Biofilm 101 Podiatry
Dr Matthew Malone will discuss wound biofilm, its relevance in clinical practice and how to manage chronic wounds using a biofilm targeted wound care approach.
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Hello, I'm Ruth Timmins from Smith and Nephew and it's my pleasure to be here today for our biofilm 101 podcast episode with our very special guest, Dr Matthew Malone. Matthew will take us through some biofilm fundamentals to help you gain a better understanding of what they are, how they impact on wound healing, and how to effectively manage these in clinical practice. 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. So welcome Matthew, and thank you for joining us.
Hey thanks, Ruth. It's a pleasure to be here with you and appreciate the opportunity to go through basically, what are biofilms, what's the role in wounds and you know, how is this important to clinicians? I think you know, we're seeing a lot more evidence for biofilms and how they may impact clinical care. And so hopefully, we're just going to go through some of this information with clinicians today.
Yeah, and I know many clinicians will be dealing with you know, delayed wound healing and the impact of wound biofilm and that in their practice, so this would be really useful information. So I guess let's start at the beginning. What are biofilms and what's the issue?
Yeah look hopefully, I would think that you know, a large proportion of clinicians that may be listening to this podcast have been made aware of what biofilms are. We're certainly in a biofilm bandwagon where every man and his dog are trying to talk up biofilms. So you know look, I think the key issue here is in some ways, that the terminology biofilm is a sort of it's been a bit confusing for people. Biofilms really, are just the bacteria. It’s just that they behave a little bit differently than what we have become accustomed to learning about. And so, through biology, we've learnt that planktonic bacteria are these free-floating microorganisms that are very active and rapidly divide. Biofilms are quite different. From the evidence we’ve built up, we know that these bacteria like to come together and form aggregates, or basically, just lots of clumps of bacteria together. We know that they like to attach and adhere to things. That could be a surface, a living surface or a non-living surface, or it could be just attaching to each other and forming what would be like a bunch of grapes floating around in some wound fluid. We also know that they start to behave differently when they attach together. They change certain genes to alter their behaviour. We know that they start to produce a protective coat or a matrix that we call the extracellular polymeric substance. We know that these altered behaviours and growth occur. We know that they slow their growth, reduce their metabolism, and we know that in some cases, they can reduce virulence mechanisms so they don't sort of induce this big host response. What we know is in these behavioural changes, they seem to have quite a lot of protection from host defences and to many forms of treatment, including antimicrobials. We know that they're present in about 80% of the wounds because I was part of a group that published that research (1). And we also know that maybe, health care professionals don't sort of routinely treat for biofilms, because it may not be one of the first things that comes to their mind.(2) We know that biofilms in human health and disease and the evidence for them is growing. We've seen them been discussed in contact lenses, in medical devices, in breast implants and tissue fillers, urinary tract infections. My own group has done a lot of work with bone and skin and soft tissue infections and medical device infections. We've published biofilms as being a cause of chronic diabetic foot osteomyelitis (3) .We've shown biofilms are ubiquitous in diabetic foot ulcers (4). We found biofilms in vascular stents. So you know, in all there's a growing plethora of information.
When they're in wounds, often people ask me, "So, you know, so the biofilms are there, what's their role?" “You know, what do they do?” Some people may think they delay wound healing. One of the biggest things I want to get across, one of the messages is you know, if we're talking about biofilms on their context to wounds, for me we are talking about chronic and persistent infections. And that was something which has been clearly outlined by the European Society for Clinical Microbiology and Infectious Diseases. There's a publication in 2014 and the summation is biofilms are a cause of chronic and persistent infections(5)
So what's the impact of biofilms in wounds, then Matthew?
