Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast Narrator - ? 00:11 is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice, and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk episode 115 I'm your co host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is what every pharmacist should know to conquer Staph aureus infections. Today, we're talking about the historical significance of Staphylococcus aureus, its patterns of antimicrobial resistance, and also preferred treatment options for Staph aureus as well. Dr. Khyati Patel 00:54 I am super excited about the history part. That sounds really exciting. Dr. Sean Kane 00:58 Well, why don't we kick it off with a basic patient case that probably is going to be familiar to many people who have spent any time in the emergency department, in the hospital setting, or really even in the ambulatory care setting, where someone comes in with a skin and soft tissue infection. So this is Ronald. He's a 46 year old male. He actually came to the hospital for a COPD exacerbation. So while he was there, it was kind of noted that he had an a small abscess on his left forearm, and it has been developing over the past several days. It's not his chief complaint, but it kind of comes up during rounds, and we're kind of asked, well, what should we do about it? In terms of past medical history, Ronald has diabetes, hypertension and heart failure. Again, he's here for a cop exacerbation. This is not his primary issue. He really has no systemic signs of infection, so no chills, fever, no leukocytosis, no tachycardia. So an incision and drainage or an IND is done, where they drain out the pus from that abscess, they send it for culture, and it grows back as MRSA, methicillin resistant staphylococcus Auris. So really the question that's going to come up to the pharmacist on rounds is going to be, well, what do we do about antibiotics for Ronald? And that's really the setting that we'll talk about, the context for Staph aureus here. Dr. Khyati Patel 02:13 And you know, before, it's a great case, to give the audience an idea of, you know, what kind of infection and what situations they come up with. I just like to add being an outpatient side treating patients with diabetes. I see this occurring in outpatient settings all the time, and so might be applicable to those who are working on a clinic base or outpatient primary care base outstanding. Dr. Sean Kane 02:35 So it sounds like this is going to be relevant to a variety of different practice areas, and which is great. Well, why don't we go back in a kind of a time machine here? So you know, back in the 1940s before 1940 if you had a serious Staphylococcus aureus infection, your mortality rate exceeded 80% now just think about that for a second. We basically had very few treatments for Staph aureus infections. Staph aureus is a very virulent, very pathogenic bacteria. And if you got it, you had an eight out of 10 chance of dying from that infection. That is insane. Dr. Patel, Dr. Khyati Patel 03:08 I mean, if you put that in context right now. Dr. Kane, I can't imagine. And so that gives you appreciation for how much science and healthcare has evolved. Dr. Sean Kane 03:18 And then the reason that we talked about pre 1940s is that in around 1940 the FDA actually approved a drug called penicillin, and penicillin was dramatically effective in reducing mortality rates in serious staph Auris infections. And at the time, that was a really big deal, obviously, to dramatically drop the mortality of staph aureus infection. Dr. Khyati Patel 03:39 And so how does penicillin work? An a simple answer would be that it inhibits the bacterial cell wall, meaning it does not let the bacteria survive, basically, and they die. Yeah. Dr. Sean Kane 03:52 And if you want to go for more of a in depth, microbiology oriented answer, what's going on is that especially gram positive bacteria have thick peptidoglycan cell walls. And peptidoglycan is what makes up the cell wall. Is this multi layered polymer, so different layers of peptidoglycan are stacked on top of each other. And what gives this cell wall its strength is what's called cross links. And cross links are basically links from one layer of peptidoglycan to the next layer of peptidoglycan. And this is actually an essential component of the cell wall. The way that those cross links occur is through an enzyme called PBP, or penicillin binding protein, and if you don't have a functioning PBP, the cell wall will not have its cross links. Therefore you won't have the structural integrity of your peptidoglycan or your cell wall, as the name would suggest, PBP. This is where penicillin will bind. That's how it got its name. So really, beta lactam antibiotics like penicillin, will bind to the PBP and make it not work. So no PBP means no cross links between the different layers of peptidoglycan. And again, that's in A. Structural component of that cell wall. So the cell wall becomes unstable, and then the cell contents leak out, and the cell the bacteria will die because of not having those cross links. Dr. Khyati Patel 05:10 And so that makes complete sense. We got this penicillin in 