Clostridioides difficile Colitis: Diagnosis and Management

Introduction

Clostridioides difficile (formerly Clostridium difficile) is a Gram-positive, spore-forming, anaerobic bacillus and the leading cause of healthcare-associated infectious diarrhoea in the developed world.¹ It causes a spectrum of illness from mild self-limiting diarrhoea through pseudomembranous colitis to life-threatening fulminant colitis with toxic megacolon.

It is a major target of infection prevention and antimicrobial stewardship programmes, and rates in the UK fell substantially following national initiatives around antibiotic prescribing and hospital hygiene, though it remains an important cause of morbidity and mortality in older, hospitalised patients.

Pathophysiology and risk factors

The colon's normal bacterial flora provides colonisation resistance, preventing pathogenic overgrowth. Antibiotics disrupt this flora, allowing ingested C. difficile spores - which are highly resistant to heat, acid and alcohol-based hand gels - to germinate and proliferate.¹

Pathogenic strains produce two exotoxins: toxin A (an enterotoxin causing fluid secretion and mucosal inflammation) and toxin B (a more potent cytotoxin causing cytoskeletal disruption and cell death). Together they produce mucosal inflammation, ulceration and the yellowish adherent plaques of fibrin, mucus and inflammatory debris known as pseudomembranes. The hypervirulent ribotype 027 (NAP1/BI) strain produces additional binary toxin and is associated with more severe disease and higher relapse rates.

Risk factors

• Antibiotic exposure - the dominant risk factor. Remember the 4 Cs: clindamycin, co-amoxiclav, cephalosporins and ciprofloxacin (and other fluoroquinolones). Risk persists for up to 3 months after a course
• Age over 65
• Hospitalisation or residence in a care home, and prolonged length of stay
• Proton pump inhibitors and other acid-suppressing drugs
• Immunosuppression, chemotherapy and serious comorbidity
• Previous C. difficile infection - the strongest predictor of a further episode
• Gastrointestinal surgery, nasogastric feeding and inflammatory bowel disease

Clinical features

The typical presentation is watery, offensive-smelling diarrhoea beginning during a course of antibiotics or within several weeks of finishing one. Associated features include:

• Crampy lower abdominal pain and tenderness
• Fever and general malaise
• Nausea and anorexia
• A markedly raised white cell count, which can be strikingly high and may precede the diarrhoea
• Dehydration and electrolyte disturbance
• Blood is usually absent or only present in small amounts, distinguishing it from many invasive bacterial causes

Severity ranges widely. Some patients have only mild diarrhoea, while others develop fulminant colitis with severe abdominal pain, distension, systemic toxicity and haemodynamic instability. Paradoxically, diarrhoea may cease as ileus and toxic megacolon develop, which can falsely reassure - worsening abdominal distension and systemic upset in a patient whose diarrhoea has suddenly stopped is an ominous sign.

Investigations

Stool testing

Testing is performed on diarrhoeal (unformed) stool only, since formed stool from an asymptomatic carrier will give a positive result without indicating disease. UK practice uses a two-stage testing algorithm.²

Other investigations

• Full blood count: white cell count is a key severity marker and can exceed 25 × 10⁹/L in severe disease
• Urea, electrolytes and creatinine: for acute kidney injury and dehydration
• Albumin, CRP and lactate: low albumin and raised lactate indicate severe disease
• Abdominal X-ray: for colonic dilatation, mucosal thumbprinting or evidence of toxic megacolon
• CT abdomen: in severe or complicated disease, showing colonic wall thickening, the accordion sign and pericolonic stranding, and identifying perforation
• Flexible sigmoidoscopy: not routine and carries perforation risk in severe colitis, but may show pseudomembranes where the diagnosis is uncertain

Severity assessment

Severity determines the treatment setting and intensity, and should be reassessed daily.³

Management

General measures

• Stop the precipitating antibiotic wherever clinically possible, or switch to a lower-risk agent
• Review and stop proton pump inhibitors and other non-essential acid suppression
• Avoid antimotility agents such as loperamide, and opioids - these retain toxin and increase the risk of toxic megacolon
• Fluid and electrolyte replacement, with nutritional support as needed
• Isolate the patient in a side room with enteric precautions. Use soap and water for hand hygiene, as alcohol gel does not kill spores, and clean the environment with a chlorine-based disinfectant

Antibiotic treatment

Vancomycin is given orally because it is not absorbed from the gut, delivering high luminal concentrations exactly where the infection is; intravenous vancomycin is ineffective for C. difficile colitis. Conversely, metronidazole is well absorbed and reaches the colon via biliary and inflammatory exudate, which is why the intravenous route is used when ileus prevents oral drug reaching the colon. Metronidazole is no longer first-line, having been shown to be less effective than vancomycin.³

Recurrent infection

Around 20-25% of patients relapse after a first episode, and the risk rises with each subsequent recurrence. Faecal microbiota transplantation (FMT) - instillation of processed stool from a screened healthy donor - restores colonisation resistance and is recommended by NICE for patients who have had two or more previous episodes, with cure rates around 90%.⁴ Bezlotoxumab, a monoclonal antibody against toxin B, is an alternative adjunct for reducing recurrence in selected high-risk patients.

Surgery

Urgent surgical review is needed for fulminant colitis, toxic megacolon, perforation, or deterioration despite maximal medical therapy. Subtotal colectomy with end ileostomy is the usual procedure and can be life-saving, though it carries high mortality in this frail population, so early rather than delayed involvement of the surgical team is important.

Complications

• Pseudomembranous colitis
• Toxic megacolon: colonic dilatation over 6 cm with systemic toxicity, risking perforation
• Bowel perforation and faecal peritonitis, carrying very high mortality
• Paralytic ileus, which may cause diarrhoea to cease deceptively
• Severe dehydration, acute kidney injury and electrolyte disturbance
• Hypoalbuminaemia from a protein-losing enteropathy, with oedema
• Sepsis and multi-organ failure
• Recurrent infection, affecting a quarter of patients after a first episode
• Post-infectious irritable bowel syndrome

Red flags

Prognosis

Most patients with mild to moderate infection respond well to stopping the precipitating antibiotic and a course of oral vancomycin, with symptoms improving over several days.³ Recurrence is the principal problem, affecting around a quarter of patients after a first episode and a higher proportion after each subsequent one - which is the rationale for fidaxomicin and, in repeated relapses, faecal microbiota transplantation.

Severe and fulminant disease carries substantial mortality, particularly in elderly patients with significant comorbidity, and mortality after emergency colectomy for fulminant colitis is high. Because the dominant risk factor is modifiable, prevention through antimicrobial stewardship, judicious use of proton pump inhibitors, isolation and rigorous environmental cleaning remains the most effective way to improve outcomes at a population level.