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. Narrator - ? 00:11 This podcast 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 73 I'm your co host, Dr. Kane. I'm Dr. Schuman, and I'm Dr. Patel, and the title of today's episode is, don't go with the flow. How antibiotics cause diarrhea, and what you can do about it. So we'll be focusing on the use of probiotics to prevent both antibiotic associated diarrhea and also the evidence for probiotics and preventing Clostridium difficile associated diarrhea. So we have an elderly lady, an 85 year old woman, who is filling a prescription for clindamycin, and that's because she has strep throat. So during this mandatory counseling in Illinois, at least, she mentions that she's heard horror stories about how antibiotics can cause diarrhea, and she even had a friend in her bridge club that had recently been hospitalized because of what she called C Diff diarrhea. And so really, this is the clinical question that you may, may have even asked yourself, is, Can probiotics reduce the risk of diarrhea caused by antibiotics? And if they can, can they reduce the risk of C diff, Clostridium difficile associated diarrhea caused by antibiotics? Dr. Khyati Patel 01:36 So I guess the question here is to really delve into and see why antibiotics cause diarrhea? Right? Like we know, Probiotics have other proposed use, but our discussion today is focused on antibiotic associated diarrhea, or C Diff associated diarrhea. So how do antibiotics, or why do they cause diarrhea? Speaker 1 01:55 One thing we know is that, again, there's lots of bacteria that live within the body, within the gut. Antibiotics, by nature of what they do, can destroy some of the normal, normal flora or microflora, and then that allows overgrowth of less desirable bacteria in the gut that can cause diarrhea, or even one of the reasons we look for Super infections. As we get rid of a lot of the the more friendly tenants and leave get in some more of the the bad boys in the neighborhood. Dr. Sean Kane 02:19 One of those bad boys is Clostridium difficile, or C diff, as we'll call it for the rest of the episode. So when we do have antibiotic associated diarrhea, roughly about 10, maybe 20% of the time, if you're in the hospital setting, you'll actually get what some people call infectious diarrhea, which is Clostridium difficile associated diarrhea, which is basically an overgrowth of C diff. And everyone has C Diff in your GI tract. The difference is how much of it you have and whether it produces toxins or not. So really, C Diff associated diarrhea is where you have overgrowth, because you've killed off some of the other normal floor of your GI tract. And that overgrowth, that type of bacteria, ends up producing toxins that gives you the symptoms of diarrhea. And the problem is that this can actually not just be diarrhea, but can cause fever, cramping, dehydration. You can even progress through sepsis and end up in an ICU if your C diff, diarrhea gets bad Dr. Khyati Patel 03:10 enough, and most commonly, this is related to health care facilities if you spend too much time into it, if you're receiving other antibiotics, if you're severely ill, and whatnot. But we have also seen its growth in community based C Diff infections as well. Speaker 1 03:26 So again, the one thing to look at is going to be risk factors, and this is a case where not every antibiotic is quite the same. There are certain ones that are worse than others. As far as their likelihood of causing these things, about five to 25% of individuals will have diarrhea from antibiotics. Most antibiotics, though it's around five to 10% Dr. Kane, which are those kind of main offenders here? Dr. Sean Kane 03:45 So for me, the main offender that I think about is clindamycin, not only because it causes a lot of diarrhea, it's very hard on the GI tract, but it's also by far the worst one for C Diff associated diarrhea. In addition to that, though we also see a lot of diarrhea, maybe not C Diff diarrhea with augmentin, which is amoxicillin/clavulanate, and also with one of the cephalosporins called cefixime, which isn't very common. And one thing that all three of these antibiotics, augmentin, clinda and cefixime have in common is that they cover anaerobes. And anaerobes are really important in your GI tract. If you kill them off, it gives more opportunity for these opportunistic infections and for destroying a lot of that normal floor of your GI tract, and Dr. Khyati Patel 04:25 a lot of the time it depends on how long patient is receiving the antibiotic, and what's the frequency of them getting this antibiotic. Are they getting antibiotic like weeks after weeks, over short period of time, regardless of these agents? Correct? Dr. Sean Kane 04:39 Yeah. In addition to that, if you're taking multiple antibiotics, or you've been exposed to a number of different antibiotics, more is worse in terms of longer durations and more antibiotics higher doses, those are going to be big risk factors, regardless of the agent that you're considering as an antibiotic. Speaker 1 04:55 And so when we're looking specifically at that caused by C, differ with C, dad the highest risk. Again, appears to be clindamycin, and so it's actually got a boxed warning