1940 everybody was super excited and happy. And then something happened in 1942 and that's when the first penicillin resistant Staphylococcus aureus was identified. So that was a big moment. Dr. Sean Kane 05:28 And I feel like at that time, people probably were hoping that this wouldn't get any worse, but unfortunately, it did, and by 1948 the majority, more than 60% of staph aureus isolates were penicillin resistant. And this is one of those situations where, like, Wait a minute. You know, in an eight year period, we went from miracle drug to now, the majority of cases are now resistant to this drug that was this awesome miracle cure when it made it to the market in 1940 and even just several years later after that, really, at this point, basically 100% of staph aureus is now penicillin resistant. So we went from almost no resistance to now almost all isolates are now resistant to penicillin. Dr. Khyati Patel 06:11 Wow, that's incredible. So let's talk about the resistance, right? What? What's, what's causing the resistance to penicillin, and what do we do about that resistance? Dr. Sean Kane 06:21 So the mechanism of penicillin resistance for Staph aureus is that Staph aureus produces an enzyme called beta lactamase. And beta lactamase is an enzyme that will degrade beta lactam rings. So this makes it so the penicillin is degraded chemically, so that it no longer has any functionality to cause an antibacterial effect. This type of beta lactamase that Staph aureus produces also is effective for other similar penicillins, like ampicillin and amoxicillin. So that means that you can never use penicillin, ampicillin or amoxicillin alone for the treatment of staph aureus, because it will make an enzyme that will degrade that antibiotic. Dr. Khyati Patel 06:59 So that sounds interesting because we normally associate beta lactamases with gram negative bacteria, but here Staphylococcus aureus, we're talking about a gram positive bacteria. What's going on? Dr. Sean Kane 07:13 Yeah, so that's really interesting, and that is one reason why Staph aureus is kind of a really unique and smart bacteria, is that it's using this resistance mechanism that is way more common with gram negative bugs, and it's picking it up instead. So logically, if we know how resistance occurs really, the next question is, okay, well, what do we do about it? And there's really two different treatment approaches. One is that we use what are called anti staphylococcal beta lactams, or number two is that we use suicide inhibitors. So Dr. Patel, why don't you walk us through our first treatment approach, which is actually the preferred treatment Dr. Khyati Patel 07:46 approach, and so that's the approach where we are going to develop an anti Staphylococcus aureus antibiotic. A good example of this is methicillin. This was initially approved by FDA in 1959 so most of these anti staph beta lactams use a principle called steric hindrance to evade the beta electamase, that's the enzyme that degrades the antibiotic. The steric hindrance, basically, is attaching this big functional group on the drug molecule to use up extra space and prevent the beta lactamase enzyme from getting too close to the target area where it would then start to degrade the antibiotic, the beta lactam antibiotic, Dr Dr. Sean Kane 08:31 Patel, what you're saying then is that we have a beta lactam still, but it has other components on its drug structure, so that the enzyme can't get to where It needs to go in order to degrade that antibiotic. Dr. Khyati Patel 08:43 Then correct in order for, you know, the enzyme and the site to kind of fit with each other, it has to create a good model that kind of fits in this, you know, 3d model type thing. But if you have this big molecule just kind of hanging in there, and it doesn't let the key fits in the lock. Basically, that's the mechanism here. So we are avoiding the key to go inside the lock. Dr. Sean Kane 09:06 So I know that you know, our listeners have likely heard of methicillin just because of acronyms like MRSA, methicillin resistance, but it's actually not on the market anymore. But there are some other closer cousins. Dr. Patel, what are some that come to your mind? Dr. Khyati Patel 09:20 So, IV wise, we have oxacillin and nafcillin, and as far as the oral version of that goes, is dicloxacillin. Dr. Sean Kane 09:31 And you know, on top of that, we also have some cephalosporin based beta lactams. Now these aren't necessarily called anti staphylococcal beta lactams, because generally, they're not really intended or developed for staphylococcus Auris. However, they're pretty good at it. So from an IV standpoint, we have cefazolin depending on who you ask. The brand name is Ancef. And then orally, we have cephalexin or Keflex, which is a very commonly prescribed antibiotic for Staph aureus, but more commonly for a. A variety of other kinds of infections as well. Dr. Khyati Patel 10:02 And so Dr. Kane, you kind of alluded that the second treatment approach, if you're not going with the anti cephalococcus Beta lactin type of principle. Here it's the suicide inhibitors. Can you tell us a little bit more about it? Yeah. Dr. Sean