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Tony: Hello and welcome to Microbe Matters, presented by ID Pitstop, where we talk all things infectious diseases. I’m Tony Morrison and today I am joined by Dr. Alex Viehman, who is an Assistant Professor of Medicine in the Division of Infectious Diseases at the University of Pittsburgh.

Alex: Hello. Thanks for being with us today.

Tony: And our special guest today is Dr. Ryan Shields, who is an Associate Professor of Medicine at the University of Pittsburgh as well, and the Co-Director of the Antimicrobial Management Program at UPMC Presbyterian Hospital.

Ryan: Great to be with you guys. Look forward to the discussion.

Tony: Our topic today is about superbugs, an area of interest for both of the faculty members here. What is a superbug, though? Well, it’s not very well defined and it can be quite confusing to understand. We’re going to discuss some of the important details of these organisms and the infections that they cause. We will also delve into what researchers, physicians and pharmacists are doing to combat some of these difficult to treat organisms.

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Alex: Thank you, Tony. I’m really happy to be joined today by my colleague Brian Shields. just to give us a little background on the topic, He works in microbial stewardship, which is the field of optimizing antibiotic use by decreasing unnecessary use and streamlining appropriate use. He also performs research on antimicrobial resistance, where he helps determine the most optimal medications for different types of resistant bacteria and fungi. So, Ryan, when someone reads about a superbug in the news, what do they mean and where do these definitions come from?

Ryan: Yeah, it’s a great question, Alex, because superbugs is really a term that’s been used to describe and bring attention to bacteria, fungi, viruses and even parasites that have developed resistance to the most common treatments we use to treat infections. Now, most commonly in the popular media and press You’ll see the term superbug used synonymously with bacteria that have evolved resistance to antibiotics, including many of our first line antibiotics, and in some cases, all available antibiotics. But superbugs is really getting at the crux of a broader issue, and that’s around antimicrobial resistance. And the World Health Organization has identified antimicrobial resistance as one of the top ten threats to global health. And in a recent publication published just last year, they use predictive statistical modeling to estimate the overall burden of antimicrobial resistance across the globe.

And to do so, they focused on 23 bacterial pathogens, 88 bug drug combinations, and reviewed data from 204 countries that accounted for an astounding 471 million individual patient records. So truly a Herculean effort. Now, using the same predictive statistical modeling, we know by the year 2050, this rate may surpass 10 million deaths per year due to antimicrobial resistance, which is a staggering number in its own right, but also a number that will be more than cancer and diabetes combined at that point. For instance, some urgent threats include carbapenem resistant Acinetobacter or carbapenem resistant Enterobacteriaceae, and certainly something that many of our listeners have heard about recently, Candida Auris. Some other serious threats include extended spectrum, beta lactamase producing organisms, Mersa or MRSA, and vancomycin resistant enterococci or VRE. 

Alex: So this is a group of organisms that’s really diverse, and it’s not really just one or two things that people have to worry about here. What are some resistant organisms that we see that can be acquired outside the hospital, say, in the community that we should be worried about?

Ryan: Antibiotic resistance can affect really any person, but we know that those people

that are receiving health care or maybe other patients that have a weakened immune system are going to be at a higher risk. And in the community, there’s really two pathogens I think about that are particularly problematic. The first of which is MRSA or Mera something that our audience has certainly heard about. And the risk with Mersa really increases and places that involve close skin to skin contact or shared equipment and supplies. So we think about like sports teams, for instance, sharing showers or supplies. This is where we can see MRSA infections. Also, the same is true for daycares and school students, military personnel and barracks. These are common examples where we see MRSA outbreaks. I think the other thing to be aware of with MRSA or Mersa infections in particular, is that we see certain high risk populations in our community setting as well. 

The opioid epidemic has been a good example of this, where we see a disproportionately higher rate of MRSA infections in persons who inject drugs which are 16 more times more likely to develop a staph infection than a normal patient. Now, as you know, in your clinical practice, MRSA typically is causing skin and soft tissue infections and its least severe form. But in its most severe form, patients would need to be admitted to the hospital for bloodstream infections or bone, bone and joint infections and even endovascular infections that might affect the heart valves. The other problematic pathogen in the community is a group of organisms  we categorize as ESBLs, which really stands for the mechanism of resistance in these gram negative organisms. ESBL stands for Extended Spectrum beta lactamase, which is really an enzyme produced by bacteria that hydrolyzed or break apart. 

