Clostridioides difficile infection: management

Clostridioides difficile (C. difficile) is a spore-producing Gram-positive anaerobic bacterium and a leading cause of healthcare-associated infection. C. difficile is a commensal organism within the human intestinal flora found in up to 66% of newborn babies; colonisation rates drop over time and around 3% of healthy adults remain colonised​[1]​. Most colonised patients remain asymptomatic; however, disturbances of the enteric microbiome — typically following antibacterial therapy — can cause C. difficile to proliferate and induce toxin production resulting in local inflammation and C. difficile infection (CDI). 

CDI is characterised by inflammation of the large intestine, or colon, which manifests as diarrhoea, abdominal pain and distension. Complications include life-threatening toxic megacolon (an acute and severe dilatation of the colon) and pseudomembranous colitis (an acute and severe inflammation of the colon). Diagnosis is confirmed with the presence of symptomatic diarrhoea (≥3 stools/24hours) and either microbiological confirmation of C. difficile organism in a stool sample, radiological evidence of pseudomembranous colitis or histopathological characteristics of CDI​[2]​.

Cases of toxin-confirmed CDI in England have fallen from 55,498 in 2007/2008 to 13,177 in 2019/2020, owing to improvements in infection, prevention and control (IPC), antibacterial prescribing practice and the introduction of antimicrobial stewardship services​[3,4]​. However, despite improvement, CDI is still associated with significant patient harm with 30-day all-cause mortality high at 13.5% post CDI diagnosis​[5]​. Early diagnosis, avoidance of CDI triggers (e.g. antibacterials) and prompt targeted treatment is essential for improving patient outcomes.

The Public Health England guidance on CDI diagnosis and management, last updated in 2013, has now been superseded by the recent publication of the National Institute for Health and Care Excellence (NICE)​[6,7]​. This article summarises the important updates related to the management of CDI and the implications for pharmacy practice across primary and secondary care​[7]​. As the diagnosis and classifications of CDI severity remain unchanged from the PHE advice, please refer to ‘Clostridium difficile: diagnosis and treatment update’ for further information​[6,8]​.

Pharmacological management

Vancomycin

The oral glycopeptide vancomycin remains an important therapeutic option for the management of CDI infection. It is well tolerated and achieves therapeutic concentrations within the lumen of intestines. Owing to cost, it has traditionally been limited to severe infections where it has been used in preference to metronidazole with superior outcomes (overall clinical cure 97% vs. 84%, P=0.006, respectively)​[9]​. Severe infections are associated with a white cell count >15×10⁹/L, 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)​[6,9]​. The number of stools may be a less reliable indicator of severity. For non-severe CDI, metronidazole was associated with non-inferior outcomes (90% vs. 98%) (P=0.36) and has been previously recommended for use​[6]​.

More recent analysis demonstrates superiority of vancomycin over metronidazole for CDI in both severe and non-severe infection​[10]​. A recent Cochrane review has confirmed this initial analysis and has seen vancomycin replace metronidazole as treatment of choice for CDI, irrespective of initial severity (relative risk [RR]: 0.9; 95% CI: 0.84−0.97)​[11]​. NICE’s health economic analysis presents vancomycin as the most cost-effective treatment for CDI, replacing metronidazole as treatment of choice for non-severe CDI episodes, and is in line with other international guidance​[7,12,13]​. 

Combination therapy of oral vancomycin with intravenous metronidazole is thought to increase luminal penetration of antibacterials in CDI and is recommended by NICE for treatment-resistant or severe/life-threatening CDI​[14]​. However, this may not translate into successful patient outcomes and further evidence is needed​[7,15]​.

Administration and monitoring

Vancomycin must be administered enterally; little to no faecal concentration is obtained by parenterally administered vancomycin. A licensed oral capsule (125mg and 250mg) and a vial of injectable powder (which may be reconstituted and administered enterally) are currently available, with the latter advised for patients with swallowing difficulties or enteral tubes​[7]​. Unlicensed liquid preparations may be sourced in community settings if patients and/or carers experience difficulty when reconstituting a vial.

The rectal route of administration may be utilised in addition to the oral route, or as an alternative route, in patients with severe/life-threatening disease or if ileus present​[7]​. Rectal or intra-colonic administration of vancomycin is unlicensed in the UK but may be prepared by reconstituting one 500mg vial in 100ml of normal saline, which is subsequently given as a retention enema four times a day​[12]​. Caution is advised in any manipulation of an injectable powder for enteral or rectal administration owing to the risk of accidental parenteral administration. Confusion regarding route may occur when an oral solution is prepared using syringes and needles for parenteral use​[16]​.

Oral vancomycin has minimal systemic absorption hence the risk of systemic adverse effects associated with glycopeptide antibacterials (such as ototoxicity and nephrotoxicity) is negligible​[7]​. Therapeutic drug monitoring is not routinely advised at the standard dosage of 125mg four times a day for ten days​[17]​. In patients with high-dose oral vancomycin therapy (500mg four times a day) and end-stage kidney dysfunction, random serum vancomycin levels may be useful to exclude any potential accumulation but this is not universally recommended​[18]​.

The standard oral vancomycin dose of 125mg four times a day is recommended by NICE as previous data showed no statistically significant difference in symptomatic cure between standard and high dosing regimens​[7,11]​. Tapered or pulsed dosing regimens, thought to target spores of C.difficile (which are resistant to antibiotics), allowing time for spores to germinate into vegetative forms that can be subsequently treated upon dose administration are not currently recommend by NICE​[7,19]​.

It is thought that increased use of oral vancomycin can create a selective pressure and increase the incidence of vancomycin-resistant enterococci (VRE); however, the risk remains unconfirmed in practice​[20]​.