Kane 10:16 So a suicide inhibitor is where you take your beta lactam, but then you add a second drug molecule in the same formulation or same preparation. So an example of this would be clavulanate, where you have clavulanate is a suicide inhibitor or a beta lactamase inhibitor, and you add that to your beta lactam. So a common example is augmentin, which is an orally available product combination of amoxicillin, which is a beta lactam, and then clavulanate, which is a suicide inhibitor. Now what's going to happen is that suicide inhibitor will bind to that Staph aureus, beta lactamase, occupy it, make it so it can't do anything, and then that allows the amoxicillin to get in, bind to that penicillin binding protein and inhibit cell wall synthesis without being degraded, because that beta lactamase enzyme is being occupied by that suicide inhibitor. So clavulanate is a common example. Other common examples would be sulbactam. This would be present in Unasyn, which is ampicillin/sulbactam, which is IV only, and also everyone's favorite, piperacillin and tazobactam. Tazobactam would be a suicide inhibitor. Dr. Khyati Patel 11:20 That's a very neat principle. And like, like, the name says suicide inhibitors. Basically, these additionally added inhibitors prevent the actual antibiotic from dying or from committing suicide, exactly. Dr. Sean Kane 11:35 So, you know, in the 1950s all the way to the 1990s the world was pretty happy when it came to Staph aureus. So again, 1959 methicillin came out. Over the next several decades, many other beta lactams came out. When the 1970s came about, we started seeing this thing that we now call MRSA, which is methicillin resistant Staphylococcus aureus, and it was observed in the United States, but it really wasn't to the point where it was a huge concern. However, when the 1990s rolled around, that's when we really started to see MRSA, both in hospital setting, but also in the community setting as well. And at this point, it's endemic, meaning that it is all over the place, Community Hospital. It's a very, very, very common pathogen. Now, whereas, you know, several decades ago, this was really the exception to the rule, and now it's very commonly observed in a variety of different scenarios. Dr. Khyati Patel 12:27 So Dr. Kane, you're saying we have yet another way that the staph aureus figured out how to resist the antibiotic. How did this? MRSA really happen? Dr. Sean Kane 12:38 It uses a new resistance mechanism that it really didn't use historically, it's actually one single gene mutation, and that gene mutation does involve what we talked about earlier, which is a penicillin binding protein. The gene is called the MEK a gene, and the Mac a gene is responsible for encoding the amino acid sequence of the penicillin binding protein. And what it does is that it mutates that penicillin binding protein enough that it no longer will bind to a variety of different beta lactam antibiotics, but it can still do its job in creating those cross links between the different peptidoglycan layers. So it's mutated enough now that penicillins definitely won't bind anti staphylococcal penicillins Won't bind. Methicillin won't bind. Cephalosporins, for the most part, won't bind carbapenems, our broadest, baddest beta lactams won't bind. All of these rely on having a penicillin binding protein that isn't super mutated, and that Mac a gene that makes MRSA. MRSA makes that penicillin binding protein very mutated and very hard to bind to. Dr. Khyati Patel 13:41 So Dr. Kane, we understand the MEK a gene is causing the mutation. Does that gene has any implication on, let's say diagnostics at all? Yeah. Dr. Sean Kane 13:51 So you know one unique thing about having a single gene mutation is that now you can use PCR polymerase chain reaction, you can actually detect that one single gene mutation fairly easily and expensively and quickly versus if you had a bacteria that had, you know, a multitude of different gene mutations that coalesce in a given resistance pattern. So in this case, because we have one gene mutation, we can test using PCR for that one gene, the Mac a gene. And this basically takes, like, less than an hour to run a diagnostic test, versus if you were to grow Staph aureus in a machine, wait a couple days for it to grow and then test it against a couple different antibiotics to see what it was sensitive or resistant to, that takes days. So by being able to use PCR, that means that now we can take, you know, a patient's blood sample, run it against a mech, a PCR, and see if Mecca a gene which is specific to MRSA, if it's present in a patient's blood. So if we see Mecca gene in a patient's blood, then it's pretty sure that they have MRSA present in their blood. Same is true with the nose. So we commonly will do mr. Say, nasal swabs to look for colonization of staph aureus, specifically MRSA. And again, we get that result back in less than an hour. And in certain circumstances, kind of beyond the scope of today's podcast, but in certain circumstances, knowledge of that patient's nasal colonization may impact our empiric antimicrobial therapy. So again, to have a single gene mutation