So look, we know biofilms are there in wounds. And we know in a certain number of cases they can start to misbehave. There's been, most of the evidence available is formed from sort of in vitro studies and animal models. And in some of those mouse models, we've found that the presence of biofilm delays healing. And those studies have found that when you knock out the genes in the bacteria to form biofilm that those wounds then go on to heal. So we've identified that biofilms as a cause of chronic and persistent infections in wounds also go on as a mechanism to delay that wound healing. We still don't fully sort of understand the whole process, but we think in the majority that what biofilms do is incite a host, a low-level host response and cause at the biological level, excessive inflammation. And I do say that broadly because we are still trying to learn a little bit more about biofilms. But the predominant thing is that they are a cause of chronic and persistent infection that can delay wound healing and at a level, they may cause lots of inflammation. So we know that they do cause problems in wounds, and we know that they exhibit tolerance, but how do biofilms do that? Hopefully, some people may have heard about the extracellular matrix, they form this protective coat. We know that has a ionic charge and it can interfere with compounds and certain things like antibiotics. If you look at the aminoglycosides, antibiotics such as gentamicin, that seems to have a charge which in Pseudomonas aeruginosa biofilms can sort of stop the action of it. If it is able to get through some of the matrix, there's a slow penetration of the compounds because they're faced with lots of challenges from bacteria in the environment. And during that slow progression, those compounds can be deactivated. We know that the bacteria in the wound have mechanisms to deal with antibiotics. Antibiotic resistance mechanisms, efflux pumps and other things. We also know that there's a micro environment within these biofilms and actually, the surface of the biofilms can be quite oxygen rich. But then, as you get down to the base of the biofilms, they can sort of have depleted oxygen or no oxygen. And so those diffusion gradient and changes again can alter the compounds which may be used. And then last segment, we briefly touched on the slow growth, and basically, there can be a proportion of cells in the biofilm that just virtually are dormant-like and antibiotics do not work on. So with this in mind, they can sort of really develop quite extreme tolerance to many things we do.
Yeah, so I mean, it sounds like it's a real challenge to manage biofilms in wound care. So how do we treat biofilm?
Yeah, look I think the best thing for clinicians to do is to look at available resources. And certainly, there are a few available now. I was part of a group in 2017 who published the consensus guidelines for the identification and management of chronic wound biofilms. In this we talked about a step-down approach, which really a foundation core is performing debridement, doing it very frequently, doing lots of other therapies, wound bed cleansing, appropriate and evidence-based antimicrobials, making sure we've managed the host, etc. And we put all of these together, we do it very, very frequently. And then as we maybe start to see or if we see improvements, tailor off (6). We also see other decision tools, and in particular we have TIME and TIME 2.0 and that can help clinicians work through managing biofilm, removing non-viable tissue and managing the infection... the local infection and chronic inflammation, for example(7). So there are a lot of resources there to help clinicians. I've developed my own sort of clinical practice approach through treating many of these patients and just throwing some ideas down. And they sort of bring together lots of these paradigms and for want of a better word, the first sort of thing I would do if a patient walked in would be to do an assessment, a patient level assessment and I'd be doing the A, B, C, D that's part of TIME. Part of that is to make sure that you know, I'm not just concentrating on the bacteria but I'm looking at the host, the person, making sure their glycaemic control is good, making sure they're offloaded or they have compression therapy. Number step two might be then if I think there's a need for systemic antibiotics, I'll obtain an appropriate culture to try and identify the microorganisms. And then the next step after that would be to start picking up a scalpel blade because I know that one of the best forms of treatment is to debride the wound physically with a scalpel blade or a curettage. I want to physically remove as much bacteria as I can. And then once I've done that, I know then I just want to clean it up. There might be some overspill of blood, there might just be some other tissue. I know that I might not have removed everything so I'm gonna give the wound a good clean, so I might use an antiseptic wound solution for a short period of time just to mop up anything right there and then. But obviously, going forward until the next time I see the person, I want to make sure I've got something that keeps releasing an anti-microbial frequently into the wound that has some evidence to show that it works against biofilm. And then obviously, on the side peripheries I want to make sure I'm managing the moisture of the wound and so forth. So the key thing here for clinicians to get through is debridement, physical removal. I know it's a problem for some clinicians who are not able to perform debridement, sharp debridement, anyway and in those cases, I would just suggest you try and utilise anything available to physically try to disrupt and remove biofilm from tissue. You've got to remember the slough on the surface that will not just be containing biofilm. The biofilm will be in below that in a tissue you think might look nice. And that's why we need to really try and be quite aggressive as we can. One of the problems with debridement is we do it frequently hopefully, but we know that we can't see bacteria and so we may miss things. And this has been published and results have shown that when we do debridement, and we look at the level of bacteria before and after treatment, we actually just don't remove as much as what we think we do. There's some nice evidence by Randy Wolcott that's shown that when you perform debridement, you sort of disrupt the biofilm a little bit because you're physically trying to remove things (8). And in that disruption, you sort of make them become quite active because basically, they're being stressed. When bacteria are being stressed they will respond, they will have to increase their activity and so again, during that time they may become a bit more susceptible to the treatments, such as your antibiotics or your topical-based therapies. And so that's why we debride and then we use the anti-microbials immediately after. But then, what happens is biofilm re-forms over a couple of days, back to its normal level and that's where we're talking about doing things frequently, so debride, cleanse, use antimicrobials, a couple of days, repeat the same method so that we can break a vicious cycle.
