Clostridium difficile

Clostridium (now Clostridioides) difficile infection is one of the most well-recognised hospital-acquired infections.

C. difficile (CD) is a gram-positive bacillus (rod-shaped), which is both spore-forming and toxin-producing. It is found in < 2% of healthy adults as a commensal organism within the bowel. This increases to 7% in patients within long-term care facilities and 3-26% among inpatient populations.

There are two important strains of C. difficile:

• Toxigenic (70-90%): produce and release two exotoxins (A & B). Central to pathogenicity.
• Nontoxigenic (10-30%): cannot produce exotoxins. Colonises colon without causing disease.

C. difficile infection (CDI) is an important hospital-acquired (nosocomial) infection that is responsible for 20-30% of antibiotic-associated colitis. Luckily, cases of CDI have been falling within the UK through better recognition, infection control and antibiotic stewardship.

C. difficile is a highly infectious organism that is spread via the faecal-oral route.

CD can release spores from asymptomatic or symptomatic carriers into the environment. These spores are highly resistant to acid, heat and antibiotics. After ingestion, they convert to their fully functioning state within the host intestines. 

Antibiotics are central to the pathogenesis of most CDIs. Antibiotics disrupt the normal colonic microbiota, which allows toxigenic strains of CD to multiply and release toxins. These damage colonocytes and causes colitis. In addition, more virulent strains of CD are resistant to certain antibiotics (clindamycin, fluoroquinolones), which provides a survival advantage. 

Toxins

The two principle exotoxins are ‘A’ and ‘B’. Both toxins promote colonic inflammation, intestinal fluid secretion, mucosal injury, neutrophil chemotaxis and activation. Toxin B has approximately 10x the virulence of toxin A. 

Use of antibiotics is a major risk factor for the development of CDI.

• Antibiotic use: most occur within two weeks of antibiotics
• Age: ≥65 years old significantly increases risk
• Hospitalisation
• Severe underlying co-morbidities
• Others: gastric acid suppression (i.e. PPI use), enteral feeding, obesity, GI surgery and chemotherapy.

Antibiotics

Although any antibiotic can be associated with CDI, some pose a much higher risk. These include fluoroquinolones, clindamycin, and broad-spectrum penicillins and cephalosporins.  

Other factors that increase the risk of CDI include use of multiple antibiotics or prolonged duration of antibiotics. These factors are important to address during antibiotic stewardship (see below). 

The principle symptom associated with CDI is diarrhoea.

Diarrhoea is defined as the passage ≥3 loose bowel motions within 24 hours. Other features of CDI include abdominal pain, anorexia, nausea and fever. Diarrhoea is classically watery, but a small amount of blood may be seen. Overt bleeding is rare. 

Patients with more severe disease may have evidence of haemodynamic instability (tachycardia and hypotension) and severe systemic symptoms (low GCS, poor urine output, peritonitis). 

Severity

CDI should be graded according to the severity of the colitis, which is based on clinical features, biochemical tests and imaging (if indicated – severe disease).

1. Mild: diarrhoea without systemic features. Typically ≤ 3 bowel motions. WCC normal
2. Moderate: 3-5 bowel motions per day. Raised WCC but < 15 x10⁹/L
3. Severe: WCC > 15 x10⁹/L, rising creatinine (e.g. >133 umol/L), fevers > 38.5º, evidence severe colitis (abdominal or radiographic signs), bowel motions less reliable.
4. Fulminant: hypotension and shock, partial or complete ileus, toxic mega colon, CT evidence of severe disease.

CDI is suspected clinically by the presence of an acute diarrhoeal illness and confirmed with stool testing.

To confirm CDI, stool testing is required to demonstrate CD toxin(s) or the toxigenic strain of CD. The main tests include nucleic acid amplification testing (NAAT) and enzyme immunoassay (EIA). 

• NAAT (PCR-based testing): detects one or more genes specific to the toxigenic strain.
• EIA (C. difficile enzyme glutamate dehydrogenase): detects enzyme produced by all strains. Good sensitivity, quick. Unable to distinguish between toxigenic and nontoxigenic strains. 
• EIA (C. difficile toxin A & B): detects toxin produced by toxigenic strains. Most produce both toxins, some only B. Testing both increases sensitivity. High false-negative rate. Inexpensive, quick. 

