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Keywords:

  • Clostridium difficile;
  • guidelines;
  • treatment

Abstract

  1. Top of page
  2. Abstract
  3. Summary of definitions and recommendations
  4. Introduction
  5. Objective
  6. Update Methodology
  7. Definitions
  8. Overview of Medical Treatment Options Available for CDI
  9. Recommendations for the Treatment of CDI
  10. On behalf of the Committee
  11. Authorship
  12. Transparency Declaration
  13. References

Clostridium difficile infection (CDI) is a potentially fatal illness with an increasing incidence worldwide. Despite extensive ongoing research into CDI treatment, management of CDI still poses important problems, such as a high propensity to relapse and refractoriness to treatment, especially when there is an ileus and oral drugs cannot be adminstered. This guideline evaluates the available literature, discusses criteria for disease severity and provides recommendations for CDI treatment, indicating level of evidence and strength of recommendation.


Summary of definitions and recommendations

  1. Top of page
  2. Abstract
  3. Summary of definitions and recommendations
  4. Introduction
  5. Objective
  6. Update Methodology
  7. Definitions
  8. Overview of Medical Treatment Options Available for CDI
  9. Recommendations for the Treatment of CDI
  10. On behalf of the Committee
  11. Authorship
  12. Transparency Declaration
  13. References

Definitions

Episode of CDI :

  • 1
     a clinical picture compatible with CDI and microbiological evidence of toxin-producing Clostridium difficile in stool without evidence of another cause of diarrhoea or
  • 2
     pseudomembranous colitis (as diagnosed during endoscopy, after colectomy or on autopsy)

Clinical pictures compatible with CDI:

  • 1
    diarrhoea :
    • a. 
      loose stools, i.e. taking the shape of the receptacle or corresponding to Bristol stool chart types 5–7 and
    • b. 
      a stool frequency perceived as too high by the patient
  • 2
    ileus :
    • a. 
      signs of severely disturbed bowel passage such as vomiting and absence of stool and
    • b. 
      radiological signs of bowel distension
  • 3
    toxic megacolon :
    • a. 
      radiological signs of distension of the colon and
    • b. 
      signs of a severe systemic inflammatory response

Signs of severe colitis:

  • • 
    fever (core body temperature > 38.5°C)
  • • 
    rigors (uncontrollable shaking and a feeling of cold followed by a rise in body temperature)
  • • 
    hemodynamic instability including signs of septic shock
  • • 
    signs of peritonitis, including decreased bowel sounds, abdominal tenderness, rebound tenderness and guarding
  • • 
    signs of ileus, including vomiting and absent passage of stool
  • • 
    marked leukocytosis (leukocyte count > 15 × 109/L)
  • • 
    marked left shift (band neutrophils > 20% of leukocytes)
  • • 
    rise in serum creatinine (>50% above the baseline)
  • • 
    elevated serum lactate
  • • 
    pseudomembranous colitis (endoscopy)
  • • 
    distension of large intestine (imaging)
  • • 
    colonic wall thickening including low-attenuation mural thickening (imaging)
  • • 
    pericolonic fat stranding (imaging)
  • • 
    ascites not explained by other causes (imaging)

Severe CDI :

an episode of CDI with one or more signs of severe colitis.

CDI without signs of severe colitis in patients with advanced age (≥65), serious comorbidity, ICU admission, or immunodeficiency may be regarded as severe.

 CDI treatment response :

  • 1
    stool frequency as perceived by the patient decreases or stool consistency improves after 3 days and
  • 2
    no new signs of severe colitis develop

 CDI treatment failure :

 absence of CDI treatment response

 CDI recurrence :

  • 1
    stool frequency as perceived by the patient increases for two consecutive days and stools become looser or new signs of severe colitis develop and
  • 2
    microbiological evidence of toxin-producing C. difficile in stools without evidence of another cause of diarrhoea after an initial CDI treatment response

Recommendations (implementation category between brackets)