now for that reason. And about estimated, and this is, this is incredible, 17 to 20 times the risk compared to no antibiotic exposure. I mean, just looking at that, that's a huge, huge counseling point. Dr. Sean Kane 05:14 And just to put it into context, even our next worst antibiotic class, which would be quinolones like Levaquin, Avelox, or ciprofloxacin, cephalosporins, and then some of the IV agents that we use in the hospital, like aztreonam or carbapenems, all of those guys are like 5x your risk of C Diff versus having no antibiotic. And again, clindamycin is 17 to 20x your risk of getting C diff. So clindamycin deserves that boxed warning because the risk of C diff is incredibly high with clindamycin versus any other agent, to the point we're in the ICU, where we do see a lot of C Diff in the intensive care unit setting. We are very reticent to use clindamycin, simply because of its C Diff risk. We're that worried about it. We will still use it if we need it, but it's really not our preferred agent because of that risk. Dr. Khyati Patel 06:04 And for those who are allergic to penicillins and cephalospherins, you know, clindamycin becomes like, the easier go do medications, even in community based practice or even hospital based practice. So those patients may get the antibiotic of their choice, but not necessarily the safer antibiotic in terms of getting C diff? Speaker 1 06:21 Yeah, I think a lot of times that applies in dental settings. If you're looking at a prophylaxis for a tooth extraction or a major, major dental procedure, those things are done fairly commonly and again, clindamycin, the situations you mentioned, Dr. Patel at the penicillin allergies, there you go. So so be moving beyond these high risk what about, what about moderate and low risk types of agents, what else is there that can be used? Dr. Khyati Patel 06:43 So we do have penicillin and macrolides and Bactrim, they're about three times or two times the risk of getting C Diff compared to having no antibiotic exposure. And then tetracyclines are deemed to be the lowest risk at all. So looking at antibiotic specific risk factors. We do have other risk factors to keep in mind that put patient at risk, and some of them include patient with older age, like our patient that presented to the pharmacy. Speaker 1 07:12 Other things, again, frequent hospitalization, both the number of hospitalizations, total duration of hospitalizations, these are big factors. Dr. Sean Kane 07:19 And then there are a ton of other risk factors that aren't as well described as older age and healthcare exposure, but some of the other risk factors that come up fairly commonly are basically being sick, so it could be in a critical care setting, or just having a lot of chronic comorbidities, being immunosuppressed, things like that. Then also something like PPIs has been a hotter topic. We don't have as good of an idea of what is the actual risk of C Diff with ppi therapy, but it's something that has come up a lot more as we've been focusing more on chronic PPI use and the adverse effects associated with that. Speaker 1 07:51 So now that we've kind of established again, why there's a concern and significance of it, goes back to the question, Can probiotics be used to prevent this antibiotic associated diarrhea. Dr. Sean Kane 08:01 And I think the best answer is yes with an asterisk, and the asterisk comes because we do have limited data, in the sense of, we don't have this one awesome, big, randomized, controlled trial saying this is definitely the right thing to do. Instead, we have a ton of small trials that, when you group them together, and a meta analysis shows benefit. And I would say as a whole, there's very few trials that really negate the benefit of probiotics, and there's a lot of data that reinforces the perceived benefit of the probiotics for antibiotic associated diarrhea. Dr. Khyati Patel 08:31 And so I think the meta analysis that you're referring to is Hempel and his associates, who did it in 2012 we do have link in the reference in the show notes at HelixTalk.com which included about 82 different trials. So it was quite a large meta analysis, which comprised of total of 11,000 patients. And 24 of these trials looked at patients who were actually hospitalized. So most of these other trials looked at maybe community based prescribing probiotics, Dr. Sean Kane 09:01 and what they found was a relative risk of point five eight, which means roughly a 40% reduction in the risk of antibiotic associated diarrhea. The confidence interval there was between point five, which would be a 50% reduction, all the way up to point six eight, which would be roughly a 30% reduction in probiotics preventing antibiotic associated diarrhea. So we see a pretty good effect size. Here. We see a fairly small confidence interval. If you did a number needed to treat, it's going to be around 13, which is a pretty good number needed to treat for that. And if you just do the math, 82 trials, about 11,000 patients on average. These were fairly small trials of just over 100 patients per trial. And that's really the weakness in the data, is we have a bunch of small trials, and we don't have two or three well conducted large, randomized, controlled trials. Speaker 1 