means that we can use certain diagnostic procedures to get results back really, really quickly, way faster than we could with more traditional, you know, growing bacteria in a lab kind of procedure. Dr. Khyati Patel 15:32 And obviously this has implications on like you alluded already, treatment strategy too, right? So having to weight less and starting the patient on the right antibiotic is really important, and this gene detection technology with PCR allows us to do that quickly, Dr. Sean Kane 15:49 exactly, and that's a great segue Dr. Patel into kind of preferred treatment options. And for the most part, we distinguish treatment options for MRSA between severe life threatening infections. This would be like pneumonias, bacteremias, very severe skin and soft tissue infections, and we're going to use IV therapy for hospitalized patients. And then the other kind of treatment approach is going to be for non severe infections. 99% of the time, that's going to be non severe abscesses and other skin and soft tissue infections. So we'll separate those you know, as part of this podcast, why don't we go ahead and start then with severe, life threatening MRSA infections among hospitalized patients. Dr. Khyati Patel 16:28 And these are going to the patients that you encounter more frequently on the hospital side of setting, Dr. Kane. And so what we know is the mainstay of therapy is vancomycin given IV. This was also, according to the IDSA 2014 guideline is for the skin and soft tissue infection drug of choice as well. Can you tell us a little bit more about the drug and how that impacts MRSA infections? Yeah. Dr. Sean Kane 16:53 So what's really interesting about vancomycin is when it came to the market. So it was actually FDA approved in 1958 if you remember, 1959 was when methicillin made it to the market. And basically it wasn't used that much in the 60s, 70s and 80s, because at the time, we had drugs like methicillin that were more effective than vancomycin. So really, this is kind of an older dog new tricks, kind of scenario where it was out on the market, we didn't really use it. We put on the shelf, and now that we have this MRSA issue with it being epidemic in both community and in the hospital setting, we do use vancomycin much more commonly. Now what's interesting about vancomycin is how it works. So we already talked about that cross links between the different peptidoglycan layers with vancomycin, instead of binding to that mutated penicillin binding protein, which basically is hard to bind to because it's so mutated, vancomycin, will actually bind to the area where the cross links occur. So instead of relying on the penicillin binding protein, it will then impact the area where the cross links occur and make it so that those cross links can't happen. So the net effect is really similar to beta lactams, but the binding site is a different area of that peptidoglycan. The key point here is that, because we don't rely on the penicillin binding protein, any mutation of that penicillin binding protein will not impact the efficacy of vancomycin. Dr. Khyati Patel 18:13 That makes sense. And just you know, working with vancomycin long, long time ago in a hospital setting, I do know that this drug doesn't come easy, meaning it has its other side effects and stuff to keep take care of, so we have nephrotoxicity as an issue. I remember having to monitor the vancomycin levels so there's some pharmacokinetic parameters and Matt that's involved in it. And another unfortunate part about this medication is that it's IV only. There's no po options available for the infections we are trying to treat. Dr. Sean Kane 18:46 So there is oral vancomycin for C diff. That's a great point, Dr. Patel, and this is actually a very common question I used to get more in a teaching hospital, is patient is on IV vancomycin for severe skin and soft tissue infection, they're ready to go home. And the question is, well, how do I give this orally? There is no oral option of vancomycin to treat MRSA. It's IV only because you don't absorb it into your blood when you take it orally. And we should note that you know, in terms of the complex pharmacokinetic considerations with vancomycin, there are new 2020, guidelines out specifically for vancomycin dosing, and I would say it's gotten even more complex than it used to be in terms of now reliance on Bayesian modeling and computers to come up with doses and things like that, so we still have our traditional pharmacokinetic equations. But I'd say that, you know, it's not as simple as one might think when they look up vancomycin and micro medics are up to date to come up with a dose for that patient. I 100% Dr. Khyati Patel 19:41 agree with that. And so another tool that we have in our pocket to treat these severe MRSA infection is another IV drug deptamycin. The brand name is cubicin. So Dr. Kane working, you know, with this drug as well in your setting. Can you tell us how depto myosin? And work, and what are some of the issues that we need to be aware of. Dr. Sean Kane 20:03 So daptomycin, if you look at the chemical structure, it has this very long lipophilic tail, and the drug