Pseudomembranous colitis

Synonyms: Clostridium difficile-associated diarrhoea/disease, CD-positive diarrhoea, antibiotic-associated colitis

Pseudomembranous colitis (PMC) is an acute, exudative colitis usually caused by Clostridioides difficile (C. difficile - formerly Clostridium difficile). PMC can rarely be caused by other bacteria - for example, Staphylococcus spp. or enterotoxigenic Clostridium perfringens, Campylobacter spp., Listeria spp. and Salmonella spp.

What is pseudomembranous colitis?

PMC has emerged, particularly in recent years, as a major and very expensive healthcare problem. Spores formed by the organism are implicated in spread of infection and have implications for hygiene and prevention of infection. C. difficile is an anaerobic Gram-positive rod which secretes two types of toxin (A and B), which cause disruption to the barrier function of the colonic mucosa. They are cytotoxic to cells of the intestinal tract. Toxin B is about 1,000 times more potent than Toxin A. Transmission of infection is via an indirect faeco-oral route, through spores left on surfaces. The spores can survive for months and patients can become carriers. The risk of colonisation increases with length of hospital stay.

C. difficile is classified into strains by polymerase chain reaction (PCR) ribotyping:

• Ribotype 001 is a common cause of C. difficile infection (CDI) in the UK.

• C. difficile 027 (also known as C. difficile NAP1/027 or C. difficile BI/NAP1/027) is associated with higher mortality, severity and relapse rate.

• C. difficile 078 has a higher incidence among community-acquired C. difficile infection (CA-CDI).

How common is pseudomembranous colitis? (Epidemiology)¹

• The incidence of primary and recurrent CDI has increased around the world, even after considerable efforts in the last decade. Increased risk of primary CDI is due in part to increasing age of populations and increasing numbers of residents in long-term care facilities. Antibiotic overuse and the emergence of resistance to commonly-used antibiotics such as vancomycin are contributory factors to recurrent infections. Increased recognition and reporting of infections may however account for some of this apparent increase.¹

• However, in the UK, counts and rates for CDI are falling across the NHS. In England, while rates remained substantial, they were seen to taper between 2009 and 2016 and have subsequently remained fairly stable. In 2009 NHS trusts in England reported 100.3 cases per 100,000 population. By 2017 this had decreased to 24 cases per 100,000. In 2022 there were 28 cases per 100,000 people.²

• An American study found an incidence of 8.3 cases of hospital-associated CDI per 10 000 patient-days.³

• Any antibiotic can increase the risk of CDI, including metronidazole and vancomycin, which are also used in the treatment of CDI.⁴

• Disease has been reported following as little as one dose of antibiotic.

• Although the attributable risk has varied among studies, fluoroquinolones, macrolides, clindamycin, beta-lactam/beta-lactamase inhibitors and cephalosporins have been shown to pose a significant risk for the development of CDI.⁵

• Antineoplastic agents and proton pump inhibitors have also been associated with CDI.⁶

Risk factors⁷

• Prolonged courses of antibiotics.

• Multiple antibiotic usage.

• Increasing age.

• Severe comorbidity.

• Non-surgical invasive gastrointestinal procedures.

• Presence of a nasogastric tube.

• Inpatient residence on ITU.

• Current use of proton pump inhibitors or H2 receptor antagonists.

• Increasing duration of hospital stay; patients in long-term care facilities.

• Immunocompromised patients.

Symptoms of pseudomembranous colitis (presentation)

Colonisation with C. difficile can be associated with a range of possible clinical states:

• The asymptomatic carrier state.

• Mild self-limited diarrhoea.

• Pseudomembranous colitis.

• Fulminant colitis.

Generally there is a history of antibiotic exposure together with risk factors for colonisation.

• Typically, symptoms come on between 5 and 10 days after antibiotic therapy. Occasionally patients will not have had antibiotic exposure.

• Most patients become unwell during their course of antibiotics, but 25-40% may not do so for as many as 10 weeks afterwards.⁸

• Most affected individuals experience watery diarrhoea (varies from self-limiting to severe and debilitating) ± blood-stained stools, abdominal cramps, fever (especially so in severe cases), rigors ± sepsis.

• Severe abdominal pain is uncommon but may mimic an acute abdomen.

• Frank rectal bleeding suggests other causes (for example, inflammatory bowel disease).

Differential diagnosis

• Antibiotic-associated diarrhoea

• Inflammatory bowel disease

• Diverticular disease.

• Other infections:

  • Gastroenteritis.

  • Campylobacter.

  • Salmonella.

  • Shigella.

  • Cholera.

  • Amoebiasis.

• Acute abdomen due to surgical pathology.

• Ischaemic colitis.

Diagnosing pseudomembranous colitis (investigations)⁹

• FBC (WCC elevated in 80%, often very high).

• Renal function tests and electrolytes.

• Hypoalbuminaemia may be present (due to a protein-losing enteropathy).

• Diagnosis in CDI and PMC focuses on detection either of C. difficile or of its toxins in stool samples. The particular method used and the number of samples required will depend on the laboratory. The UK Health Security Agency advise that more than one test per patient may be required if the first test is negative but where there is a strong clinical suspicion of CDI. Retest a second sample 24 hours later. Further tests might be necessary in light of clinical evidence. ¹⁰Samples can usually be frozen or refrigerated if more than a four-hour delay in processing is expected. Liaison with the laboratory may be helpful to avoid delay. Methods of testing by NHS laboratories include toxin enzyme immunoassays (EIAs), toxin gene (NAAT or PCR) and glutamate dehydrogenase (GDH) EIA,

• Testing for C. difficile or its toxins should be performed only on diarrhoeal (unformed) stool, unless ileus due to C. difficile is suspected. Testing of stool from asymptomatic patients is not clinically useful.¹¹

• Sigmoidoscopy (or colonoscopy):

  • Shows the characteristic pseudomembranous plaque appearance in about half of affected patients.