One of the key antibiotics we use in treatment known as the beta lactams. Now for ESBLs is in the community. The classic example is E.coli. Now what’s problematic about ESBLs is almost half of these infections occur in the community and not inside the hospital. And the rates of ESBL infections in the community is also increasing.

 Now, typically we think of E coli and we think of either intra abdominal infections, but in the community it’s probably mostly urinary tract infections as a portal of entry for E coli to be causing infections. Now, in its least severe form, oftentimes we can manage both MRSA and E coli infections with oral antibiotics. But if we see complications or more severe infections, these are the kinds of patients that often do get admitted to the hospital. So I’m curious then, Alex,

kind of your experience in seeing patients in the clinic with these kinds of infections and how you’ve typically managed them?

Alex: So very commonly in the office will see patients who have recurrent skin boils or skin infections, often due to MRSA or MERSA, and these will often start out as little pimples or boils

that will become painful, swollen sometimes to be associated with fever and often require to have surgical drainage if they don’t drain on their own. Now, one of the good things is that there’s usually 3 to 4 oral antibiotics that work against this MRSA. The usual antibiotics such as penicillins like amoxicillin or Augmentin and cephalosporins are just maybe people know Keflex don’t work against this type of staph, which is why it makes the resistance more complicated. But we do have a few different types of antibiotics by the mouth that, along with drainage, can help. for the urine infections when they have resistant organisms such as the ESBLs as you mentioned, we still have a couple of different oral medications that work. If the infection is limited to the bladder, which is a very common site of infection. However, if patients have drug allergies or if they have other complicating factors, it can be difficult to treat these patients

with oral antibiotics. We focus on trying to limit antibiotics to only when there’s a documented infection and also to treat the other causes of urinary tract infection, which may be overflow incontinence or renal stones or other reasons that patients may have frequent urinary tract infections.

Tony: Ryan Whenever people in the hospital or outside of the hospital are concerned about acquiring one of these superbugs, how do you counsel them and how do you recommend that they keep themselves safe from it?

Ryan: Yeah, it’s it’s an excellent question. And I’m curious to hear Dr. Viehman’s input on this as well. But as we know, every patient is at some risk. But typically speaking, our patients in the community that are most vulnerable to infections due to resistant organisms are the very young patients, the elderly and those who are sick enough to require health care exposure. One of the key milestones of counseling is to make sure if you are at increased risk, you’re aware of that. And for instance, if you have vascular catheters at home or maybe you’re on hemodialysis, you need to keep those sites very clean to prevent bacteria from being introduced into an otherwise sterile site. But there’s other very common things that we learned about during COVID that patients can do good hand hygiene and proper hygiene overall is a great way to reduce skin to skin contact. Get vaccinated routinely. There are vaccines available for certain types of bacteria, so we should always stay up to date with our vaccines, practice safe sex, and certainly have safe food preparation. 

Now, those risk factors are a bit different for patients that we see in the hospital. These bacteria have a remarkable ability to survive on innate objects, and because of that, then the other major mechanism of transmission is through health care personnel.  These bacteria are in our hospitals and we know that. So it’s a good reminder that both inside and outside the hospital, doing something simple like washing your hands is very important. 

Alex: So one of the things I like to counsel my patients about is avoiding risk factors for infection. So one of these is avoiding antibiotics when they’re not necessary. We know that a lot of antimicrobial use in the outpatients are not needed for things like viruses, and taking antibiotics within a certain period of time puts you at risk for a drug resistant organism. So I always counsel my patients that if you really don’t need an antibiotic, please don’t take it. The other thing, just managing health conditions, as Ryan mentioned, hygiene is very important. Wound care is also very important. People, they have chronic wounds or a cut. I always recommend keep things clean and covered. Those are important things. And then other risk factors, such as things like diabetes, patients who have diabetes are at increased risk of developing infections in general, and if their diabetes is not under great control, then they can be at higher risk of infections, need more antibiotics and be more likely to require one of these resistant bacteria.