OK, so following debridement then, what should we do? What would you recommend?
So there's some really cool sort of guidance again with regards to this. There's a new infection management pathway that actually, Smith and Nephew have developed. I quite like it because it's very simple and it just has a really nice statement. Right treatment, right time. And so, it's all about deciding which treatment you're gonna use and why are you gonna use that? And an example for that is you know, you've debrided the wound. OK, let's say you've debrided a wound and you think that there's no biofilm and it's...but these planktonic microorganisms, and that's what you're trying to affect. And this right treatment at the right time algorithm would say the optimal sort of anti-microbial in these scenarios are things like silvers because they're highly effective against planktonic cells. But after debridement, if you are thinking that you wanted to follow up with a topical anti-microbial and you're dealing with biofilm, then actually, we just talked about, maybe in a podcast about myth-busting stuff, that silvers are not that effective against mature biofilms. So you should maybe need to consider a different treatment. And as we touched on, iodines have by far, the highest level of evidence to show that they are effective against biofilms. So after debridement, clean, wound bed prep and then apply a topical anti-microbial.
OK, well you mentioned there about iodines, cadexomer iodine in particular. So with the Iodosorb, how does that work and why is it so effective against biofilm?
Yeah, look so we know, for those that have used the cadexomer iodine, we know that the cadexomer beads absorb exudate when it comes into contact with it. And as the beads swell and absorb the slough and debris, and bacteria, as well. It actually breaks bonds internally and iodine is released. And you know, one of the key things here is there's a significant amount of data which has shown cadexomer iodine over multiple different models and its effectiveness. As I touched on in the myth-busting biofilm podcast, across every different sort of model in vitro and animal models, we see that it has some of the highest levels of kill rates against biofilm in the laboratory on an animal. And just to highlight on that point that does not necessarily mean you're going to achieve the same objectives in a human wound. But we have as a group, my own research group published two publications on the effectiveness of cadexomer iodine in human wounds. One is available on the 'Journal of Antimicrobial Chemotherapy'. If you just type in Malone and cadexomer iodine, it's freely available to download (9,10). We're really one of the first groups to use sort of complex molecular microscopy techniques to show that you are able to, or cadexomer iodine is able to reduce the total amount of bacteria in biofilm in chronic DFU’s. So some really sort of intriguing stuff from this.
That's great information, Matthew. So what are your thoughts around the use of antimicrobial wound solutions? They're quite commonly used in wound care so it would be great if you could share your thoughts.
Yeah look, this is I think, at the top of my list as being one of my sort of pet hates. I think you know, I've spent numerous hours coursing through the entirety of biofilm evidence with regards to sort of topical treatments for wound care. The summation of all of the things I've read is that overall, the general level of evidence as a whole for topical agents is quite low and for wound solutions is even worse, is quite poor.
