Clostridioides difficile infection: antimicrobial prescribing

This guideline sets out an antimicrobial prescribing strategy for managing Clostridioides difficile infection in adults, young people and children aged 72 hours and over in community and hospital settings. It aims to optimise antibiotic use and reduce antibiotic resistance. The recommendations do not cover diagnosis.

# Recommendations
The recommendations in this guideline update existing Public Health England guidance on treating Clostridioides difficile infection.

# Managing suspected or confirmed Clostridioides difficile infection

## Assessment
For people with suspected or confirmed C. difficile infection, see Public Health England's guidance on diagnosis and reporting.
For people with suspected or confirmed C. difficile infection, assess:
whether it is a first or further episode (relapse or recurrence) of C. difficile infection
the severity of C. difficile infection
individual factors such as age, frailty or comorbidities that may affect the risk of complications or recurrence.
For people with suspected or confirmed C. difficile infection, review existing antibiotic treatment and stop it unless essential. If an antibiotic is still essential, consider changing to one with a lower risk of causing C. difficile infection.
For people with suspected or confirmed C. difficile infection, review the need to continue any treatment with:
proton pump inhibitors
-ther medicines with gastrointestinal activity or adverse effects, such as laxatives
medicines that may cause problems if people are dehydrated, such as non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin2 receptor antagonists and diuretics.
For a short explanation of why the committee made these recommendations, see the rationale section on assessment .
For more details, see the evidence review.
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## Treating suspected or confirmed C. difficile infection
For adults, offer an oral antibiotic to treat suspected or confirmed C. difficile infection (see the recommendations on choice of antibiotic). In the community, consider seeking prompt specialist advice from a microbiologist or infectious diseases specialist before starting treatment.
For children and young people under 18 years, offer an oral antibiotic to treat suspected or confirmed C. difficile infection. Treatment should be started by, or after advice from, a microbiologist, paediatric infectious diseases specialist or paediatric gastroenterologist.
For people with suspected or confirmed C. difficile infection who cannot take oral medicines, seek specialist advice from a gastroenterologist or pharmacist about alternative enteral routes for antibiotics, such as a nasogastric tube or rectal catheter.
Manage fluid loss and symptoms associated with suspected or confirmed C. difficile infection as for acute gastroenteritis. Do not offer antimotility medicines such as loperamide.
Do not offer bezlotoxumab to prevent recurrence of C. difficile infection because it is not cost effective.
Consider a faecal microbiota transplant for a recurrent episode of C. difficile infection in adults who have had 2 or more previous episodes (see NICE's interventional procedures guidance on faecal microbiota transplant for recurrent C. difficile infection).
For a short explanation of why the committee made these recommendations, see the rationale section on treating suspected or confirmed C. difficile infection .
For more details, see the summary of the evidence.
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## Advice
Advise people with suspected or confirmed C. difficile infection about:
drinking enough fluids to avoid dehydration
preventing the spread of infection (see recommendation 1.3.1)
seeking medical help if symptoms worsen rapidly or significantly at any time.
For a short explanation of why the committee made this recommendation, see the rationale section on advice .
For more details, see the evidence review.
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## Reassessment
Reassess people with suspected or confirmed C. difficile infection if symptoms or signs do not improve as expected, or worsen rapidly or significantly at any time. Daily review may be needed, for example, if the person is in hospital.
If antibiotics have been started for suspected C. difficile infection, and subsequent stool sample tests do not confirm C. difficile infection, consider stopping these antibiotics (see Public Health England's guidance on diagnosis and reporting for recommendations on stool sample tests).
For a short explanation of why the committee made these recommendations, see the rationale section on reassessment .
For more details, see the evidence review.
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## Referral
Refer people in the community with suspected or confirmed C. difficile infection to hospital if they are severely unwell, or their symptoms or signs worsen rapidly or significantly at any time. Refer urgently if the person has a life-threatening infection.
Consider referring people in the community to hospital if they could be at high risk of complications or recurrence because of individual factors such as age, frailty or comorbidities.
Ensure that people in hospital with suspected or confirmed C. difficile infection have care from a multidisciplinary team that may include a microbiologist, infectious diseases specialist, gastroenterologist, surgeon, pharmacist or dietitian, as needed.
For a short explanation of why the committee made these recommendations, see the rationale section on referral or seeking specialist advice .
For more details, see the evidence review.
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# Choice of antibiotic
When prescribing antibiotics for suspected or confirmed C. difficile infection in adults, follow table 1.
When prescribing antibiotics for suspected or confirmed C. difficile infection in children and young people under 18 years, base the choice of antibiotic on what is recommended for C. difficile infection in adults. Take into account licensed indications for children and young people, and what products are available (see the BNF for Children for dosing information).
Use clinical judgement to determine whether antibiotic treatment for C. difficile is ineffective. It is not usually possible to determine this until day 7 because diarrhoea may take 1 to 2 weeks to resolve.
Treatment
Antibiotic, dosage and course length
First-line antibiotic for a first episode of mild, moderate or severe C. difficile infection
Vancomycin:
mg orally four times a day for 10 days
Second-line antibiotic for a first episode of mild, moderate or severe C. difficile infection if vancomycin is ineffective
Fidaxomicin:
mg orally twice a day for 10 days
Antibiotics for C. difficile infection if first- and second-line antibiotics are ineffective
Seek specialist advice. Specialists may initially offer:
Vancomycin:
Up to 500 mg orally four times a day for 10 days
With or without
Metronidazole:
mg intravenously three times a day for 10 days
Antibiotic for a further episode of C. difficile infection within 12 weeks of symptom resolution (relapse)
Fidaxomicin:
mg orally twice a day for 10 days
Antibiotics for a further episode of C. difficile infection more than 12 weeks after symptom resolution (recurrence)
Vancomycin:
mg orally four times a day for 10 days
Or
Fidaxomicin:
mg orally twice a day for 10 days
Antibiotics for life-threatening C. difficile infection (also see recommendation 1.1.16)
Seek urgent specialist advice, which may include surgery. Antibiotics that specialists may initially offer are:
Vancomycin:
mg orally four times a day for 10 days
With
Metronidazole:
mg intravenously three times a day for 10 days
See the BNF for appropriate use and dosing in specific populations, for example, hepatic impairment, renal impairment, pregnancy and breastfeeding. Also see medicines safety.
See Specialist Pharmacy Service guidance on choosing between oral vancomycin options. If ileus is present, specialists may use vancomycin rectally.
For a short explanation of why the committee made these recommendations, see the rationale section on choice of antibiotic .
For more details, see the summary of the evidence.
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# Preventing C. difficile infection
For how to prevent C. difficile infection through good antimicrobial stewardship, infection control and environmental hygiene measures, see:
Public Health England's guidance on C. difficile infection: how to deal with the problem
NICE's guidance on healthcare-associated infections
              and
NICE's guidance on antimicrobial stewardship.
Ensure a diagnosis of C. difficile infection is recorded (particularly when a person transfers from one care setting to another). This is so that it can be taken into account before any future antibiotics are prescribed.
Do not offer antibiotics to prevent C. difficile infection.
Do not advise people taking antibiotics to take prebiotics or probiotics to prevent C. difficile infection.
For a short explanation of why the committee made these recommendations, see the rationale section on preventing C. difficile infection .
For more details, see the summary of the evidence.
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# Terms used in the guideline