Tony: So if someone develops an infection with one of these superbug organisms, is it going to persist in their bodies for the rest of their lifetime? Is it going to be stuck with them? Will they have recurrent infections or will it lay dormant like some viruses do?

Alex: So this is a really good question and one we get a lot in the office after people have been flagged with a type of bacteria that is resistant or they develop an infection with them. And the difficult thing is that someone will have an episode and then have a recurrent episode. They’ll often be in areas like under the arm or on the legs or in the groin. And this is because the the patient has become colonized with this bacteria. Now, the other bacteria that live on the skin can compete with that bacteria to try to eliminate it. And if they’re colonized, they don’t have an active infection, but they can be at risk for developing another infection like one of those skin infections I mentioned. And usually we see that in 3 to 6 months, patients who are healthy have a good chance of becoming decolonized with this bacteria. The main thing to focus on is not having other antibiotics and having good hygiene and having the medical conditions under control.

Ryan: Yeah, it’s an excellent point, Alex, because it is a very common question that we hear from patients. And I think the simplest way that I think about risk factors for infection is there’s really two big buckets that we think about. And you mentioned these- prior exposure to antibiotics and exposure to the health care setting. If you do have an MRSA infection or maybe an ESBL infection in the community, that is certainly a risk factor for having an infection due to that same organism in the future. Now, we don’t know if they’re necessarily stuck with it long term. There’s not been great chronological surveillance studies to see how long people carry these certain organisms and we can, in some cases of MRSA, decolonize them. But it’s important for patients to know if they are infected within these organisms. 

They are at a higher risk for reinfection with that same organism, and that should increase their level of vigilance to make sure they’re doing some of the public health measures that we mentioned. 

Alex: So while we usually treat these MRSA and ESBL infections in the community, if they’re more severe, you mentioned earlier, Ryan, that they require hospitalization, but there’s also some superbugs that we see almost exclusively in the hospital. You mentioned that carbapenems are one of our most important agents for resistant organisms. However, we do see some carbapenem resistant infections. Can you tell us about those? 

Ryan: Yeah. So, this is a really important point because carbapenems we typically think of as ID clinicians as one of our last lines of defense against antimicrobial resistance, right? And in the hospital in particular, we typically reserve the carbapenems for infections where we have no other treatment options. So when bacteria develop resistance to carbapenems, it’s really problematic because that’s a good indicator that you have very few treatment options available. The other thing that’s notable about carbapenem resistant gram negative bacteria in particular is that infection with these organisms leads to disproportionately high rates of morbidity and mortality for patients. And a lot of that is synonymous with having fewer antibiotic treatment options available. We also see that patients infected with these kinds of organisms tend to stay in the hospital longer and at a higher risk for recurring infections. Now, let’s talk about some of the specific examples of carbapenem resistant organisms that we encounter fairly frequently, the first of which are CRE, part of this alphabet soup that we really like in Infectious Diseases. CRE stands for carbapenem resistant Enterobacteriaceae, and typically CRE or the mechanism of carbapenem resistance is caused by two different types of resistance.

 The first of which is really important, it’s the acquisition of carbapenems enzymes and much like ESBLs that we mentioned before, Carbapenem enzymes are enzymes produced by bacteria that hydrolyzed the antibiotics we’re trying to use to treat them, and in this case carbapenems. The other problem with carbapenems is, is they also hydrolyze all the other beta lactams. So they’re not just hydrolyzing The most important class in this case the carbapenems, but many classes of antibiotics. When we see carbapenems producing enzymes, we know that we have very few options available. But the good news here is that this has been a major focus of drug discovery to try to identify new inhibitor molecules that inhibit various types of carbapenems. The other major mechanism of carbapenem resistance is a little bit different. These are bacteria that we typically see that have some types of beta lactamaces, like SBL, for instance, but usually there’s a secondary mechanism of resistance and that may be either through the decreased permeability of the outer cell membrane or other mechanisms like antibiotic efflux. And typically what’s different about these types of carbapenem resistant organisms is that that resistance almost always develops after exposure to carbapenems. So going back to what we talked about previously, exposure to carbapenems is a risk factor for carbapenem resistant organisms, in this case CRE. 

