Good afternoon. Welcome to my discussion on the current updates for Clostridioides, previously Clostridium difficile colitis. My name is Dr. Ramsey Rimawi. I'm an assistant professor of medicine at Emory University in Atlanta, Georgia. I'm duly certified in infectious diseases and critical care medicine. C. diff infection, as well as other infections in the ICU, are my clinical interests. I have no relevant financial disclosures to disclose. To begin, C. diff remains a major burden in the U.S. Although the incidence of C. diff is reportedly dropping, as illustrated here in the graphs on the right, it continues to be a problem even after the pandemic. It still affects approximately 4% of our ICU patients. One would imagine that with the pandemic came a change in the incidence of C. diff given the rise of our use of protective equipment. However, since COVID, the publications have been mixed in regards to incidence. Some have shown a rise in C. diff, some have shown a reduction, and others without any change. Nursing home remains a common place where patients with C. diff are admitted from. The majority of publications report a reduction in the need for ICU, the risk of surgery, and death related to C. diff. The causes of C. diff are growing. Regarding the ICU, intensive care providers need to be aware of the common causes of clostridioides difficile. And those are including enteral feedings, inflammatory bowel disease, any kind of chemotherapy or antibiotics, proton pump inhibitors, laxatives, infections, skin breakdown, burns, hemodynamic instability is a common cause, malnutrition, and dehydration. Some antibiotics are more likely to cause C. diff than others. Previously, fluoroquinolones and clindamycin were the well-known antibiotics that put patients at risk of developing C. diff. Since 2018, third generation cephalosporins are now the most common cause of antibiotics that place patients at the highest risk of developing C. diff. Phytocycline, macrolides, and aminoglycosides are less common causes, maybe because these are prescribed less frequently. Pipericillin-tazobactam, or zosyn, is the least common cause of a broad-spectrum antibiotic that's associated with C. diff. With regards to testing, there wasn't really that much that has changed in recent years. Glutamate dehydrogenase with toxin assays arbitrated by nucleic acid amplification tests or NAT, still remain the most commonly utilized form of testing. With its high sensitivity and moderate specificity, it's for these reasons why this is the test of choice. NAT used alone remains another modality, however, certain things are used less often, such as culture because of the low specificity, or simply using immunoassays for toxin A and B because of the low sensitivity. Historically, providers used to send three stools for C. diff testing. Now the question is raised, is there any role for repeat testing? Testing has improved so much that now repeat testing within a seven-day period is no longer necessary. In fact, some institutions may cancel a repeat test if ordered within a seven-day period. There are biomarkers that have been published that help providers in making the diagnosis of C. diff. However, at this time, the data regarding them is still insufficient. This includes biomarkers such as Lactoferrin, Calprotectin, Interleukin-8, and Interleukin-1b. Infection control measures remains paramount. Patients should be cohorted to private rooms with dedicated toilets, if possible, to reduce spore transmission for as long as the patient is ill. Despite the resolution of diarrhea, the skin can remain contaminated in 60% of patients, the environment in 27% of patients, and the stool test can remain positive for up to one month after the infection, despite resolution of symptoms. Due to the higher temperatures and industrially high temperatures regarding the hospital laundered scrubs, hospital laundered scrubs are therefore cleaner than home-washed scrubs and recommended if exposed to patients with C. diff. It is vital to remember that spores are highly resistant to alcohol. Although a study reports that spores can be reduced by 14% with chlorhexidine-containing antiseptics, this data was not reproducible. Gloves and hand hygiene using soap and water is preferred. Even plain soap, 88% of personnel still had C. diff recovered from their hands. There is increasing data published regarding the use of automated terminal sporocytal disinfectants. This includes ultraviolet radiation and hydrogen peroxide vapors. The surface area that can be disinfected is much larger and therefore institutions are more often adapting to these measures. There's been numerous publications published in different journals over the past couple years describing the benefits of these terminal sporocytal disinfectants. Let's take a little snapshot into history. During the guidelines, the first published guidelines for C. diff was from that of the Infectious Disease Society of America and the Society for Healthcare Epidemiology of America. This was published in 2010. At the time, for an initial episode of C. diff, metronidazole was the recommended initial drug for mild to moderate C. diff given at 500 mg three times orally. This drug was heavily utilized. An alternative was oral vancomycin with or without metronidazole for severe, complicated C. diff. For patients with recurrent C. diff, now metronidazole was discouraged and oral vancomycin, whether in a tapered or pulsed regimen, was the preferred option. This is a list of some of the major publications that was used for those 2010 guidelines. It included data comparing metronidazole to vancomycin for the resolution of diarrhea at the end of a 10-day treatment and whether or not patients were developing recurrence. It also includes some of the data regarding fidoxamycin and vancomycin. I'll talk about that in the next slide. With that said, the guidelines were updated in 2017 and no longer recommended metronidazole regardless of disease severity unless oral vancomycin was unavailable and the disease was not severe. Vancomycin given at 125 mg orally for 4 times a day or fidoxamycin given 200 mg twice a day for 10 days was superior to metronidazole, both in the initial episode and the recurrent episode. For