basically causes depolarization of that cell wall using that long lipophilic tail. I kind of think of it like a drill bit, where it kind of pokes holes in that cell membrane, and that, you know, obviously causes the continents of the cell to spill out because of that mechanism. It has a similar mechanism in terms of its toxicity profile as well. So it can actually cause muscle damage, elevated Cpk levels, even rhabdomyolysis, because it can also poke holes, if you will, in human muscle tissue, just like it can in terms of that depolarization of gram positive cell walls. So because of that, we have to get weekly Cpk monitoring. And obviously, if you know Dr. myself, a patient is on a statin, for example, our worry about rhabdomyolysis is going to be a little bit higher because of that. So monitoring is really important here. Dr. Khyati Patel 20:56 And I get that there are some dosing controversies as well as there is variations on, you know what dose to treat with? Yeah. Dr. Sean Kane 21:04 So when the FDA approved deptamycin, they approved it for skin and soft tissue infections at four milligrams per kilogram per day, for normal renal function, and then for something like a bacteremia, more serious infection, they approved it at six milligrams per kilogram per day. Now, as time has gone on and the drug has been on the market longer, we've seen some therapeutic failures where the drug deptamycin doesn't fully treat certain MRSA infections, especially more deep seated infections, certain types of endocarditis, those with prosthetic valves, things like that. So as time has gone on, we think that maybe we should be pushing that dose up, especially for more severe infections, to maybe eight or even 10 milligrams per kilogram per day. And that controversy makes people uneasy, because you want to know what is the best dose to give a patient. You definitely don't want to underdose them, but you also don't want to cause toxicity by overdosing them. So there's some hesitation in using this drug given certain circumstances, just because we aren't exactly sure what the the optimal dose is. Dr. Khyati Patel 22:00 And I guess the other issues with Dapto is, you know, it's expensive, and as we alluded earlier, this is only an IV option. There is no po option for it. So when we have to de escalate therapy, and, you know, transition patients from IV to PO, we have to make those consideration as well, yeah. Dr. Sean Kane 22:18 And then the other thing that is commonly forgotten about is that deptamycin cannot treat any infection in the lung, and the reason is that you have pulmonary surfactant in your lung, and that deactivates or inactivates the drug molecule. So this is really not appropriate for severe pneumonia infections, or really any pneumonia infection. So more commonly, you're seeing this for skin and soft tissue infections, urinary tract infections and bacteremias as well, Dr. Khyati Patel 22:43 and then so moving on to maybe some of the PO option we have Lange zelide in our pocket. The brand name is zyvox. The way it works by inhibiting gram positive bacterial ribosomes. So basically it prevents the protein synthesis that's necessary for the bacteria to survive. I suppose, Dr. Kane, there is lot to love about this drug. I remember working with a transitioning patient from, you know, vancomycin IV, for example, and they're going home and, you know, converting them to a PO regimen using Lange zellite, but apparently there is IV linezolid. And you know, you can also convert that one on one dosing to a PO regimen as well. The dosing is simplified. The it's like one dose goes for everyone. That's 600 milligrams twice daily, without regard to what their renal function is. And unlike Wanko, we don't have to do drug levels. So these are all the pluses for Lange zelite, some of the not so pluses or negatives for Lina zoide. Well, up until just very recently, it was brand name. So it was, you know, expensive. We were looking at about $100 a tab. So sometimes we had to worry about getting it a approved from hospital formulary, if not getting it, you know, approved by a patient's insurance if you're transitioning them to outpatient therapy, although that's not the case anymore, it has become available as much of a cheaper option now, about $5 to tap, something that we looked for when transitioning patient to Lange zelight was making sure that they weren't on any medication, or if they were that they were aware of serotonin related issues, the Lin is a light is a weak MAO inhibitor. So there is some potential risk for serotonin syndrome, especially if the patient is on any serotonergic drug, such as the, you know, the SSRI or SNRI, or tricyclic antidepressants and etc. So definitely further monitoring and patient education would have to go in hand. Dr. Sean Kane 24:44 Dr. Patel, we've covered basically three of the most common options that you know, pharmacists and other healthcare providers are likely to see in patients with severe MRSA infections. What's interesting about this, though, is that this is actually a really hot area when it comes to new drug. Development, and we've seen kind of an explosion of anti MRSA drugs