Clostridium difficile and PMC

OVERVIEW

• Clostridium difficile enterocolitis and pseudomembranous colitis (PMC)
• acute inflammatory disease of colon commonly associated with antibiotic use
• C. difficile implicated as a causative organism in 1970’s

PATHOPHYSIOLOGY

Mechanism

• antibiotic exposure -> overgrowth of C. difficile -> increased toxin production -> mucosal damage -> inflammation and necrosis
• rarely other organisms have been implicated: Staph aureus, Salmonella, Clostridium perfringens, Yersinia, Shigella, Campylobacter, CMV, Entamoeba, Listeria

Complications related to diarrhoea

• Hypovolaemia
• Electrolyte disturbance: hypokalaemia, hypomagnesaemia

Complications related to intestinal infection

• Sepsis and septic shock
• Perforation
• Toxic megacolon
• Bleeding

CLINICAL FEATURES

• diarrhoea 3-9 days post initiation of antibiotics
• may start weeks after discontinuation of antibiotics
• loose stools -> toxic megacolon and colonic perforation

• profuse, watery/mucoid, foul-smelling stool
• may contain blood and pseudomembranes
• fever
• rarely: oligoarthritis and iridocyclitis

RISK FACTORS

Antibiotic exposure – any antimicrobial can incite disease

• Likely – beta-lactams, clindamycin
• Uncommon – quinolones, aztreonam, imipenem, metronidazole
• Rare – vancomycin, erythromycin, tetracycline, gentamicin

Other

• age >65y
• previous GI surgery
• renal impairment
• prolonged hospitalisation
• gastric acid suppression
• renal failure
• immunocompromised and chemotherapy patients

INVESTIGATIONS

General

• leucocytosis
• low albumin
• AXR: mucosal oedema, thumb-printing
• CT: distension, diffuse and focal thickening of colonic wall

Specific

• faecal leucocytosis
• stool cultures
• stool assay for C. difficile toxins (takes 2 days)
• ELISA for toxin A and B (takes 2 hours)
• PCR (false positives are problematic)
• mucosal assessment: proctosigmoidoscopy, flexible sigmoidoscopy, colonoscopy

MARKERS OF SEVERITY

Clinical

• fever T>38
• peritonism
• ileus
• hemodynamic instability

Investigations

• WBC >15 and <20% neutrophils
• elevated lactate
• 50% increase in baseline creatinine
• albumin <25
• megacolon on imaging

MANAGEMENT

Resuscitation

• fluid therapy
• extreme hypovolaemia and septic shock requiring fluid resuscitation and inotropes

Correct metabolic disturbance

• metabolic acidosis from diarrhoea + lactate
• hyponatraemia
• hypochloraemia

Specific Therapy

• antibiotics according to severity (See below)
• early surgical referral if severe as colectomy may be needed
• relapsing disease can be a problem – a variety of different antibiotics may be used
• stool transplant aka fecal bacteriotherapy in resistant cases
• a polymer called tolevamer was developed to bind enterotoxin directly, but is inferior to antibiotics in studies and is not used

Treat underlying cause

• isolation
• stop offending drugs
• avoid antidiarrheal drugs and narcotics
• toxic megacolon -> surgery

Prevention

• avoid excessive antibiotic use; antibiotic stewardship
• isolation
• hand washing with soap and water

ANTIBIOTICS THERAPY

If mild to moderate disease:

• metronidazole 400 mg (child: 10 mg/kg up to 400 mg) orally or via nasogastric tube, 8-hourly for 10 days
• Metronidazole can be given intravenously in patients who cannot tolerate the oral formulation (see dose below)

If severe:

• vancomycin 125 mg (child: 3 mg/kg up to 125 mg) orally or via nasogastric tube, 6-hourly for 10 days
• Intravenous vancomycin is not effective against C. difficile

If complicated (eg hypotension or shock, ileus, megacolon), in addition to vancomycin, use:

• metronidazole 500 mg (child: 12.5 mg/kg up to 500 mg) IV, 8-hourly for 10 days
• if ileus present  vancomycin can be administered as a retention enema (500 mg in 100 mL sodium chloride 0.9% rectally, 6-hourly) in addition to oral or nasogastric vancomycin and intravenous metronidazole

References and Links

Journal articles

• Dupont HL. Diagnosis and management of Clostridium difficile infection. Clin Gastroenterol Hepatol. 2013 Oct;11(10):1216-23; quiz e73