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Thank you. Hello, my name is Karen Burns and I work in Beaumont Hospital in Dublin in Ireland. Um I'm a consultant, clinical microbiologist. And this talk, I'm going to um talk in part one about the problem, um describe the epidemiology and I'm gonna spend a bit of time on these two bits because I think in order to uh to talk to patients, it's really important that healthcare providers have an understanding of the issue of carb pro producing organisms and their epidemiology depending on the part of the world that you are based in. Um I'm going to start talking about the prevention and control measures with a focus on antimicrobial stewardship or a MS in this part of the talk. And in the second part of the talk, I will um give a recap of, of part one and focus in more on the infection prevention and control measures and the importance of effective communication with healthcare providers and with patients. So we'll move on with part one. So the reason I want to spend a bit of time on this is because of the alphabet soup that is to use to describe this problem. And depending on the part of the world that you're in. Um all of these acronyms you may encounter in your day to day practice and essentially what we're talking about the same thing when it boils down to it. But I'm going to explain what a lot of these mean. And hopefully, um we have a better understanding by the time I'm done. So the problem is gram negative bacteria or bacilli or GNB for short, they're also known as gram negative rods or GNR S and we divide them as follows. So we talk about the enterobacterales and they used to be called the enterobacteria. A A. They are a large group of DMD S that are typically found in the enteric trac or the bowel. So the clue is in the name enterobacterales. And there are many different types of enterobacterales. But the ones I'll focus on on this talk are the ones that are typically covered in terms of surveillance systems worldwide and common causes of infection such as Eric E coli or E coli for short and clsa pneumonia. Um But there are many other types of enterobacterales that are not covered in these surveillance systems, but they still cause infections in humans. And antimicrobial resistance is associated with them such as citrobacter proteus. And we also have zoonotic enterobacterales which typically are found in the guts of animals but can be transmitted to humans via the food chain where they can cause infections in humans. And sometimes those infections can be resistant antimicrobial. So those are things like salmonella and shigella um separately. Then we have pseudomonas, aeruginosa and acinetobacter bowmannii. And these don't fall into that group. Enterobacter rallies and pseudomonas and acinetobacter are ubiquitous in the environment. Pseudomonas is very fond of moist environments and acinetobacter is a hardy organism that can survive in, in, in dry and dusty environments and resistant to, to disinfection. Um And so these organisms tend to be more opportunistic infection causing agents. Um They, they, they, they don't tend to affect healthy people, but they will take an opportunity in a susceptible host like an immunocompromised patient or somebody in the intensive care unit um where they can cause significant infections. The the antibacterials that are of concern or the topic of this talk are the betalactam group and these are very effective treatments that we use for treating infections caused by enterobacterales. And they can range from very narrow spectrum antimicrobials like amoxicillin um to the broadest of spectrum bet Latins, the carbenin um such as meropenem and these antimicrobials work to stop the bacterial cell wall from being produced. And if a bacteria can't make it cell wall, it can't protect itself. And so the bacteria will die. And so, so that's why these are very effective antimicrobials. When we look at pseudomonas and acinetobacter baumannii, beta lactams have a role in treating these infections. But the problem is is that pseudomonas is already inherently resistant to many common beal lactams and that we would never ever choose them to treat infection caused by pseudomonas because they just don't work. So we have even fewer antibacterial agents in the betalactin class that are effective against pseudomonas. Aeruginosa and acinetobacter are worse again because the only type of betalactam that is reliably, um, used to treat acinetobacter infection are the carbapenems. So, uh from a starting point, the these bugs are already resistant to, to common bet lactams. I'll point to you in the direction of this recently published antimicrobial resistance concise update from lancet micro a couple of months ago. It really gives a nice overview of antimicrobial resistance in, in, in all bacterial types and and, and some novel and emerging treatments for them. Um It, it's I think it's an open access article. Um So in addition to being inherently resistant to certain antimicrobials, bacteria are smart because they can exchange genetic material with each other. They talk to each other and that genetic material encodes instructions or recipes to create enzymes that can destroy the betel actin antimicrobials. And those enzymes are known as Betty actin Maes. And these are acquired antimicrobial resistance mechanisms in, in a lot of bacteria. They pick them up from other bacteria and as I said, bacteria are smart. So they figured out how to become resistant to betalactam. Guess what? They've also figured out how to become resistant to other antimicrobial classes such as the fluoroquinolones or the aminoglycosides. And so this terminology is used um multidrug resistant. It describes a AAA bacterium that is resistant to three or more different classes of antimicrobials and extremely drug resistant or XD R is used to describe a that is susceptible to less than fewer than two classes of antimicrobials. Um And, and so a