## C. difficile infection
This is defined (by Public Health England, 2013) as diarrhoea and:
a positive C. difficile toxin test or
results of a C. difficile toxin test pending and clinical suspicion of C. difficile infection.

## Further episode (relapse or recurrence) of C. difficile infection
A further episode of C. difficile infection could either be a relapse, which is more likely to be with the same C. difficile strain, or a recurrence, which is more likely to be with a different C. difficile strain. There is no agreement on the precise definition of relapse and recurrence, and it is difficult to distinguish between them in clinical practice. In this guideline, it was agreed that a relapse occurs within 12 weeks of previous symptom resolution and recurrence occurs more than 12 weeks after previous symptom resolution.

## Severity of C. difficile infection
This is defined (by Public Health England, 2013) as:
Mild infection: not associated with an increased white cell count (WCC). Typically associated with fewer than 3 episodes of loose stools (defined as loose enough to take the shape of the container used to sample them) per day.
Moderate infection: associated with an increased WCC (but less than 15  109 per litre). Typically associated with 3 to 5 loose stools per day.
Severe infection: associated with a WCC greater than 15  109 per litre, or an acutely increased serum creatinine concentration (greater than 50% increase above baseline), or a temperature higher than 38.5 degrees Celsius, or evidence of severe colitis (abdominal or radiological signs). The number of stools may be a less reliable indicator of severity.
Life-threatening infection: symptoms and signs include hypotension, partial or complete ileus, toxic megacolon or CT evidence of severe disease.

## Probiotics
Probiotics are live bacteria and yeasts that are promoted as having various health benefits. They are usually added to yoghurts or taken as food supplements. They are often described as 'good', 'friendly' or 'healthy' gut bacteria, and are thought to help restore the natural balance of bacteria in the gastrointestinal tract.

## Prebiotics
Prebiotics are a source of food for the 'healthy' bacteria in the gastrointestinal tract. They are a group of non-digestible food ingredients, such as fructo-oligosaccharides, that are a source of food for these bacteria. Prebiotics are found naturally in many fruits and vegetables, but can also be taken as supplements.# Recommendations for research
The guideline committee has made the following recommendation for research.

# Oral teicoplanin compared with oral vancomycin or oral fidaxomicin for treating Clostridioides difficile infection
What is the clinical effectiveness, cost effectiveness and safety of oral teicoplanin 100 mg to 200 mg twice a day for 7 to 14 days compared with oral vancomycin or oral fidaxomicin for treating C. difficile infection in adults?
For a short explanation of why the committee made the recommendation for research, see the rationale section on choice of antibiotic .
Loading. Please wait.# Rationales
The recommendations in this guideline are based on the evidence identified and the experience of the committee.

# Assessment

## Why the committee made the recommendations
Recommendations 1.1.1 to 1.1.4
The committee agreed that although diagnostics and reporting were out-of-scope for this guideline, a recommendation should be included on where to find such information. They concluded, from experience, that people should see Public Health England's updated guidance on the diagnosis and reporting of Clostridioides difficile.
The committee discussed that, in practice, there has been a change in the definition of the severity of C. difficile from the 4 categories (mild, moderate, severe and life threatening) used by Public Health England to 3 categories (non-severe, severe and life threatening). However, the Public Health England categories still apply because this is current national guidance.
The committee discussed the findings of the economic model, which took into account severity by adjusting for older age, increased risk of recurrence, increased hospitalisation and a higher risk of fulminant colitis (see the economic analysis in the evidence review for full details; there was a lack of useful direct evidence for severity that could be used in the economic model). The economic model found that severity did not cause a substantial change in which antibiotic was the most cost effective. Therefore, the committee agreed that the main reason to assess severity was to identify the appropriate place of care, overall management, and any subsequent improvement or worsening. They also agreed that an assessment of whether the current infection was a first or further episode (relapse or recurrence) of C. difficile infection should be included. This was because recurrence was a driver in the economic model and determines antibiotic choice (see also the rationale on choice of antibiotic).
The committee recognised that C. difficile infection most commonly affects people who are taking or have recently taken antibiotics. They discussed that, even though antibiotics being taken may be associated with the C. difficile infection, the person may still need antibiotics for the original infection. They agreed that, in line with good antimicrobial stewardship, prescribers should review existing antibiotic treatment and:
stop it unless essential, or
if an antibiotic is still essential, consider changing to one with a lower risk of causing C. difficile infection.
The committee agreed that it is good prescribing practice to review the continuing need for existing proton pump inhibitor (PPI) treatment in people with suspected or confirmed C. difficile infection, in line with NICE's guideline on medicines optimisation. They were aware that, although some associations have been made between PPI use and the risk of C. difficile infection or recurrence, there is no definitive evidence of a causal or exacerbator effect. Also, no evidence from systematic reviews or randomised controlled trials was found to support stopping current PPI treatment. The committee agreed that suddenly stopping a PPI during an acute episode of infection may cause additional gastric symptoms. Additionally, some people will need ongoing gastroprotection for a clinical indication. However, they were aware that many people may be taking a PPI without a clear indication, so concluded that the use and need for a PPI should be reviewed.
The committee agreed that, when people present with suspected or confirmed C. difficile infection, it is good prescribing practice to review other medicines with gastrointestinal activity or adverse effects (such as laxatives) being taken. They also agreed that it is good practice to review other medicines being taken that may have detrimental effects if people are acutely ill and dehydrated. These include non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin2 receptor antagonists and diuretics.
Return to the recommendations