that have now made it to the market that to be fair and honest with you, I haven't seen a lot of these. However, I think in the next five to 10 years, it's very likely that we'll start seeing more and more of these as we research it more and identify what patient populations may benefit, either from an efficacy or a safety standpoint. So a couple examples that are well beyond the scope of today's podcast. One is tigacycline, or tygacy, which is actually an older drug. It's a tetracycline derivative, but that does potentially have anti MRSA activity. There's some reasons why we don't use it, compared to the other options. Again, beyond the scope of today's podcast, but a newer tetracycline derivative is called hematocycline or new Zyra. That one's new we also have a fifth generation cephalosporin called cefterolene or teflaro And what's interesting about that one is that it's a beta lactam. So even though we talked about these crazy mutations in the PBP where basically very few beta lactams can bind to that PBP enzyme anymore, cephtaroline, this fifth generation cephalosporin is the like one exception there, where you still have a beta lactam that could be active against MRSA, an older drug called quinapristin Dolph pristine. Brand name is synercid. This is a combination protein synthesis inhibitor drug has some toxicities associated with it, which is why we don't use it that often. But it is another option. And then finally, this newer area that really has exploded are these newer glycopeptides. So we have oridovanson or orbactive, televansan, or vibe active, and double vansin or DOL Vance. All three of these have, you know, this glycopeptide drug structure, some of which you can give, like a single dose of the drug, and it has a very long half life for treating, you know, skin and soft tissue infections. So again, I haven't seen a lot of these in clinical practice at this point because they're fairly new, fairly expensive, and it'd be nice to have better efficacy and safety comparative data. But this is an area very likely in the next five to 10 years that we're going to see a lot more of in the future. Dr. Khyati Patel 26:59 It seems pretty promising. You know, it seems like staph aureus is, like we said, pretty smart. It's always evolving. It's a resistant mechanism, so it's good to have some additional tools in the pocket. Dr. Sean Kane 27:10 So Dr. Patel, that's really my neck of the woods, the inpatient side, where we have these severe MRSA infections, where we're giving IV therapy. Why don't we transition to your side of the fence, where we're talking about non severe skin and soft tissue infections, where we're suspecting or no, it's MRSA, like in the example of our patient case. So we're mostly focusing on abscesses and purulent cellulitis. But what are some considerations in that patient population? Dr. Khyati Patel 27:35 So yeah, we get to encounter some of these patients in our clinic, especially when they have diabetes. You know, they're commonly coming up with infections that have either abscesses or has purulence to it. As we know, rule of thumb, MRSA should be accepted in skin and soft tissue infections. When we are seeing a pus or abscess, you know, or any sort of drainage. Rule of thumb is also that, you know, if we don't see the purulence in the satellite is then we don't typically need MRSA coverage. So the way we define non severe skin and soft tissue infection is certain criteria. Again, they haven't failed incision and drainage, plus they're able to take oral antibiotic that it's not septic. The patient's not dehydrated or immunocompromised. That's again, condition for considering them as non severe infection does not involve things on face, hands or genital areas. And then we also look at the IDSA guidelines, serious criteria for we were looking at the temperature about 38 heart rate, above 90. Respiratory rate, about 24 or the white counts are above 12k or less than 4k however, these are probably a little bit nonspecific and probably too inclusive. Clinical judgment will play along as well, but this four items that we discussed kind of serve to discern whether the patients are presenting with non severe or severe aversion and what way we would need to treat them. Dr. Sean Kane 29:07 Dr. Patel, I just want to emphasize that last point you made, which is, you know, if you look at the IDSA skin and soft tissue infection guidelines, they definitely rely on sirs criteria. And as a critical care pharmacist, sirs criteria is something that we used to really define sepsis and septic shock and severe sepsis and things like that. And it's really fallen out of favor using Service criteria because it's so non specific. Unfortunately, you know that's what the guidelines talk about. So officially on a multiple choice exam, service criteria is probably what you should be using. However, in real life, it's a lot of your clinical judgment here in terms of, is this a more severe or less severe infection? One easy thing to say is that, you know, if a patient has to be hospitalized for that infection, that is almost certainly a more severe infection versus a non severe this is going to be