[Music] [Music] I'm Dr fer and this is clusterid defal infection in adults clusterid defal or C was formerly known as clust trium defil when nomenclature changed in 2018 CI is a grand positive anoro and it has two important characteristic the first one is that it's Spore forming it can survive in Aerobic conditions by forming spores and alcohol rubs are ineffective against spores which makes washing hands with soap and water extremely important spores are stable in acidic environment as well in such as uh the stomach the second aspect of CI is that some strains are toxy enic meaning that they can produce toxins specifically Sidi toxen Sidi can produce toxin a and toxin B and I'll explain what the consequences of these toxins are CF infection is extremely important because it is attributed to extreme Healthcare cost as well as 5% infection related mortality and 15 to 20% all cause mortality in fact the CDC has classified Sidi as an urgent level of threat because of its prevalence and Associated death Al although the rate of Sidi has been going down in recent years thanks to antimicrobial stship efforts the annual cases requiring hospitalization are still in excess of 200,000 now to demonstrate how prevalent Sidi is you can see the rate of sidiff on the left hand side compared to the rate of es infections which is much more common than multi-drug resistant pseudomonas which is more common than carop resistant inaeris which is more common than carop panusis and Asino bacteria so you can see that CIF infection is a serious infection that's very prevalent and to make things worse it is also associated with increased rate of of death and you can see that the rate of mortality from cff is significantly higher than mortality due to es infections which is significantly higher than multi-drug resistant pseudomonas Which is higher than CR and CR Asino let's take a look at the pathophysiology of sidif infection it requires both acquisition of C as well as disruption of the God macrobiota because the God macrobiota has has a protective role against CI although the exact mechanism of symptomatic infection is unclear toxins play an important role the toxins produced by Sidi can disrupt the epithelial cells inside the GI tract which can result in release of inflammatory mediators and this immune response can be severe in many patient in fact the clinical manifestations range from diarrhea to pseudo brainless colitis to toxic meacon colon perforation and death as I mentioned the healthy gut macrobiota have protective role against C when patients are exposed to antibiotics the normal gut macrobiota is disrupted this leads to decrease species abundance as well as decrease diversity in the gut macrobiota in patients with disrupted gut macrobiota the C of spores find the opportunity to germinate to vegetative cells and then they can grow and dominate the G tract and then once CIF colonizes in the colon some patients May remain asymptomatic that depends on whether their immune system will respond to toxins produced by CF for some patients these toxins will re will induce an immune response and depending on the severity of the immune response there can be uh serious consequences such as hypotension or shock ilas or toxic megacolon these patients are the most difficult to treat and have the highest risk of mortality or need for surgical intervention to manage CDI when patients receive treatment with antibiotics for CIF infection the clinical symptoms will be resolved over time the healthy God microbiota will be restored protecting the patient against future CIF recurrences however if the gut macrobiota cons continues to be disrupted then the patient will be at risk of getting recurrent Sidi infection all right let's take a look at how someone acquires Sidi infection so okay initially someone is sidif negative and when this person gets exposed to the healthcare setting they are immediately at risk of acquiring clusterid defil and one thing that can happen is that this person can actually acquire non-toxigenic variant of c defil and of course because this non-toxigenic this patient will not have symptoms so this will be a asymptomatic colonizer another thing that can happen is that someone can be exposed to toxy genic variant of CDE and their immune system can actually mount imunoglobulin g response to the toxy toxin a and because this immune uh imunoglobulin will actually neutralize the toxin this patient also will not have a symptomatic will not have symptoms so this patient will be a symptomatic colonizer a third option is that when someone is exposed to toxygene their immune system cannot mount imunoglobulin g response to the Toxin and because the immune system cannot neutralize the toxins the toxins will develop symptoms so this will be symptomatic sidif infection now all three of these can transmit uh CI to other people especially if they are asymptomatic and they get discharged uh home prior to being treated now with the initial case of asymtomatic colonization with a non-toxigenic this is not a problem because uh you know this is pretty benign this strain of C the problem is with the toxen S so someone who's asymptomatic can go home and transmit this to other people like family members or friends which can lead to community transmission of Sidi and this symptomatic Sidi of course will