C. difficile

FDA Approved Fecal Therapy for C. Diff vs. Healthy Preventative Options

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C. diff is a bacteria that notably has a hospitalization rate of about 50 percent and carries a list of symptoms including diarrhea, fever, and stomach tenderness or pain. (Kateryna Kon/Shutterstock)

C. diff is a bacteria that notably has a hospitalization rate of about 50 percent and carries a list of symptoms including diarrhea, fever, and stomach tenderness or pain. (Kateryna Kon/Shutterstock)

C. difficile (C. diff) is a bacterial infection that affects nearly half a million Americans each year. Paradoxically, treatment for the disease often uses strong antibiotics—yet antibiotic use is a major risk factor for contracting the disease. Despite issuing warnings three years ago, the U.S. Food and Drug Administration (FDA) recently approved the first-ever standardized fecal therapy to treat C. diff infections. 

C. Diff Infections Occur When Good Bacteria Dies

A balance persists in the gut microbiome that allows us to live a healthy life. It is a system that ensures we have the right amount of each bacteria needed in our intestinal tracts. More research is emerging showing that an imbalance in the gut microbiome can lead to a number of issues—one of them being a C. diff infection.

C. diff is a bacteria that notably has a hospitalization rate of about 50 percent and carries a list of symptoms including diarrhea, fever, and stomach tenderness or pain. Although C. diff can affect anyone, it is more likely for someone to be infected after taking antibiotics.

Antibiotics neutralize a large number of good and bad bacteria which results in the gut flora being out of balance, creating an environment in which C. diff can thrive. Other risk factors for C. diff include being 65 and older, having a weakened immune system, and visiting a high-risk environment such as a hospital or nursing home. It is important to note that anyone can be affected by C. diff.

Treating C. diff is a bit paradoxical in practice. Typically, doctors prescribe antibiotics against bacterial infections—yet taking antibiotics is the largest risk factor for contracting C. diff. Still, some doctors prescribe a stronger antibiotic for about 10 days should the symptoms be severe.

Another therapeutic treatment for C. diff infection is an IV infusion prophylaxis marketed under the name Zinplava, a concentrate with its active ingredient being the human monoclonal antibody bezlotoxumab. In two clinical studies, Zinplava reduced recurring episodes of diarrhea to about 16 and 17 percent compared with 26 and 28 percent from the control group, meaning it was slightly more effective than the placebo.

Recently, the FDA approved a novel treatment method: Stool based colon injections to treat C. diff.

Fecal Microbiota Product to Treat C. Diff

On Nov. 30, 2022, the FDA officially approved the first “Fecal Microbiota Product” called Rebyota. These products, also known as stool transplants, generally fall under the category of fecal microbiota therapy, or FMT.

“Today’s approval of Rebyota is an advance in caring for patients who have recurrent C. difficile infection,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research. He noted that recurrent C. diff infections “can also potentially be life-threatening” and says the approval marks “an important milestone” in treating the disease.

Rebyota has been granted fast track, breakthrough therapy, and orphan drug designations in 2013, 2014, and 2015 respectively. The FDA fully approved the treatment method just before December 2022.

Rebyota was developed by Rebiotix, which was later acquired by Ferring Pharmaceuticals, Inc. In development over the past decade, Rebyota is a microbiota-based, live biotherapeutic that works to facilitate restoration of the gut microbiome to prevent further episodes of infections. It is manufactured from human feces donated by individuals and screened for transmissible pathogens such as Hepatitis, HIV, and other diseases per doctor recommendations.

Stool donations are purified and processed for administration to the patient. Reintroducing processed stool from healthy individuals has shown some success in clinical trials. The overall success rate in preventing a recurrent C. diff infection was about 70.6 percent in the FMT group compared with 57.6 percent in the placebo group, somewhat similar when compared to results using Zinplava.

However promising the data may look, there are some side effects to consider with this novel treatment. 