  • Biopsy may be required to confirm diagnosis.

  • Is not used routinely but is usually performed if rapid diagnosis is needed or in a patient who has ileus (often as part of work-up for other colonic disease).

• Imaging studies:

  • Plain X-rays and CT scanning may be helpful.

  • Useful in severe disease but not likely to be helpful in early or mild colitis.

  • Can detect complications (perforation, toxic dilatation).

  • Barium enemas can be harmful and should be avoided.

Reporting

Any of the following defines a C. difficile infection case in patients aged 2 years and above and must be reported to UKHSA or the equivalent agency in Northern Ireland, Scotland and Wales.⁹

• Diarrhoeal stools where the specimen is C. difficile toxin-positive.

• Toxic megacolon or ileotomy where the specimen is C. difficile toxin-positive.

• PMC revealed by lower gastrointestinal endoscopy or computerised tomography.

• Colonic histopathology characteristic of CDI (with or without diarrhoea or toxin detection) on a specimen obtained during endoscopy or colectomy.

• Faecal specimens collected post-mortem where the specimen is C. difficile toxin-positive or tissue specimens collected post-mortem where pseudomembranous colitis is revealed or colonic histopathology is characteristic of CDI.

Management of pseudomembranous colitis

• Correct fluid losses or electrolyte imbalance with oral or intravenous (IV) electrolyte solutions.

• Avoid antiperistaltic agents such as loperamide or opiates (codeine) because of the risk of retention of toxins in the lumen.

• Ceasing the causative antibiotic (if possible) allows resolution in ~3 days in 22%. Consider changing to an antibiotic less likely to cause PMC - for example, aminoglycosides, macrolides, vancomycin or tetracyclines.

• Adherence to the recommended infection control measures and the judicious use of antibiotics should also be part of the global management of CDI in long-term care facilities.¹²

Choice of antibiotic

The National Institute for Health and Care Excellence (NICE) recommends the following antibiotics for adults aged 18 years and over:¹³

There is insufficient evidence of any benefit with probiotic therapy as an adjunct to antibiotic therapy for C. difficile colitis. There is no evidence to support the use of probiotics alone in the treatment of C. difficile colitis.¹⁴

• Use clinical judgement to decide whether vancomycin has worked, but wait seven days before making this decision.

• Check with the British National Formulary (BNF) for contra-indications and special populations - for example, patients with hepatic or renal failure.¹⁵

• Children can be treated as for adults, but check the BNF for Children (BNFC) for dosages, licensed indications and available preparations.¹⁶

Faecal microbiota transplant¹⁷

• Faecal microbiota transplant (FMT) is recommended by NICE as an option to treat recurrent Clostridioides difficile infection in adults who have had two or more previous confirmed episodes. Clinical trial evidence shows that FMT treatment is significantly better than antibiotics alone at resolving a C. difficile infection in those who have had two or more previous infections.

• FMT aims to restore a healthy gut microbiome in people who have recurrent or refractory Clostridioides difficile infections. It involves transferring intestinal bacteria and other microorganisms from healthy donor faeces into the gut of the recipient.

• FMT can be given as a fresh or frozen preparation or in capsule form. Administration can be via a lower gastrointestinal route ( enema, colonoscopy or flexible sigmoidoscopy), upper gastrointestinal route (using a nasogastric tube, nasoduodenal tube or nasojejunal tube) or via oral capsules.

Surgery¹⁸

• Surgery may be life-saving for patients with acute severe colitis.

• Referral for a surgical opinion is required if the patient fails to respond to treatment or has signs of an acute abdomen, radiological signs of acute disease, a rising white blood cell count, a rising creatinine concentration, or a rising lactate concentration.

NICE criteria for a diagnosis of severe colitis:¹³

A white cell count greater than 15 x 09 per litre, or an acutely increased serum creatinine concentration (greater than 50% increase above baseline), or a temperature higher than 38.5°C, or evidence of severe colitis (abdominal or radiological signs). The number of stools may be a less reliable indicator of severity.

Prognosis

• In healthy individuals a good response to treatment is usually expected but the illness can cause severe debility and prolonged hospital stays.

• CDI is implicated as a significant cause of morbidity and mortality among hospitalised patients.⁸

• Recurrent colitis and diarrhoea occur in approximately 25% of patients.⁸

• Early identification of CDI and prompt initiation of therapy with the most appropriate agent are critical to minimise morbidity and mortality.¹²

Complications of pseudomembranous colitis

Complications of severe C. difficile colitis include dehydration, electrolyte disturbances, hypoalbuminaemia, toxic megacolon, bowel perforation, hypotension, acute kidney injury, systemic inflammatory response syndrome, sepsis and death.¹¹ Extraintestinal manifestations are rare and include:⁸

• Bacteraemia.

• Splenic abscess.

• Osteomyelitis.

• Reactive arthritis or tenosynovitis.

Prevention of pseudomembranous colitis¹³

• Administration of currently available probiotics is not recommended to prevent primary CDI, as there are limited data to support this approach.

• Overall preventative measures, such as strict handwashing and patient isolation policies for patients with diarrhoea, seem to be effective. There is less evidence of benefit for environmental cleansing measures.

• Handwashing should be done correctly to be effective. Alcohol gels do not kill spores and are not recommended.¹⁹

• Appropriate antibiotic prescribing; minimise the frequency and duration of antimicrobial therapy and the number of antimicrobial agents prescribed.²⁰