09:45 And one of the things I look at, I know, when I teach some of the herbal lectures and the vitamins and supplements, one of the things becomes kind of a heterogeneity about what's available. And I know the same thing here is there's multiple types of products that can tout as a probiotic. So the kind of, you know, the devil is in the. Details here as far as what you're going so are there certain ones that are better than others? If you Dr. Khyati Patel 10:04 focus mainly on the meta analysis and the trials and what kind of probiotic strains that they use, most of the data revolves around use of lactobacillus and Saccharomyces. So I would say 70% of the preparation in the meta analysis looked at using lactobacillus as one of their strains for the probiotic, Dr. Sean Kane 10:21 and we'll definitely talk about it later. Dr. Truman, in terms of the big limitations and heterogeneity comes up time and time again. And even if we accept that lactobacillus is important as an ingredient in these probiotic formulations, sometimes they combine it with other things. They had different species of lactobacillus. They had different doses, for sure. That's another huge limitation and a symptom of having a bunch of small trials, as opposed to a couple really well done trials. Dr. Khyati Patel 10:48 And of course, these are not FDA approved medications. They're over the counter, so it's hard to regulate that over the counter product, so we don't really know what's on the boxes, what's really inside the medication? Speaker 1 10:59 Oh, yes, and that's its own topic, right there. So I guess the next question then is looking at, do probiotics specifically prevent C Diff associated diarrhea? And I think the answer is the same, am I correct? Dr. Sean Kane 11:09 Yeah. So the answer is probably yes with an asterisk as well, for the same reasons of we have a number of smaller trials that do show benefit, and we don't really have a lot of evidence to say it doesn't work with, again, an asterisk of one particular trial that we'll talk about in a second. But basically, the answer is probably yes, and that comes out of another meta analysis. Dr. Khyati Patel 11:29 And this meta analysis was actually recently published in 2017 that looked at 19 different trials with a little bit more than 6000 hospitalized patients. So again, no community based C Diff prevention shown from these trial or meta analysis. And what we found was so we found Dr. Sean Kane 11:48 a relative risk of point four, two. So we'll call it a 60% improvement in the risk of C diff. And that confidence interval range from point three, 70% reduction all the way up to point five, seven, about a 40% reduction. So again, we see a fairly tight confidence interval, and that number needed to treat for that is around 43 and the reason why, even though we have a better effect size, we have a larger number needed to treat is that the incidence of C Diff associated diarrhea is actually less common than just antibiotic associated diarrhea. So when your incidence rate is lower, you have to treat more people with your probiotic to see one patient to not have C Diff associated diarrhea as an example. Dr. Khyati Patel 12:25 And just like antibiotics, for them to be effective, they need to be started in patients within certain period of time of diagnosis of a condition. Is that something similar the case with probiotics, that we have to start within certain time period of starting the antibiotic Dr. Sean Kane 12:40 for sure. So in that meta analysis, they actually discriminated out between, did they start the probiotic within two days of the first antibiotic dose, or did they wait after two days? What they found was that if you started the probiotic within the first two days of your first antibiotic dose, that's where the efficacy was best in terms of preventing C diff. Speaker 1 12:57 So I think, and again, something I kind of spoiled a little bit earlier. But one of the big things to look at is the limitations to this data. So we do have some data, it's it's good, but it's maybe not the robust. And some of it, I think I already again mentioned, is, is heterogeneity is going to be a big piece of it. I think the first one to start with is heterogeneity of the populations that were studied. So one thing that's noted is in with C diff, it's much more common in the hospital setting. So by nature of that, the population is confounded. Those individuals are going to be in the hospital, and maybe they're more sicker. There's a lot of other factors involved versus, you know, other types of diarrhea, just general antibiotic associated diarrhea, maybe is a less acute setting. So you've got some difference there in the setting. That's a big piece of it. You know, what other antibiotics they could be on the same time again, depending upon the setting, what other hospital infections or things you're concerned with? Dr. Khyati Patel 13:47 There other things to consider about heterogeneity is, again, the probiotic preparations. You know, every trial looked at different strains mix of different strains together. So that's important to consider whether the probiotic is a single strain versus multiple strains, and then consider the dose as well. You know, it can vary as by the factor of 10 