... hundreds of thousands of millions of dollars into looking at biofilm research for, you know, a topical wound agent, for example. So, it's a big problem for clinicians when they're trying to decide what to use and, you know, they might see some piece of evidence which says, you know, this is a great wound agent and it's been done in a totally inappropriate model and think that the results you're going to get are going to be exactly the same when you take that to a human person. And that could not be further from the truth. You know, things that you may see in in vitro designs do not often work out to be the same that happens in any human being.
So, there has been significant spotlight placed on the role of biofilms in wounds over the last, let's say, five years. And there are so many products out there which you know sort of claim to work against biofilm. So yeah, how is a clinician supposed to make informed decisions on what to use, in your opinion?
I think, you know, the first port of call that clinicians have to do is just to go to potentially where the bulk evidence is and that's often mostly in the form of guidelines. Again, you know, I was part of a group in 2017 who published the consensus guidelines for the identification and treatment of biofilms and chronic non-healing wounds. This is a good start to get an overview of the types and levels of evidence that are available. I've even, you know, sort of published some other expert reviews, approaches to biofilm associated infections and the need for standardised relevant biofilm methods. And basically, this paper was a preamble, because, you know, I was just hearing lots of claims and looking at the evidence and they just weren't making sense. And lots of the problems we have with companies when they do an in vitro model is they may all use different models, and different setups and different designs, and you know what that means is when you come to look at the evidence, you can't really compare apples with apples. And so, it makes it really difficult to understand whether the results you see in there are going to go forward and you're going to see them in human beings.
I believe your research group has invested a lot of time into tackling this problem and is trying to provide evidence and importantly raise awareness to clinicians about making evidence-based decisions?
Yeah, look let's just use this this paper you talk about as a primary focus of talk about for a minute. This was my research fellow here in the Limb Preservation unit, Saskia Schwarzer, she'd done an amazing job of basically going through every single piece of published evidence on anyone that has looked up wound agents against, sorry, topical agents for use against wound biofilms and we have published this now in the Journal of Infection, it's the efficacy of topical agents used in wounds for managing chronic biofilm infections a systematic review. So, as some of the key people and players around the globe, biofilm experts and, you know, was a huge, huge piece of work. Basically, what Saskia did was use a very structured systematic review approach. She did a lit’ review and found about 640 articles... of people who had done tests against agents for wound biofilm. We had an inclusion and exclusion criteria for these. They must have stated certain things and, you know, once we got rid of really extremely poor methodologies and designs, we actually were left with about 461 to review. Then, when we applied our more stringent inclusion criteria, that actually ended up being 43 studies. So, 43 studies were accepted for full review and this was mostly because there was either a lack of appropriate visualisation techniques to confirm, they grew biofilm in a model or in human and or maybe the topical agent was not really in the context of chronic wounds. You know, it might have been a very novel design of a super-agent that I've never been... sort of been used commercially before and so that was one of the things we're looking at was whether there were commercially available agents. So, in total, we had about 43 papers to look at and what we found was there was a total of 43 commercially available topical agents that could be grouped into 12 categories. You know, your silver, honey's, iodine's, your polyhexamethylene biguanide, your poloxamer 188, your super absorbent, your melaleuca oil, your hypochlorite acetic acids, your pyridines, chlorhexidine's, ringer solution,electroceutical), so basically an awful lot of... wound care products available. You know what the most interesting thing from this paper was? Out of all the evidence which we found, the whole 600 and plus papers, 90% of all evidence for biofilm, or for agents being test against biofilm, 90% is in vitro studies, in vitro studies. Basically, there was three human studies to choose from. And so, you know, when you start to look at that you can really see there's a massive disparity in the levels of actually human evidence. Most of the models were something called EMBEC. And this is a really simple screening tool and that's all it's used for. You can run lots of tests at the same time and you know, if you put 90 tests on an 80-year-old fail, the ten that looked like they're doing well, you can then take forward into more stringent tests. So, EMBEC was the well play essay was the most commonly used sole laboratory model in most of the tests. And in total, I think we found 39 different models we used. I think it was 39, Hold me to that, read the paper everyone. I think we found about 39 different models, different 39. Again, that is a ridiculous number to have when you're then trying to compare whether you know, this iodine product work like this iodine product, so there is a problem. So, what did we find when we will, look at the evidence? So, we got all these levels, silvers, iodine's, PHMBs. We then broke them down into the different individual brand names and you know what did all of these tell us when we combine them all together? Well, we touched on before in total, silvers, if you look at how well any agent, how well any silver agent works against a biofilm models combined all the tests in general as a mean average a hard two-log reduction. Iodine's were able to achieve near a seven-log reduction PHMBs, where about a 3.5 log reduction and poloxymers was about 3.7 log reduction. And then as we go into animal models, silvers were only able to achieve a 0.85 log reduction, iodine is a 4.5, PHMB's 2.3, hypoclorous acid was 0.67 so you can see that those figures drop and drop as we start to move to different models from in vitro to animal, and obviously, there is some significantly higher efficacy rates in iodine's.
