CONTINUING EDUCATION :: C DIFFICILE
both provide laboratory results that help physicians assess CDI severity and identify patients at high risk. The onset of sporadic irritable bowel syndrome-like symp- toms (IBS) may occur after CDI.5-7
It is not uncommon for post-
infectious IBS to develop after severe intestinal disease. This can happen, for example, following a norovirus infection. The triggering events in post IBS following CDI are unclear. Perhaps the persistence of spores is a complicating factor, although this has not been proven. In the absence of toxin-mediated mucosal damage, the ACG suggests that consideration of conditions “such as microscopic colitis or inflammatory bowel disease” be included as part of a clinical follow-up.3
Another possibility
in the onset of post IBS is the persistence of chronic low-grade inflammation. Low grade inflammation persists in patients with inflammatory bowel disease (IBD) who are in clinical remission, and is characterized by histological damage to the colon, which is a triggering event in clinical relapse in IBD patients. Perhaps a similar situation develops during severe inflammatory CDI.
Treating CDI The disruption of the normal diverse intestinal microbiota predisposes a patient to CDI, especially in hospital settings. Antibiotics are very good at causing this disruption, and treat- ment with antibiotics continues to represent the primary trig- gering event for CDI. Other predisposing factors are conditions such as IBD in which the intestinal microbiota is less diverse or treatment with certain medications such as proton pump inhibitors that reduce the innate protective mechanism of stomach acidity. Mild CDI may be treated simply by stopping the inciting antibiotic and allowing the intestinal microbiota to become reestablished, an approach recommended in the 2021 ACG guideline.3
In more severe CDI, the disease typically is treated
with metronidazole, vancomycin, or fidaxomicin, although vancomycin is now considered clinically superior to metroni- dazole. Fidaxomicin, which has a more narrow spectrum than vancomycin, is used increasingly because it has been associated with lower rates of recurrent disease. Monoclonal antibody therapy with Bezlotoxumab (brand name Zinplava) was approved by the FDA in 2016 as a treatment for recurrent CDI in patients receiving antibiotics. The antibody, which is given as an intravenous infusion, binds to a specific epitope located in the combined repetitive oligopeptide (CROP) region of toxin B that constitutes the binding domain. Thus, protection is mediated by preventing the toxin from binding to its intestinal receptor. Fecal transplants represent the latest efforts to treat CDI, especially in patients with recurrent CDI. The protection is based on the restoration of a more diverse intestinal microbiota capable of outcompeting C. difficile. Efforts are now underway to develop a more defined consortium of protective bacteria. The intestinal microbiota functions as a food pyramid with layers of diverse bacteria feeding off the byproducts produced by other bacteria, and it is challenging to identify specific consortia of bacteria that are protective. However, progress is being made in this area, and clinical trials are underway to establish efficacy in preventing recurrent CDI. Patients who receive fecal transplants continued to carry
C. difficile spores even though they become asymptomatic. This persistence of spores also occurs in patients following antibiotic treatment for CDI. Recommendations in Europe and the U.S. include antibiotic therapy for initial onset of CDI and consideration of fecal transplants in patients with recurrent disease.
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CDI during COVID-19 pandemic The Fall 2021 surge of the SARS-CoV-2 Delta variant over- whelmed hospitals, and resources such as laboratory instru- mentation, reagents, and plastics have been limited. For these reasons, labs have looked for alternative ways to make testing more flexible and improve lab workflow. Modified approaches such as rapid testing for CDI have helped lower the burden. During the early stages of the COVID-19 pandemic, antibi-
otics were heavily overused to treat COVID-19 patients due to the lack of alternative treatments and because of concerns about secondary bacterial pneumonias often seen with influ- enza illnesses. This overuse raised concerns about increased rates of CDI. By mid-2020, antibiotic overuse had been cur- tailed because secondary pneumonias were not being seen in COVID-19 patients at the levels seen, for example, following flu outbreaks. Although little data has been reported on rates of CDI in COVID-19 patients, it is no surprise that mitigation efforts against COVID helped reduce the incidence of CDI and other hospital-acquired infections. Many COVID-19 patients, perhaps up to 25%, develop di-
arrhea.8
The association of respiratory viruses with intestinal disease is not a new observation and has been reported, for example, with influenza virus. The SARS CoV-2 ACE2 receptor is present in high numbers in the intestine, so the binding of the virus to its intestinal receptor likely causes diarrhea due to cellular damage. SARS CoV-2 and other respiratory viruses appear to lower the diversity of the intestinal microbiota, raising the question of how this occurs and whether virus-induced dysbiosis is a predisposing factor for CDI.9-11
Conclusions • The burden of CDI on healthcare continues to be a major problem, and elderly hospitalized patients treated with antibiotics continue to be a primary susceptible popula- tion. Rates of hospital-acquired CDI are decreasing, but community-acquired cases continue to increase due to spores in the environment, exposure in healthcare facili- ties, and variants.
• There are numerous tests available in immunoassay and NAAT formats. Each offers advantages and each has limita- tions. An algorithm approach brings together the advantages of these tests and helps physicians establish an accurate di- agnosis when used in conjunction with patient history. This approach results in optimal patient healthcare, minimizes overdiagnosis, and represents good antibiotic stewardship.
• With the epidemic strain 027 that appeared in the early 2000s, fluoroquinolone resistance developed following a single mutation in the gyrase gene. Variants of C difficile, such as the toxin B-only variant causing outbreaks in Asia, continue to be problematic. Surveillance efforts need to continue to identify variants, determine their involvement in CDI, and ensure that they are accurately detected in laboratory tests.
• Inflammation is a primary reason why CDI becomes severe. Elevated white blood cell counts and elevated fecal lactoferrin, a marker of intestinal inflammation, indicate severe CDI. Elevated levels of either marker are associated with worse clinical outcome.
• SARS-CoV-2 replicates in the intestine and is present in fecal specimens from COVID-19 patients. This respiratory virus binds to ACE2 intestinal receptors, causes diarrhea, and has been associated with co-infections with C. difficile, leading to questions about the etiology of intestinal disease in these patients.
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