# Treating suspected or confirmed C. difficile infection

## Why the committee made the recommendations
Recommendations 1.1.5 to 1.1.10
The committee agreed that an oral antibiotic should be offered for suspected or confirmed C. difficile infection in adults, young people and children.
For adults presenting in the community, the committee agreed that GPs may be unfamiliar with diagnosing and treating C. difficile infection, so may want to seek prompt specialist advice from a microbiologist or infectious diseases specialist before starting treatment. The committee noted that, for people in hospital, once diagnosed, they would be under the care of a multidisciplinary team, which would ensure appropriate review and care.
The committee discussed the lack of evidence on treating C. difficile infection in children and young people. They were aware that, in practice, very few children have C. difficile infection. The committee agreed that a positive test for C. difficile in children 2 years and under is often because of high carriage rates of the bacteria rather than because of actual infection. They considered that this may lead to overprescribing of antibiotics. The committee concluded that treatment for C. difficile infection in children and young people should only be started by a microbiologist, paediatric infectious diseases specialist or paediatric gastroenterologist, or after advice from such a specialist.
The committee discussed the most appropriate route of administration of antibiotics for C. difficile infection. They agreed that the enteral route is best because sufficient concentrations within the intestinal lumen need to be reached. The committee concluded that it is preferable to take antibiotics orally or, if this is not possible, enterally in some other way (such as a nasogastric or enteral feeding tube, or rectally). They advised seeking specialist advice on administration from a specialist gastroenterologist or pharmacist if the oral route is not available.
The committee agreed that, in line with the general management of gastroenteritis (see the NICE clinical knowledge summary on adult gastroenteritis and NICE's guideline on diarrhoea and vomiting caused by gastroenteritis in under 5s), prescribers and other care staff should monitor and manage fluid loss and gastroenteritis symptoms. Antimotility drugs such as loperamide should be avoided because they slow down the action of the gut. This can lead to C. difficile toxins being retained for longer, which may make a person more unwell.
Bezlotoxumab was not recommended as adjunctive therapy to antibiotics to prevent recurrent C. difficile infection. The committee discussed the clinical evidence, which showed that bezlotoxumab was more effective than placebo at preventing recurrence. However, they also reviewed the economic analysis and agreed that adding bezlotoxumab to either vancomycin or fidaxomicin was not a cost-effective option (there is a 0% probability of it being cost effective at 30,000 per quality-adjusted life year  gained). The committee agreed that this finding was robust, even in people with a higher risk of recurrence, and were confident in making a recommendation for bezlotoxumab not to be used.
The committee noted that faecal microbiota transplantation (FMT; a procedure done in a small number of specialist centres) was not effective as a first-line treatment for C. difficile infection compared with vancomycin. They were aware that long-term safety data on, and regulations about the use of, FMT are minimal compared with medicines. They were aware of variation in mortality rates associated with FMT use, and that there is almost no evidence for its use in children. NICE's interventional procedures guidance on FMT for recurrent C. difficile infection states that 'current evidence on the efficacy and safety of FMT for recurrent Clostridium difficile infection is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit'. In the economic model, FMT was placed as a third-line treatment (for people with continuing symptoms after first- and second-line antibiotics) that may help prevent serious complications. The committee agreed that FMT may be useful in adults who have had 2 or more previous episodes of C. difficile infection in addition to the current episode to prevent recurrence of C. difficile infection. They were aware of ongoing developments around the screening of faecal microbiota donors to identify multidrug-resistant organisms.
For more details, see the summary of the evidence on treating initial or first recurrent C. difficile infection.
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# Advice

## Why the committee made the recommendation
Recommendation 1.1.11
The committee discussed what advice on self-care people with a C. difficile infection would need and agreed that, from their experience, 3 key areas of advice were needed:
maintaining fluid intake to avoid dehydration (and on the symptoms or signs of dehydration that people should be aware of)
the need to help reduce the spread of C. difficile infection, which is contagious (that is, people should follow the advice in the NICE clinical knowledge summary on adult gastroenteritis and in NICE's guideline on diarrhoea and vomiting caused by gastroenteritis in under 5s)
when to seek medical help.
Return to the recommendation

# Reassessment

## Why the committee made the recommendations
Recommendations 1.1.12 to 1.1.13
The committee were aware that C. difficile infection should be managed as a diagnosis in its own right. They agreed that the management and progress of suspected or confirmed C. difficile infection should be monitored during treatment. This could include assessing the severity of the infection and symptoms, and the need for hydration. The committee concluded that, from their experience, it would be good practice to reassess people if symptoms or signs of infection do not improve as expected or worsen rapidly or significantly at any time. They agreed that daily review is usual in hospital and that, in the community, people should be given appropriate safety netting advice to ensure that they return for reassessment if needed.
The committee also agreed that clinicians should consider stopping antibiotics for C. difficile infection if they have been started for clinically suspected C. difficile infection before stool sample test results are available and subsequent results do not confirm infection.
Return to the recommendations

# Referral or seeking specialist advice

## Why the committee made the recommendations
Recommendations 1.1.14 to 1.1.16
The committee agreed that people with suspected or confirmed C. difficile infection in the community should be referred to hospital if they are severely unwell, or their symptoms or signs worsen rapidly or significantly at any time. For life-threatening infection, an urgent referral is needed. The committee recognised that there are some individual factors (such as age, frailty and comorbidities) for which it may also be appropriate to consider referral to hospital. This is because they are associated with a higher risk of complications or recurrence.
The committee agreed that people who develop C. difficile infection while in hospital are unlikely to be having care from a microbiologist or infectious diseases specialist at diagnosis. However, once diagnosed they should be under the care of a multidisciplinary team to ensure appropriate review and care. The team could include, as needed, a microbiologist, infectious diseases specialist, gastroenterologist, surgeon, pharmacist and dietitian. This would depend, for example, on the severity of illness and need for surgery.
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# Choice of antibiotic
Recommendations 1.2.1 to 1.2.3