be treated and will be in isolation to have infection control although Healthcare and chronic care facilities have been typical places in which patients acquire s if infection in the past decade more patients are presenting with Community acquir C if infection now let's let's take a look at reliable resources so in general we have idsa and acgs American College of gastroenterology have recommendations for CIF infection in 2017 idsa actually released a guideline for infectious diarrhea this is for management of infectious diarrhea due to other causes other than CI so CI is not included in this guideline but in 2017 they also released a guideline specifically for infection so any diarrhea due to CI this was in collaboration with Shay recently in 20121 ACG American College of gastroenterology also released updated guidelines for C infection and these guidelines are actually in agreement with the 2017 idsa guidelines and then shortly after ACG guideline was released in 20121 idsa also released a focused update which basically updat the three recommendations so this is a supplement to the 2017 idsa guidelines so there are a lot of recommendation in 2017 guidelines and this Focus updates basically as three recommendations or updates uh a couple of old recommendations and lastly there is a 2020 guideline from American gastroenterology Association specifically for the role of probiotics in the management of GI disorders the first learn Lear objective is describe the pkpd properties of antibiotics used for CDI metronidazol essentially disrupts the DNA and inhibits nucleic acid synthesis it is available both as IV and po note that with the PO 80 it is 80% bioavailable now for CDI the infection the site of infection is actually in the G track so it's actually best if the drugs are not absorbed because when they are absorbed they go away from the site of infection so when 80% of oral metronidazol is absorbed about 20% of it stays in the site of infection and of course for with IV 100% uh bioavailability means that it the entire drug goes into the bloodstream and then uh a portion of it may uh actually uh go from the blood to the GI tract one adverse effect that's unique to metronidazol is that the patients might uh get metallic taste now this is specifically with the oral formulation not with the IV uh for vanoy we have two oral vancomycine formulations so we have vosene uh which is uh basically a capsule and we have more recently uh fank which is a oral solution now because uh these for oral formulation of vancomycine are very expensive uh we actually in the hospital we can use the IV formulation of Vancomycin as oral uh because the IV formulation which is meant for injection uh is uh quite inexpensive can actually give it orally but regardless for uh treatment of CF infection vomisin must be administered orally so IV voming uh as an injectable is not an option and this is really important because uh pretty much less than 1% of Vancomycin is uh absorbed so it actually uh stays at the site of infection so this is excellent now we also have fidaxomicin which is available as oral tablet this also uh does not get absorbed so stays at the site of infection we also have refax Amin uh which is also not absorbed and more recently we've had uh Botox which is a human monoclonal antibody which basically binds to the toxin B and it prevents uh the toxin from uh having in it its effects on the cells and this is specifically IV and I'll explain more about this now one thing that's important about the bxu map is that heart failure was actually reported more commonly uh in the patients that receive this um this agent uh with in patients with a history of congestive heart failure so in patients with a the history of CHF bezo toxa should be reserved for use when the benefit outweighs the risk and this is from the package insert now I want to draw your attention to the feal concentration of these drugs because the site of infection is in the GI track you will say that because uh oral metronidazol is mostly uh absorbed you get the significantly lower concentration uh in the feces and this is in microgram per gram of the feces whereas with wyosine and fomine you get significantly higher concentration so I want you to keep that in mind when we talk about the efficacy of these agents now let's take a look at macrolite allergy hypers sensitivity reactions from macroy occur infrequently as low as4 to 3% reactions that are reported in the literature range from skin reactions to anapilis including fality now in the package insert there is a warning from the FDA for deficit so this is fedom myosin which is a macroy so essentially the FDA says some patients with hypers sensitivity reaction to deficit also reported a history of allergy to other macro ltes physician prescribing uh deficit to patients with a non macrolite allergy should be aware of the possibility of hypers sensitivity reaction now one thing is that this uh reaction to macroy are very rare so let's take a look at some cross reactivity between different macroides so in general macroy you can think of as natural or synthetic or semisynthetic products so the natural products on the market include arthy and fidaxomicin whereas synthetic or semisynthetic includes ayine and kyin you can also think of it based on chemical structure of these Macro Light