outpatient oral therapy that we're talking Dr. Khyati Patel 29:56 about, and that the first treatment option, um. That is recommended for non severe sstis is incision and drainage. This is particularly really important. It's it's not a medication therapy we were talking about, but it is because antibiotics don't penetrate abscesses very well. So even if we give a course of antibiotic, it's not going to take care of that infection, because it doesn't go to the site of infection. So ind alone could be really effective. I've actually seen physicians you know that I work with perform this on a routine basis in the clinic. The cure rate we're looking at is 74% with ind alone, versus if we combined it with an antibiotic, it's 81% so there is the good support for how ind alone can work and become really effective. Dr. Sean Kane 30:49 And you know, just to highlight that particular study, the 74 versus 81% that was from New England Journal 2016 the first author was Talen T, a, l, a n in that article, even though it was a significant P value, showing, in this case, Bactrim increased the cure rate from 74 to 81% just the fact that three quarters of patients were cured with ind alone is a really big deal, emphasizing that, yes, you get a little bit of added benefit from adding that antibiotic, but not having the antibiotic is going to be curative in The vast majority of cases, Dr. Khyati Patel 31:21 and let's say if you're adding an antibiotic. So again, that's going to be obviously after ind. Ind should be performed whenever possible. As Dr. Kane, you mentioned 75 almost 75% of the cases, Ind alone has a good cure rate. And so we are adding antibiotics. Typical duration is five to 10 days. But in most cases, five days is going to work just as good as 10 days, of course, especially when we are combining it with the IND, Dr. Sean Kane 31:51 there's two main treatment options, oral treatment options that we're considering, and then a third one that we'll talk about. The two main ones are going to be Bactrim, which is sulfamethoxazole, trimethoprim. And then doxycycline. The case of Bactrim, the way it works is that you have these two drugs that work on two different pathways of the folic acid synthesis pathway for the bacteria. So you're making it so that the bacteria can't get folic acid, which it's required for to live. Some basic issues with Bactrim, you know, we could talk for a whole podcast episode about Bactrim, but some key issues are, when you take it, you're more sensitive to UV light, so you have to be careful. And we see lots of patients have sulfa allergies. And usually when someone says that they have a sulfa allergy, they're referring to an antibiotic like Bactrim. So we worry about rash or avoiding this in patients with a history of sulfa allergies, and then also it binds to albumin. So in very young children, like less than two months of age, because of bilirubin being kicked off albumin, we would potentially avoid this in very young children less than two months of age, Dr. Khyati Patel 32:52 and one of the bigger issue I see on the outpatient side Dr. Kane, because I treat patients taking warfarin as well, that there is a huge drug interaction between and so, you know, it goes without saying to educate our patients, to let us know if they're on any antibiotic or not, but we we may have to adjust certain medications like warfarin when they go on Bactrim type meds. The other oral antibiotic is doxycycline. Again, this is going to be your tetracycline derivative, as we know it, inhibits the bacterial ribosomes. Some of the common concern with doxycycline, just like Bactrim, it can increase photosensitivity. So again, avoiding the sun, sunscreen, all that education needs to be there. And then avoiding in younger patients, younger than eight years of age, doxycycline tends to discolor the tooth enamel and make it yellow, and in younger kids, it also can stunt the bone growth. And so these are some of the things that we need to be aware of when prescribing doxycycline. Dr. Sean Kane 33:53 And then, you know another basic counseling point is that really any of these tetracyclines can chelate to calcium and other divalent or trivalent cations. So you can't take it with Tums. You can't take it with dairy products and things like that as well. Dr. Khyati Patel 34:07 Yeah, so again, emphasizing the drug interaction is important, and the last but not the least on our toolbox is clindamycin (Cleocin). This also inhibits bacterial ribosomes. Clindamycin is interesting. According to the 2014 IDSA ssti guidelines, it's not really recommended. Bactrim and Doxy are preferred, and that's why we discussed those two earlier. But in patients who have either allergy to Bactrim, like sulfa allergy we mentioned, or doxycycline, this clindamycin can play a role, especially in younger kids who are not able to take doxycycline, or pregnant women who are also not able to take doxycycline, there could be prescribed clindamycin. Dr. Sean Kane 34:54 Dr. Patel, one of the main issues with not recommending doxycycline is actually both safety and. And efficacy issues. Why don't you walk us through what those Dr. Khyati Patel 35:03 