  • 1
    Antiperistaltic agents and opiates should be avoided. (B-II)
  • 2
    In general, strive to use antibiotics covering a spectrum no broader than necessary and narrow the antibiotic spectrum of treatment after results of cultures and/or susceptibility tests become known. (B-III)
  • 3
    Mild CDI (stool frequency < 4 times daily; no signs of severe colitis), clearly induced by the use of antibiotics, may be treated by stopping the inducing antibiotic. Observe patients closely for any signs of clinical deterioration and place on therapy immediately if this occurs. (B-III)
  • 4
    Treatment for an initial episode and a first recurrence of CDI:

 If oral therapy is possible:

  •   non-severe: metronidazole 500 mg tid orally for 10 days (A-I)
  •   severe: vancomycin 125 mg qid orally for 10 days (A-I)

 If oral therapy is impossible:

  •   non-severe: metronidazole 500 mg tid intravenously for 10 days (A-III)
  •   severe: metronidazole 500 mg tid intravenously for 10 days (A-III) + intracolonic vancomycin 500 mg in 100 mL of normal saline every 4–12 h (C-III) and/or vancomycin 500 mg qid by nasogastric tube (C-III)
  • 5
    Colectomy should be performed to treat CDI in any of the following situations:
  • • 
     perforation of the colon
  •   systemic inflammation and deteriorating clinical condition not responding to antibiotic therapy; this includes the clinical diagnoses of toxic megacolon and severe ileus. Colectomy should preferably be performed before colitis is very severe. Serum lactate may, inter alia, serve as a marker for severity (operate before lactate exceeds 5.0 mmol/L).
  • 6
    Treatment for a second recurrence of CDI and later recurrences:

 If oral therapy is possible:

  • • 
     vancomycin 125 mg qid orally for at least 10 days (B-II)
  •   consider a taper (for example, decreasing daily dose with 125 mg every 3 days)/pulse (for example, a dose of 125 mg every 3 days for 3 weeks) strategy (B-II)

 If oral therapy is impossible:

  •   metronidazole 500 mg tid intravenously for 10–14 days (A-III) plus retention enema of vancomycin 500 mg in 100 mL of normal saline every 4–12 h (C-III) and/or vancomycin 500 mg qid by nasogastric tube (C-III)
  • 7
    In all the above-mentioned cases, oral vancomycin may be replaced by teicoplanin 100 mg twice daily, if available.

Introduction

  1. Top of page
  2. Abstract
  3. Summary of definitions and recommendations
  4. Introduction
  5. Objective
  6. Update Methodology
  7. Definitions
  8. Overview of Medical Treatment Options Available for CDI
  9. Recommendations for the Treatment of CDI
  10. On behalf of the Committee
  11. Authorship
  12. Transparency Declaration
  13. References

Clostridium difficile infection (CDI) may arise when a patient’s bowel is colonized by C. difficile after ingestion of spores; the spores subsequently germinate and the vegetative bacteria start producing toxins. Colonization is inhibited by the normal intestinal flora, which is hypothesized to compete with C. difficile for nutrients and space on the mucosal surface. Therefore, the use of antibiotics is the most important risk factor for CDI. The vegetative state of the bacterium is resistant to a varying but broad range of antibiotics and the spores are highly resistant to antibiotics and can withstand many forms of chemical attack, e.g. most high-level disinfectants. The most important problem in treating CDI is the high recurrence rate. Various factors, such as the need to continue treatment with the inciting antibiotic, have been associated with this (see ‘Prognostic criteria and criteria for disease severity’). The antibiotics needed to kill the vegetative bacteria do not kill the spores and might even contribute to recurrence by disrupting the normal gut flora even further. Individuals who suffer a recurrence may enter a repetitive cycle of recurrences, leading to exhaustion and protein-losing enteropathy. A second problem in treating CDI is the fact that, in severe forms of CDI, antibiotics may fail, resulting in progressive colitis with high morbidity and mortality. Several factors may play a role in this, such as a time lag for antibiotics to reach adequate intracolonic levels [1] and possibly the fact that a systemic inflammatory response due to severely damaged colonic mucosa may persist some time after removal of the etiological agent.