Now, of all the carbapenem resistant organisms that we talk about, one that I think our audience may have heard of before that is frequently used synonymously with Superbug is something known as KPC. KPC stands for Klebsiella pneumoniae Carbapenems, and this is by far the most frequent carbapenem enzyme identified in the United States. I would be remiss with talking about carbapenem resistant gram-negative bacteria in the hospital if I didn’t at least mention Pseudomonas aeruginosa, which often is kind of the elephant in the room. But Pseudomonas is this bug that almost every hospital in the U.S. sees, right? What’s important and what differentiates Pseudomonas from other types of carbapenem resistant organisms is this particular bacteria is already primed to be resistant to therapeutic countermeasures. And what I mean by that is Pseudomonas has intrinsic mechanisms of resistance, which means it’s much harder for antibiotics to get across the outer cell membrane to work and have their mechanism of action. In addition to that, Pseudomonas produces efflux pumps. And these are constitutively expressed, which means they’re always working and they’re always pumping molecules out of the cell. And, [Stutters] and in this case, they also pump out antibiotic molecules out of the cell. 

And the third kind of innate line of defense for Pseudomonas is they produce chromosome encoded beta lactamases known as AMC .And by chromosomal encoded, what we mean by that is these are present in every Pseudomonas strain.  They’re not acquired like we talked about with plasmids. They are in every pseudomonas strain. And the expression of these AMCs

can be regulated by various stressors in the environment. In this case, also including antibiotics. So even at your basal level, pseudomonas is already has higher levels of resistance. And for that reason, we have fewer options to treat them. Now, when you compound that by developing

further resistance in the face of exposure to antibiotics like the carbapenems, you really have a hospital superbug that are very difficult to treat. They can cause a range of diseases from either a chronic colonization in some patients to very acute severely ill infections in other patients.

Tony: Ryan That brings me to my next question. What types of medications do you use to treat these resistant bacteria?

Ryan: I’m glad you asked, Tony, because this is probably my favorite topic to talk about is new antibiotics. And it’s really important to kind of set the stage for where we’ve been with antibiotics overall for treating hospital superbugs because prior to the year 2015, really what we were left with is a dearth of available treatment options such that we were using antibiotics that we knew were relatively toxic to patients. We weren’t all that sure how to dose them appropriately because they have limited data and the pharmacokinetics or the way the drug distributes throughout the body is not ideal. So prior to 2015, we really did our best as clinicians to use these drugs to the best of our ability because it’s all we had available to us. Since 2015, we’ve had a number of new antibiotics developed that have completely changed this paradigm. The first of which was Ceftazidime/avibactam. And I mentioned avibactam because it is the first beta lactamase inhibitor that inhibits KPC, That common type of carbapenems enzyme that we talked about. 

 So finding small molecules that could inhibit certain types of resistance mechanisms was really essential in moving our field forward. Now, since Ceftazidime/avibactam has been developed and licensed in the United States and globally, so too has Meropenem/vaborbactam and Imipenem/Relebactam.  And what’s consistent across all three of those drug combinations is they each include a beta lactamase inhibitor hat inhibits KPC, as well as other types of beta lactamases. Treatment with one of these new beta lactamase inhibitors is not only much safer for patients, but results in much higher efficacy for patients. So the good news for our audience is we now have a number of new antibiotics that are available to us in our hospital that enable us to much more safely and much more effectively treat infections with many of these resistant hospital superbugs.

Alex: Ryan, that’s a great point. When I think back onto the patients I treated during my medical training and early in my career, you had patients who were very sick in the ICU, perhaps with a lung infection like pneumonia, and they already had one or two organ systems that weren’t working well due to their infection. The drugs that we would give for these resistant organisms would often hurt their kidneys and cause another organ system to just function poorly. And as we’ve progressed over the past 5 to 8 years, we’ve seen that we’ve been able to use these less toxic and more effective medications that we use really only in these patients who have these specific resistant organisms. It’s able to help treat these patients who are already very ill to begin with, because that’s one of the risk factors for these resistant because that’s one of the risk factors for these resistant organisms in these superbugs.