Treatment is usually delivered via colonoscopy, or less commonly, through a tube inserted via the nose to the duodenum—a method associated with a higher risk of side effects such as aspiration pneumonia. Other side effects may include stomach pain, diarrhea, bloating, gas, and nausea. Patients are instructed to not take any oral antibiotics for 8 weeks after Rebyota treatment.

The manufacturers have noted that because Rebyota is manufactured from human fecal matter, patients should prepare themselves for adverse allergic reactions after treatment as allergens may well be in the donor’s sample.

Warnings From the Past

History has not always been in FMT’s favor. The FDA issued a statement warning against the possible risk of allergen transmission when administering FMT in 2019 citing the possibility of allergen transmission and a potentially hazardous spread of what are known as superbugs that include bacteria, fungi, etc., resistant to antibiotics and other common forms of medication. 

Superbugs have been a growing concern for the medical community as they have the potential to render prescribed medication less or ineffective. In 2019, a study showed that superbugs have directly caused the death of over a million people around the world, with almost 5 million deaths related to them.

FMT treatment is usually screened for possible pathogens before entering the stool bank to ensure that unwanted agents are not transmitted. However, the process has been updated over the past few years since incomplete screenings have resulted in hospitalizations or even death.

Most pathogens, once they infect the host, are present in most parts of the body including the stool. A pathogen simply needs a medium such that it can be transmitted from one host to another, this includes stool.

In 2020, the FDA issued a statement detailing the report of six patients who were infected with a form of E. Coli after receiving FMT. Four of six patients required hospitalization and attributed the infections to an incomplete screening process. Similar cases have appeared in the past which resulted in companies that perform FMT releasing statements in order to acknowledge the phenomenon and announce changes to their screening process.

A study shows that stool donations are usually accepted from volunteers up to two or three months after they were screened for pathogens and receive minimal processing. There is concern about the possibility that a donor may become infected with the disease between the screening time and the actual donation time.

Concerns still persist regarding this form of treatment.

A Simple Way to Keep Your Gut Healthy

FMT treatment, nevertheless, has seen increasing availability and has found gradual acceptance in the medical community over the past decade, yet it was mostly performed on a direct patient-to-donor basis. Rebyota simply industrialized the process and made it more commercially available, marking a milestone in the medical industry.

In recent years, it seems that the FMT industry has consolidated itself in the area of treating C. diff with other drugs in the pipeline—preparing itself for phase 3 trials. However, some manufacturers have the ambition to tackle inflammatory bowel disease, or IBD, a disease that affects more than 3 million Americans each year. IBD is an inflammatory disease that is strongly linked to a disruption in the balance of gut microbes, thus researchers are pitching FMT as a possible IBD cure to their investors.

Why FMT has an effect on C. diff is that it can replenish the gut microbiome in the intestines and restore the balance needed for good health. The bacteria spores from C. diff are especially likely to be activated in people who have undergone antibiotic treatment because it wipes out most of the pre-existing organisms, turning the intestines into a sandbox for C. diff to unleash havoc.

This is why in the case of gut-related diseases like C. diff and IBD, it is important to focus on the balance of gut microbes before infection occurs. 

The gut is an organ closely connected to the brain via the longest cranial nerve, the vagus nerve. The vagus nerve creates an interactive information exchange between the two organs and is responsible for mood and digestion amongst other body functions. As a healthy gut can put you into a good mood, a calm mindset can shift your gut into the right composition.

Studies conducted at the University of California and New York University have shown that meditation can smooth out gut irregularities and has a positive impact on the gut microbiome.

A comparison study between meditating and non-meditating groups of people showed that meditation results in stronger and more diverse gut microbes. Rather than wiping the intestine clean with antibiotics, it seems better to replenish and restore the balance in the gut.

Other papers focusing on meditation and gut-related diseases have shown that the positive aspects don’t stop there. New York-based researchers demonstrated in their experiment that the meditating group, when compared with the control, “was associated with significant … [reductions in] C-reactive protein [levels].” C-reactive proteins are an indicator of inflammation, a common cofactor in gut diseases, and a staple symptom of C. diff.