lot of the bacteria I'm talking about can be categorized into the MDR category as well. So the, the DNBS are smart, they have lots of tricks at their disposal that they can use to become resistant to be lactam antimicrobials. And the focus of this talk is that production of the enzyme, the beta lactamase that can destroy the betalactin antimicrobial. And when we talk about Betty LAMAs, there are kind of two common categories, the extended spectrum Betty lactamases or ESBL S and they destroy the Betty lactams that have extended spectrum of antibacterial activity up to the level of the third generation cephalosporins and atrium. And so ESBL S are a big problem in enterobacterales. Carbapenemases go a step for further because they can destroy everything up to the level of the, the, the carbapenem, which as we know is our last resort. Betalactam and carbapenemases are a problem in enterobacterales and depending on where in the world you are, they can be referred to as carbapenemase, producing enterobacterales or CPE or carbapenem resistant enterobacterales. C but carbapenemases are also problematic and pseudomonas and, and an acinetobacter um in which case, we would call them carpene producing organisms or CP because they're not Enterobacter, all we can't call them CPE. And if it's a acinetobacter, it could be a carbapenem resistant he acinetobacter or crab for short or similarly for, for pseudomonas. So you can see where I'm coming from with all of this complex acronyms and terminology. Um We, we divide then the carbapenemases even further into two groups. Those that are called non metall ofet lactamases. And the commonest types of those are K PC or OX 48. And then the metall lactamases are MBL S and so called because they need the heavy metal iron zinc at their active site in order to be effective. And there are three big types of MBL S MDM I and VIM. And the reason we make this distinction between metallo and non metall beyl lactamase is, is because typically it's the MBL metall beal lactamase producing gram negative bacilli that tend to be resistant to even more antimicrobials than the non MBL type. Um carbapenemase producing GMBS. So that's just the distinction that we use. And depending on whether you're enterobacterales, pseudomonas or Acinetobacter, the most prevalent carbapenemases within each of these groups differs. So we can see with Enterobacter rallies. DM can appear as the metalobalis that causes problems in pseudomonas. Aeruginosa, all three of the big metalobalis cause problems there. And in acinetobacter baumannii, it's, it's DM is the predominant MBL found in, in acinetobacter. And when we look at the the world in terms of global distribution. Um and we look at the Enterobacter rallies, we can see the light blue as shading is, is, is, is seen distributed worldwide. And that means that DM S are found worldwide, but perhaps they're not the most prevalent carb in the countries that are shaded in light blue. But we look at the countries that are shaded in dark blue, such as Southern Asian countries that DM is the predominant carbapenemase found in, in those countries. And with regard to pseudomonas, Aeruginosa, again, we see in dark pink, a global distribution of vim as the predominant carbapenemase in pseudomonas, aeruginosa, but in Southern Asia, it's DM in pseudomonas that, that is the carbapenemase predominant predominating there whereas you have I in, in, in South American countries. So what is the bottom line here? What I'm talking about is the problem of antimicrobial resistance or a MR for short, in certain DM BS that are commonly carried in humans and animals and that are also found in the environment, be that water, soil, food or organic material. And they have the potential to be transmitted between humans, animals, environment and food and to cause infection in humans which can be mild or it can be severe and it requires antimicrobial treatment. However, we have limited and or expensive options for treating infections due to these organisms and they're also associated with the delay in recognition that the infection is due to antimicrobial resistant bacteria with associated consequences for patient care and patient outcomes. And so A R is a complicated public health issue because it's intersectoral. As I said, it affects humans, it affects animals, it affects food, the environment, the soil and the drinking water. And so a one health approach to tackling this problem is required. And you might say, well, I'm a healthcare professional, why would I care about antimicrobial resistance in, in veterinary medicine? Um, but, but unfortunately, these things are interlinked. If we give an to food producing animals, which is common practice, then the bugs and enterobacterales in their bowels become resistant and then can be transmitted to us by food. And we develop, then antimicrobial resistant enterobacterales that we carry in our bowels and equally giving antimicrobials to humans can promote and select out for resistant enterobacterales in the gut of humans. So all of this is like a vicious cycle. It's a worldwide issue. It's global, it's continental or regional, it's national, it's local, it's in your community, it's in your local residential care facility. It's in your hospital. It affects all of the population from the most premature neonate to the most elderly of our, our, our, our citizens and it can affect the individual at any stage, um, whether they're healthy or at their end of their life. So, so a MR is certainly complicated and when we look at control measures, we can think about them on a very global region and national level and, and that's extremely important. Um but we also need to think about them in terms of organizational and individual control measures. And so where you work? Is there governance? Is there diagnostics? Is there stewardship? Is there an IPC infection prevention and control? And as an individual, are we practicing antimicrobial