Tony: Sometimes when patients are in the hospital, they’re flagged for having a resistant organism, even if they do not have a current infection. And so in the health care system, they will put on gowns or protective materials to see the patients. What does this mean for the patient and why does this practice occur?

Alex: That’s a good question, Tony. So each hospital has slightly different policies regarding different types of bacteria and fungi that they’ll isolate people for. And this can be for an infection and also for colonization. The reason is that if that bacteria or that superbug  is transmitted to another patient, that person could have an infection. So it may be that you,

the patient who’s flagged, has an infection with a resistant organism. And as we talked about,

we have a lot of treatments for those organisms, but we’re always looking for more. However, we don’t want another patient who may be in the same unit or or related part of the hospital

to develop that same bacteria. So it’s trying to keep the organism contained. However, some patients may not have an infection or may have an infection that’s related to a more sensitive organism, but testing of their nose or their GI tract indicates that they do harbor this organism,

a resistant one, in their flora. And in that case, they may often still be isolated. And sometimes it can be difficult for the patients. And we try to reassure them that this is just part of our overall policy to keep everybody safe. Because when we’re in a hospital, we’re all together and things are coming in and out of rooms and there’s risk for transmission.

Ryan: Yeah. And I think these isolation precautions you’re talking about are really confusing point for both patients as well as their family members that are coming in to visit them, right? Why do they need to put a gown on and put a mask on when they’re going to see their loved one? And really, the reason you hit the nail on the head is to protect the other patients. It’s probably one of the most important things we do to try to limit the spread of hospital superbugs is use contact precautions to prevent the spread from one patient to another.

Alex: So, Ryan, what’s one of these superbugs that really keeps you up at night when you’re worried about the future and one of your patients developing an infection with it?

Ryan: Yeah, I’m up at night for a lot of different reasons. One of them is certainly thinking

about these types of what I’ll call “nightmare bacteria.”  There’s a couple of them that are particularly problematic that have kind of escaped recent drug discovery. The first of which is a type of carbapenems known as NDM or New Delhi metallo beta lactamase.  And what’s notable about NDM bacteria or NDM producing bacteria, I should say, is that NDM is not inhibited by any of those new beta lactamase inhibitors that we mentioned. AVibactam, relebactam, or vaborbactam. And so for that reason, we’re kind of still left to where we were prior to these new drugs and having to put together either combinations of antibiotics or having some inferior treatment options. NDM have this remarkable propensity to really invade multiple bacterial hosts. So we may see this in E. coli or Enterobacter or Klebsiella. And that diversity is really important because it makes it more difficult to treat patients when you have different bacteria that have the same mechanism of resistance. So indium producing bacteria is certainly one that does keep me up at night a bit.  

The other is carbapenem resistant Acinetobacter, which we like to call CRAB. CRAB is important because like NDM, it’s really escaped the recent drug development pathways and we just have so few options to treat CRAB. It’s one of the few bacteria that we still do look to older antibiotics like Colistin in some extenuating circumstances. And what’s particularly frustrating

about CRAB as a clinician and certainly as a scientist is that none of the things that we have tried, either antibiotic combinations or monotherapy, have really worked. There’s just a lot of challenges around managing both of these bugs. 

Alex: So far, we’ve focused mostly on bacteria, but other organisms can become drug resistant in the hospital. Occasionally, people will develop infections with yeast. These can be infections of the bloodstream when patients have intravenous catheters or also infections in the abdomen

after surgery or perforation of a the gut. Can you tell us a little bit about Candida auris, which is a new superbug that’s a yeast?

Ryan: Yeah, Candida auris has really been prominently displayed now that popular media is widespread because Candida Auris is a relatively new pathogen for us. It is a yeast like other Candida species that you mentioned, and it was really first discovered in 2009. So it’s not all that old. But what’s really interesting about Candida auris is that there are four clades or four kind of clones of Candida auris that arised all over the globe almost simultaneously across different continents. What also makes   Candida auris unique is that it is really equipped to cause nosocomial infections. 