to 100 times the CFUs, which is the colony forming units. Dr. Sean Kane 14:13 And then, of course, even the timing of the probiotic. So, as we saw in the meta analysis, not all trials started the probiotic, basically when you start the antibiotic. So again, all of this heterogeneity is a symptom of the fact that we don't have three or four huge trials to really influence which probiotic to pick and when to start it what dose to pick. But instead, we have a bunch of small ones, and there's no clear winner here in terms of what the actual treatment regimen is supposed to look like, Dr. Khyati Patel 14:40 and not only the timing of the probiotic, but then how long do we give the probiotic, around the time of their antibiotic course as well, so that was also introducing heterogeneity. Is whether do we do a one week treatment regimen? Do we do two to three weeks, or do we continue it for longer than that, three to 14 days? So those are all the different durations, tried and trialed. Speaker 1 15:03 So I think what this all sets up is that there should be a goal of kind of having one big, nice, robust study that can really come in, well designed, randomized, Big N value come in and really tell us what we need to know. Do we have that right now? Dr. Sean Kane 15:18 Yes, with an asterisk. A lot of these asterisks. So really, what was supposed to be the holy grail of having this very large randomized control trial was called the placid or placade trial, and this was really supposed to solve the issues of all this heterogeneity, all these small studies. And what it was was a British study that enrolled almost 3000 hospitalized elderly patients who are getting antibiotics from the past seven days. So if you think about risk factors for C diff, this was a slam dunk for their inclusion criteria, hospitalized people who are elderly, who are getting antibiotics. That's like the main three risk factors for C diff. Speaker 1 15:54 And a nice thing too is we had a nice randomized, we had a good solid, I guess, decision as far as which which ones do. So we had the randomized to lactobacillus plus Bifidobacterium or a placebo, and for a 21 day. So again, nice, solid. Course, we have the standardized probiotic. Dr. Sean Kane 16:10 What they found was their primary endpoint, which was antibiotic associated diarrhea within eight weeks. Was not different between the two groups. It was 10.8% versus 10.4% with placebo. And then a secondary endpoint that they had was the risk of C Diff diarrhea within 12 weeks, which was also not different, point 8% versus 1.2% Speaker 1 16:28 so let's write it all off. Right now, no more probiotics, right? Dr. Sean Kane 16:31 And here's where the asterisk comes in again. So this was the promised land of probiotics for antibiotic associated diarrhea, and the study failed for a big reason, and it was issues with study design and actual implementation of the study. So granted, it is the biggest, best study that we have for probiotics, but there are huge limitations and make it really difficult to accept the findings of the study. Dr. Khyati Patel 16:52 And what were this limitation? I'm assuming, because they didn't have enough patients included, so Dr. Sean Kane 16:58 they actually met there in their intended patient enrollment, but they thought they'd have a C Diff rate of 4% and it was closer to 1% so that dramatically hurt their statistical power and increased the risk of a type two error, where they would conclude no difference, but there really was a difference. They just didn't have enough people to show it. And I think that you can actually really observe that in the confidence interval in the study. So the relative risk for C Diff prevention range from point three four all the way up to 1.47 meaning that it included a potential benefit of preventing C Diff of 66% all the way up to causing C Diff at a 47% increase of C diff, huge confidence interval. Dr. Khyati Patel 17:37 And also, the study did not test all the patients for C diff, right? Or they were about only 60% of patients in the trial were actually screened for having C diff, and Speaker 1 17:47 that just seeing that, I had to double check. That seems very surprising, if your goal of your study is to differentiate that so now we've got another 40% that, again, may have been lumped into the wrong group there, as far as that overall assessment. Dr. Sean Kane 17:59 And really for me, one of the biggest issues here is when they started the probiotic. So as we talked about earlier, it's probably important to start it earlier on versus later on. And within the study, their study design methodology allowed for them to start the probiotic up to seven days after starting the first dose of the antibiotic in some treatment courses, you're basically done with your antibiotics by day seven. So it's so late in the game, you really wonder, did they not give it early enough to really even observe a benefit, if a benefit would have existed there Dr. Khyati Patel 18:29 and then, the regimen was, what 21 days? Do you think all the patients finished the 21 day regimen? Speaker 1 18:35 So again here, only about half the patients even completed the 21 day regimen in and of itself. So huge dropout rate, loss of treatment effect, all seems to come