are, right? So efficacy wise, you know, we have seen geographic resistance in certain area. I think, Dr. Kane, you mentioned that, you know it could be as up to 40% in your area. So that's something that we have to be aware of. As far as the safety is concerned. I mean, the big thing here is C diff, right? So we know clindamycin is associated with causing C Diff type infection. This is the only oral antibiotic with boxed warning on C diff. So this shouldn't be taken lightly. And the reason there is a box warning is because the risk of C diff is 20 times higher versus no antibiotic therapy. Whereas we know, you know, antibiotics can cause diarrhea and there is some potential for causing C diff, however, this other antibiotics we're referring to may cause it, you know, five times more of the risk versus with clindamycin. It's well documented, and it causes significantly increased risk of C diff, so something that we need to aware of when prescribing clindamycin. Dr. Sean Kane 36:10 So why don't we go back to Ronald, our patient case. So he has a non severe, mild to moderate skin and soft tissue infection, which is an abscess. The ind has already been done. So Dr. Patel, what are you thinking in terms of preferred antibiotics for our patient, Ronald here? Dr. Khyati Patel 36:26 So I like the fact that ind is already done, right? It was a purulent abscess, and that's been drained. We know that, you know, 74% of the time it's going to cure Now, the other option is that we don't add any antibiotic on. The second option is, obviously we add the antibiotic, and this is going to really depend on the patient you have on hand. The Case for not adding antibiotic could be made based on how big was the abscess, how well the physician doing the IND was able to drain it, and what kind of comorbidities does the patient have? If none of that is true, you know, the IND was done well, it was a small size abscess. The physician doesn't see the chance of abscess returning, or the purulence, purulent discharge returning, then perhaps there is no reason to add the antibiotic. However, for Ronald, on the alternate hand, if we think that he has additional comorbidities, we can also consider adding doxycycline or Bactrim for five to 10 days now, as we made the case for ind, probably five days would be enough, because if the IND is already done, 10 days not really warranted. Another thing to consider when we are prescribing medication is to consider cost, and both of these are relatively inexpensive, and so that's another reason to say five days of therapy should be appropriate for this patient. Dr. Sean Kane 37:52 Well, Dr. Patel, why don't we run through some key concepts from today's podcast about Staph aureus? So number one, I think it's important that everyone realizes that almost all Staph aureus produces beta lactamase, and that's the enzyme that's going to degrade penicillin, ampicillin, amoxicillin, those aren't going to work. So you really should never use those as monotherapy for Staph aureus. Dr. Khyati Patel 38:12 And the methicillin resistant staph aureus, the MRSA, is going to be resistant to nearly all beta lactam antibiotics, you know, their penicillin, cephalosporin, carbapenem, because of that single gene mutation, the Mac a that makes it really difficult for the beta lactam antibiotic to bind to the PBP, the penicillin binding protein. Dr. Sean Kane 38:33 And for those severe infections, there's in patients that have life threatening pneumonias, bacteremias, very severe skin and soft tissue infections, vancomycin is the drug of choice for those MRSA infections. We do have other anti MRSA drugs like daptomycin, Lange said, and then a whole host of other options as well, and they can be considered in certain patients, but the drug of choice for most patients is going to start with vancomycin Dr. Khyati Patel 38:59 and the MRSA, the methicillin resistant staph aureus skin and soft tissue infections are usually going to be purulent in nature, especially when they're associated with abscesses. We're going to see puss and drainage. And if that's the case, you know, incision and drainage should be considered curative. However, if we have to add antibiotics in mild to moderate cases, then doxycycline and Bactrim are going to be our preferred options. Perfect. Dr. Sean Kane 39:29 So if you are curious about knowing a little bit more about the evolution and the history of staph aureus, we have an excellent review article that's posted on HelixTalk.com episode 115 also, if you want to take a look at those 2014 IDSA skin and soft tissue and tissue infection guidelines that is also posted on our website as well. We love the five star reviews in iTunes. We love when listeners email us with suggestions for future episodes. And we're also on Twitter at HelixTalk. So come find us somewhere on the internet and let us know that you're there and what you would like to hear more of. From HelixTalk. So with that, I'm Dr. Kane and I'm Dr Dr. Khyati Patel 40:03 Patel, and as always, study hard. Narrator - Dr. Abel 40:06 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 40:17 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.