Clostridium Difficile Infection ( CDI ) in Adults ( >16 years of age ) - Diagnosis and Management of

Publication: 20/05/2008  --
Last review: 21/08/2019  
Next review: 21/08/2022  
Clinical Guideline
CURRENT 
ID: 1254 
Approved By: Improving Antimicrobial Prescribing Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2019  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Diagnosis and Management of Clostridium Difficile Infection (CDI) in Adults (>16 years of age)

  • Treatment Algorithm
  • Summary
    Clostridium Difficile Infection ( CDI ) in Adults ( >16 years of age )

    Criteria for use of guidelines
    All adult patients (>16 years of age, and including immunosuppressed) with diarrhoea (type 5-7 stool, Bristol stool chart) and a positive Clostridium difficile result (a positive result requires both positive glutamate dehydrogenase (GDH) and toxin assays) OR C. difficile infection (CDI) suspected clinically but not yet confirmed.

    Investigations required

    • Diarrhoeal stool sample (for “CDI testing”).
    • FBC, U&Es.
    • Lactate (severe and life-threatening infection).
    • Radiology: Abdominal X-ray and/or CT abdomen (if there is any clinical evidence of colitis).

    Severity assessment (see table 1 below or severity section)

    Non-Antimicrobial Management

    • Fluid resuscitation and electrolyte replacement as appropriate.
    • Immediate instigation of Isolation policy and Clostridium difficile Infection Control Policy
    • Review ALL antimicrobials and any medicines that can produce diarrhoea.
    • Record stool frequency and consistency daily on a Bristol Stool Chart.
    • Daily monitoring for signs of increasing severity of disease.
    • Review and where possible stop proton pump inhibitors (PPIs)
    • Dietetic input and review in patients with (Malnutrition universal screening tool) score ≥2
    • Nutritional supplements
    • Consider transfer to CDI cohort facility (J17A or J20).
    • Refer patients with >1 episode to infectious diseases for consideration of faecal microbiota transplant (FMT).

    Initial antimicrobial treatment
    *Do not wait for laboratory confirmation before starting therapy if suspicion is high, use severity/recurrence to guide therapy - but please review in light of subsequent results

    Table 1. Clostridium difficile infection (CDI) initial treatment regimens*

    Severity

    Criteria (any ONE of)

    First line regimen

    Recurrence (within 28 days)**

    Non-severe

    Diarrhoea without features of severe or life-threatening infection

    ORAL/NG:Vancomycin electronic Medicines Compendium information on Vancomycin 125mg 6-h

    ORAL Fidaxomicin electronic Medicines Compendium information on Fidaxomicin200mg 12-h (approval code needed). Use Metronidazole electronic Medicines Compendium information on Metronidazole in pregnancy

    Severe

    • Raised WCC >15 x 109/L.
    • Acute kidney injury (e.g. >50% rise in serum creatinine above baseline).
    • Temperature of >38.5°C.
    • Evidence of severe colitis (e.g. guarding, abdominal tenderness).

    ORAL/NG:Vancomycin electronic Medicines Compendium information on Vancomycin  125mg 6-h

    IF requiring antibiotic treatment for another infection or multiple comorbidities :
    ORAL Fidaxomicin electronic Medicines Compendium information on Fidaxomicin 200mg 12-h (approval code needed)

    Please note the reason for fidaxomycin use in the patient notes/drug chart.

    Oral Fidaxomicin electronic Medicines Compendium information on Fidaxomicin 200mg 12-h (approval code needed) UNLESS received Fidaxomicin electronic Medicines Compendium information on Fidaxomicin previous 28 days, then
    ORAL/NG:Vancomycinelectronic Medicines Compendium information on Vancomycin125mg 6-h

    Life-threatening

    • Hypotension (not responsive to fluid challenge).
    • Partial or complete ileus or toxic megacolon

    NG: Vancomycin electronic Medicines Compendium information on Vancomycin ***
    125 mg 6-h AND
    IV: Metronidazole 500mg 8-h

    NG: Vancomycin electronic Medicines Compendium information on Vancomycin*** 125mg 6-h AND
    IV: Metronidazole electronic Medicines Compendium information on Metronidazole 500mg 8-h

    ** Laboratory confirmation required.
    ***Consider NG Vancomycin electronic Medicines Compendium information on Vancomycin 500mg 6-h if evidence of ileus or use of rectal enema (Discuss with Microbiology or infectious diseases).