Fidaxomicin

The macrocyclic antibacterial fidaxomicin exhibits bacteriocidal activity against C. difficile and is recommended as second-line therapy for CDI (of any severity) as an alternative to vancomycin​[7,21]​. In previous national guidance, it was reserved for patients with recurrent CDI infections and was only to be used following local microbiology recommendations​[6]​.

Two large prospective randomised control trials have helped demonstrate the efficacy of fidaxomicin for treatment of CDI. Initial work by Louie et al., randomised 629 patients to receive oral fidaxomicin (200mg twice daily) or vancomycin (125mg four times daily) for ten days​[22]​. Clinical cure of active CDI with fidaxomicin was non-inferior to that of vancomycin​[22]​. Rates of reoccurrence, indicated by diarrhoea and positive stool toxin test within four weeks post-treatment, was significantly lower in patients treated with fidaxomicin with around a number needed to treat of ten to prevent one reoccurrence​[22]​. Cornely et al. confirmed this finding with similar clinical cure achieved with both fidaxomicin and vancomycin​[23]​. Again, a reduction in recurrence rates of CDI was evident with the fidaxomicin treatment group​[23]​. Based on the favourable reoccurrence rates, fidaxomicin appears to be an appropriate treatment option for patients at higher risk of disease reoccurrence (e.g. those with previous reported relapses/reoccurrence and those requiring continuing concomitant broad-spectrum antimicrobial therapy despite new CDI disease)​[7]​.

The EXTEND study explored the use of tapered fidaxomicin therapy (200mg twice daily for five days then 200mg every 48 hours) and demonstrated low rates of disease reoccurrence with this tapered course​[24]​. However, no direct head-to-head studies have examined this with the licensed fidaxomicin dosing regimen. NICE currently states that there is insufficient evidence of benefit to recommend this approach​[7]​.

Administration and monitoring

Fidaxomicin is generally well tolerated and has negligible systemic absorption. Rates of adverse effects are similar between fidaxomicin and oral vancomycin​[22]​. A licensed 200mg tablet is currently available on the NHS with a new 40mg/mL granule oral suspension expected soon to market, allowing for more convenient dose administration for those with swallowing difficulties​[25]​. Limited information is available related to crushing of the film-coated tablet but there are cases where this has been done to facilitate safe administration​[26]​.

Faecal microbiota transplant 

NICE approved the use of faecal microbiota transplant (FMT) in 2014 for recurrent or refractory CDI​[27]​. The procedure involves the transfer of enteric bacteria from donor faeces to a patient with active infection to help re-establish a healthy balance of bacteria. Donor faecal matter is formulated into frozen aliquots of suspension, which is subsequently administered orally via capsules or nasogastric tube or rectally via colonoscopy (see Figure)​[27]​.

Source ​[8]​

FMT was more efficacious at achieving clinical cure of recurrent CDI unresponsive to antibacterials rather than refractory CDI infections​[28,29]​. A 2020 systematic review and meta-analysis found that both single and repeated FMT procedures were superior then oral vancomycin alone at treating recurrent CDI​[30]​. Consequently, in hospital settings, FMT is used as a third-line option in recurrent CDI patients who have had repeated antibacterial therapy. NICE recommends FMT in patients who have previously had two or more episodes of CDI that were unresponsive to antibiotics​[7,27]​.  

Patients may experience mild gastrointestinal effects such as nausea, diarrhoea and bloating post-FMT. NICE acknowledges that FMT carries a small risk of transmitting multi-drug resistant bacteria (in particular Escherichia coli) from the donor to the patient but this is minimised by donor screening and sample testing prior to use​[7]​.

Bezlotoxumab

The human monoclonal antitoxin antibody bezlotoxumab is licensed for the prevention of recurrent CDI in adults and has been shown to reduce recurrence by up to 12 weeks​[31,32]​. However, it is no longer recommended owing to a lack of cost-effectiveness​[7]​.

Supportive and non-pharmacological management

Alongside evidence-based pharmacological treatment options for the management of CDI, pharmacists should consider the following supportive and non-pharmacological options:

• Stop or review use of broad-spectrum antibacterials

Broad-spectrum antibacterials (e.g. co-amoxiclav, clindamycin and ciprofloxacin) disturb enteric flora and can cause proliferation of C. difficile​[6,7]​. All antibacterial prescribing should be limited to the shortest effective duration and rationalised in line with available microbiological data.  

• Stop or review use of proton pump inhibitors (PPIs)

PPI agents such as omeprazole support the acquisition and proliferation of C. difficile in the intestine by reducing the acidic nature of gastric contents​[6,7]​. The need for a PPI should be reviewed in patients at-risk of or confirmed CDI, with unnecessary PPI use stopped where possible to reduce risk of future CDI disease.

• Avoid using antimotility agents

Using an agent such as loperamide in a patient with CDI risks the C.difficile toxin being retained in the intestine and subsequent development of toxic megacolon disease​[6,7]​.

• Avoid prebiotics and probiotic supplements in patients taking antibacterials

There is a lack of convincing evidence for these supplements to be routinely prescribed for prevention of CDI​[7]​.

• Ensure patients are appropriately hydrated

Patients should be encouraged to drink fluids or use oral rehydration sachets to avoid dehydration associated with severe diarrhoea.

• Provide infection prevention and control advice

Patients with CDI should be encouraged to practice good hand hygiene regularly and wash down contaminated surfaces. Patients should stay at home until at least 48 hours after their most recent episode of diarrhoea.

Impact on pharmacy practice

Updated guidance on management will significantly impact the practice of pharmacy teams within community and hospital settings in a variety of ways (see Box), including the potential number of prescriptions seen in practice. Clinical commissioning groups are advised to review local guidelines for the clinical management and antibacterial prescribing in CDI that considers the increased cost of fidaxomicin and the implication on local prescribing budgets.