with a territory the way, the way all these things played out. Dr. Sean Kane 18:46 So at the end of the day, if you consider all of these limitations, and you put the PLACIDE trial against these meta analyzes that are primarily composed of smaller trials, I find it really difficult to accept the findings of this trial, even though it had a stronger overall study design because of the limitations that we've talked about. Dr. Khyati Patel 19:05 So Dr. Kane, we talked about a lot of things. We talked about the risk factors, different antibiotics implicated in it, and then talked about some meta analysis, and then even looking at the PLACIDE trial results, even though we can't really take it and apply it. So can we safely say that probiotics are probably effective. Dr. Sean Kane 19:21 That's such an interesting choice of words, because before we talk about efficacy, we also have to touch on safety, right? All right, so what's the risk? So really, some of the risks, probably the biggest risk, to be honest with you, at least in the community setting, is cost. So these are generally not super cheap. Probiotic formulas that are available, some are cheaper than others, but cost is probably the biggest factor, especially in someone like our patient who may have a fixed income that that won't be covered on insurance if it's over the counter and it's a dietary supplement. So the cost is probably the number one issue that we have to consider in potentially recommending or not recommending this therapy. Dr. Khyati Patel 19:57 And then we talked about lot of heterogeneities, and. Um, that can muddy some of the specific recommendation as to what probiotic to pick, single strain, multi strain, you know, what should be the recommended dose? When should we start it? How long should we prescribe it? Right? So that that's also kind of a little bit of a muddy point right now, Dr. Sean Kane 20:16 and if you think about it, because there's so much heterogeneity with exactly what you just said. There is no right answer, and anyone that says that they have the right answer is lying. They have no idea. Sure you can take a trial of a particular probiotic that looks really good, but there's a bunch of other trials that have similar efficacies, and almost all of the data is made up of really small trials. So there is no one best probiotic, dose, duration, or just generally, treatment regimen. Dr. Khyati Patel 20:45 So that's good to keep in mind when we're looking at different products that are available over the counter. So I have to ask probiotics. Obviously, they have bacteria in them. Maybe those are good bacteria. They're our friend. But can they cause harm? Dr. Sean Kane 21:02 Yes, they can, actually, and this is one of the reasons why the ICU patient population is under studied. And even worse than that are the immunosuppressed patients are almost always excluded from these probiotic trials. And the rationale there is the risk of fungimia and bacteremia, where the probiotic strain basically translocates through the GI tract into your blood, and then you end up with a bloodstream infection of whatever the probiotic strain is. It's really important that we note that this is incredibly rare, but there's a number of case reports that have confirmed that the probiotic that you ingested ended up in your blood one way or the other, mostly in people who are really, really sick, really, really young neonate type patient population, and in the immunosuppressed patient population. Dr. Khyati Patel 21:47 And so do we have more details as to why these patients tend to get infections besides the fact that they're immunocompromised, they're severely sick, they have other comorbidities? Dr. Sean Kane 21:59 Well, for sure, the going theory is that bacterial translocation through the GI tract. Really Interestingly, though, in my neck of the woods, the ICU patient population, there's pretty good data that some of that risk of Bloodstream Infection can be transmitted from the hand of a healthcare worker to a central line in a critically ill patient. Dr. Khyati Patel 22:18 Wow, that is just mind boggling. So basically, you're maybe giving probiotic to one patient haven't really cleaned your hands, and then you're doing something with another severely sick patient in the ICU, and that transmits the cells, the active bacteria Dr. Sean Kane 22:32 absolutely so most of the data on fungemias is actually from a particular strain of probiotic called Saccharomyces boulardii, and this is fairly common, because there's actually really good data for hospitalized patients with this particular strain. And although it's rare, there are case reports of fungemia from this particular strain, which is not normal flora in your GI tract. And what they've actually shown is that even if you as a patient, aren't the receiver of the probiotic, if you're adjacent to a patient who was getting it, and you shared the same nurse or healthcare worker that potentially that was transmitted through the healthcare workers hands to your central line. That causes the fungemia, yeah. In addition to that, they've done studies proving that when you open the powder packets for this Saccharomyces probiotic formula, which is what you'd have to do to give it through an NG or