    Duration of Treatment
    For vancomycin: if symptoms have resolved at 10 days, stop antimicrobials; if symptoms improving but not resolved, complete 14 days. (Fidaxomycin is a 10 day course).

    Specialist Consultations
    If symptoms are no better at day 7 see algorithm.

    If at any point the patient develops evidence of colitis contact surgeons urgently.

    If this is the second or later episode, refer to infectious diseases for consideration of FMT.

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    Background

    Clostridium difficile is a Gram-positive spore forming bacterium that a common cause of infectious diarrhoea acquired in the healthcare setting. Some patients are colonized by C. difficile and are asymptomatic. C. difficile infection (CDI) is defined as symptomatic illness (usually diarrhoea) caused by toxin production.
    CDI is associated with excess morbidity and mortality, particularly in frail elderly patients. It is also responsible for considerable costs to both patients and the healthcare services. C. difficile is spread via the faecal-oral route by the transmission of spores from infected individuals to other patients. Infection is a major infection control hazard and Trust guidelines regarding this should be followed; see Source Isolation and Hand Hygiene Techniques for more details.
    CDI usually requires specific treatment to reduce the duration of symptoms and the risk of spread (see Empirical antimicrobial therapy).
    Risk Factors

    • Old age (>65 years).
    • Hospitalized patients.
    • Previous antimicrobial therapy, especially 2nd generation (e.g. cefuroxime) and 3rd generation (e.g. cefotaxime) cephalosporins, Co-Amoxiclav (Amoxicillin-Clavulanate), clindamycin and quinolones.
    • Long duration of antibiotic use (>7 days).
    • Multiple antibiotic courses.
    • Severe underlying disease.
    • Presence of nasogastric tube.
    • Non-surgical gastrointestinal procedures.
    • Proton pump inhibitors.

    Infection control recommendations can be found at Clostridium difficile Infection Control Policy

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    Clinical Diagnosis

    Recommendation: Clostridium difficile infection (CDI) should be considered in any hospitalized (or at risk patient) suffering one (or more) episode(s) of diarrhoea, defined either as stool loose enough to take the shape of a container or as Bristol Stool Chart types 5-7 [3]. [Evidence level B]

    Recommendation: Clinical features are unreliable for the diagnosis of CDI, necessitating microbiological testing (see investigations section, see also LTHT gastroenteritis guideline). [Evidence level B]

    Recommendation: Patients with suspected or confirmed CDI should be assessed daily for severity of infection including signs and symptoms of colitis [3]. [Evidence level B]

    Recommendation: Patients with suspected or confirmed CDI should have the frequency and severity of diarrhoea assessed and documented using the Bristol Stool Chart [3]. [Evidence level B]

    Patients with C. difficile infection often have diarrhoea, which is profuse, watery and may have a characteristic smell, although none of these clinical features are specific for C. difficile infection and a microbiological diagnosis is required for confirmation.

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    Severity Assessment

    Recommendation: A severity assessment should be carried out in all patients with suspected or confirmed CDI [3, 5, 6]. [Evidence level B]

    Non-severe CDI: [Evidence level D]

    • Diarrhoea without any features to suggest severe or life-threatening infection.

    Severe CDI any of the following: [Evidence level C]

    • Raised WCC >15 x 109/L.
    • Acute kidney injury (e.g. >50% increase in creatinine above baseline).
    • Temperature of >38.5˚C
    • Evidence of severe colitis (e.g. guarding, abdominal tenderness).

    Life-threatening CDI any of the following: [Evidence level B]

    Public Health England (PHE) guidelines categorise CDI into mild, moderate, severe and life-threatening [3]. The main features distinguishing mild from moderate disease are the frequency of diarrhoea and a moderate increase in white cell count. At the same time, the PHE guidelines acknowledge that stool frequency is not necessarily a reliable marker of severity. As in the previous version of this guideline, in order to provide a less complex severity assessment that promotes therapy in symptomatic patients with less severe symptoms, we have combined the “mild” and “moderate” severity cases into a single “non-severe” CDI category. In a retrospective analysis of intensive care unit admissions, patients requiring vasopressors, over 75 year old, with serum lactate ≥ 5 mmol/L, immunosuppression or white cell count ≥50x109/L had an increased risk of dying [4].

