Clostridiodes Difficile (C. difficile) Infection

Previously known as Clostridium difficile, Clostridioides difficile (C. difficile) is a bacterium that produces toxins leading to diarrhea and inflammation of the colon. 

While C. difficile was once considered an infection contracted in healthcare settings, such as hospitals and long-term care facilities, it’s increasingly being diagnosed in community settings. This is primarily due to the emergence of a new strain, known as North American pulsed-field gel electrophoresis type 1 (or NAP1), which is more infectious and resistant to fluoroquinolone antibiotics. The arrival of this new strain has led to an increase in both frequency and severity of C. difficile infections over the past 20 years.

What causes C. difficile infections?

C. difficile is a spore-forming bacterium. This means it can survive on surfaces for an extended period. Since C. difficile bacteria and spores are found in feces, people who touch contaminated surfaces and then touch their mouths are at risk of contracting an infection. Once C. difficile is able to proliferate in the colon, it produces toxins that are key factors in the development of colon inflammation (colitis) and diarrhea.

Who is at risk of C. difficile infections?

People who have taken broad-spectrum antibiotics, such as penicillins, cephalosporins, fluoroquinolones, and clindamycin, are at an increased risk of developing a C. difficile infection. This happens because antibiotics disrupt the balance of the gut microbiota (the community of trillions of microorganisms living in the gut). When a person takes antibiotics, beneficial bacteria that were previously preventing C. difficile from growing may be killed. This opens the door for C. difficile to proliferate, leading to infection.

Other risk factors for developing a C. difficile infection include:                                  

• Taking proton pump inhibitors (PPIs, used to treat conditions like acid reflux).
• Having a suppressed immune system (such as people undergoing cancer chemotherapy).
• Having other underlying medical conditions.
• Have had a C. difficile infection in the past.
• Kidney or liver failure.
• Recent or prolonged hospital stays.
• People who work in healthcare settings.
• Elderly people.

What is recurrent C. difficile infection?

While most people who receive treatment for C. diff get better, about 25% of people develop a relapse and return of symptoms within 2 months. This is known as recurrent C. difficile infection(recurrent C. diff). The risk of recurrent C. diff increases with each subsequent infection, and over 50% of people who have had three infections will experience another recurrent infection. The risk of recurrent C. diff remains elevated until the patient’s intestinal microbiota is recovered.

Symptoms of C. difficile can vary. Some people are asymptomatic carriers, meaning the bacteria or spores are present in their colon but do not cause any symptoms. 

Some of the most common symptoms associated with a symptomatic C. difficile infection include:

• Watery diarrhea, sometimes with mucus or blood in it
• Loss of appetite
• Nausea
• Vomiting
• Mild fever
• Abdominal pain
• Abdominal distention
• Hypovolemia (when your body doesn’t have enough blood or fluid, which can lead to low blood pressure and not enough oxygen getting to your organs)

Some people also experience non-GI symptoms such as reactive arthritis.

Risks of untreated C. difficile

Untreated C. difficile infections can cause significant damage to the colon, resulting in:

• Toxic megacolon (a rare but life-threatening condition where the colon becomes extremely swollen and inflamed).
• Bowel perforation with peritonitis (an infection in the lining of your abdomen).
• Sepsis (which can lead to organ failure and even death).

Tests

If a person experiences three or more episodes of diarrhea within 24 hours, especially if they’ve recently been in the hospital or have used antibiotics, C. difficile should be considered. However, diagnosing a C. difficile infection isn’t always straightforward, and no single test gives a full clinical picture. For this reason, doctors typically use a two-step approach to confirm the diagnosis.

How is C. difficile diagnosed?

Here are some of the most common tests used to diagnose a C. difficile infection:

Glutamate dehydrogenase (GDH) test

This test detects a protein called glutamate dehydrogenase, which is produced by all C. difficile bacteria. It helps detect whether C. difficile is present in the stool. However, it doesn’t tell us if the bacteria are producing the toxins that cause symptoms.

Nucleic acid amplification tests (NAATs)

NAATs (like PCR tests) look for the genes that allow C. difficile bacteria to produce toxins. While they’re very sensitive and accurate in detecting the bacteria, they do not confirm whether the presence of the genes leads to toxin production. If either the GDH or NAAT test is negative, it usually means that C. difficile isn’t the cause of the symptoms, and other causes should be investigated.

Toxin enzyme immunoassays (EIAs)

This test detects toxins A and B, which are the substances produced by C. difficile that cause symptoms. This test confirms whether the C. difficile in your body is producing toxins. A positive GDH or NAAT result needs to be followed up with a confirmatory test, such as an EIA, to verify an active infection.

Toxigenic culture and cell culture tests

These tests grow C. difficile bacteria in a laboratory from a stool sample and assess whether they can produce toxins. While it’s a very accurate way to identify the presence of C. difficile (and whether it’s producing toxins), it takes several days to get results and isn’t used in most urgent cases.

Imaging and endoscopy

If doctors suspect the infection is severe (such as causing colitis or toxic megacolon), they may order abdominal X-rays or CT scans to assess for swelling or intestinal damage. They may also use lower GI endoscopy, such as a colonoscopy, to see the inside of your colon directly.

Overall, most experts recommend using two types of tests to assess for a C. difficile infection: one to test for the presence of the bacteria (such as a GDH or NAAT test), and another to confirm whether it’s producing harmful toxins (such as an EIA). This approach provides the most accurate diagnosis and can help guide proper treatment.