So, what evidence do we have for iodine's?
Well, I think here, by far, the bulk of the evidence that's available from any iodine, whether it'll be povidone or cadexomer iodine is for Iodosorb. You know, when we look at the levels of evidence for cadexomer iodine, what we can see is or as a scientist, you know, if someone comes to me and said and you know, the first thing I ask really for is, Do we have any human trials? And they say, "No." OK, so that's a problem. But we know it's an inherent problem. So, what I want to see is I want to see an agent that has a broad level of evidence, maybe across lots of different testing. And so, I know if you were to come to me and just show me one in vitro test like the CDC, that may really not be very reflective of how that is actually going to work. And so, you know, when you look at iodine, it has a basically broad level of evidence across many in vitro models the colony... colony models, the drip flow models, the Lubbock sort of poly microbial model, the mouse model, the porcine explant. So, it actually has a significant level of evidence across both in vitro and in animal models where it's able to demonstrate high levels of efficacy. It's also one of the few agents that has human and data available and in particular that's from from our group who've published two articles to show that cadexomer iodine can reduce the total number of bacteria in biofilms in chronic DFU's. So, you know, really what you want to see an if there's a lack of human evidence that someone's able to demonstrate that if at least looks across many different models because as I say, you'll get different results as you look at these models and so you want to sort of try and blend an overall picture of how well it's looking and then maybe use that to say, "Well, look OK, there is a potential and that is evidence is of a higher standard."
So, you've already sort of touched on some of the results particularly in relation to cadexomer iodine and so could you elaborate a little bit more perhaps, particularly, in the human trials that you've first done.
Yeah. Look, we're really proud of these trials of the research unit here, and I think that's because there really are some of the first types of trials that have really attempted to better understand what happens when we put a topical agent on to a wound with regards to trying to affect biofilm. And so the first one was published in the Journal of Antimicrobial Chemotherapy it's free to download if you type my name in and cadexomer iodine. And basically, what we did was we had about 17 patients, we applied cadexomer every second day for a week. We obtained tissue punch biopsies from the wound before and after treatment, and we subjected those biopsies to quite advanced techniques. We did 16S amplicon sequencing so we're able to look at the microbiome or microbial communities of the wounds. We did QPCR so we could look at the total microbial load in the wound before and after treatment. And we also looked to confirm the presence of biofilm on those cadexomer altered any architectural biofilm structure using scanning electron microscopy and a technique called PNA FISH or peptide nucleic acid fluorescent in situ hybridisation. You know, look, what we found was about 11 patients of the 17, we were able to reduce the total amount of bacteria by about one log. We were actually really surprised that we were able to achieve those sorts of results. We didn't think we'd be able to get that. I think people have to very much understand that we're not in planktonic realm where you expect you know, an on a, in vitro dish to get greater than three log. We know biofilms are really tolerant and so to actually prove that, what we've probably got is some of the most tolerant biofilms you're ever going to get because you know these aren't grown for three days in a lab. These are been there for months and have probably been tried to be treated with all the things so these can be the most tolerant biofilms you gonna come across. And in a week, we we're able to reduce the microbial load by about one log and we're also able to show that we had an effect with the biofilm structure. The interesting thing actually with that is we did, we looked at MMPs and we showed that when we reduced the level of the bacterial, MMP 9 reduced as well. More recently we then got on to just quickly do a study where we looked at the effect of cadexomer iodine over two- or six-week period because, you know, I thought that if you've got biofilm, they are a lot more tolerant, you have to treat them for a lot longer. So, we did a study in 20 people where we looked at patients who were given it for two and six weeks, and we looked at again the amount of bacteria in the wounds. We found some really interesting and what we found is actually, is the amount of bacteria was exactly the same at the end of the two week treatment at the end of the six weeks treatment. So, what it probably says is when you apply cadexomer, it has its action very quickly and it achieves what it can achieve within that short period of time. And after that time, it will just maintain those sorts of levels and we think of it like an antibiotic, it might get rid of the the some of the biofilm that may be susceptible but those very strong persisters might still be there. But look we found something even more interesting and we found that whilst we achieved about a half log to one log in patients, we found it really had an unusual effect against the microbial community. So, if you think you've got these wounds that are not healing, and the made up of say ten or eleven different types of bacteria, you know, if you reduce the numbers equally over those bacteria, you've still got all of those bacteria in the