## Why the committee made the recommendations
The committee discussed the evidence for the effectiveness and cost effectiveness of the different antibiotic options for treating C. difficile infection. They were aware that antibiotic resistance is not a major concern when treating C. difficile infection.
Oral vancomycin was recommended by the committee as the first-line antibiotic for a first episode of C. difficile infection of any severity. Fidaxomicin was recommended as the second-line antibiotic for a first episode of C. difficile infection of any severity when vancomycin is ineffective (treatment failure). The committee noted that, although fidaxomicin was more effective than vancomycin for sustained symptomatic cure in the network meta-analysis, the cost of fidaxomicin is substantially higher. In the base-case analysis, there was only a 2% probability of first-line fidaxomicin being cost effective compared with first-line vancomycin (at 30,000 per QALY gained). They also discussed that vancomycin treatment failure should not be judged too early. Diarrhoea can take 1 to 2 weeks to resolve, and it is not usually possible to determine whether antibiotic treatment for C. difficile is ineffective until day 7.
The committee agreed that, when teicoplanin and second-line metronidazole were excluded from the economic model, the remaining results clearly showed that vancomycin was the most cost-effective first-line antibiotic across a range of scenarios. This was the case when results from people at both higher and lower risks of recurrence were included (in particular, it was more cost effective as a first-line option than either metronidazole or fidaxomicin). They also agreed that fidaxomicin was the appropriate second-line option.
The committee noted that, from experience, some hospital trusts use fidaxomicin for first-line treatment of C. difficile infection in people who are older or frailer as a strategy to reduce recurrence and readmission. The aim is to offset the cost of using fidaxomicin by reducing future costs. The committee were made aware of a real-world evaluation of fidaxomicin in which its use first line had a greater effect on reducing mortality than its use second line after vancomycin. However, they heard that the economic model considered a range of benefits and harms (including deaths), as well as the costs of each strategy. Vancomycin (not fidaxomicin) was still the most cost-effective first-line option, even in people at higher risk of recurrence. The committee concluded that a recommendation to use fidaxomicin first line would incur unreasonably large opportunity costs that are not appropriate in the wider context of overall healthcare resource allocation. There are possible rare exceptions when vancomycin may not be acceptable, such as for an infection that is vancomycin resistant.
The committee noted that, when taken orally, vancomycin is not well absorbed from the gut into the circulation (although absorption may increase if the gut is damaged). So, the likelihood of side effects (such as ototoxicity) is lower with oral than with intravenous administration, although there is still a need to monitor for this in some people (see medicines safety). They also discussed the development of drug-resistant bacteria, in particular, vancomycin-resistant enterococci. However, they agreed with expert testimony that this is not a major concern in clinical practice when vancomycin is used orally for C. difficile infection.
The committee discussed that vancomycin capsules would usually be the preferred formulation for taking vancomycin orally. They were aware that vancomycin powder for solution is also licensed to be taken orally for C. difficile infection, and that it is used in some settings (particularly if people cannot take solid oral medicines). However, they discussed that locally agreed protocols should be in place to reduce the risk of medication errors around reconstitution and administration, and to take account of the practicalities of administration, particularly in community settings. This is discussed further in Specialist Pharmacy Service guidance on choosing between oral vancomycin options.
Fidaxomicin was recommended by the committee for a further episode of C. difficile infection of any severity occurring within 12 weeks of symptom resolution. They defined this as a relapse. For a further episode of C. difficile infection occurring more than 12 weeks after symptom resolution (defined as recurrence), either vancomycin or fidaxomicin was recommended, with choice being an individualised patient decision.
The committee noted there was no clinical evidence comparing vancomycin with fidaxomicin in a population having a further episode of C. difficile infection after initial cure. Their decisions were therefore heavily influenced by the threshold analyses around risks of future recurrence. This was because they agreed that 1 key difference with a further episode of infection is the higher risk of subsequent additional recurrences. The committee noted that the risk of future recurrence needed to be around 30% to 40% for fidaxomicin to be cost effective as a first-line option compared with vancomycin (at 30,000 per QALY gained). While they did not believe that this would be the case for all people with a recurrent infection, they did agree that there would be people with a risk of recurrence that high. They therefore agreed that it was appropriate for both vancomycin and fidaxomicin to be first-line options for further episodes. They concluded that the choice would come down to an individualised patient decision based around severity, the risk of additional recurrences (which increases after each recurrent episode) and the time between recurrences. The committee favoured fidaxomicin for more severe, more recent or multiple recurrent episodes. They thought that vancomycin would be suitable for less severe or first recurrent episodes, or if there had been a long time between episodes.
The committee were aware that there is poor agreement on the definition of relapse or recurrence in C. difficile infection, both nationally and internationally. They discussed different time periods and agreed, based on expert opinion, that 30 days from resolution of symptoms was too short a time period to define recurrence. They thought that further symptoms within this time period after initial symptom resolution were more likely to represent relapse with the same strain of C. difficile infection. The committee heard that, in practice, further symptoms within 12 to 24 months may be considered a recurrence, likely with a different strain of C. difficile infection. However, they were also aware of evidence that suggested recurrence generally relates to a further episode within 20 weeks. Defining relapse or recurrence is outside of the remit of the committee, and evidence on this issue was not searched for. So, the committee agreed that it could not be certain about the time period but thought that 12 weeks was a reasonable cut-off point between relapse and recurrence.
The committee agreed that specialist advice should be sought about the choice of antibiotics for C. difficile infection that has not responded to either first- or second-line antibiotics, or for a life-threatening infection. However, they recognised that, in practice, specialists will often initially recommend high-dose oral vancomycin with or without intravenous metronidazole for this. If ileus is present, specialists may use vancomycin rectally.
Teicoplanin was not recommended by the committee for treating C. difficile infection. It was ranked first in the network meta-analysis results. However, the committee were concerned about the extensive limitations of the 2 small studies of teicoplanin included in the network meta-analysis, both of which were at considerable risk of bias. The committee noted that the point estimate of effect was important. However, the 95% confidence intervals were wide, revealing much uncertainty in the estimate. This meant that there was little difference from, and overlap with, the estimate of effect for vancomycin. The committee were also aware of the limited clinical experience with using teicoplanin in the UK for C. difficile infection. They concluded that further research was needed on teicoplanin for treating C. difficile infection and made a recommendation for research.
The committee had an initial discussion about the findings from the economic model. They noted that, if the results from the studies of teicoplanin were considered robust, it would come out clearly as the most cost-effective first-line treatment. However, they were not convinced by either the sample size or quality of the studies on teicoplanin. They agreed there was not enough clinical evidence to recommend it, so focused on the economic model results excluding teicoplanin.
Metronidazole was not recommended by the committee for treating C. difficile infection. The committee agreed that not using metronidazole first line for mild and moderate C. difficile infection represented a change in practice for some clinicians. However, they were confident in the evidence that metronidazole was neither clinically nor cost effective compared with vancomycin. In the network meta-analysis results, metronidazole was ranked lowest out of all the antibiotics available in the UK (below teicoplanin, fidaxomicin, vancomycin, rifaximin and fusidic acid). In the economic modelling, when the costs of rehospitalisation were included in the analysis, metronidazole was a less cost-effective first-line treatment than vancomycin, which was dominant in most scenarios (meaning using vancomycin was both less costly and more effective than using metronidazole). From the evidence, metronidazole had lower initial cure rates and higher recurrence rates than vancomycin. The committee heard that metronidazole is comparatively inexpensive compared with other antibiotic treatments. However, they discussed that, from experience, many hospital trusts have already moved away from using metronidazole, prompted by lower efficacy compared with other antibiotics and potential side effects. The committee also heard expert testimony that cure or improvement may take longer with metronidazole compared with other antibiotic treatments. A longer period before treatment becomes effective is concerning. This is because it may lead to increased transmission of the infection, particularly in hospital or residential care settings. Neither of these issues were addressed in the economic model.
When considering the economic model, the committee agreed that it was appropriate to exclude strategies in which metronidazole was used as a second-line intervention. They noted that a limitation of the analysis was that interventions were assumed to be equally effective as second-line options compared with first-line options. This was because there were no data to test this assumption. They agreed that, when C. difficile is not clinically cured using first-line vancomycin or fidaxomicin it is likely to represent infection that is harder to treat. So, it would also be less likely to respond to metronidazole, meaning it would not be effective as a second-line agent.
The committee recognised that intravenous metronidazole may be a treatment option in the rare event that C. difficile infection fails to respond to either vancomycin or fidaxomicin, or in people with a life-threatening infection. The committee noted that, from experience, intravenous metronidazole (as an adjunct to vancomycin by the enteral route) is used in practice for some people in these circumstances.
The committee noted the evidence showing no statistically significant difference in clinical effectiveness with low-dose (125 mg four times a day) compared with high-dose (500 mg four times a day) vancomycin. The committee concluded that the standard licensed dose of oral vancomycin 125 mg four times a day for 10 days was sufficient to treat a first episode of mild, moderate or severe C. difficile infection, or a further episode of infection more than 12 weeks after symptom resolution (recurrence). The committee were also aware that specialists may use higher licensed doses of oral vancomycin (up to 500 mg four times a day) for C. difficile infection not responding to first- or second-line antibiotics or for life-threatening infection.
Oral vancomycin can be taken as capsules or the powder for solution can be reconstituted and taken orally as a drink or by nasogastric tube (a licensed use). The committee discussed that capsules would be the preferred formulation, particularly in community settings, for ease of use and to avoid any safety concerns around reconstitution and administration.
A tapered or pulsed regimen of vancomycin was not recommended because, in the evidence review, its use was limited to studies in which there was co-administration of FMT. The committee were aware that there are ongoing trials which might provide evidence for wider use of pulsed or tapered vancomycin.
The committee noted the evidence suggesting that fidaxomicin 400 mg daily was more clinically effective than 100 mg or 200 mg daily. They concluded that the standard licensed dose of oral fidaxomicin 200 mg twice a day for 10 days was sufficient to treat C. difficile infection.
The committee considered the comparison of the standard and extended-pulsed regimens of fidaxomicin in the economic model. The unlicensed extended-pulsed regimen of fidaxomicin is 200 mg twice a day on days 1 to 5, then 200 mg once a day on alternate days from days 7 to 25. The committee noted that the point estimates were in favour of extended-pulsed fidaxomicin. However, there was considerable uncertainty in this conclusion (with a 36% chance of standard fidaxomicin being more cost effective than extended-pulsed fidaxomicin at 30,000 per QALY gained). Also, the absolute magnitude of the differences was small. The committee agreed that there was insufficient evidence of benefits from the extended-pulsed regimen to justify recommending an unlicensed treatment regimen over a licensed one.
The committee agreed that treatment for C. difficile infection in children and young people should only be started by, or after advice from, a specialist. And that antibiotic choice can be based on recommendations for adults, taking into account the varying licensed indications for children and the availability of suitable products.
Vancomycin capsules are licensed to treat C. difficile infection only in people aged 12 years and over (see the vancomycin capsules summary of product characteristics). Vancomycin powder for solution taken orally is licensed to treat C. difficile infection in all age groups (see the vancomycin powder for solution summary of product characteristics).
Fidaxomicin tablets are licensed to treat C. difficile infection in children with a body weight of at least 12.5 kg (see the fidaxomicin summary of product characteristics). Fidaxomicin granules for oral suspension are licensed to treat C. difficile infection from birth (and are likely to become available in the UK). However, there is a caution for use in babies less than 6 months and in babies with body weight less than 4 kg (see the Medicines and Healthcare products Regulatory Agency information on fidaxomicin granules).
For more detail see the summary of the evidence on antibiotic dose.
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# Preventing C. difficile infection