stewardship? IPC um practices robustly and consistently in our care of our patients and demonstrating leadership in this regard and providing education around this issue of a more to um to our colleagues and to, to students and, and to, to, to, to people who are coming up the ranks behind us um in my country in Ireland, we, we are on our second National One Health Action plan to combat antimicrobial resistance. And that's due to expire at the end of 2025. And so last year, a midterm review was, was published. And I think that's really important because there's lots of these national action plans floating about and if, if they're sitting on a shelf gathering dust, they're, they're not really doing anything. And so it's, it's very important that there are actions and targets that are measurable and, and, and, and achieved if we're going to be successful in tackling this issue. And it's really timely actually that I was asked to give this talk at this time of year because we, we were kind of hitting the time when who has the annual World a more Awareness Week. Um And so hopefully, um with the objectives of education, advocating and acting um to combat a more um you may get some tools from, from these talks and that can help you to raise aware where you work and, and we need to be concerned because this review published, it was commissioned by the British government and published in 2016, predicted that by 2050 A, Mr would be responsible for 10 million deaths globally, which is, which is pretty stark. It's, it's even more than cancer. Um This was a nice review or study that was published in Lancet in 2022. Looking at the potential global burden of our A Mr in 2019 and it involved 204 countries and estimated that in that year A Mr caused 1.27 million deaths, played a role in almost 5 million deaths. And when they looked at the pathogens of concern and you can see here that in the top six pathogens um that, that were either contributing to or associated with um patient death and gram negative bacilli that I'm talking about here today. In this talk such as E coli, CBS aac and pseudomonas were players in in mortality and the distribution varies depending on the part of the world that you're in. So we can see in high income countries, um bacteria like staphylococcus aureus and E coli are the commonest causes of, of, of a and more related death. Um However, when we move to more resource limited settings such as Sub Saharan Africa, we see Klebsiella and we see um uh e coli um as, as major players and, and a bacter also um is it is very common in certain countries and there we see it in the, the kind of the the blue green, blue color. So the World Health Organization established a global antimicrobial resistance surveillance system or glass for short. And it's nice to see that by the end of 2021 that, that many of the world's countries were enrolled in, in glass. So it gives us an opportunity to, to to gather data. And so what glass is looking at is, is countries to submit data on isolates from bloodstream infections and from urinary tract infections. And um the commonest pathogen by far in bloodstream infections globally is E coli and it accounts for about three times more bloodstream infections than klebsiella and about 10 times more bloodstream infections than a a bacter. And it is by far the commonest cause of urinary tract infection. Um with almost 2.4 million isolates reported to the system from 2020. And when we look at um the E coli and the percentage resistance to carbapenems, um you can see that, you know, kind of it is concerning that one of the commonest causes of bacterial infection in humans. Um we are hitting maybe 10% resistance to carbapenem antibiotics from this surveillance system as an enterobacterales, klebsiella tends to be more resistant than E coli. It tends to be better at picking up the carbapenemases. So, resistance rates in klebsiella to carbapenems are even more frightening. Again, looking at the acinetobacter is it, it's very scary because, um, remember we said that for acinetobacter, carbo pens are really the only effective betalactam that we have for treating infections due to acinetobacter. And in, in some countries, resistance rates are are in bloodstream infections caused by acinetobacter are ranging up to 80% and beyond. So essentially, these drugs cannot be effectively relied on as empiric treatment if you think you're dealing with an acinetobacter invasive infection. So, so that class is effectively lost as an option. So why is all of this important? And I would ask you, do you know what the situation is in your country, your local community or the hospital or the health care setting that you work in? Because these surveillance systems are great. But essentially what they're doing is they're looking at the problem of antimicrobial resistance in typically in invasive infections, bloodstream infections. And they're looking at them in e coli and klebsiella and acinetobacter. But, but they're not capturing those antimicrobial resistant bloodstream infections due to things like Enterobacter or ceracia or cro bacter. And, and there's very little data on on globally, on antimicrobial resistance in noninvasive infections such as surgical site infections or hospital acquired pneumonias or we do have that glass data on E coli and UTIs, which is, which is useful and is pointing us to, to increasing rates of resistance there. And then the, the, the base of that iceberg is all of those people out there who are asymptomatically carrying antimicrobial resistant gram negatives, carbapenemase producers in their bowel. It's not causing them any harm or any signs of infection. And the other thing to understand or to be mindful is of a surveillance system is only going to measure or manage what is measured. And, and so if you're not looking for something, you, you're not going to find it. And so there are variations in how people have access to diagnostic microbiology