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    Investigation

    Microbiology
    Recommendation: Send a single diarrhoeal stool specimen for C. difficile infection testing [3]. [Evidence level B]

    Only send stools for testing from symptomatic patients, i.e. only liquid/loose stools that take the shape of a container or as Bristol Stool Chart types 5-7.

    Recommendation: Do not retest C. difficile toxin positive cases if patients are still symptomatic within a period of 28 days unless symptoms resolve and then recur and there is a need to confirm recurrent CDI [3]. [Evidence level B]

    Recommendation: Where there is a strong clinical suspicion of CDI but the first toxin test is negative, send a second sample 24 hours later. See Table 2 for test interpretation [3]. [Evidence level B]

    Table 2. Clinical interpretation of Clostridium difficile laboratory test results.

    Test result

    Interpretation

    GDH negative

    No C. difficile infection or colonisation.

    GDH positive / Cytotoxin negative

    Potential C. difficile excretor.
    C. difficile treatment not usually required.

    GDH positive / Cytotoxin positive

    C. difficile infection probable.
    Treatment usually required.

    Samples which are GDH positive, cytotoxin negative from in-patients will then have a further PCR-based test to detect if the toxin genes are present. If the genes are absent, the C difficile strain is non-pathogenic. The result will be reported as either “toxigenic strain present” or non-toxigenic strain present.

    Imaging
    Recommendation: In suspected cases of ‘silent’ CDI, such as ileus, toxic megacolon or pseudomembranous colitis without diarrhoea, request abdominal imaging e.g. abdominal x-ray and CT scanning [3]. [Evidence level B]

    Blood tests
    Recommendation: Send Full blood count and Urea and electrolytes in all cases.
    [Evidence level D]
    White cell count and creatinine are required for the severity assessment. NB. Particular attention should be given to serum potassium levels, as large losses may occur in diarrhoeal faeces.

    Recommendation: Measure serum lactate in severe infection, and monitor levels as clinically indicated (e.g. until the patient improves, levels start to fall or until surgery.)
    [Evidence level D]

    In a retrospective analysis of intensive care unit admissions, patients with a serum lactate ≥ 5 mmol/L had an increased risk of dying (Adjusted Odds Ratio, 12.4; 95% CI, 2.4-63.7), whereas those with lactate between 2.2 and 4.9 mmol/L appeared to benefit from colectomy [4]. As in other causes of severe sepsis, serum lactate can be a useful marker of deterioration requiring surgical assessment. DOH guidelines recommend monitoring lactate in life-threatening infection [3], but it may be too late at this point; hence the recommendation for earlier testing.

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    Treatment
    Non-Antimicrobial Treatment

    NB Infection control recommendations can be found at Clostridium difficile Infection Control Policy

    Recommendation: Patients should be reviewed daily and agreed plans regarding fluid resuscitation, electrolyte replacement and nutrition should be clearly documented in the patient’s notes [3]. [Evidence level B]

    Recommendation: The need for antimicrobials [7], proton pump inhibitors (PPI) and any medicines that can produce diarrhoea should be reviewed (Do not stop PPI where there is a history of gastrointestinal bleeds). [Evidence level B]

    Recommendation: Life-threatening CDI or patients with evidence of severe colitis (e.g. guarding, bloody diarrhoea, abdominal tenderness or radiological evidence) require specialist surgical input. Colectomy is required in some patients with megacolon (dilatation >10cm), perforation or septic shock [4, 8]. [Evidence level B]

    Recommendation: Colectomy is best performed before blood lactate rises >5 mmol/L, when survival is extremely poor. [4] [Evidence level B]

    Recommendation: In severe infections that are not responding to antimicrobial regimens, intravenous immunoglobulin may be considered in consultation with an infection specialist. Approval of the immunoglobulin will be required (see DTC web pages). [Evidence level B]

    For any adult patient positive for toxin positive / toxigenic strain of C difficile, consider if suitable for transfer to a Trust-wide C difficile cohort facility. These are located on J17A (under Care of the Elderly) or J20 (Infectious Diseases). Such transfers should be agreed in advance both between appropriate nursing and medical staff.  If transfer not appropriate, then this should be documented, with the reason(s) at the time, in the patient’s records. The decision / reason(s) not to transfer should be kept under ongoing review whilst the patient remains an LTHT in-patient [Evidence level C].