recurrent episodes, vancomycin was the drug of choice as a tapered or pulsed regimen rather than repeating a 10-day course all over again. And you can then follow that with rifaximin or fidoxamycin. In 2021, the guidelines were updated once again. Now fidoxamycin has become the preferred drug. An alternative, vancomycin given PO or PR, can be given with IV metronidazole for fulminant C. diff, to which they defined as hypotension, ileus, or megacolon. In patients not responding to vancomycin and metronidazole, alternatives include IV titanocycline, IV immunoglobulins, but not enough randomized control trials have been performed with these. And finally, if the patient fails to improve with those measures, subtotal colectomy with rectum preservation is the preferred surgical approach. An alternative, surgically, is a diverting loop ileostomy with colonic lavage followed by antigrade vancomycin flushes. However, this, although less invasive, can salvage the colon and may lead to improved outcomes. For recurrent episodes, fidoxamycin has been shown to be superior to vancomycin in maintaining a sustained response after therapy. Previously, variables such as age, creatinine, white blood cell count, the number of stools per day, the presence of abdominal pain or discomfort, C-reactive protein, fever, ICU requirements, and evidence of pseudomembranous colitis were used to determine if a patient was considered mild, moderate, or severe C. diff. The 2021 guidelines now define C. diff as a white blood cell count over 15,000 and a serum creatinine over 1.5, though notably, these might not perform so well in patients with hematologic malignancies or renal insufficiency. So let's dive a little bit more into the use of vancomycin versus fidoxamycin. With regard to these two drugs, there's two major randomized control trials involving 1,105 patients that showed that there was a similar degree of resolution, 88 versus 86%. However, the risk of recurrence at day 25 was less with fidoxamycin and the risk of death was also less, 1% versus 3%, as well as a reduced risk of overgrowth of VRE and candida. Unfortunately, up to a quarter of the patients can be resistant to vancomycin, therefore increasing our utilization of fidoxamycin. As mentioned earlier, there are other drugs that we can use that have antibacterial activity against Clostridioides difficile. However, the clinical impact remains either inadequate or not enough data. This includes drugs such as nidazoxonide, furcetic acid, rifaximin, and basitracin. Tigecycline has demonstrated mixed results in K-series and can be considered for salvage therapy. It has activity against C. diff, including toxin secretion, suppression, and resistant strains. Benzalotoximab, otherwise Benzalo, is a monoclonal antibody targeting C. diff toxin B. In the updated 2021 guidelines, Benzalotoximab is now suggested as a one-time infusion to be used as an adjunct standard of care antibiotics for patients with recurrent C. diff within a six-month period. It should be noted that this is a drug to be used in caution for patients who have CHF. In regards to fecal microbiota transplant, it's recommended for patients with multiple C. diff recurrences within a period of time. There's problems with utilizing this form of treatment. It's not only difficult getting it into ICU patients for several reasons. ICU patients are typically on broad-spectrum antibiotics that are likely to destroy the transplanted bacteria, and ICU patients, especially those with severe C. diff, often develop an ilias, where delivering stool would be dangerous. Stool delivered endoscopically may lead to aspiration, and stool delivered via colonoscopy may cause colonic perforation. It should also be noted that since 2017, there's been three separate FDA safety alerts, two pertaining E. coli transmission from the donor to the transplant recipient, and one pertaining COVID-19 transmission. In January 2022, the New England Journal of Medicine published data regarding the oral microbiome therapy with SER-109, and found that it was superior to placebo for patients with recurrent C. diff. Further studies on this are still needed. So what about preventing C. diff? You may have heard that there's a connection between proton pump inhibitors and C. diff. However, should we be discontinuing PPIs to prevent C. diff? Data on this is still insufficient. We can conclude that if a patient needs the PPI, continue it. If the patient doesn't, it would be prudent to discontinue it. With regards to probiotics, data on this is insufficient as well. The guidelines do not recommend it to be used universally, and providers should be aware of the risk of causing systemic bacterial infections with these organisms, such as Saccharomyces and Lactobacillus. And so to summarize, the 2021 guidelines have been updated, and it follows as such. For initial episode, the first drug suggested is Fidaximicin 200 mg BID for 10 days. An alternative is Oral Vancomycin. It can be given PO or PR at 125 mg QID for 10 days. And finally, as a third line, for patients with non-severe C. diff, if those alternatives are not available, metronidazole can be used at 500 mg three times a day for 10 to 14 days. On the first recurrence, Fidaximicin is still the first line, at 200 mg twice a day or five days and then Q daily for 20 days. An alternative agent can be Oral Vancomycin, either at 125 mg four times a day for 10 days or in a tapered pulsed dose fashion. And third line is Benzalotoximab, given as a one-time infusion intravenously. For more than two recurrences, the first line is again Fidaximicin 200 mg POBID for 10 days or as the first recurrence, given for five days BID and then daily for 20 days. Again, Vancomycin is an alternative that can be given for 10 days and then Rifaximin 400 mg TID or as a tapered pulsed dose. And Benzalotoximab, given as a one-time infusion, can be considered then. And also, fecal microbiota transplantation can be considered there as well. For patients with fulminant C. diff, Vancomycin is the recommended agent. It should be also recommended to consult surgery for possible surgical intervention. Thank you for your time.

Clostridioides difficile infection

ICU patients

antibiotics

nucleic acid amplification tests

fidaxomicin