Objective

  1. Top of page
  2. Abstract
  3. Summary of definitions and recommendations
  4. Introduction
  5. Objective
  6. Update Methodology
  7. Definitions
  8. Overview of Medical Treatment Options Available for CDI
  9. Recommendations for the Treatment of CDI
  10. On behalf of the Committee
  11. Authorship
  12. Transparency Declaration
  13. References

Since treatment of CDI can be complicated by these many problems, the need for this evidence-based guideline seems obvious. The objective of this study was to evaluate the available evidence concerning treatment of CDI and formulate recommendations for treatment.

Update Methodology

  1. Top of page
  2. Abstract
  3. Summary of definitions and recommendations
  4. Introduction
  5. Objective
  6. Update Methodology
  7. Definitions
  8. Overview of Medical Treatment Options Available for CDI
  9. Recommendations for the Treatment of CDI
  10. On behalf of the Committee
  11. Authorship
  12. Transparency Declaration
  13. References

Studies on CDI treatment were found with a computerized literature search of PUBMED using the terms ‘Clostridium difficile AND (treatment OR trial)’. All randomized and non-randomized trials investigating the effect of an intervention on the clinical outcome (resolution or recurrence of diarrhoea; incidence of complications) of CDI published in any language were included. Studies investigating carriage or other purely microbiological parameters were not considered sufficient evidence for treatment strategies. The resulting literature from 1978 was reviewed and analyzed. Furthermore, systematic reviews from the Cochrane Library and the guidelines of the Infectious Diseases Society of America (IDSA) were evaluated. Recommendations were based on a systematic assessment of the quality of evidence. For indicating the quality of evidence and weight of recommendations the system of the Canadian Task Force on the Preventative Health Care was used (Table 1).

Table 1.   Strength of recommendation and quality of evidence according to the Canadian Task Force on Preventative Health Care
Strength of recommendation
 A: Good evidence to support a recommendation
 B: Moderate evidence to support a recommendation
 C: Poor evidence to support a recommendation
Quality of evidence
 I: Evidence from ≥one properly randomized, controlled trial
 II: Evidence from ≥one well-designed clinical trial, without randomization; from  cohort or case-controlled analytic studies (preferably from ≥one centre); from  multiple time-series; or from dramatic results from uncontrolled experiments
 III: Evidence from opinions of respected authorities, based on clinical  experience, descriptive studies, or reports of expert committees

Definitions

  1. Top of page
  2. Abstract
  3. Summary of definitions and recommendations
  4. Introduction
  5. Objective
  6. Update Methodology
  7. Definitions
  8. Overview of Medical Treatment Options Available for CDI
  9. Recommendations for the Treatment of CDI
  10. On behalf of the Committee
  11. Authorship
  12. Transparency Declaration
  13. References

Criteria for the diagnosis of CDI

Pseudomembranous colitis, which is an endoscopic diagnosis, is caused by C. difficile in the vast majority of cases and therefore may suffice for the diagnosis of CDI in the absence of an obvious other cause. In the rest of the cases, a combination of symptoms and signs, in conjunction with microbiological evidence of toxin-producing C. difficile in stools and the absence of another cause is necessary. Compatible clinical pictures are diarrhoea, ileus and toxic megacolon. Diarrhoea is defined as loose stools, i.e. taking the shape of the receptacle or corresponding to Bristol stool chart types 5–7 [2], plus a stool frequency perceived as too high by the patient. Faecal incontinence may be a part of the disease. Ileus in the context of CDI is defined as signs of severely disturbed bowel passage such as vomiting and absence of stool, combined with radiological signs of bowel distension. Toxic megacolon is defined as radiological signs of distension of the colon combined with signs of a severe systemic inflammatory response. The above-mentioned criteria are largely in line with the recommendations of the American Ad Hoc C. difficile surveillance working group [3] and the European Study Group for C. difficile [4].

