Minoclonal Antibodies Against Clostridium Difficile

While probiotics may be a good choice for Clostridium difficile prevention, antibiotics may be required for infection.  Antibiotic resistance is becoming a problem.  Here is an interesting study on monoclonal antibody therapy for this difficult infection.  Abstract:

Background Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. Methods We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. Results In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, -10.1 percentage points; 95% confidence interval [CI], -15.9 to -4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, -9.9 percentage points; 95% CI, -15.5 to -4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, -11.6 percentage points; 95% CI, -17.4 to -5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, -10.7 percentage points; 95% CI, -16.4 to -5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. Conclusions Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239 .).

Bezlotoxumab seems to be a promising therapeutic agent against this problem infection.

Priobiotics, Intestinal Integrity, and Health

More evidence for the importance of the proper intestinal bacteria, and possible utility of probiotics. Abstract:

Intestinal barrier integrity is a prerequisite for homeostasis of mucosal function, which is balanced to maximise absorptive capacity, while maintaining efficient defensive reactions against chemical and microbial challenges. Evidence is mounting that disruption of epithelial barrier integrity is one of the major aetiological factors associated with several gastrointestinal diseases, including infection by pathogens, obesity and diabetes, necrotising enterocolitis, irritable bowel syndrome and inflammatory bowel disease. The notion that specific probiotic bacterial strains can affect barrier integrity fuelled research in which in vitro cell lines, animal models and clinical trials are used to assess whether probiotics can revert the diseased state back to homeostasis and health. This review catalogues and categorises the lines of evidence available in literature for the role of probiotics in epithelial integrity and, consequently, their beneficial effect for the reduction of gastrointestinal disease symptoms.

Note that disruption of the integrity of the intestinal epithelium (in layman’s terms: lining of the gut) is associated with a wide variety of important diseases, and that probiotics can enhance that integrity and reduce symptoms of gastrointestinal disease. The paper discusses various mechanisms whereby “good bacteria” help fight against “bad bacteria” and in so doing reduce inflammation and help maintain the proper structure of the intestines, hence helping reduce disease. The good bacteria occupy space and use nutrients that otherwise could be exploited by the bad bacteria, the good bacteria can secrete molecules that are toxic to the bad bacteria, and the good bacteria can help stimulate immune responses that target the bad bacteria. One home measure that I and people in my immediate family do is to make sure we eat yogurt with active cultures when we are on antibiotics, and after the antibiotic course is finished, to make sure the proper intestinal bacteria are being replenished as they are being killed, as a side effect, by the antibiotics. The aim is to inhibit colonization of the guy by the bad bacteria, especially once the antibiotic course is finished, by making sure that enough of the “good guys” are present. Of course, consult with your physician before doing this yourself and be aware that some antibiotics should not be taken with dairy products (and of course, be aware if you are lactose intolerant – although many intolerant individuals can tolerate yogurt, or have a dairy allergy). We usually eat yogurt anyway, so doing so in this case is nothing unusual.

Probiotics For Clostridium Difficile Prevention?

At left, how probiotics work; By Rachelshoemaker - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=54240651

Clostridium difficile is a common cause of acquired GI infections in the medical setting, often cuaing severe diarrhea. There is a school of thought that suggests that colonizing the gut with beneficial bacteria can inhibit infection with harmful bacterial species. This study suggests "moderate quality evidence" that probiotics can be used to prevent diarrhea from Clostridium difficile.  The conclusions from their abstract:

AUTHORS' CONCLUSIONS:
Based on this systematic review and meta-analysis of 23 randomized controlled trials including 4213 patients, moderate quality evidence suggests that probiotics are both safe and effective for preventing Clostridium difficile-associated diarrhea.

If supported by further research, this would certainly be welcome news, to reduce the incidence of the severe problems that accompany these sorts of infections, and once again demonstrates the positive value of a proper gut microbiota.