Treatments

How is C. difficile treated?

The main treatment for C. difficile infection is antibiotics. However, in the case of recurrent C. diff, fecal microbiota transplant (FMT) may be used. If a person tests positive for C. difficile but doesn’t have any symptoms, they don’t require treatment.

Antibiotic therapy

Two main antibiotics are now considered first-line treatments for C. difficile infection. Fidaxomicin is the first choice, but vancomycin is a suitable alternative if fidaxomicin is unavailable. While metronidazole was previously used to treat C. difficile, it’s associated with an increasing failure rate (i.e., it doesn’t effectively treat the infection), so it’s now only recommended if the other antibiotics aren’t an option.

Microbiome restoration therapy

Restoring the gut microbiota is essential for preventing recurrent C. difficile infections. These therapies aim to restore the gut microbiota to its original state, ensuring that there are sufficient “good” bacteria to outcompete “bad” bacteria, such as C. difficile. There are two main ways of restoring the gut microbiota:

• Fecal microbiota transplant (FMT): FMT is a treatment in which healthy bacteria from a donor’s stool are transferred to the gut of a person with C. difficile. The goal is to restore a healthy balance of bacteria in the gut, thereby crowding out harmful bacteria like C. difficile. It’s usually done using an enema (but sometimes also given in a capsule or colonoscopy), which inserts the healthy bacteria directly through the anal canal and into the rectum. While FMT has been studied in clinical trials (particularly in people who also have underlying inflammatory bowel disease), Health Canada considers it to be an investigational drug (meaning that it’s still being studied and hasn’t yet been approved by health authorities for general use). However, there is an interim policy that allows for the use of FMT patients with recurrent C. diff who have not responded to antibiotic therapy.
• Fecal microbiota, live (^PrRebyota®): Rebyota was approved by Health Canada in March 2025 for the prevention of recurrence of C. diff in adults following antibiotic treatment for recurrent C. difficile infection. It contains live, healthy bacteria from human stool and is administered as a single-dose enema to help restore gut microbiota balance and prevent C. difficile from recurring.

A person is considered recovered from their C. difficile infection if their stools return to normal for at least 48 hours after finishing treatment. If symptoms come back within 8 weeks, it’s considered a recurrence.  

• C. difficile is ubiquitous (meaning that it’s found everywhere) and is found in the large intestines of 3% to 5% of healthy people without causing symptoms.
• C. difficile is the leading cause of infectious diarrhea in hospitals and long-term care homes in Canada. 
• C. difficile is responsible for approximately 15% to 20% of cases of antibiotic-associated diarrhea.
• There were approximately 37,932 C. difficile infections in Canada in 2012. Of these, 20,002 were in hospitals, 16,326 were in the community, and 1,604 were in long-term care facilities. Quebec had the most infections (16,562), followed by Ontario (9,962), British Columbia (5,168), and Alberta (3,659).
• It’s estimated that the economic burden of C. difficile infections in Canada in 2012 surpassed CAD $280 million. Extended hospital stays and rehospitalizations made up 92% of this figure.
• There’s an estimated 1.4 to 2.75-fold increased risk of C. difficile infections after using proton pump inhibitors (PPIs).
• The NAP1 strain of C. difficile is associated with significantly higher mortality rates compared with non-NAP1 strains.
• The rate of healthcare-associated C. difficile infection in Canada decreased from 5.9 to 4.3 per 10,000 patient days between 2009 and 2015.

Is C. difficile contagious?

C. difficile is spread through the fecal-oral route. If a person touches a surface contaminated with feces that contain C. difficile bacteria or spores and then touches their mouth, they may contract a C. difficile infection.

Can C. difficile come back after treatment?

Yes, in approximately 25% of cases, C. difficile recurs after treatment. This is known as a recurrent C. difficile infection (recurrent C. diff). After a person has had three or more CDIs, the risk of having the infection recur again increases to over 50%.

Why do antibiotics increase the risk of C. difficile infection?

Using antibiotics (especially broad-spectrum antibiotics that target a wide range of bacteria) in high doses or over a long time period increases the chance of developing a C. difficile infection because antibiotics can cause dysbiosis (an imbalance of bacteria in the gut). When our gut has fewer “good” bacteria, C. difficile bacteria are able to proliferate and produce toxins that can damage the gut, causing diarrhea.

What makes C. difficile infections so difficult to treat?

C. difficile is a spore-forming bacterium. Spores are tough, protective “shells” that the bacteria create to survive harsh conditions, such as stomach acid or antibiotics. They can remain dormant for a long time, becoming active only when the conditions are suitable for growth. C. difficile spores are resistant to stomach acid and can pass through to the large intestine. Once they reach the large intestine, they either remain as spores or grow into vegetative forms (bacteria). While a healthy gut microbiota usually prevents C. difficile from proliferating, disruptions to the normal gut microbiota (such as following broad-spectrum antibiotic therapy) may lead to overgrowth of C. difficile.

Can probiotics help prevent C. difficile infections?

While research into the role of probiotics in preventing C. difficile infections is emerging, the Association of Medical Microbiology and Infectious Disease (AAMI) Canada guidelines state that “at this time, there is insufficient evidence to support the use of probiotics for primary prevention of C. difficile infection.”