## Why the committee made the recommendations
Recommendations 1.3.1 to 1.3.4
The committee agreed that, although preventing C. difficile infection through good antimicrobial stewardship, infection control and environmental hygiene were out-of-scope for this guideline, a recommendation should be included on where to find such information. They concluded, from experience, that people should see Public Health England's guidance on C. difficile infection: how to deal with the problem, and NICE's guidance on healthcare-associated infections and antimicrobial stewardship.
The committee also discussed the importance of ensuring that a diagnosis of C. difficile infection is recorded in a person's medical records. This is particularly important when transferring from one care setting to another, so that it can be taken into account before prescribing any future antibiotics, to help minimise the risk of recurrent episodes.
The committee noted the lack of evidence of clinical or cost effectiveness to prevent C. difficile infection with antibiotics. They recognised that there was some evidence for rifaximin preventing further recurrences from a single study in people who already had recurrent infection. However, the intensive way in which antibiotics were used in the study has raised concerns about the possible emergence of rifamycin resistance, which has been reported in C. difficile infection cases, and prolonged flora disturbance.
The committee also recognised the limited evidence of benefit for:
fidaxomicin in preventing C. difficile infection in people having a haematopoietic stem cell transplant who had fluoroquinolone prophylaxis
vancomycin in preventing C. difficile infection in people who are in hospital.
The economic model only included treatment options, including adjunctive treatment with bezlotoxumab (which is used to prevent recurrent infection) and FMT to determine sequencing of treatments. It did not include comparisons for preventing a first episode of C. difficile infection with antibiotics, prebiotics or probiotics. The committee concluded that, because of the lack of evidence and concerns about antimicrobial resistance, antibiotics should not be offered for preventing C. difficile infection.
The committee noted the lack of convincing evidence of effect for prebiotics (oligofructose), which showed little difference in preventing C. difficile-associated outcomes in the included studies. They concluded that prebiotics conferred no benefit and that people taking antibiotics should not be advised to take prebiotics to prevent C. difficile infection.
The committee agreed that there is some evidence of a small effect with probiotics in preventing C. difficile infection. However, there were many limitations in the evidence, including:
a high number needed to treat
aggregation of the results of different types of probiotics in meta-analyses
the lack of effectiveness when using confirmed cases only (in everyone, but particularly in children).
The committee also noted concerns from expert testimony about the high prevalence of C. difficile infection in the placebo arms of some studies, which does not reflect clinical practice in the UK. The single study done in a UK setting found no evidence of effect for probiotics in people aged over 65 years. They further noted that NHS England's guidance on conditions for which over the counter items should not routinely be prescribed in primary care states that probiotics should not routinely be prescribed.
The committee concluded that, because of concerns about the evidence base (including cost effectiveness), people taking antibiotics should not be advised to take probiotics to prevent C. difficile infection.
Return to the recommendations# Context
Clostridioides difficile is a bacterium that can infect the bowel and cause diarrhoea. Certain groups, such as older people, are at higher risk of C. difficile infection. The infection most commonly affects people who are taking, or have recently taken, antibiotics, and it can be transmitted very easily. It can be mild, moderate, severe or life threatening, and is treated with antibiotics.# Summary of the evidence
This is a summary of the evidence, for full details (including the economic analysis) see the evidence review.
The evidence for treating Clostridioides difficile infection in adults specifically included antibiotic efficacy, choice, dose and dose frequency, faecal microbiota transplantation (FMT), bezlotoxumab and prebiotics. The evidence for treating C. difficile infection in children included antibiotic choice and probiotics.
For C. difficile infection in adults, young people or children, no evidence from systematic reviews or randomised controlled trials (RCTs) was identified for antibiotic prescribing strategies, course length or route of administration. There was also no evidence found for probiotics for C. difficile infection in adults, nor for antibiotic efficacy, dose or dose frequency, FMT, bezlotoxumab or prebiotics for infection in children.
There was evidence found for prophylactic antibiotics (in adults having a stem cell transplant or in hospital), prebiotics and probiotics to prevent C. difficile infection in adults. There was evidence for probiotics to prevent C. difficile infection in children.
Interventions included in the search were antimicrobial interventions, non-antimicrobial interventions (bezlotoxumab and intravenous immunoglobulin), and non-pharmacological interventions (probiotics, prebiotics, FMT, and stopping current antibiotics or proton pump inhibitors). No evidence from systematic reviews or RCTs was found for intravenous immunoglobulin or stopping current antibiotics or proton pump inhibitors. In addition, the following interventions were outside the scope of this guideline because there is no UK licensed product available: ridinilazole, cadazolid, surotomycin, nitazoxanide, tolevamer, LFF517, bacitracin and tolevamer.