    Specialist Consultations
    If symptoms fail to improve or worsen despite following this guideline, consult with microbiology or infectious diseases and gastroenterology as clinically indicated.

    For any adult patient with recurrent infection and who has previously received treatment with either vancomycin or fidaxomicin, however long ago, refer to infectious diseases for consideration of FMT.

    Dietetic input and review in patients with (Malnutrition universal screening tool) score ≥2.

    NB. Concurrent antimicrobial therapy is associated with lower cure rates, hence the need to review all antimicrobial prescriptions and stop them whenever possible [3, 7].

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    Empirical Antimicrobial Treatment

    Recommendation: In all cases the need for (non-CDI) antimicrobials should be reviewed as these are associated with poorer outcome. [Evidence level B]

    Recommendations: If there is a strong clinical suspicion of CDI empirical treatment should be initiated pending the results of C. difficile toxin assays:

    Non-severe CDI [9-12] [Evidence level A]
    ORAL/NG*: Vancomycin electronic Medicines Compendium information on Vancomycin 125mg 6-hourly
    If oral/NG route is unavailable, intravenous Metronidazole electronic Medicines Compendium information on Metronidazolecan be used.

    Severe CDI [9] [Evidence level A]
    ORAL/NG: Vancomycin electronic Medicines Compendium information on Vancomycin 125mg 6-hourly IF the patient is UNABLE to swallow tablets (the injection is licensed to be used orally), OR does NOT require additional antibiotics OR has NO multiple comorbidities present.

    ORAL: Fidaxomicin electronic Medicines Compendium information on Fidaxomicin200mg 12-hourly (only if patient requires concomitant antibiotics for a different infection OR if multiple comorbidities present). Please note the reason for fidaxomycin use in the patient notes/drug chart.

    Life-threatening CDI [Evidence level B/C]
    NG* or PR: Vancomycin electronic Medicines Compendium information on Vancomycin 125mg 6-hourly**
    AND
    IV: Metronidazole electronic Medicines Compendium information on Metronidazole500mg 8-hourly [13]
    *Given via a nasogastric tube, which is then clamped for one hour
    **Consider NG Vancomycin electronic Medicines Compendium information on Vancomycin 500mg 6-h if evidence of ileus or use of rectal enema (see appendix 1).

    Recurrent infection
    ORAL: Fidaxomicin electronic Medicines Compendium information on Fidaxomicin200mg 12-hourly, unless the patient has previously received this therapy in the last 28 days, or is pregnant. Then use ORAL/NG Vancomycin electronic Medicines Compendium information on Vancomycin125mg 6-hourly. Use Metronidazole electronic Medicines Compendium information on Metronidazolein non-severe pregnant patient with recurrence. Please note the reason for fidaxomycin use in the patient notes/drug chart.

    Evidence review/justification.
    Vancomycin electronic Medicines Compendium information on Vancomycin and Metronidazole electronic Medicines Compendium information on Metronidazole are long established therapies for CDI but both are associated with treatment failures and relapses. Vancomycin electronic Medicines Compendium information on Vancomycin and Metronidazole electronic Medicines Compendium information on Metronidazole  were previously thought to have similar efficacy for non-severe CDI.  Recent data has though shown Vancomycin electronic Medicines Compendium information on Vancomycin  is superior [9-11,27]. The recommendation for vancomycin as first line treatment for CDI requires vigilance for the emergence of Vancomycin electronic Medicines Compendium information on Vancomycin resistant bacteria e.g. vancomycin resistant enterococcus [12, 14].

    Oral therapy is generally preferred to intravenous therapy because the pathogen, and thus the source of toxin production, is located in the bowel lumen, however, intravenous Metronidazole electronic Medicines Compendium information on Metronidazole also reached bactericidal concentrations in faeces [13]. There is no robust evidence that higher doses of Vancomycin electronic Medicines Compendium information on Vancomycin(e.g. 2g/day) are more efficacious than lower doses in severe infection, and standard 125mg dosing provides more than adequate stool concentrations), hence the dosing recommendation for life-threatening infection. However, if there is evidence of ileus then, in life threatening infection, an increased dosage of oral vancomyin (up to 500mg four times daily) may be prudent. Intravenous therapy is advised in addition to oral/ng therapy in life-threatening infection because impaired gut motility may slow/impair delivery of the antimicrobials to the site of infection.