laboratories, um practices with regard to when people would tend to send clinical specimens for culture to the laboratory and what the laboratory does with the microorganisms that it cultures, does. The laboratory routinely test these gram negative bacilli for carbenin resistance because if you don't look for it, you won't find it. And we have to be mindful that everybody is carrying Enterobacter allies in their bowel and that's called colonization or carriage and it's of no harm to the person. Um Pseudomonas and acinetobacter are ubiquitous in the environment and they can be acquired and carried asymptomatically by humans. Also, um people who are colonized with bacteria, um can those bacteria can be susceptible to antimicrobials. They don't have to be antimicrobial resistant and any colonizing bacteria can go on to cause infection if they're given the opportunity to do so. And in health care, we give lots of opportunities for those bacteria to get in and cause infection by surgery. We create surgical wounds. We breach the normal skin barrier, which is protects people from invasive infection. We stick bits of plastic into patients, we stick implants into them and they are potential portals of entry for bacteria. We immunocompromise our patients by chemotherapy and transplant medications. Um and and, and also patients in hospital tend to be more immobile. They're, they're in bed, they're not up and about as much as they would. So relieving them prone to things like pressure sores or developing hospital acquired pneumonia. So, you know, there these are clinical scenarios that any clinician depending on your setting is going to encounter on a daily basis. For example, a lady attending her GP with dysuria frequency and E coli is grown from the urine or a patient in the neurointensive care unit having had a traumatic brain injury, develops an a Baar ventilator associated pneumonia or a premature neonate, develops early onset sepsis and meningitis with e coli cultured from their c. So, in any interaction with the patient, you have to do a risk assessment, you're asking is this colonization in the case of a urine, a catheter urine from a, a resident in the nursing home or frequently colonized with bacteria? Um What are the likely pathogens in this scenario is antimicrobial resistance, likely do I need to give an antimicrobial or can I wait and see? And if I do have to give a prescription, what am I going to prescribe? And what if I get it wrong? And that's always in the back of all of our minds because we know in severe infections, the stakes are high if, if our patient is, is becoming or developing sepsis or septic shock that that has the potential to kill them. And so, you know, there's a lot of, a lot of emphasis on on early recognition of sepsis because uh we have seminal studies that are many years old now. But that have clearly shown that if you don't give the right initial empiric therapy, then the increased risk of mortality and severe infection is, is is much higher and also at the timing of giving those antimicrobials. So for every hour of, of, of, of, of delay in administering antimicrobials to somebody with hypotension due to severe infection, there was a 7.77 0.6% increase in mortality. Um So, so that's always in the back of our minds. We don't want to miss infection, we don't want to get it wrong, but we do also have to be sensible about how we use antimicrobials and that's caused antimicrobial stewardship. And in my country, we, we have fairly up to date a MS guidelines for all healthcare settings which are freely available. And I think a good resource. Um If you're, if you're involved in stewardship and it's not just the, the, the, the infection specialist or the antimicrobial pharmacist. Anybody who prescribes who dispenses or who gives patients antimicrobials is a steward and the patient themselves can play a role if we support them. And you know, these are basic principles of making sure that we're only giving antimicrobials for the right reason. And, and another useful resource that we would follow is is the antibiotic care bundle. Start smart, then focus. So only give antimicrobials. If there's good evidence of bacterial infection cultures before you start antibiotics, document what you're doing, prescribe it, right? Make sure everyone knows why the patient is on the antibiotic. And obviously in in in the case of severe infection, make sure that the antibiotics are given promptly, that they're prescribed and then given and not left delayed in administration and then focusing 24 48 hours later, go back and see what the story is. Is this patient getting better? If that was suspected pneumonia turned out to be a pulmonary embolism, then that's not infection, stop the antibiotics. Look at the laboratory results. Um Can we deescalate from a broad spectrum agent to a narrower spectrum agent or do we need to escalate? Is the patient getting worse? Do they have an a more resistant infection? Um So, so it's just a really practical approach to, to what to do. And obviously, if you think you're dealing with an AMR infection, then it's really important to involve your local infection specialist to make sure that the patient is getting the best possible effective treatment for, for that particular pathogen. So just in finishing part, one of the talk enterobacterales, pseudomonas and acinetobacter are among the commonest causes of bacterial infection, particularly in the healthcare setting or HC for short and losing those Carnes as effective treatment is a global public health issue, requiring a global and intersection approach for sure. But that's not to undermine the importance of organizational and individual responses and, and be mindful that the control measures are multidimensional. They're going to encompass A MS which I've talked about and, and I'm going to talk more about IPC and patient involvement in part two of the talk. So just to thank you for your attention.