# Treating initial or first recurrent C. difficile infection in adults

## Antibiotics
A statistically significant improvement was seen in symptomatic and bacteriological cure with vancomycin 125 mg four times daily for 5 days compared with placebo in adults with first-episode pseudomembranous colitis (some associated with evidence of C. difficile infection; Nelson et al. 2017).
In 1 network meta-analysis, different antibiotic treatments were compared for treating the initial or first recurrent episode of C. difficile infection. Vancomycin was used as the reference treatment (Beinortas et al. 2018), and the treatments were ranked using P scores. Of the antibiotics available in the UK, sustained symptomatic cure was most effective with teicoplanin (P score=0.9386), followed by fidaxomicin (P score=0.7922), vancomycin (P score=0.4850), rifaximin (P score=0.4296), fusidic acid (P score=0.3794) and metronidazole (P score=0.2411). P scores are calculated as the average p value for superiority for that intervention compared with all the other interventions in the network meta-analysis. They take account of the magnitude of the difference and the level of uncertainty. Higher P scores (on a 0 to 1 scale) represent treatments in which there is more confidence that they are better than the other alternatives in the network meta-analysis.
A sensitivity analysis was done in which the effect was explored of removing studies with fewer than 50 people per arm, studies that were published before 2000, and unblinded studies. When non-blinded studies or studies with fewer than 50 people per arm were removed, fidaxomicin was the highest ranked treatment available in the UK. When studies published before the year 2000 were removed, teicoplanin was the highest ranked treatment available in the UK, followed by fidaxomicin.
Subgroup analysis was done for severe C. difficile infection, non-severe C. difficile infection, initial C. difficile infection, non-initial C. difficile infection, people aged 65 years and over and people aged under 65 years. For all subgroups, fidaxomicin was the highest ranked treatment available in the UK, and metronidazole was the least effective (being ranked either the fifth, sixth or seventh most effective option in the different subgroups).
There were no statistically significant differences in clinical effectiveness (recurrence of C. difficile infection, clinical resolution of C. difficile infection, relapse of C. difficile infection at 5 weeks and adverse events) for oral vancomycin compared with fidaxomicin (Hvas et al. 2019).
There was no statistically significant difference in clinical effectiveness (symptomatic cure) with low-dose (125 mg four times a day) compared with high-dose (500 mg four times a day) vancomycin, both taken for 5 to 15 days (Nelson et al. 2017).
There was a statistically significant improvement in clinical effectiveness (symptomatic cure) with fidaxomicin 400 mg daily compared with fidaxomicin 100 mg or 200 mg daily, all taken for 10 days.
There was no statistically significant difference in clinical effectiveness (symptomatic cure) with 100 mg of teicoplanin twice daily compared with 50 mg of teicoplanin four times daily (Nelson et al. 2017).

## FMT for treating initial C. difficile infection
There were no statistically significant differences in clinical effectiveness (resolution of C. difficile infection, treatment failure, all-cause and C. difficile infection attributable mortality or length of stay) of:
the first dose of FMT compared with vancomycin
the second dose of FMT compared with vancomycin (Camacho-Ortiz et al. 2017).