    Vancomycin electronic Medicines Compendium information on Vancomycin (500mg in 100ml sodium chloride 0.9% per rectum four times daily) can also be given by retention enema in such situations but the evidence to support this practice is limited to case reports [15-17] and it has been associated with bloodstream infection and vancomycin-resistant enterococcal bacteraemia (in 44% of patients in one small series). [18]

    Fidaxomicin electronic Medicines Compendium information on Fidaxomicin is a new and recently licensed agent for the therapy of CDI. For a more detailed review of the literature pertaining to Fidaxomicin electronic Medicines Compendium information on Fidaxomicin please also see DTC submission. The clinical efficacy of Fidaxomicin has been evaluated in two, multi-centre, randomised, double-blind trials, [19, 20] which had similar study designs and produced similar results. Both trials compared 10 days treatment with either Fidaxomicin electronic Medicines Compendium information on Fidaxomicin (200 mg twice daily) or Vancomycin electronic Medicines Compendium information on Vancomycin (125 mg four times daily) in patients aged 16 years or older with mild to severe CDI. This was defined by more than three bowel movements in the 24 hours before randomisation and presence of either C. difficile toxin (A or B). One of these studies [20] included patients from North America only, where the epidemiology of CDI differs from in Europe. The other [19] included European patients (40%) as well as patients from Canada and North America. The primary endpoint was clinical cure, which was defined as resolution of symptoms of diarrhoea and no requirement for additional treatment. The proportion of patients who were cured but subsequently had recurrence during a four-week or 30-day follow up was also investigated as a pre-specified outcome. The total proportion of patients who did not have a recurrence during follow up (termed sustained response or global cure) was also analysed. Non-inferiority was pre-specified with a margin of 10%. In both studies Fidaxomicin electronic Medicines Compendium information on Fidaxomicin was found to be non-inferior to Vancomycin electronic Medicines Compendium information on Vancomycin with regard to clinical cure, and recurrence rates were significantly lower, based on modified intention-to-treat (ITT) and per protocol (PP) analysis.

    NICE recommend that current evidence for the safety and efficacy of FMT supports its use for patients with recurrent C. difficile infections that have failed to respond to antibiotics and other treatments. [28] Duodenal infusion of donor faeces was compared with oral vancomycin and oral vancomycin with a bowel lavage in a prospective, open-label, randomised trial of 42 patients with a relapse of C. difficile infection after at least one course of adequate antibiotic therapy (≥10 days of oral vancomycin ≥125mg QDS or Metronidazole electronic Medicines Compendium information on Metronidazole 500mg TDS). The primary cure rate in the FMT group was 81.3%, rising to 93.8% after three patients received a second infusion. The cure rates in the Vancomycin electronic Medicines Compendium information on Vancomycin and Vancomycin electronic Medicines Compendium information on Vancomycin with bowel lavage groups were 23% and 30.8% respectively. [29]

    This guideline has been reviewed and updated in response to updated guidelines from Health Protection England. [21] Fidaxomicin electronic Medicines Compendium information on Fidaxomicinshould now be considered for patients with severe CDI who are considered at high risk for recurrence; these include elderly patients with multiple comorbidities and/or who are receiving concomitant antibiotics. [21]

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    Directed Antimicrobial Treatment (when microbiology results are known)

    Please see empirical antimicrobial therapy section as this is a Clostridium difficile-specific guideline.

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    Duration of Treatment

    Recommendation: CDI treatment using vancomycin  should be reviewed at day 10, if diarrhoea has resolved, treatment can be stopped; if diarrhoea is resolving complete 14 days therapy and stop.
    [Evidence level D]

    For fidaxomycin, the standard treatment duration is 10 days.