The main issue with NAAT testing is the inability to distinguish between asymptomatic carriage of a toxigenic strain and active CDI without a positive EIA test. Therefore, an isolated positive NAAT test should always be interpreted with the clinical context. 

Depending on resources available locally, there are a number of different testing algorithms that can be employed. Always check local guidelines.

Investigations are important to determine both severity and complications associated with CDI.

Bedside tests

• Observations
• Stool samples: CD testing, MC&S, OCP, virology
• Blood glucose

Bloods

• Full blood count
• Urea & electrolytes
• Liver function tests
• Bone profile
• Lipase
• Blood cultures
• Venous blood gas (lactate)

Imaging

• Plain film abdominal radiograph: assessment for mucosal wall thickening and bowel dilatation
• CT abdomen and pelvis: indicated for clinical manifestations of severe disease, fulminant colitis or suspected complications

Special

• Endoscopy (flexible sigmoidoscopy): avoided if typical clinical presentation, confirmed CDI on stool testing and/or response to treatment. Required if alternative diagnosis suspected. Increased risk of perforation. 

NOTE: endoscopic examination may reveal the classical pseudomembranous colitis associated with CDI. This appears as numerous yellow plaques scattered over the mucosa due to toxin-induced ulcer formation that promotes inflammation. 

Antimicrobial agents and excellent infection control measures are essential in every case.

Acute management

Managing acute CDI depends on severity, allergy status and underlying co-morbidities. Patients require daily review. Any patient with fulminant colitis or a worsening condition should be discussed urgently with colorectal surgery and critical care as appropriate. 

• All patients: correct fluid losses, VTE prophylaxis, nutritional support, stop laxatives, stop antibiotics unless necessary, review need for PPI, stop anti-motility drugs (codeine/loperamide) and consider other causes of diarrhoea.
• Mild to Moderate: oral metronidazole 400 mg TDS for 10-14 days or oral vancomycin 125-250 mg QDS for 10 days.
• Severe: oral vancomycin 125-250 mg QDS for 10-14 days or fidaxomicin if high-risk of recurrence 200 mg BD for 10 days. Consider switching to fidaxomicin or adding metronidazole 500 mg IV TDS if worsening or no improvement at 7 days. 
• Fulminant: oral vancomycin 500 mg QDS and metronidazole 500 mg IV TDS. Systemic vancomycin with monitoring if ileus. Urgent surgical and critical care review.

NOTE: vancomycin given orally does not require monitoring as it is not systemically absorbed. 

Additional agents that can be considered in certain cases include rifaximin and intravenous immunoglobulins (IVIG). Generally treatment is continued for 10-14 days. If improving, but ongoing diarrhoea, treatment should continue until resolution. If no improvement, consider endoscopy to exclude an alternative diagnosis. Do not ‘test for cure’ with repeat stool samples.

Infection control

Key infection control measures include early detection and isolation with contact precautions. Patients should be cared for in a side-room and have barrier nursing with enteric precautions. Excellent hand hygiene with soap and water is essential. Soap and water is preferred to alcohol-based gels for removing spores. This is because spores are resistant to killing by alcohol.

Other important measures include an allocated private toilet, cohorting patients with the same infection and environmental decontamination. 

Antibiotic stewardship

Antibiotic stewardship describes the process of providing recommendations for the safe and effective use of antibiotics. This helps prevent antibiotic resistance, thereby preserving future effectiveness, and reduces antibiotic-associated complications.

Faecal microbiota transplantation (FMT) may be indicated in patients with refractory or recurrent CDI.

FMT refers to the process of transferring a solution of faecal matter containing bacteria from a highly selected donor into the intestinal tract of a receipt. The aim is to change the composition of the receipts intestinal microbiota for health benefit.

FMT is currently recommended in the treatment of recurrent or refractory CDI.

• Refractory CDI: no response to conventional therapy
• Recurrent CDI: a relapse of CDI symptoms within 2-8 weeks of successful treatment (10-35%)

Fulminant colitis is characterised by hypotension, ileus and/or toxic mega colon.

Fulminant colitis may lead to multi-organ failure from profound shock or bowel perforation. Some cases may present with ileus, but the most concerning complication is toxic mega colon (TMC).

TMC is defined as marked colonic dilatation (> 6 cm) and may be complicated by bowel perforation and haemodynamic collapse. Patients with any feature of fulminant colitis, require urgent surgical review for consideration of colectomy.