Additionally, a study conducted at a stress and anxiety center shows that meditation can relieve stress, abdominal pain, diarrhea, and other gastrointestinal symptoms with their patients seeing significant improvement after a period of time. Meditation works quite similarly to FMT in the sense that it replenishes your gut bacteria, with other studies showing that meditation can boost your immune system. Both are key to overcoming gut-related diseases such as C. diff.

Meditation is also quite safe. A study published in Psychological Medicine concluded that there is “no evidence that [meditation] leads to higher rates of harm” when the participants were compared with the control group. The study states meditation was, on many accounts, “significantly preventative of harm.”

Adjusting the diet may also improve gut-related issues. It is important to eat foods that contain a large number of live cultures or probiotics, such as kombucha, kefir, fermented goods such as sauerkraut, and foods rich in fiber like whole grains, fruits, and vegetables, among other things.

It is vital to avoid foods that are highly acidic, overly fatty or greasy, and raw. One also needs to stay hydrated, as that is a key in battling gut infections that commonly cause diarrhea as a cofactor. The Mediterranean diet, among many others, suits this best. It might be no coincidence at all that Italy has a low C. diff infection rate when compared with the U.S.

FMT is now an approved treatment method having gone through extensive regulatory controls with risks related to the treatment still being present. There are many methods to relieve the symptoms of an ill gut, such as the aforementioned eating and mindfulness habits one can develop. They are one of many options well worth considering to supplement the limitations of customary remedies.

AAAAI: Penicillin Allergy Label Linked to MRSA, C. difficile

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Increase attributable to use of alternative antibiotics

Patients with general practitioner-reported penicillin allergies had an increased risk for developing methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile (C. difficile) infections mediated by increased use of beta-lactam alternative antibiotics, researchers reported here.

Findings from the newly reported study suggest that addressing patient over-reporting of penicillin allergies could prove to be an effective strategy for reducing MRSA and C. difficile incidence, researchers say.

Kimberly Blumenthal, MD, of Massachusetts General Hospital in Boston, reported the study findings during a presentation at a joint meeting of the American Academy of Allergy, Asthma & Immunology (AAAAI) and the World Allergy Organization (WAO).

Blumenthal and colleagues used mediation analysis to estimate the impact of a new penicillin allergy documentation by a general physician on the use of alternative antibiotics and risk of MRSA and C. difficile over 6 years of patient follow-up.

“We found that over a quarter to half of the risk of new infection was attributable to the alternative antibiotics,” Blumenthal told MedPage Today, adding that the study is the first to show a link between new-onset use of antibiotics and a first documentation of MRSA or C. difficile.

Since the patients did not undergo formal testing to confirm their penicillin allergy, many may have needlessly been taking the alternative antibiotics, she said.

Asked for his perspective, David Lang, MD, chairman of the Department of Allergy and Clinical Immunology and director of the Allergy/Immunology Fellowship Training Program at the Cleveland Clinic, who was not involved with the study, told MedPage Today that there is growing evidence that patient over-reporting of penicillin allergy has very real clinical consequences.

While approximately one in 10 people self-report having a penicillin allergy, studies suggest that only perhaps one in 20 actually have a clinically confirmable intolerance to the drug, he said. “As many as 19 in 20 people avoiding penicillin are doing so needlessly. These people are given alternative antibiotics that are more costly, have more side effects, and predispose them to untoward outcomes.”

Lang said the newly reported research provides further evidence that a label of penicillin allergy is not clinically benign: “A large focus of the antibiotic stewardship initiative is to limit the use of these broad-spectrum antibiotics when we can. It is clear that the low-hanging fruit of antibiotic stewardship is de-labeling these people who believe they have penicillin allergy, but don’t.”

For the study, Blumenthal and colleagues used a general practice database in the United Kingdom with patient data spanning 1995 through 2015, and studied a matched cohort of adults without prior MRSA or C. difficile.

Patients with incident penicillin allergy, as reported in their medical records, were matched with up to five penicillin users without allergy by age, sex, and index date.

