Clostridium Difficile Infection ( CDI ) in Adults ( >16 years of age ) - Diagnosis and Management of
|Last review: 21/08/2019|
|Next review: 21/08/2022|
|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.
Diagnosis and Management of Clostridium Difficile Infection (CDI) in Adults (>16 years of age)
Clostridium Difficile Infection ( CDI ) in Adults ( >16 years of age )
Criteria for use of guidelines
Severity assessment (see table 1 below or severity section)
Initial antimicrobial treatment
** Laboratory confirmation required.
Duration of Treatment
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.
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.
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 . [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 . [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 . [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.
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]
Severe CDI any of the following: [Evidence level C]
Life-threatening CDI any of the following: [Evidence level B]
Public Health England (PHE) guidelines categorise CDI into mild, moderate, severe and life-threatening . 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 .
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 . [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 . [Evidence level B]
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.
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.)
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 . 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 , but it may be too late at this point; hence the recommendation for earlier testing.
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 . [Evidence level B]
Recommendation: The need for antimicrobials , 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.  [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].
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].
|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:
Severe CDI  [Evidence level A]
ORAL: Fidaxomicin 200mg 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]
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 also reached bactericidal concentrations in faeces . There is no robust evidence that higher doses of 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 (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). 
Fidaxomicin is a new and recently licensed agent for the therapy of CDI. For a more detailed review of the literature pertaining to 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 (200 mg twice daily) or 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  included patients from North America only, where the epidemiology of CDI differs from in Europe. The other  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 was found to be non-inferior to 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.  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 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 and Vancomycin with bowel lavage groups were 23% and 30.8% respectively. 
This guideline has been reviewed and updated in response to updated guidelines from Health Protection England.  Fidaxomicin should 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. 
|Directed Antimicrobial Treatment (when microbiology results are known)|
Please see empirical antimicrobial therapy section as this is a Clostridium difficile-specific guideline.
|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.
For fidaxomycin, the standard treatment duration is 10 days.
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 or Vancomycin ). [Evidence level D]
Recommendation: Treatment failure should not be assessed before day 7 of therapy . [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 125mg 6-h, or Fidaxomicin 200mg 12-h if already on oral 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.
Recommendation: Seek a surgical opinion when symptoms are worsening. [Evidence level C]
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 200mg 12-hourly (duration and review as for other agents) unless patient has received Fidaxomicin in the last 28 days, then Vancomycin should be used. This will be a restricted antimicrobial requiring a microbiology/ID approval code. [Evidence level C]
If a recurrence occurs after therapy with 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 . Tapering doses of Vancomycin have been used to treat CDI recurrence and remain an option but the regimens have not been standardized or adequately evaluated . Donor stool transplants are occasionally required but this is an area requiring specialist input.
NB. Death certification :
Clostridium difficile infection
|Target patient group:||Patients with diarrhoea and suspected Clostridium difficile infection|
|Target professional group(s):||Pharmacists
Secondary Care Doctors
- 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.
- 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.
- Department_of_Health, Clostridium difficile infection: How to deal with the problem, D.o. Health, Editor. 2008.
- 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.
- 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.
- 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.
- 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.
- Lipsett, P.A., et al., Pseudomembranous colitis: a surgical disease? Surgery, 1994. 116(3): p. 491-6.
- 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.
- 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.
- 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.
- Gerding, D.N., Metronidazole for Clostridium difficile-associated disease: is it okay for Mom? Clin Infect Dis, 2005. 40(11): p. 1598-600.
- 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.
- 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.
- 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.
- Osler, T., et al., Cefazolin-induced pseudomembranous colitis resulting in perforation of the sigmoid colon. Dis Colon Rectum, 1986. 29(2): p. 140-3.
- Pasic, M., et al., Intracolonic vancomycin for pseudomembranous colitis. N Engl J Med, 1993. 329(8): p. 583.
- 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.
- 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.
- Louie, T.J., et al., Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med, 2011. 364(5): p. 422-31.
- Wilcox, M.H., Updated guidance on the management and treatment of Clostridium difficile infection 2013, Public Health England
- Wilcox, M.H., et al., Recurrence of symptoms in Clostridium difficile infection--relapse or reinfection? J Hosp Infect, 1998. 38(2): p. 93-100.
- SMC. Fidaxomicin (791/12). . 2012
- NICE. Clostridium difficile infection: fidaxomicin. 2012;
- Chief_Medical_Officer, Healthcare Associated Infections and Death Certification. PL CMO (1007)8. 2007.
- Pasic, M., et al., Systemic absorption after local intracolonic vancomycin in pseudomembranous colitis. Lancet, 1993. 342(8868): p. 443.
- 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
- NICE, Faecal microbiota transplant for recurrent C. difficile infection. Interventional procedures guidance [IPG485]. March 2014.
- Van Nood et al., Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med, 2013. 368(5):p. 407-15.
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)
- Clostridium difficile Infection Control Policy
- Bristol Stool Chart
- Hand Hygiene Techniques
- Isolation policy
Improving Antimicrobial Prescribing Group
LHP version 1.0
Protocol for the administration of intracolonic 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 and intravenous Metronidazole should continue while the patient is receiving intracolonic Vancomycin .
- 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
- Wash hands with soap and water, then dry hands.
- Identify the correct patient e.g. check name band and verbally confirm identity where possible, explain the procedure and obtain verbal consent where appropriate.
- 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.
- Prepare all the equipment required on a cleaned trolley.
- Reconstitute the 500 mg vial of Vancomycin with 10 ml of sodium chloride 0.9% drawn from the 100 ml bag of sodium chloride 0.9%. Shake well to dissolve.
- Withdraw the resulting dissolved solution and add to the remaining volume of 0.9% sodium chloride in the bag to give 500 mg Vancomycin in 100 ml of 0.9% sodium chloride (5 g/L concentration).
- Label the bag to identify that it contains Vancomycin and date and time prepared.
- Invert the infusion bag several times to ensure the Vancomycin is distributed throughout the bag.
- 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).
- Place the infusion bag on a drip stand.
- Insert the Foley catheter into the patients’ rectum with care.
- Inflate the Foley catheter balloon with 30 ml of sterile water.
- Open the tap on the giving set to instill the 100 ml Vancomycin solution into the colon under gravity.
- Clamp the foley catheter, the enema should be retained for as long as practically possible, up to one hour’s duration.
- 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 levels as colonic administration can result in high systemic levels, particularly in renal impairment . Repeat Vancomycin levels every 3-4 days while the patient is receiving Vancomycin intracolonically. The level of Vancomycin should be less than 10 mg/L. If the level is above 10 mg/L, discontinue the 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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