so there is the 14 or there are 14 membered lactones Arroyos and clomin the 15 member lactone isomyosin and fidaxomicin is quite different so this is a 18 membered lactone and ithy and clomin have reported cross reactivity which makes sense because they are chemically more similar as 14 member lactones now aryin specifically is a semisynthetic derivative of aryin and cross reactivity with ery has been reported however fidaxomicin is quite different so limited evidence and there is one small observational study that suggests that it is unlikely for cross reactivity with uh other ma other macroy and fidaxomicin there are some live biotherapeutic products or for lbps um two of them are FDA approved and there are others that are under development so specifically re biota is a microbiota suspension created for uh created from healthy donor stool to be administered as an enema now this does uh require a wash out period of 1 to 3 days because these are not for treatment so you know someone who has CDF must receive antibiotic treatment and then once they are finished uh this product should be administered within 1 to 3 days now V is an oral capsule composed of live purified uh firmicutes bacterial spores derived from healthy donor stools which were chosen based on their ability to metabolically compete with ciff for essential nutrients and or modular bile acid profiles to reestablish colonization resistance now V uh does need a wash out period of 2 to 4 days now while both of these have um you know GI adverse effects concern that these patients have CI these are typically uh associated with the underlying condition we describ the pkpd properties of antibiotics used for CIF infections now let's identify risk factors for the development of new onset and recurrent CIF infection the idsa guidelines require two things for the CD infection case the presence of diarrhea or evidence of megacolon or severe ilas and either a positive laboratory diagnostic test result or evidence of pseudo membranes demonstrated by endoscopy or histopathology recurrent CI infection is defined as repeated episodes within 2 to8 weeks of the previous episode of CIF infection so repeat infection after 8 weeks is actually considered new episode C infection let's take a look at the effect of antibiotics on the normal gut Flora in healthy patients with no risk factors for CED if infection the gut Flora includes both a high quantity of bacteria as well as a high diversity represented by the red graph now if someone takes antibiotics in this BL represented in the Blue Zone here the quantity and diversity of normal flora will drop which will place the patient at the risk of getting Sidi infection and of course the CI strains that are resistant to whatever antibiotic that was used actually have selective advantage in this disrupted Flora of course these are antibiotics used for other infections such as pneumonia now once the treatment of antibiotic for whatever infection is done then there is a period of no antibiotic this allows for the normal flora to return to the normal State now as the normal flora is restored then the risk of sidif goes back down to the level that there will be no risk for sidif infection now when antibiotics are discontinued in patients the time that it takes for Flora to return to normal state is very very and it takes a long time therefore there is a gap between this because of variability in patients it often takes several months for the Flora to return to normal State let's look at risk factors for new unset C if infection antibiotic usage as I explained is an huge risk factor for C infection so is age greater than 65 years about 94% of all CIF infection cases have a recent Healthcare exposure so recent hospitalization is a risk factor as well as VRE colonization so patients who receive antibiotic uh are more likely to have Vancomycin resistant ocus colonized GI tract so this makes sense that people who have VR in fact about half of the patients with CF infection often have V colonization other risk factors include the key receive receipt of chemotherapy immune compromise or neutropenia uh feeding tube residence in nursing home chronic kidney disease and something that's a bit controversial is the receipt of proton pump inhibitors in observational studies proton pump inhibitors have been associated with CIF infection in fact more so than um you know histamine to receptor antagonists and this Association is typically in chronic of PPI so typically patients who are on a PPI for more than 28 days are at increased risk of uh CDF infection and this may be more of a marker so someone who's receiving PPI chronically might have other comorbidities that are more likely to expose them to CIF infection rather than the acid separation itself leading to SF infection because as we know clust troides defil uh can present as spores and spores are actually stable to the acidic environment so whether the acids are inhibited or not is not really going to have an impact have a direct impact on CDE infection but this is an association um to increase risk of C if infection things that manipulate the GI tract such as feeding tube gastrointestinal surgery are considered risk factor for CF infection because they can disturb the Flora now let's talk about the elephant in the room antibiotic usage the highest risk