- Clinical science
Clostridioides difficile (C. difficile; formerly known as Clostridium difficile) is a gram-positive bacillus that may cause antibiotic-associated diarrhea. Rates of C. difficile infection are particularly high among hospitalized patients and residents in long-term care facilities because C. difficile spores are easily transmitted (fecal-oral route) and difficult to eradicate. The bacterium is resistant to multiple antibiotics, so colonization with C. difficile most commonly occurs following antibiotic treatment of other diseases. The resulting damage to the intestinal flora promotes infection, which may be accompanied by high fever, abdominal pain, and foul-smelling diarrhea. The most severe form of C. difficile infection is pseudomembranous colitis, which can lead to ileus, sepsis, and toxic megacolon. In most cases, however, colonization results in asymptomatic carriage. Diagnosis is usually made via detection of the C. difficile toxin, C. difficile glutamate dehydrogenase antigen, and/or corresponding genes in stool samples. C. difficile infection is treated with oral vancomycin or oral fidaxomicin. Following diagnosis, strict adherence to hygiene measures and patient isolation is essential, especially in hospitals and other healthcare settings.
- ∼ 220,000 cases in hospitalized patients and ∼ 13,000 deaths per year in the US 
- Individuals > 65 years old are at increased risk for the hospital-acquired infection. 
- Patients affected by community-acquired infections are typically younger (average age 50 years). 
Epidemiological data refers to the US, unless otherwise specified.
Pathogen: Clostridioides difficile 
- Gram-positive bacillus, obligate anaerobe
- Can be toxigenic or non-toxigenic; must be toxigenic to cause the disease
- Forms environmentally-resistant spores (capable of withstanding heat and acid)
- Highly contagious
- Present ubiquitously
- Oral route of transmission (fecal-oral in community-acquired cases; via contaminated surfaces and medical equipment in hospital-acquired cases)
- Antibiotic treatment 
- Other risk factors 
The C. difficile strain must be toxigenic to cause the disease. Intestinal colonization by nontoxigenic strains will result in asymptomatic carriage.
C. difficile possesses a range of virulence factors, the most important of which are toxins A and B. 
Toxin A (enterotoxin)
- Active site at N-terminal domain
- Central hydrophobic domain
- Binding site at C-terminal domain
- Mechanism of action: binding to brush border of enterocytes: → receptor-mediated endocytosis → change of conformation → exposure of active domain → glycosylation of target proteins (e.g., Rac, Cdc42, RhoA) → disruption of actin cytoskeleton functioning → increase in epithelial permeability and apoptosis → diarrhea
Toxin B (cytotoxin)
- Mechanism of action: same as in toxin A, but can also cause pore formation within the endosomal membrane via insertion of the translocation domain → release of endosomal content into the cytosol → cytopathic effect
Symptoms of C. difficile-associated diarrhea (CDAD) usually develop during antibiotic treatment or 2–10 days following its initiation; however, 25–40% of cases manifest as late as 10 weeks following treatment.
- Watery diarrhea, characteristically foul-smelling
- Cramping abdominal pain, nausea, anorexia
- Fever and dehydration (especially in severe cases)
- Fulminant colitis: abdominal distention and severe hypovolemia
- Recurrent disease: symptom reoccurrence 2–8 weeks following the end of treatment
Clostridioides difficile Causes Difficult Diarrhea.
Patient history and clinical presentation are strong indicators for diagnosis of infection, which is then confirmed by identification of the pathogen's genes or corresponding toxins in the stool. Further diagnostics, such as blood tests or imaging, may be used to assess the severity of disease and/or the presence of complications.
- Treatment with antibiotics in the last three months
- Recent hospitalization
Stool tests 
- Children < 12 months old: if pseudomembranous colitis or toxic megacolon is suspected or if there is clinically significant diarrhea that cannot be explained by other causes
- Children 1–2 years old: if all other infectious and noninfectious causes have been ruled out
- Children ≥ 2 years old: if there is prolonged or worsening diarrhea in children with risk factors (e.g., inflammatory bowel disease, immunocompromising conditions) or relevant exposures (e.g., recent antibiotic treatment, contact with the healthcare system)
- Adults: unexplained, new-onset, loose stool ≥ 3 times in 24 hours
- Confirmatory tests of choice
- Other tests: bacterial culture of C. difficile
- Elevated serum creatinine (possible kidney injury caused by dehydration) 
- Lowered serum albumin 
- Electrolyte imbalance, particularly hypokalemia (caused by severe diarrhea)
- Elevated lactate levels 
- Evidence of pseudomembranous colitis
- Not indicated if C. difficile is suspected based on clinical findings, laboratory tests, and/or response to empiric treatment
- Perform cautiously (increased risk of perforation).
Disease severity 
- Nonsevere: leukocytosis < 15,000/mm3 and serum creatinine < 1.5 of baseline
- Severe: leukocytosis ≥ 15,000/mm3 OR serum creatinine ≥ 1.5 of baseline
- Fulminant: decreased blood pressure, shock, ileus or toxic megacolon
General measures 
- Discontinue the precipitating antibiotic.
- Fluid replacement
- Infection prevention and control: See “Prevention” below.
- Avoid antidiarrheals (e.g., loperamide).
Medical therapy 
If clinical suspicion for CDAD is high, empiric antibiotic treatment may be initiated before laboratory confirmation of C. difficile. 
- Nonsevere cases
- Severe cases
- Fulminant cases
C. difficile infection is one of the rare indications for oral administration of vancomycin!
Medical therapy in children 
- Initial episode
Fecal microbiota transplantation (FMT) 
- Indication: recurrent C. difficile infections in a patient who has not responded to at least two appropriate antibiotic regimens
- Implementation: Sterile normal saline solution is added to donor stool and the mixture is blended to a smooth, liquid consistency.
- Nasogastric or jejunal tube
- Detection: C. difficile toxin stool test for at-risk patients with recent onset of diarrhea
- Single-bed room with designated bathroom facilities (up to 2 days after symptoms subside)
- Cohort isolation is possible if control measures are implemented.
- Personal protective equipment: Wear gloves and a protective gown (change after each patient); a mask is not necessary.
- Hand hygiene: Wash thoroughly with soap and water (C. difficile spores are resistant to alcoholic disinfectants).
- Consistent disinfection of potentially contaminated surfaces with sporicidal oxidants such as peracetic acid or sodium hypochlorite; ; autoclaving is also sporicidal and can be used to sterilize equipment.