an OG administration, it ends up on the hands of the healthcare worker. It ends up as viable cells up to a meter away from where you open the packets, and it stays viable for up to two hours on whatever surface it gets exposed to. Furthermore, even if the healthcare worker washes their hands, they've been able to detect viable Saccharomyces cells on the hands of that healthcare worker as well, right? Dr. Khyati Patel 23:44 So kind of summarizing it, this is more for your extremely sick patient in the ICU, and therefore we don't have many studies looking at use of probiotics in this patient population. But perhaps not the case so much on the patients who are on a hospital, regular hospital floor side, Dr. Sean Kane 23:58 yeah, and we're clearly focusing on kind of the worst case scenario, these are literally between 30 and 100 case reports total of any patient having a fungemia or a bacteremia caused by their probiotic. The vast, vast, vast, vast majority of patients will have very minimal, if any, adverse effects from a probiotic formula. So I'd consider these extremely safe, as long as it's done in people who aren't incredibly sick or incredibly immunocompromised. Well, that's Dr. Khyati Patel 24:25 good to know, but we kind of mentioned earlier about how probiotics are not a prescription medication, meaning they're not FDA regulated. They're available over the counter as dietary supplements. So again, we kind of have to take the package as a face value and kind of see what's written on there versus what could be really packaged inside the medication itself. Dr. Sean Kane 24:45 They've actually done studies of probiotics that are commercially available and shown either they have no probiotic in them at all in terms of active cells, they've shown that it doesn't contain the dose that was described in the packaging. They've also described it having other strains of a different bacteria that it wasn't supposed to have, but it did have, potentially from cross contamination during the manufacturing process. So you may not be getting exactly what you think you're getting, which is kind of consistent with a lot of these dietary supplements anyway, but again, it kind of reinforces the question marks, heterogeneity issues with the actual product formulation itself when we're using a probiotic. Dr. Khyati Patel 25:23 So it was really good to look at the first hand evidence, such as meta analysis and this large, placid type trial. But are there any big organization? Are there any guidelines out there that recommend probiotic use one way or the other? Dr. Sean Kane 25:40 Yeah, so if you look at a number of different guidelines that are available, the overall theme is they probably work for antibiotic associated diarrhea, but we aren't really sure of what the cost benefit analysis is, because we have so many of these really small trials. Furthermore, for C diff, we again, probably have a benefit there, but the cost benefit is so much of a question mark, it doesn't seem logical that everyone gets a probiotic that gets an antibiotic, and until we have better data to really distinguish who is at highest risk and to use it only in those patients for the most part, guidelines either don't recommend it or say maybe in certain patients, but not in most patients. Dr. Khyati Patel 26:20 And then it's also to make sure we clarify that for the C Diff patients, this is probiotics are not studied if the patient already had the C Diff infection. This is more to prevent the C Diff infections from occurring Absolutely. Dr. Sean Kane 26:34 So this is always primary prevention, not during treatment, or even secondary prevention, which sometimes people will use it for that. But it's important to note that almost all of the data, literally, 99% of the data, is for primary prevention of C diff, not anything else, right? Dr. Khyati Patel 26:48 So good discussion. Kind of rounding it back to our patient, who is an 85 year old woman, let's break it down and see what her individual risks are first, right? Dr. Sean Kane 26:59 So first of all, clindamycin is the worst antibiotic for both antibiotic associated diarrhea and, more specifically, for C Diff associated diarrhea. So that's by far her biggest risk factor that she has. And then Dr. Khyati Patel 27:11 perhaps the age, as we established, that's one of the other established risk factor for having either AAD or CDAD. Dr. Sean Kane 27:17 And good for her, she hasn't been in the hospital, as far as we know, but that would be her other major risk factor, but she doesn't have that, which is good. Dr. Khyati Patel 27:25 And so information that we don't know is things like, you know, what was her recent antibiotic use, or when was that antibiotic use, and did she have any kind of diarrhea that were associated with that antibiotic use? Dr. Sean Kane 27:37 Yeah, and I would say for me, one of my main decision points and potentially recommending a probiotic is the patient's history of having diarrhea when they take antibiotics. Do they have, quote, unquote, a sensitive stomach? If they do, maybe they are someone who would be willing to pay the, you know, 10 to $20 for a course of probiotics. And if they've never had that problem the past, maybe they aren't as good of a candidate. Dr. Khyati