of CF infection is during receive of antibiotics and in the first month after finishing the antibiotic and we're talking about antibiotics for other indications such as urinary tract infections or bacteria now this risk can continue to exist up to 3 months after cessation of antibi iotics and it is dose dependent that's associated with increasing cumulative antibiotic dose so the higher the dose the higher the risk as well as increasing number of antibiotics so combination therapy higher risk than a monotherapy with antibiotics and of course increasing number of days of antibiotic exposure so every single day of antibiotics will increase the risk of CIF infection so the sooner we can discontinue anti antibiotics the better it is in protecting the patients from getting C if infection now certain antibiotics have higher risk of antibiotics in general pretty much every antibiotic has been associated with CF infection because one way or another they they have the propensity to distur Flora but some antibiotics significantly more than others so you can see that at the on the top of the list we have clintom myosin which has been historic ly associated with one of the highest rates of CIF infection along with sefalosporin folon carop penams penicillins and this includes penicillins combined with betal lactam Inhibitors such as pyin tacam as well as combination therapy so if you combine multiple antibiotics uh for example when you do empiric treatment now at the same time there are certain antibiotics that have low risk of antibiotics and at the top of the list is tetracycline specifically dxic cycline has been shown to have very low risk of antibiotics and some Studies have even suggested that dxic cycline might protect from getting CIF infection other antibiotics with low risk include glycopeptides acco donon such as L lenol metronidazol nrer and triop suol or berrum let's talk about risk factors for recurrent CIF infection about a quarter of patients will actually have recurrent CIF infection after the first episode you will immediately see that risk factors for recurrence basically are the same risk factors as getting the first episode of CIF infection such as advanced age and receive antibiotics and the patient's immune system plays a role here so when we give antibiotics to a patient which will uh disrupt the normal flora the patient will be at risk of getting toxen clust clerides defic and then inside the patient the uh the bacteria will start the toxin production and then once the toxin is uh produced then the immune system can actually respond so if the patient has sufficient immune response meaning that the body will actually have antibodies against the toxin so antitoxin response this patient will actually be a symptomatic uh car carrier now if the patient has inadequate uh immune response these patients will have symptoms including complications such as colitis and then if this uh inadequate uh immune response continues that's when these patients will have recurrence of CI infection now if it is possible for someone who had delayed immune response they might have a first episode of CIF infection and then in time they can have uh immune response and their body will have antitoxin um antibodies and then they will have resolution so that explains why uh even uh with these patients who have recurrence after the first episode pretty much 60% will have cure these are the patients that had delayed immune response and then there are um you know about 40% of patients that just don't have immune response so they will continue have recurrence uh C infection so it's important to note that recurrence is not thought to reflect an antimicrobial failure but rather is a failure of the host to either reconstitute his or her microbiota to establish colonization prevention or failure of the host to develop a protective antitoxin antibody immune response during the initial infection or both it also makes sense that advanced age is a risk factor because Advanced age is associated with low antitoxin B antibody in fact antitoxin B titer uh at Baseline and uh at week four correlate inversely with the recurrent CIF infection in studies we looked at pkpd properties of antibiotics used for CD infection and identif risk factors for the development of new onset and recurrent CD infection now let's assess clinical presentation and diagnostic laboratory findings to determine if a patient has CDI clinical presentation of CDI can range from asymptomatic in those who have immune response to the toxins producing antitoxin antibodies to patients who do not have um immune response and develop diarrhea and for some patients fever abdominal abdominal pain nausea and vomiting and complications of CDI can include pseudomembranous colitis toxic megacolon shock and of course death in severe cases diarrhea is the point where clinicians have to decide if it's due to CDI or due to other causes diarrhea can range in severity from minimal self-limited disease to profuse with two or more episodes per day now by a quarter of patients can actually be expected to resolve the symptoms by simply stopping the offending antibiotics without using any specific sidif infection treatment now one significant finding in patients with sidif infection includes present with white blood cells more than 25,000 cells per uh ML and