## FMT for treating recurrent C. difficile infection
There were statistically significant increases in clinical effectiveness (resolution of symptoms, resolution of diarrhoea, relapse of diarrhoea) with:
a 4- to 10day course of vancomycin followed by FMT compared with 10 days of vancomycin at 1- and 8week follow up (Hvas et al. 2019)
a 4- to 10day course of vancomycin followed by FMT compared with 10 days of fidaxomicin at 8week follow up (Hvas et al. 2019)
a 4- to 5day course of vancomycin plus bowel lavage followed by FMT compared with either 14 days of vancomycin (with or without bowel lavage) at 10week follow up, and at 5week follow up for relapse (van Nood et al. 2013)
a 3day course of vancomycin followed by FMT compared with a standard then a pulsed course of vancomycin at 10week follow up (Cammarota et al. 2015).
There were no statistically significant differences in all-cause or C. difficile infection-related mortality for a short course of vancomycin plus bowel lavage followed by FMT compared with 14 days of vancomycin or 14 days of vancomycin plus bowel lavage (van Nood et al. 2013).
There were no statistically significant differences in adverse events for:
a short course of oral vancomycin followed by FMT compared with either 10 days of vancomycin or fidaxomicin (Hvas et al. 2019)
a short course of vancomycin followed by FMT compared with vancomycin, either with or without bowel lavage (van Nood et al. 2013).
There was a statistically significant lower mean number of days of diarrhoea compared with a course of vancomycin followed by FMT compared with tapered vancomycin (Hota et al. 2017). However, a short course of vancomycin followed by FMT or bowel lavage plus FMT statistically significantly increased treatment-related diarrhoea, bloating or cramping (Cammarota et al. 2015; van Nood et al. 2013).
Serious adverse events were reported in 2 RCTs. In 1 RCT, a sepsis-like response occurred (possibly related to FMT) but resolved without admission or treatment (Hvas et al. 2019). In the other RCT, 3 serious adverse events were noted but none were thought to be treatment related (Hota et al. 2017).

# Preventing recurrence in people with C. difficile infection in adults

## Antibiotics
In adults who had an initial or first recurrent episode of C. difficile infection treated with vancomycin or metronidazole, immediate rifaximin for 20 days was statistically significantly more effective than placebo at reducing recurrence of both C. difficile infection-confirmed diarrhoea and self-reported diarrhoea. However, when the outcomes of recurrent C. difficile infection-confirmed diarrhoea and recurrent self-reported diarrhoea were analysed separately, there was no statistically significant difference between rifaximin and placebo in either group (Garey et al. 2011).
In adults who had an initial, first recurrent, or second or later recurrent episode of C. difficile infection treated with vancomycin or metronidazole, there was no statistically significant difference between immediate rifaximin for 28 days and placebo for recurrent C. difficile infection at 12 weeks or 6 months, or for rehospitalisation for C. difficile infection within 6 months. When subgroup analysis was done for standard care antibiotic treatment with metronidazole or vancomycin, there was no statistically significant difference between rifaximin and placebo for C. difficile infection recurrence. There was also no statistically significant difference in effect between rifaximin and placebo on C. difficile infection recurrence when posthoc analyses were done for C. difficile infection history (Major et al. 2019).
A KaplanMeier analysis showed that rifaximin led to a statistically significant increased time to both recurrent C. difficile infection-confirmed diarrhoea and recurrent self-reported diarrhoea compared with placebo (Garey et al. 2011). However, when the time to C. difficile infection-confirmed diarrhoea and time to self-reported diarrhoea were analysed separately, there was no statistically significant difference between rifaximin and placebo.
There were no statistically significant differences between rifaximin and placebo for mortality, serious and non-serious adverse events (Major et al. 2019).

## Monoclonal antibodies
In adults with an initial or recurrent episode of C. difficile infection treated with standard care antibiotic treatment (that is, metronidazole, vancomycin or fidaxomicin), bezlotoxumab was statistically significantly more effective than placebo for recurrent C. difficile infection, 12 weeks of sustained cure and recurrence of diarrhoea (regardless of whether it was associated with a positive toxin test; Wilcox et al. 2017). A KaplanMeier analysis suggested that bezlotoxumab increased time to recurrence of C. difficile infection compared with placebo, but it was unclear if the differences were statistically significant.
Various subgroup analyses for C. difficile infection risk factors and stratification variables were done. Bezlotoxumab was statistically significantly more effective than placebo for recurrence of C. difficile infection for the stratification variables of inpatients and outpatients, and whether people had vancomycin or metronidazole as their standard care antibiotic treatment. However, there was no statistically significant difference between bezlotoxumab and placebo for the outcome of recurrence of C. difficile infection for the stratification variable of people having fidaxomicin as their standard care antibiotic treatment.
There were no statistically significant differences between bezlotoxumab and placebo for the outcomes of initial clinical cure at 2 days and mortality.
There was no statistically significant difference between bezlotoxumab and placebo for infusion-specific adverse events or adverse events leading to treatment being stopped at 24hour follow up. There was also no statistically significant difference between bezlotoxumab and placebo for drug-related adverse events, other adverse events (most commonly abdominal pain, diarrhoea, nausea, vomiting, fatigue, pyrexia, serious C. difficile, urinary tract infection or headache), serious adverse events or for drug-related serious adverse events, occurring during the 4 weeks after the bezlotoxumab infusion.

## FMT for preventing C. difficile infection recurrence
In NICE analyses, there were no statistically significant differences in the clinical effectiveness (recurrence) of the following doses of FMT taken after antibiotic treatment for a current episode of C. difficile infection in adults with multiple recurrent infections:
a single dose of FMT compared with placebo
doses of FMT compared with placebo
doses of FMT compared with a single dose of FMT
-r 2 doses of FMT (pooled) compared with placebo (Dubberke et al. 2018).
There was no statistically significant difference in adverse events. However, 3 severe adverse events were reported and thought to be related to FMT in the '2 doses of FMT' group. There were 6 deaths (3 in the '2 doses of FMT' group and 3 in the '1 dose of FMT' group) in the FMT arms of the trial and none in the placebo group.

## Prebiotics for relapse of diarrhoea
There was a statistically significant decrease in relapse of diarrhoea with metronidazole or vancomycin plus the prebiotic oligofructose compared with metronidazole or vancomycin plus placebo for diarrhoea associated with C. difficile infection in adults aged over 65 years (Lewis et al. 2005a). No statistically significant difference was noted for C. difficile culture positivity at 30- or 60day follow up.

# Treating initial or recurrent C. difficile infection in children and young people

## Antibiotics choice
There was no statistically significant difference in clinical effectiveness (C. difficile infection cure rate or recurrent C. difficile infection) with oral metronidazole compared with oral rifaximin for a first episode of C. difficile infection in children with inflammatory bowel disease (Gawronska et al. 2017).
There was no statistically significant difference in confirmed clinical response or resolution of diarrhoea with oral fidaxomicin compared with oral vancomycin for confirmed C. difficile infection in children and young people aged under 18 years (Wolf et al. 2020).
In the total study population and subgroup of children aged under 2 years, there was no statistically significant difference between oral fidaxomicin and oral vancomycin for the outcome of global cure. However, in other subgroups (those aged 2 years and over and those with a positive toxin test aged 2 years and over), fidaxomicin was statically significantly more effective than vancomycin for global cure.
Oral fidaxomicin statistically significantly reduced C. difficile infection recurrence compared with oral vancomycin in children and young people aged under 18 years. When results were stratified by age, fidaxomicin was statistically significantly more effective than vancomycin in children aged 2 years and over and in children with a positive toxin test aged 2 years and over, but the effect was no longer statistically significant in those aged under 2 years.
There was no statistically significant difference for treatment-emergent adverse events (including serious events, drug-related events, those leading to death or withdrawal from treatment).