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    Treatment Algorithm

     

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    Treatment Failure

    Recommendation: Diarrhoea should resolve within 1-2 weeks, if diarrhoea has improved but persists at 14 days but the patient is otherwise stable, the WCC is normal, and there is no abdominal pain or distension, the persistent diarrhoea may be due to post-infective irritable bowel syndrome, consider an anti-motility agent such as loperamide 2 mg as required (instead of Metronidazole electronic Medicines Compendium information on Metronidazole or Vancomycin electronic Medicines Compendium information on Vancomycin ). [Evidence level D]

    Recommendation: Treatment failure should not be assessed before day 7 of therapy [3]. [Evidence level C]

    Recommendation: If symptoms are not improving or worsening at day 7 and the patient was originally categorised as non-severe CDI (and continues to show no evidence of severe infection) then change to ORAL/NG: Vancomycin electronic Medicines Compendium information on Vancomycin 125mg 6-h, or Fidaxomicin electronic Medicines Compendium information on Fidaxomicin200mg 12-h if already on oral Vancomycin electronic Medicines Compendium information on Vancomycin ). [Evidence level C]

    Recommendation: If symptoms are not improving or worsening at day 7 and the patient was originally categorised as severe CDI (or they now show features of severe infection) treat as for life-threatening CDI.
    [Evidence level D]

    Recommendation: Seek a surgical opinion when symptoms are worsening. [Evidence level C]

    Recurrence
    Recommendation: Recurrence of CDI is usually defined as recurrence of diarrhoea (at least 3 consecutive type 5-7 stools) and a positive C. difficile toxin assay within 30 days of a previous CDI episode and after resolution of previous symptoms (i.e. no diarrhoea for at least 48 hours) [19].

    NB. Patients with previous CDI who do not fulfil criteria for a recurrence should be treated as a new episode of CDI, according to this guideline.

    Recommendation: For a recurrence of CDI use oral Fidaxomicin electronic Medicines Compendium information on Fidaxomicin200mg 12-hourly (duration and review as for other agents) unless patient has received Fidaxomicin in the last 28 days, then Vancomycin electronic Medicines Compendium information on Vancomycin should be used. This will be a restricted antimicrobial requiring a microbiology/ID approval code. [Evidence level C]

    Evidence review/justification
    Recurrent CDI can be a debilitating and costly problem but the majority of recurrences are re-infections as opposed to relapses [22]. Recurrence occurs in 15-30% of cases after a first episode [19] but 30-60% after a second episode. [6] Complication rates and further recurrences are very high after an initial relapse and prevention is therefore important. Fidaxomicin electronic Medicines Compendium information on Fidaxomicinis superior to Vancomycin electronic Medicines Compendium information on Vancomycin in reducing the risk of recurrence [19]. The effectiveness of Fidaxomicin electronic Medicines Compendium information on Fidaxomicinis unknown in life-threatening CDI [21], until further information becomes available it was felt it should not be advised as routine therapy in this situation [24].

    If a recurrence occurs after therapy with Fidaxomicin electronic Medicines Compendium information on Fidaxomicin, the case should be discussed with microbiology or infectious diseases and consideration given to stopping all antimicrobial therapy. Intravenous immunoglobulin may be appropriate (in consultation with microbiology/infectious diseases and the immunoglobulin review panel) in cases of recurrence in patients with low/deteriorating serum albumin [2]. Tapering doses of Vancomycin electronic Medicines Compendium information on Vancomycin have been used to treat CDI recurrence and remain an option but the regimens have not been standardized or adequately evaluated [1]. Donor stool transplants are occasionally required but this is an area requiring specialist input.

    NB. Death certification [25]:
    Doctors have a legal duty to mention CDI on a death certificate if it was part of the sequence of events directly leading to death or contributed in some way.

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    Provenance

    Record: 1254
    Objective:

    Aims

    • To improve the diagnosis and management of Clostridium difficile infection (CDI) in adult patients (>16 years old) including immunosuppressed patients.

    Objectives

    • To provide evidence-based recommendations for appropriate diagnosis and investigation of Clostridium difficile infection.
    • To provide evidence-based recommendations for appropriate non-antimicrobial management of Clostridium difficile infection.
    • To provide evidence-based recommendations for appropriate antimicrobial therapy of Clostridium difficile infection.
    • To recommend appropriate dose, route of administration and duration of antimicrobial agents.
    • To set-out criteria for referral to specialists.
    Clinical condition:

    Clostridium difficile infection

    Target patient group: Patients with diarrhoea and suspected Clostridium difficile infection
    Target professional group(s): Pharmacists
    Secondary Care Doctors
    Adapted from:

    Evidence base

    1. McFarland, L.V., G.W. Elmer, and C.M. Surawicz, Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol, 2002. 97(7): p. 1769-75.
    2. Wilcox, M.H., Descriptive study of intravenous immunoglobulin for the treatment of recurrent Clostridium difficile diarrhoea. J Antimicrob Chemother, 2004. 53(5): p. 882-4.
    3. Department_of_Health, Clostridium difficile infection: How to deal with the problem, D.o. Health, Editor. 2008.
    4. Lamontagne, F., et al., Impact of emergency colectomy on survival of patients with fulminant Clostridium difficile colitis during an epidemic caused by a hypervirulent strain. Ann Surg, 2007. 245(2): p. 267-72.
    5. Pepin, J., et al., Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity. CMAJ, 2004. 171(5): p. 466-72.
    6. Pepin, J., et al., Management and outcomes of a first recurrence of Clostridium difficile-associated disease in Quebec, Canada. Clin Infect Dis, 2006. 42(6): p. 758-64.
    7. Mullane, K.M., et al., Efficacy of fidaxomicin versus vancomycin as therapy for Clostridium difficile infection in individuals taking concomitant antibiotics for other concurrent infections. Clin Infect Dis, 2011. 53(5): p. 440-7.
    8. Lipsett, P.A., et al., Pseudomembranous colitis: a surgical disease? Surgery, 1994. 116(3): p. 491-6.
    9. Zar, F.A., et al., A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis, 2007. 45(3): p. 302-7.
    10. Wilcox, M.H. and R. Howe, Diarrhoea caused by Clostridium difficile: response time for treatment with metronidazole and vancomycin. J Antimicrob Chemother, 1995. 36(4): p. 673-9.
    11. Musher, D.M., et al., Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis, 2005. 40(11): p. 1586-90.
    12. Gerding, D.N., Metronidazole for Clostridium difficile-associated disease: is it okay for Mom? Clin Infect Dis, 2005. 40(11): p. 1598-600.
    13. Bolton, R.P. and M.A. Culshaw, Faecal metronidazole concentrations during oral and intravenous therapy for antibiotic associated colitis due to Clostridium difficile. Gut, 1986. 27(10): p. 1169-72.
    14. Pharmacists, A.S.o.H.-S., ASHP therapeutic position statement on the preferential use of metronidazole for the treatment of Clostridium difficile-associated disease. American Journal of Health-System Pharmacy, 1998. 55: p. 1407-1411.
    15. Griebie, M. and G.L. Adams, Clostridium difficile colitis following head and neck surgery. Report of cases. Arch Otolaryngol, 1985. 111(8): p. 550-3.
    16. Osler, T., et al., Cefazolin-induced pseudomembranous colitis resulting in perforation of the sigmoid colon. Dis Colon Rectum, 1986. 29(2): p. 140-3.
    17. Pasic, M., et al., Intracolonic vancomycin for pseudomembranous colitis. N Engl J Med, 1993. 329(8): p. 583.
    18. Cohen, S.H., et al., Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol, 2010. 31(5): p. 431-55.
    19. Cornely, O.A., et al., Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis, 2012. 12(4): p. 281-289.
    20. Louie, T.J., et al., Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med, 2011. 364(5): p. 422-31.
    21. Wilcox, M.H., Updated guidance on the management and treatment of Clostridium difficile infection 2013, Public Health England
    22. Wilcox, M.H., et al., Recurrence of symptoms in Clostridium difficile infection--relapse or reinfection? J Hosp Infect, 1998. 38(2): p. 93-100.
    23. SMC. Fidaxomicin (791/12). . 2012
    24. NICE. Clostridium difficile infection: fidaxomicin. 2012; 
    25. Chief_Medical_Officer, Healthcare Associated Infections and Death Certification. PL CMO (1007)8. 2007.
    26. Pasic, M., et al., Systemic absorption after local intracolonic vancomycin in pseudomembranous colitis. Lancet, 1993. 342(8868): p. 443.
    27. Johnson S, Louie TJ, Gerding DN, Cornely OA, Chasan-Taber S, Fitts D, Gelone SP, Broom C, Davidson DM; Polymer Alternative for CDI Treatment (PACT) investigators. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014 Aug;59(3):345-54
    28. NICE, Faecal microbiota transplant for recurrent C. difficile infection. Interventional procedures guidance [IPG485]. March 2014.
    29. Van Nood et al., Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med, 2013. 368(5):p. 407-15.