in fact for some patients in severe cases white blet can exceed exceed 100,000 in this picture we can see what the toxin can toxin A and B can do uh to the colon uh resulting in these lesions uh throughout uh basically the colon and this is where uh the patients will have complications by forming pseudomembranous colitis this is where the epithelial uh Integrity will be disrupted throughout the colon leading to these uh lesions now let's take a look at diagnosis of CIF infections the idsa guideline recommends that patients with unexplained and new onset with at least three unformed stools in 24 hours are preferred Target population for testing for CF infection in other words if someone only had one or two to uh watery stools they're not really a candidate for testing for CF infection and by two I mean within 24 hours it's important to avoid routinely testing stool uh from patients who have received a laxity within the previous 48 hours because laxative uh can lead to these frequent um unformed stools and that would be a more likely cause of watery stool as opposed to CIF infection now in general the three commonly used tests include nucleic acid amplification test or not so this is basically a PCR based essay we also have stool toxin um enzyme imuno assay test you also have a GL glutamate dehydrogen or gdh test which is considered a c if antigen now let's take a look at the differences between these the nucleic acid amplification test is by far the most uh sensitive and specific test the cost is significantly high but it's starting to go down uh compared to other tests that are available uh on the market right now now pretty much all of these tests are uh pretty rapid so the results will be available uh quickly uh in the same day the gdh test basically detects the highly conserved metabolic enzyme which we call the common antigen uh which is present in both toxen and non-toxigenic strain so it basically tells you if the CI is there it just doesn't tell you if it's toxygene now it's important to know that this test is sensitive but it's not specific with the sto toxin um enzyme imuno assay this is the test that actually tells you if the toxin is present or not so the G DH test and this toxin um imuno assay enzyme imuno aay are actually used in combination so together they will tell you if the um if the CIF organism is there and then it will tell you if it's imuno uh toxicogenic or not now with the nucleic acid amplification test because it's very sensitive it's important to only test uh the sample from patients who actually uh have signs and symptoms of CIF infection because if you were to do this on any stool sample then uh you're going to identify all the colonizes so it's very important to avoid over uh diagnosis of CIF infection so clinicians can improve Laboratory test uh relevance by only testing patients luckely to have CI disease this includes not to routinely performing tests uh on stool from a patient who has received a laxative within the previous uh 48 hours now Laboratories can also improve specificity by rejecting specimens that are not liquid or soft now the idsa guideline uh basically has uh two ways for uh diagnosis of CDF infection so for institutions that actually require clinical signs to be satisfied prior to submission of stool sample for testing uh for those institution you can either do uh the nucleic acid amplification test alone or you can use a multi-step algorithm now in institutions that there is no uh agreement between the lab and clinicians to only test the sample from those with clinical signs then a nucleic acid amplification test alone is not recommended a multi-step algorithm is recommended and here's what the multi-step algorithm looks like so basically uh on once the stool sample comes into the lab we will perform um enzyme imuno assay for the gdh so that will tell you if the C organism is there or not and then they will perform a enzyme imuno assay for the toxin A and B and this will basically tell you if the strain is toxen or non-oxygen so if both of these happen to be positive so if it's gdh positive and toxin positive then the con conclusion is that the patient has C if infection and of course on the other hand if both of them test negative then it's concluded that the patient does not have CF infection now if there is discrepancy between these two meaning that either gdh is positive and toxin is negative or gdh is negative but toxin is positive then it's recommended in this algorithm to uh do the nucleic acid amplification test just to confirm this discrepancy so if you do the PCR uh which basically pretty much the pcrs that are available they look for the gene for the toxin B and if the gene is there then the conclusion is that the patient has CIF infection whereas if the gene is not there then the conclusion is that the patient does not have uh C infection now according to idsa uh do not repeat testing within 7 days during the same episode of diarrhea and do not test the stool from asymptomatic patients except for epidemiologic studies however for symptomatic patients with a high clinical suspicion of CF infection but a negative CDF infection test particularly those in whom symptoms are worsen a repeat testing should be considered now given that recurrent stive infection occurs commonly a recurrence of symptoms following