This all started when I had a rep that had come to me one time and said, "Look, we've got a great new product and it works really well, kills biofilm." And he showed me this publication and I had a read of it. You know, it was done in a test tube with a high concentration of something. And it just...it wasn't very clinically relevant. What that did was make me go and do my own study, and so we've actually published again in the 'Journal of Antimicrobial Chemotherapy' a manuscript...a paper where we did an in vitro animal model and human studies where we tested antimicrobials wound solutions, commonly used ones in Australia and we evaluated how well they worked across those platforms(11). And importantly, we tested them on appropriate clinical exposure times. You know, if you're lucky, if you can use an antiseptic solution and leave it on the wound soaking for 15 minutes. You know, most would I would think, are less than this in the clinical reality but we tested ours in vitro for 15 minutes. We tested lots of the most commonly available ones you're gonna find and as a whole generally, at 15 minutes, we had quite variable results. Some, they, sort of surfactant-based wound agents performed quite, quite poorly as a whole against a pseudomonas and staph aureus biofilms at 15 minutes. The older school generations, your chlorhexidines and your povidones worked very well generally. And your superoxidised solutions also worked quite well. You know, we do that model at 24 hours, and they all work a lot better. And it's you know, common sense. You leave it on for a longer time, 24 hours, its gonna work a lot more. But the reality is we don't leave wound solutions on for 24 hours. So you know, if we base it on the 15-minute exposure, you get very different results. We then took one of the agents, the superoxidised solution that works very well in both 15 minutes and 24 hours. We put it into a porcine model, a pigskin, and we instilled the solution ten times over 24 hours for a ten minute dwell period. And you know that solution performed no better than saline alone. It just reduced the log by 0.7. So as soon as you start changing the models you get very different results. We then take that to... we take another surfactant-based antimicrobial to a human trial, we do the molecular and microscopy techniques in ten patients and we basically leave the wound soaking for 15 minutes every day with the solution. And we take biopsies of the wounds and we look at how much bacteria is present in the wound before and after treatment. And we find it does virtually nothing. But it reduces about 0.2, 0.1 of a log over seven days. And so, the results weren’t that surprising and in fact, it's actually what we found when we looked at the types of bacteria before and after, it made some of the more predominant staph and pseudomonas, they actually got...they increased in numbers. And so you know, look, for me the evidence really isn't there for us to be using this en masse. There's been a recent negative, there's been a recent randomised controlled trial, as well, from a colleague of mine, Larry Lavery in the US, on a significantly large sample size. Randomised trial, does negative pressure wound therapy with irrigation using another surfactant-based antiseptic, does it improve clinical outcomes? (12).The simple answer is no, it doesn't. And we have some of the microbiological evidence to suggest why it doesn't. And it's likely that they're just left on for too short of a time to actually have any effect. And that's why we really say, you want something that's a bit more of a slower or sustained release over a period of time, rather than you know, five minutes.
Thank you, Matthew. That's really given us some great insights and a good overview of wound biofilm and how we can manage chronic wounds effectively. So, what would you say is the most important thing to remember when managing wound biofilm that you can share with our listeners?
For me, it has to be debridement. If you've got really good debridement skills, you know you can pick up a scalpel and use that and that scalpel may cost you, you know, a couple of dollars if you're using a single use. You just can't beat the ratio of a couple of dollars and physically removing biofilm, instead of spending you know, hundreds and hundreds and hundreds of dollars on potential things that don't work. Obviously, because you don't... might not see bacteria. I do often propose that once you've done debridement, you follow that up with a sustained antimicrobial that has good evidence or reasonable evidence. And so, in summary you know, I think that this multifaceted approach is key for clinicians. Be aggressive and tailor off as you get control of it. These are complex patients with chronic pathologies and we need to break a vicious cycle.
Thank you. That's some really great advice and I'm sure it's going to be very helpful for many wound clinicians to take back to practice. So thank you, Matthew and thank you to our listeners for joining us today and be sure to tune in for the next podcast.
Incorrect diagnosis of infection in chronic wounds and selection of inappropriate products could lead to delayed wound healing and complications, which add further pressure on your time and unnecessary costs. To support you in identifying and effectively managing chronic wound infection, Smith and Nephew have developed the infection management pathway.(13-22) To grab your free copy, contact your local Smith and Nephew representative or email us at email@example.com.
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- Malone M, et al. The prevalence of biofilms in chronic wounds: a systematic review and meta-analysis of published data. J. Wound Care. 2017;26:20–25
- Swanson, T., et al. J. Wound Care 2017;2:426–440
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.