## Probiotics for persistent diarrhoea
There was a statistically significant reduction in the mean number of days of diarrhoea with oral rehydration solution plus the probiotic Lactobacillus rhamnosus GG compared with oral rehydration solution alone in children with a positive C. difficile stool culture (Basu et al. 2007). However, there was no statistically significant difference in the mean number of days of vomiting.

# Preventing C. difficile infection in adults without infection

## Antibiotics
In people without C. difficile infection having a haematopoietic stem cell transplant and fluoroquinolone prophylaxis during neutropenia, there was no statistically significant difference between fidaxomicin and placebo for reducing prophylaxis failure at 30, 60 or 70 days (Mullane et al. 2019). There was also no statistically significant difference between fidaxomicin and placebo for any adverse events reported in the study.
Fidaxomicin was statistically significantly more effective than placebo at reducing confirmed diarrhoea associated with C. difficile infection at 30, 60 and 70 days. A KaplanMeier analysis showed a statistically significantly increased time to recurrence of C. difficile infection with fidaxomicin compared with placebo.
In people without C. difficile infection who were hospitalised for up to 30 days before their current hospitalisation, there was no statistically significant difference between oral vancomycin and placebo for:
healthcare facility-onset (symptomatic infection more than 72 hours after hospital admission) C. difficile infection, or
community-onset healthcare facility-associated (symptomatic infection up to 3 months after hospital discharge) C. difficile infection after hospital discharge (Johnson et al. 2020).

## Prebiotics
In inpatients aged over 65 years without C. difficile infection who were prescribed a broad-spectrum antibiotic, the prebiotic oligofructose did not have a statistically significantly different effect to placebo at end of follow up for all-cause mortality or for incidence of diarrhoea, significant diarrhoea (3 loose stools or more in a 24hour period), non-significant diarrhoea (1 or 2 loose stools in a 24hour period), C. difficile-associated diarrhoea or C. difficile-associated significant diarrhoea (Lewis et al. 2005b).
In the oligofructose group, the median (interquartile range) length of hospital stay was 17 days (13 to 22) compared with 15 days (11 to 18) in the placebo group.

## Probiotics
The evidence for probiotics in the prevention of C. difficile infection in adults comes from 1 systematic review (Goldenberg et al. 2017). The population in the included studies was people aged over 18 years having antibiotic treatment for any reason.
Probiotics statistically significantly reduced the incidence of C. difficile infection compared with any comparator (follow-up time point not reported) in studies in inpatients, but not in studies in outpatients or patients in mixed settings.
Probiotics were not statistically significantly different compared with any comparator for the outcome of incidence of C. difficile infection determined by detection of C. difficile in stools, either overall or in any setting (inpatients, outpatients, or mixed settings; follow-up time points not reported).
Probiotics statistically significantly reduced the number of adverse events compared with any comparator (follow-up time point not reported). Details of the adverse events were not reported.

# Preventing C. difficile infection in children and young people without infection

## Probiotics
The evidence for probiotics in preventing C. difficile infection in children and young people comes from 1 systematic review (Goldenberg et al. 2017) and 1 RCT (Kolodziej and Szajewska 2019). The population in the included studies was children and young people aged under 18 years who were having antibiotic treatment for any reason.
Probiotics statistically significantly reduced the incidence of C. difficile infection compared with any comparator (follow-up time point not reported) in the inpatient and mixed settings studies.
Probiotics were not statistically significantly different compared with any comparator in inpatient studies for the outcome of incidence of C. difficile infection determined by detection of C. difficile in stool (follow-up time point not reported).
Probiotics were not statistically significantly different compared with any comparator for adverse events.# Other considerations

# Medicines safety

## Vancomycin
Vancomycin is a glycopeptide that is taken orally to treat Clostridioides difficile infection. With oral use, the company advises monitoring serum vancomycin concentration in people with inflammatory intestinal disorders in which absorption may be enhanced. It also advises that serial auditory function tests may help to minimise the risk of ototoxicity in people with an underlying hearing loss, or who are having concomitant therapy with other ototoxic drugs. In renal impairment or in people having concomitant treatment with an aminoglycoside or other nephrotoxic drug, the manufacturer advises serial monitoring of renal function. The manufacturer advises that vancomycin should be used in pregnancy only if the potential benefit outweighs the risk. Prolonged use of vancomycin may result in the overgrowth of non-susceptible organisms. Acquired resistance to glycopeptides is most common in enterococci, in which multiresistant strains have been seen (see BNF information on vancomycin and vancomycin summary of product characteristics).

## Fidaxomicin
Fidaxomicin is a macrocyclic antibacterial that is poorly absorbed from the gastrointestinal tract, so is not used to treat systemic infections. It is taken orally to treat C. difficile infection. Common side effects when taken orally for C. difficile infection include constipation, nausea and vomiting. The manufacturer advises that it is preferable to avoid using fidaxomicin in pregnancy as a precaution (see BNF information on fidaxomicin and fidaxomicin summary of product characteristics).

## Faecal microbiota transplant
In NICE's interventional procedures guidance on faecal microbiota transplant for recurrent C. difficile infection, it states that 'The US Food and Drug Administration has advised that stool donors for faecal microbiota transplantation should be screened with questions that specifically address risk factors for colonisation with multidrug-resistant organisms (MDROs), and individuals at higher risk of colonisation with MDROs should be excluded as donors. In addition, donor stool should be specifically tested for MDROs and not used if positive'. While short-term safety and adverse events with a faecal microbiota transplant were reported in the included studies for this guidance, the committee identified that longer-term safety of the procedure is not yet known.

# Medicines adherence
Medicines adherence may be a problem for some people taking antibiotics that need frequent dosing or longer treatment duration (see NICE's guideline on medicines adherence).

# Resource implications
See the economic analysis in the evidence review for detailed costs, including estimated costs of a faecal microbiota transplant. Vancomycin capsules and powder for solution are available as generic formulations. Fidaxomicin tablets are a proprietary product.