The researchers calculated relative risks (RRs) for the association of penicillin allergy with incident MRSA and C. difficile, adjusting for potential confounders, and also examined beta-lactam alternative antibiotic use to determine whether it was a mediator for MRSA/C. difficile incidence.

Over a mean follow-up of 6 years, among 64,141 penicillin allergy patients and 237,258 matched comparators, 1,345 developed MRSA and 1,688 developed C. difficile.

Among the main study findings:

  • The adjusted RRs among penicillin allergy patients were 1.62 (95% CI, 1.42-1.85) for MRSA and 1.27 (95% CI, 1.13-1.43) for C. difficile
  • The adjusted RRs for antibiotic use among penicillin allergy patients were 4.08 (95% CI, 4.05-4.10) for macrolides, 3.73 (95% CI, 3.51-3.97) for clindamycin, and 2.13 (95% CI, 2.10- 2.16) for fluoroquinolones
  • Increased beta-lactam alternative antibiotic use accounted for 53% of the increased MRSA risk and 25% of the increased C. difficile risk

“The message from this research and other research to general practitioners, medical specialists, and surgeons is that when they see a patient with a label of penicillin allergy, send them to us to confirm or disprove this label,” Lang said. “Nine out of 10 — or even 19 of 20 — times we will be able to reduce the patient’s risk for bad outcomes by removing this label.”

For Superbugs, Fight Fire With Fire: Non-Toxic C. Diff Bacteria Ward Off Antibiotic-Resistant Strain

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If you haven’t heard of Clostridium difficile, better known as C. difficile or C. Diff, you will soon. It’s one of the fastest growing superbugs, rivaling MRSA in both frequency and severity. Due to antibiotic resistance, a cure for C. difficile  has been elusive, but a recent study suggests that we’ve been looking in the wrong places and the only thing strong enough to fight off C. difficileis actually more C. difficile.

bacteria culture

According to a report published in the Journal of the American Medical Association, trials on 173 individuals with C. difficile infections showed that introducing a non-toxigenic C. difficile strain helped to dramatically cut the odds of repeat infections and is a promising start to finally getting an upper hand on this potentially fatal superbug.

In the study, conducted by researchers at Loyola University Health System in Illinois, patients with C. difficile infections were given spores of a non-toxin producing strain of C. difficile. Around 69 percent of the time the “friendlier” strain was able to occupy areas in the gut where the toxic C. difficile strain normally thrived. This inhibited the severe C. difficile from returning and only one in 50 of the patients experienced a recurrent C. difficile infection.

The research is still in its earliest stages, but the researchers are excited about the results. Although the patient remains infected with C. difficile, more importantly, the symptoms cease. The eventual goal of the research is to develop a treatment involving the digestion of “friendly” C. difficile spores to indefinitely prevent a patient once again falling ill from the infection.

“What we’re doing is establishing competition with the original, toxic strain,” Dr. Dale Gerding, one of the researchers involved in the study explained, as reported by the BBC. “I’m excited about this and looking forward to a phase-three [larger] trial. We think it’ll go a long way to reduce C. diff recurrence.”

C. difficile infections are almost exclusive to hospital settings, clinics, nursing homes and other health care facilities. The reason for this is that the bacteria take hold in individuals whose normal fauna of bacteria is disrupted due to antibiotic courses. Without the normal healthy bacteria standing in the way, the drug-resistant C. difficile can take hold and cause inflammation in the patient’s colon. According to the Centers for Disease Control and Prevention, C. difficile infections are widespread and each year it’s linked to about 29,000 deaths in the United States.

Symptoms of C. difficile infections include frequent diarrhea, fever, loss of appetite, nausea, and abdominal pain and tenderness. These infections are commonly treated with antibiotics, but due to the bacteria’s evolved resistance to treatment the infection returns in around 20 percent of cases. Currently fecal transplants are the most effective way to treat repeat C. difficile infections, but the recent study suggests an equally effective and far less invasive approach to the condition.