successful treatment and uh diasis ation should be assessed by repeat testing now once somebody receives treatment for CIF infection there is no clinical value in repeat CIF infection testing to establish cure because more than 60% of patients May remain uh CIF positive even after successful treatment we described the pkpd properties of antibiotics used for CIF infection and identified risk factors for the development of new onset and recurrent CI infection we also assess clinical presentation and diagnostic laboratory findings to determine if a patient has CIF infection now given a patient with new onen or recurrent CI infection recommend idsa guideline concordant treatment here are the idsa recommendations for treatment of initial CIF infection we will separately look at recurrent CIF infection but now let's take a look at the very first episode of CIF infection we should break this in into non- severe severe and fulminant episodes of SE infection and this definition of non- severe includes a white blood cell count of less than 15,000 and serum creatinine less than 1.5 and for these non severe p uh patients with uh CF infection the new 2021 idsa guideline actually recommends fomin as preferred regimen over Vancomycin this recommendation is made because it has been proven that fidaxomicin has lower rate of recurrence of CIF infection and although fexon might saying uh a full treatment course cost about um you know almost $5,000 cost Effectiveness analysis probably favors the use of fomy over vanoy in patients with an initial episode of ctive infection due to its greater effectiveness with respect to sustained clinical response but implementing this recommendation probably reduces Equity due to variation in medical insurance coverage now in settings where access to Vancomycin or fomy is limited idsa suggests using metronidazol for an initial episode of non severe SF infection only and this is because of inferior efficacy of metronidazol for this infection now it is important important to avoid repeated or prolonged courses of metronidazol due to risk of cumulative and potentially irreversible neurotoxicity now because of cost of hyomin it is likely that for the foreseeable future vom will continue to be used for most patients however as cost starts to go down and as people start to adapt these new recommendation we will see increase use of aomine for patients which will uh ultimately reduce the risk of recurrent CD CIF infection severe CIF infection is defined as white blood cell uh greater than or equal to 15,000 or a serum creatinine greater than 1.5 for these patients metronidazol is not an option because of inferior efficacy and high risk of uh comp complications and mortality in these patient so again fidaxomicin is the preferred regimen according to the 2021 guideline and vanoyan is also an option uh as an alternative to fomy and we also have a fulminant CIF defined as either hypotension or shock or ilas or megacolon and ilas is basically uh you know if there's obstruction in the colon and for these patients it is recommended to use a higher dose of vcomin at 500 mgram either po or if the patient is unable to uh take oral um medications because they're either in hypotension shock or you know because of clinical instability it can be administered through a nasogastric tube um and in addition we it should also be coupled with IV metronidazol and this is because if there is an obstruction in the GI track and this oral voming cannot get to the site uh which is basically interon uh this IV metronidazol will basically surpass that obstruction in the GI tract and with uh will be able to infuse from the blood into the GI tract and get to the side of infection and this combination has actually been uh shown in observational studies to reduce mortality and that's why it's recommended here and for ilas specifically since uh oral Vancomycin will not get to the site of infection you may consider adding retile installation of vancomycine basically at the same dose of 500 mgram four times a day and it is important to know that for fulminant CF infection fidaxomicin is not recommended because it has not been studied for these patient so all the studies of fidaxomicin excluded patients with uh fulminant uh C infection now you will see that one thing that's clear here for non severe and severe CIF infection is that fedom myosin has a clear advant Vantage of twice daily dosing So it's b whereas Vancomycin is dosed four times a day so it will actually improve adherence now one thing to note is that while these are treatment of C infection it is important to Target the under underlying cause so it is important to discontinue therapy with the citing antibiotic agents as soon as possible as this may influence the risk of CIF infection recurrence so you know if a patient is on fluo quinon for example it is important to uh you know if possible to discontinue as soon as possible now one thing that may be controversial is the use of antimotility Agents since these patients have uh diarrhea uh and because you know CI is toxy genic and you know uh some people argue that because we want the toxins to get out of the colon it might be a good idea to not use antimotility idsa guidelines say that addition of antimotility agent such as laramide as an adjunct to specific antib bacterial therapy for CIF