    Evidence levels:
    A. Meta-analyses, randomised controlled trials/systematic reviews of RCTs
    B. Robust experimental or observational studies
    C. Expert consensus.
    D. Leeds consensus. (where no national guidance exists or there is wide disagreement with a level C recommendation or where national guidance documents contradict each other)

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    Improving Antimicrobial Prescribing Group

    Document history

    LHP version 1.0

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    Appendix 1

    Protocol for the administration of intracolonic Vancomycin electronic Medicines Compendium information on Vancomycin enemas for treatment of severe Clostridium difficile infection by nursing staff using a Foley catheter

    • This protocol is not suitable for patients with toxic megacolon or peritonitis.
    • The patient should have an urgent gastroenterology or surgical review prior to starting this therapy.
    • Oral or nasogastric administration of Vancomycin electronic Medicines Compendium information on Vancomycin and intravenous Metronidazole should continue while the patient is receiving intracolonic Vancomycin electronic Medicines Compendium information on Vancomycin.

    Materials required:

    • Vancomycin electronic Medicines Compendium information on Vancomycin 500 mg vial
    • 100 ml sodium chloride 0.9% infusion bag
    • Wide gauge Foley catheter (16-18 gauge) with 30 ml balloon
    • 30 ml sterile water for balloon inflation
    • Catheter connector (green) (optional)
    • Giving set
    • Drip stand

    Method:

    1. Wash hands with soap and water, then dry hands.
    2. Identify the correct patient e.g. check name band and verbally confirm identity where possible, explain the procedure and obtain verbal consent where appropriate.
    3. The patient should be made comfortable, lying on their side with hips and knees flexed. They will need to stay lying down while the enema is in place.
    4. Prepare all the equipment required on a cleaned trolley.
    5. Reconstitute the 500 mg vial of Vancomycin electronic Medicines Compendium information on Vancomycin with 10 ml of sodium chloride 0.9% drawn from the 100 ml bag of sodium chloride 0.9%. Shake well to dissolve.
    6. Withdraw the resulting dissolved solution and add to the remaining volume of 0.9% sodium chloride in the bag to give 500 mg Vancomycin electronic Medicines Compendium information on Vancomycin in 100 ml of 0.9% sodium chloride (5 g/L concentration).
    7. Label the bag to identify that it contains Vancomycin electronic Medicines Compendium information on Vancomycin and date and time prepared.
    8. Invert the infusion bag several times to ensure the Vancomycin electronic Medicines Compendium information on Vancomycin is distributed throughout the bag.
    9. Attach the Foley catheter with a 30 ml balloon to the infusion bag, using a catheter connector adaptor (if required) and a giving set (with the giving set tap closed).
    10. Place the infusion bag on a drip stand.
    11. Insert the Foley catheter into the patients’ rectum with care.
    12. Inflate the Foley catheter balloon with 30 ml of sterile water.
    13. Open the tap on the giving set to instill the 100 ml Vancomycin electronic Medicines Compendium information on Vancomycin solution into the colon under gravity.
    14. Clamp the foley catheter, the enema should be retained for as long as practically possible, up to one hour’s duration.
    15. Deflate the Foley catheter balloon and remove the catheter.

    The enema should be administered as often as is practicable, up to a maximum of four times daily. Treatment duration is guided by clinical response. If there is no improvement after 48 – 72 hours, please discuss with a gastroenterology or microbiology consultant.

    After 24-48 hours of administration, send a blood sample for Vancomycin electronic Medicines Compendium information on Vancomycin levels as colonic administration can result in high systemic levels, particularly in renal impairment [26]. Repeat Vancomycin electronic Medicines Compendium information on Vancomycin levels every 3-4 days while the patient is receiving Vancomycin electronic Medicines Compendium information on Vancomycin intracolonically. The level of Vancomycin electronic Medicines Compendium information on Vancomycin should be less than 10 mg/L. If the level is above 10 mg/L, discontinue the Vancomycin electronic Medicines Compendium information on Vancomycin enemas and discuss further treatment with a gastroenterology or microbiology consultant.

    NB this protocol is adapted from those used by Wrightington, Wigan and Leigh NHS Foundation Trust and Birmingham City Hospital, with thanks.

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