Patel 28:00 And so talking about the cost, as you mentioned already, that these are little bit more on the expensive side. So for our patient, we'd really have to ask her, Can she afford it, right? Dr. Sean Kane 28:10 And one trick that sometimes people play is, hey, let's just charge more money and make it look like we have the best one. So we're gonna charge $40 for our probiotic regimen. Don't get fooled into that trick. We really have no idea what is the best probiotic, whether it's multi strain or single strain. Which strains to pick? So don't use cost as your litmus test to pick the best probiotic. That's a false assumption, Dr. Khyati Patel 28:36 but we probably want to tell a patient to pick a probiotic which has either lactobacillus or Saccharomyces in it. And again, when in doubt, pick the higher CFUs, the higher colony forming units, yeah. Dr. Sean Kane 28:50 And again, like it's a very, very safe product, especially on the outpatient side and non immunocompromised patients. So why not? If you're deciding between two products, why not pick the bigger dose? It's not going to hurt and it may help. We just don't know how much it may help. Yeah. Dr. Khyati Patel 29:03 And to be honest with with all these, you know, glorious cost associated with fancy probiotics available, my go to choice is to recommend patients to start eating yogurt as long as they're not lactose intolerant, yeah. Dr. Sean Kane 29:17 And I think that that's a great middle ground in recommending something that may have a benefit. We probably won't have the same CF use in yogurt as we would in a commercial probiotic. But again, we don't really know how much you need, what kind of probiotic you need, and things like that. So if you're kind of on the fence of no probiotic, or maybe probiotic, I think yogurt is an awesome middle ground. That is a good dietary recommendation anyway, and it's something that you could certainly consider for a patient, right? Dr. Khyati Patel 29:44 And again, it's hard to kind of maintain the CF use in a, you know, regularly cultured yogurt, but certain yogurt, such as Activa, which uses probiotic in it that has strains like Lactobacillus bulgaricus, Lactococcus lactis, and Streptococcus thermophilus, so the other two we didn't really talk about, but there are a couple of different strains of lactobacillus in here that could help patients. Dr. Sean Kane 30:09 So if we were to kind of wrap up some of the key points from today, one is going to be all antibiotics can potentially cause diarrhea, but certain antibiotics are way worse, especially for C diff, and we're looking at you, augmentin, amoxicillin/clavulanate, cefixime, which isn't a very common cephalosporin. And then by far and away, clindamycin is the one that we have to worry about the most, and it really does deserve that FDA boxed warning. Dr. Khyati Patel 30:33 And remember that all antibiotics can cause the Clostridium difficile associated diarrhea. But again, clindamycin is the worst culprit when it comes to it. Dr. Sean Kane 30:44 In terms of probiotics, we're pretty sure that they are efficacious for preventing both antibiotics associated diarrhea and Clostridium difficile associated diarrhea. The chink in the armor of the evidence, though, is it's a bunch of small trials that had to be metalysized into one meta analysis to really show that benefit. And unfortunately, we had this one trial that was supposed to be the end all to be all of this is the thing to do to prevent diarrhea and C diff, and it was the PLACIDE trial, and it failed. And it failed for a number of different limitations within the trial design and also the implementation of the trial itself. Dr. Khyati Patel 31:17 And even with the evidence we have available, we don't know the clear recommendation regarding the probiotic strain, to choose the dose, to give the duration, to prescribe this regimen. And again, as you said, they're not regulated by FDA. They're over the counter and more expensive. Doesn't necessarily mean better probiotic. Yeah. Dr. Sean Kane 31:38 And then finally, if you are going to pick a probiotic, regardless of what you pick, you probably should start it as soon as possible. With respect to the first antibiotic dose, we have pretty good evidence that waiting too long either doesn't give you as good of a treatment effect, or it completely negates your treatment effect. So earlier is better. Probably while they're picking up that antibiotic, if they are going to do a probiotic, they should be doing the probiotic at the same time, Dr. Khyati Patel 32:01 and I think that's the best recommendation we can provide as a pharmacist. Dr. Sean Kane 32:06 So if you want to read either the meta analysis for antibiotic associated diarrhea, the meta analysis for C Diff associated diarrhea, or the PLACIDE trial, we have references to that in our show notes at HelixTalk.com this is episode 73 we're also on Twitter. If you want to tell us what your favorite what your favorite probiotic is, we'd love to hear with that. I'm Dr. Kane, I'm Dr. Schuman, and I'm Dr. Khyati Patel 32:27 Dr. Patel, and as always, study hard. Narrator - Dr. Abel 32:31 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 - ? 32:42 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.