But the other thing that I think makes this bug really unique in comparison to other Candida species is it has the evolutionary equipment to evolve resistance to treatment very rapidly. And because of this, we do see outbreaks in certain health care settings in nursing homes or long term care facilities. Also in hospitals where we see pockets of several patients together that have developed infection due to Candida auris Because of all these traits. So certainly this is something that is now been labeled as a urgent threat by the CDC. And in terms of fungi,

it is probably the one multidrug resistant pathogen that really we need to be concerned up with. And we have several surveillance measures in place now to continue to monitor for isolation of Candida auris. This is something we report to the Department of Health as well, and we’ve now seen it in almost every state in the United States. So I suspect it’s a bug we’ll continue to hear about moving forward.

Alex: So as we’ve mentioned, some of these pathogens we have new and more effective therapies for, but others, such as Candida auris  or the CRAB- Acinetobacter, as you mentioned, we’re not quite there yet. So what are the ways that we try to decrease the development of these infections through antimicrobial stewardship?

Ryan: Yeah, I think if you take a step back preventing the spread of antimicrobial resistance or identifying strategies to mitigate resistance is really the $64,000 question. This is something that government bodies have been trying to work on now for several years, including the CDC and World Health Organization. And what makes it not an easy question to answer is that, as we know, antimicrobial resistance is really multifactorial. This not only affects individual patients, but is impacted by our environment. Think of, for instance, sewage or wastewater that comes out of our health care systems. We know we use antibiotics in agriculture as well as in farming

and other environmental stressors. And so keep in mind, our globe is really this milieu of different exposures to antibiotics and different bacteria. And those bacteria, when they’re interacting with each other, can exchange genetic information. And we have this whole hybridization of different resistance emerging. These pathogens are really a call to action for further antibiotic discovery, development and new efforts to combat this crisis that we now have on our hands.

 If we can prevent the spread of bacteria either in the community or in the health care setting from going from one patient to another, that’s something that we should be doing and certainly we know has a major impact. And studies have proven that this slows the progression and spread of antimicrobial resistant pathogens. I think COVID 19 was the perfect paradigm for showing us how good surveillance systems, either through monitoring in wastewater or for having publicly available resources, can teach our community about resistant organisms. And so I think if we apply that paradigm to hospital superbugs and we create better surveillance systems, we can see what’s coming more easily. But also we can identify some of these threats much earlier on in the process, maybe before they become major threats long term. We know that the more we use antibiotics, particularly, the more we misuse antibiotics, we increase the burden of antimicrobial resistance. And this is the focus and the crux of antimicrobial stewardship. 

We know if we limit antibiotic exposures that are unnecessary, we can improve patient outcomes. And that certainly has a major impact on antimicrobial resistance. We certainly need more investments in new vaccine technologies, novel therapeutics, which might include things like antimicrobial peptides or bacterial phages, which are viruses that attack specific bacteria. These are all novel and innovative ways of thinking about how to treat and diagnose antimicrobial resistant pathogens. But we need more investments and we need more research in this area to make sure that we can implement these strategies effectively. We know that the globe is warming. We know that we have lost microbial diversity across the globe. And we know that by introducing various antibiotics over the last five or six decades, we’ve created more antimicrobial resistance now than we’ve ever seen. And so I think as a society, we need to be thinking about these environmental stressors to a greater extent. How can we clean our wastewater from pharmaceutical companies or hospitals where antimicrobial resistant pathogens are being released back out into the public? 

How can we limit unnecessary exposure to either antibiotics or antifungals in agriculture? And certainly, maybe these are things that we think about more broadly through policy and other things. This really needs to be a global effort. And we know that there are a lot of issues and obstacles and kind of making that a reality. But those are the main strategies to try to mitigate this problem we have with hospital superbugs.

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Tony: Wow. This was a great overview of superbugs and drug resistant organisms. Thank you both for joining us today.  Thank you. Dr. Ryan Shields.

Ryan: Yeah, this is fantastic. Thanks for having me and I look forward to future episodes. I think this will be a great podcast.

Alex: All right. Thanks everyone!

Tony:  We will have much more on drug resistance and how we are combating it here at Pitt and globally on future episodes of Microbe Matters. Thanks for listening and be sure to check us out

on social media at ID Pitstop.

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