infection may be safe uh but they do acknowledge that there are no randomized uh control trials uh conducted to evaluate the safety of that okay now let's take a look at recurrent CDF infection so for the very first recurrence so this is someone who already had CD infection one time and got treat treated and then had recurrence uh 2 to 8 weeks uh after treatment again fedom mine is the preferred regimen and for these patients also an another preferred uh regimen is an extended pulse dosing version of fomy you basically give the same total number of doses so you know if if if the normal dose is 200 mgram twice a day for 10 days that's a 20 dose regimen uh you know one study looked at giving the 200 milligram poid for five days and then every other day dosing for 20 days which you end up with the total number of dose overall and this actually reduced the number of recurrents to the maximum and of course if cost is an issue alternative regiments include prolonged taper and pul vancomycine and what that means is that you basically give 125 mgram of vancom four times a day for 10 to 14 days and then you basically taper it down to twice a day for one week and then you taper it down to once a day for one week and then you taper it down even further to every 2 to 3 days uh for 2 to8 weeks so this is why it's prolonged and this has been uh shown to be um effective for recurrent CDF infection although it is not uh it has not been uh compared head-to-head with fidax myin so it's not clear if this would be um more effective than fedom so for that reason it's it is alternative and lastly of course uh you know especially if someone who initially receiv received metronidazol and then they had recurrence vancomycine uh you know the usual dose of 125 milligram four times a day for 10 days is an alternative and metronidazol is not recommended for any recurrent C if infection now let's take a look at recommendation for second or subsequent recurr recurrences and basically fomy again is the preferred recommendation as well as the extended P fed aomine uh dosing an alternative uh recommendation is prolong taper and pulse vom myosin and of course the regular vcomin dose followed with the Chaser so the the Chaser is that you do the regular 10 days of anomy and then you do refaim uh 400 MGR 3 times a day for 20 days and then at this point because you are at the second and third and fourth and fifth recurrences and this becomes really uh burdensome uh some of the effective uh treatments that are reserved for this phase includes FAL microbiotal transplantation so this is recommended for after three CF infections episodes there is also adjunctive Botox map 10 mgram per kilo uh just one time and this basically because of the long halflife of 18 to 19 days it will basically stay in the body for about 3 months so it's very effective in reducing uh recurrence of uh CF and that uh you know it's important to note that bezlotoxumab is really to reduce recurrence it's it is not for the treatment of CDF infection so that's why it's adjunctive so you know for example if you give it with vcomin the vcomin will be for treatment and Botox map would be to reduce the risk of recurrences and it's important also to note that Botox map data is in combination with Vancomycin or Metron nidol they limited data with uh you know giving Botox map along you know combined with fidom myin now in settings where Logistics is not an issue patients with the primary CIF infection episode and other risk factors for CIF in ction recurrence May particularly benefit from receiving bzum map uh because of the increase because of its Effectiveness in reducing uh recurrence especially you know people with risk factors such as recurrency infection episode within the last 6 months or age 65 years or older imuno compromised patients and severe CF infection on uh presentations now one thing that's important to note is that in patients with a history of congestive heart failure B lot toxmap should be reserved for use when the benefit outweighs the risk lastly there are some recommendations for prevention of C infection the idsa guidelines say that there are insufficient data to recommend screening for asymptomatic carriage and placing asymptomatic carriers on contact precautions they also say that uh you know it's important to minimize the frequency and duration of high-risk anti biotic therapy and the number of antibiotic agents prescribed to reduce CIF risk and also to restrict fuo quinon clomin and sefalosporin because these are very high risk for CIF infection except for surgical antibiotic prophylaxis so those should not be uh restricted so and often you will see that antimicrobial stor programs do restrict the use of flocons for example it is a bit more difficult to restrict sefalosporin and cl mine because of their clinical utility and the 20 2017 idsa guidelines regarding uh probiotics they mentioned that there are insufficient data to recommend probiotics for primary prevention of CIF infection so they need to see more clinical trials and the more recent 2021 American College of gastroenterology guidelines recommend against probiotics for prevention of CIF infections in patient ptients who are treated with antibiotics they also recommend against probiotics for prevention of CIF infection recurrent this concludes this presentation