Approach

Diagnosis is based on taking an accurate history, physical examination, and confirmation by appropriate tests. Diagnosis should be considered in patients with a history of recent antibiotic exposure who present with diarrhoea. Testing should be limited to patients with unexplained, new-onset diarrhoea (defined as 3 or more unformed stools in 24 hours). Molecular testing alone or as part of a multistep algorithm is recommended depending on local institutional protocols.

History

Patients with advanced age, recent history of antibiotic use, comorbid conditions (e.g., inflammatory bowel disease, chronic kidney disease, HIV infection), prolonged hospitalisation, residence in a nursing home, history of taking acid-suppressing drugs, history of solid organ transplant or haematopoietic stem cell transplant, or a history of Clostridioides difficile-associated disease are especially at risk.

The most common antibiotics involved are ampicillin, cephalosporins, clindamycin, carbapenems, and fluoroquinolones, especially in the preceding 3 months.[21][22]

  • Cephalosporins (third- and fourth-generation) and carbapenems are most strongly associated with healthcare facility-associated infection; modest associations were also noted for fluoroquinolones, clindamycin, and beta-lactamase inhibitor/penicillin combinations.[25]

  • An analysis of the Food and Drug Administration adverse event reporting system found that lincosamides (e.g., clindamycin) had the greatest proportion of reports of Clostridioides difficile infection, followed by monobactams, beta-lactamase inhibitor/penicillin combinations (e.g., piperacillin/tazobactam), carbapenems, cephalosporins, tetracyclines, macrolides, fluoroquinolones, and trimethoprim/sulfamethoxazole.[26]

  • However, a meta-analysis suggests that tetracyclines may be associated with a decreased risk of infection compared with other antibiotics.[27]

Patients commonly present with fever, diarrhoea, abdominal pain, nausea, or vomiting.

Physical examination

May reveal anything from little or no abdominal tenderness to signs of an acute abdomen.

Systemic symptoms of shock including hypotension and tachycardia, with severe abdominal pain and tenderness suggest fulminant colitis. Fulminant disease is defined as a complicated severe case of C difficile infection with high risk of death.

Initial investigations

Full blood count with differential should be ordered in the initial evaluation, which typically shows leukocytosis. If the WBC is very high (30,000 to 50,000/mm³), the patient is at risk of fulminant colitis.

An abdominal x-ray should be performed in patients with abdominal distension or symptoms and signs suggestive of infection. This may show dilation of the colon.[22]

Samples of unformed stool should be collected in the primary investigation and checked for presence of occult blood. Testing algorithms should include both a highly sensitive and highly specific testing modality to help distinguish colonisation from active infection.[58] However, differentiating between C difficile infection and colonisation presents a diagnostic challenge, and consensus on the best diagnostic method is lacking.

Tests detect either the organism itself (i.e., nucleic acid amplification tests [NAAT], such as stool polymerase chain reaction, glutamate dehydrogenase [GDH] enzyme immunoassay, or toxigenic culture) or its major toxins (i.e., toxin A and B enzyme immunoassays, cell culture cytotoxicity neutralisation assay) directly in the stool. Molecular testing, the most common diagnostic method used, does not differentiate between infection and colonisation. It is highly sensitive with low/moderate specificity.[2]

In the interests of good diagnostic stewardship, it is recommended that testing is limited to patients with unexplained, new-onset diarrhoea (defined as 3 or more unformed stools in 24 hours) who are not receiving laxatives in the last 48 hours; however, this recommendation is based on very low-quality evidence.[2]

  • If hospital and laboratory personnel agree on this stool submission criteria, NAAT alone is recommended as this is the most sensitive method of diagnosis in stool specimens from patients who are likely to have C difficile infection based on clinical symptoms.

  • However, if there are no pre-agreed institutional criteria for patient stool submission, a stool toxin test as part of a multistep algorithm is recommended (e.g., GDH plus toxin; GDH plus toxin, arbitrated by NAAT; or NAAT plus toxin) rather than NAAT alone.

  • Repeat testing should not be performed within 7 days during the same episode of diarrhoea, and asymptomatic patients should not be tested.​

European guidelines recommend a two-step algorithm, starting with a highly sensitive test (e.g., NAAT, or GDH enzyme immunoassay) and, if positive, confirmation with a highly specific test (toxin A/B enzyme immunoassay). Alternatively, samples can be screened with both a GDH and toxin A/B enzyme immunoassay.[70]​​

Stool cultures are the most sensitive test available, but are labour intensive, require an appropriate culture environment, and take 48 to 96 hours for results. They are not typically used in practice.[71]

Subsequent tests

Sigmoidoscopy or colonoscopy is indicated if therapy fails, or in patients whom enzyme immunoassay was negative, or if other causes are suspected such as ischaemic colitis.

A computed tomographic scan of the abdomen is indicated in patients with abdominal distension, worsening pain, or absent bowel sounds.

Emerging tests

Faecal biomarkers, such as calprotectin and lactoferrin, are increasingly being used to distinguish between inflammatory causes of diarrhoea and non-inflammatory causes. There is insufficient evidence to recommend the use of these biomarkers in the diagnosis of C difficile infection at this time.[2]​​​

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