wound. What we're able to show is we affected the community composition so we, it's almost like when we applied cadexomer, it affected maybe one of the key players in out of those ten and it's almost like if you've got a group of kids on ones and you've got a main ringleader and you bully him and you take him out, then the other sort of kids don't know what to do and they're lost. And so this is what we actually found with some of our research that we affect the bacteria in this sort of way where we disrupt the community cohesion and so the pathogenesis, the biofilm, the measures which you may be causing the wound to not heal stopped and so immediately, the patient starts to heal again. That's just an extremely interesting concept we have but what we found was the size of the wound matters and so is, you know, if you're gonna ask me what the conclusion of paper was was, you know, two weeks is really good time to use cadexomer before it seems to work quite well. You've got a really large wound though, what happens is in a small wound you apply cadexomer, you would disrupt the community, you start to get wound healing and the wound gets really quite small and then it's manageable whereas a big wound, after two weeks it's still quite big. You got to think these agents don't heal wounds per se, they kill the bacteria and then the host heals the wound. But in these really big deficits, you've still got quite a lot of tissue to heal. What you don't want to do in a chronic wound that's very large is treat for two weeks. Reduce the biofilm, it start to heal, but then because you've still got really large deficit, stop doing everything and go back to normal care. And so a biofilm restart all over again. And so what we're just saying is maybe in larger wounds, you just have to keep going for a bit longer until the wound gets smaller and manageable to maybe where, you know, you could use a single use negative pressure to try and rapidly close a wound, for example. So cadexomer is highly effective, it does it in a short period of time. But in large wounds, you just might have to extend that treatment.
That's really interesting insights into the use of Iodosorb in an actual chronic wound. So I guess, Matt, just to summarise, what would be, you know, you sort of take home message for our listeners to sort of bring this all together, there's a lot of information today.
Look, I think for me, in this day and age, you know, everything is generally freely available mostly online. You know, I'm really... most clinicians now can jump online on Google. Spend an hour or so just having a look at the evidence in the area. If they're going to use a product you have a look for the type of evidence that products got, and instead of just reading and maybe just taking the word that you know in this in vitro model it kills biofilm it's going to work in humans. You know, you have to take that with a pinch of salt and understand that that's not actually what potency is going to happen in a human person. So, educate ourselves by freely going on and on looking at the information on online and using that to maybe help guide how you... set yourself up with using particular agents and stuff. It's we're very cost driven nowadays and I think we use a significant amount of our budget potentially on things that maybe have little to no real effect. And you know we have to demonstrate that now, we have to demonstrate that the things we're using at least there's some rationale for us to do that. So, clinicians go online and see what's available. Good place to start is their publication which we've done.
Well, that's you know, thanks Matthew. It's really given us a really good overview of the evidence that's available and lots of food for thought, I think. And how we can take this back to our everyday clinical practice. So, thank you to our listeners and thank you to Matthew again for joining us today. And be sure to join us for our next podcast.
Thanks Ruth. Thanks listeners.
Know when to use silver on chronic wounds. Effective against free living bacteria and prevent biofilm reformation but cannot disrupt initial biofilms. Find out how Iodosorb 0.9% cadexomer iodine performs against biofilm.1 Contact your local Smith and Nephew representative or email us at email@example.com. The information presented in this podcast is for educational purposes only. It is not intended to serve as medical device. Products listed outlined with care are examples only. Product selection and management should always be based on comprehensive clinical assessment. The detailed products information including indications for use, contraindications, precautions and warnings. Please consult the products applicable instructions for use prior to use. Helping you get closer to zero wound infection.
1. Malone M et al. J Antimicrobial Chemotherapy, 2017; 72(7): 2093-101
PhD FFPM RCPS (Glasg)
Matthew is the current Director of Research for the newly established South West Sydney Limb Preservation and Wound Research Academic Unit, and also the Head of Department for the High-Risk Foot Service at Liverpool Hospital in Sydney. Matthew was recently appointed as a senior lecturer, Infectious Diseases and Microbiology, School of Medicine, Western Sydney University, where Matthew completed his PhD Matthew is also a Fellow, Faculty of Podiatric Medicine, Royal College of Physicians and Surgeons Glasgow, a leading researcher in diabetic foot infections and the role of biofilms and is a current member of the International Working Group for the Diabetic Foot (IWGDF) diabetic foot infection guidelines working group. He is also a member of the Global Wound Biofilm Expert Panel, and a member of the Australian Society of Microbiology, Biofilm special interest group.