Prognostic criteria and criteria for disease severity

Outcome measures of CDI comprise complications, mortality and recurrences. It is difficult to set a rigid set of criteria for the assessment of prognosis and severity of CDI. First, surprisingly little research has been done on clinical predictors of outcome. Second, prognostic markers have not been validated in prognostic studies. Third, prognosis depends on disease severity and other prognostic factors, such as age, comorbidity, admission to an intensive care unit, and antiperistaltic and immunosuppressive medication. It is unknown what the weight of these prognostic factors is in comparison with assessed disease severity.

Possible features of severe colitis that have been linked to a higher chance of recurrence are faecal incontinence [5], the endoscopic finding of pseudomembranous colitis [6], and longer cumulative duration of previous episodes of CDI [7]. Leukocytosis (leukocyte count > 20 × 109/L) has been associated with a high mortality rate in CDI [8], a complicated course [9], refractoriness to therapy [6] and risk of recurrence [9]. Hypoalbuminaemia (<25 g/L) has also been associated with a high mortality rate in CDI [8] and refractoriness to therapy [6,10,11]. However, since it may be seen as a result of malnutrition or protein-losing enteropathy in longstanding disease, as a negative acute phase protein in acute disease, and as a marker for comorbidity (e.g. liver cirrhosis, nephrotic syndrome, wasting) this feature may be too heterogeneous to be a reliable marker of severe disease.

Factors associated with unfavourable outcome that are not direct markers of severe colitis include advanced age, comorbidity, a decreased antibody response, gastric acid suppressants, and the need to prolong inciting antibiotic therapy. Advanced age has been associated with a complicated course [12] and recurrence [9,12]. Comorbidity has been associated with a high mortality rate [8] and a higher chance of recurrence [13]. A decreased humoral immune response against Clostridial toxins TcdA and TcdB has been associated with a higher chance of recurrence and longer duration of symptoms [14,15], although other studies did not find this association. Use of H2-antagonists has been associated with a higher chance of recurrence [5] and use of proton pump inhibitors has been associated with refractoriness to therapy [16]. Also, the need to continue the use of inciting antibiotic has been associated with refractoriness to therapy [16]. However, it is unclear whether the use of gastric acid suppressants and the need to continue antibiotics have a causal relationship with unfavourable outcome or whether they are markers of more severe comorbidity. Obviously, admission to an ICU is an unfavourable prognostic factor [6,11].

Markers of severe colitis

Markers that could reasonably be assumed to correlate positively with the severity of colitis are mentioned below, although we must stress that the prognostic value of these markers is uncertain. Obviously, markers should not be attributable to a concomitant disease, if they are to be regarded as a marker of severe CDI. Ideally, markers should be obtainable at the earliest stage in the disease course to be a predictor of outcome.

Physical examination
  • fever (core body temperature > 38.5°C)
  • rigors (uncontrollable shaking and a feeling of cold followed by a rise in body temperature)
  • haemodynamic instability including signs of distributive (vasodilatory, septic) shock
  • signs of peritonitis, including decreased bowel sounds, abdominal tenderness, rebound tenderness and guarding
  • signs of ileus including vomiting and absent passage of stool

Admixture of blood with stools is rare in CDI and the correlation with severity of disease is uncertain.

Laboratory investigations
  • • 
    marked leukocytosis (leukocyte count > 15 × 109/L)
  • • 
    marked left shift (band neutrophils > 20% of leukocytes)
  • • 
    rise in serum creatinine (>50% above the baseline)
  • • 
    elevated serum lactate
Colonoscopy or sigmoidoscopy
  • • 
    pseudomembranous colitis

There is insufficient knowledge concerning the correlation of endoscopic findings compatible with CDI, such as oedema, erythema, friability and ulceration, and the severity of disease.

Imaging
  • • 
    distension of large intestine
  • colonic wall thickening including low-attenuation mural thickening
  • • 
    pericolonic fat stranding
  • • 
    ascites not explained by other causes

The correlation of haustral or mucosal thickening, including thumbprinting, pseudopolyps and plaques, with severity of disease is unclear.

Prognostic markers other than disease severity

  • • 
    advanced age (≥65)
  • • 
    serious comorbidity and ICU admission
  • • 
    immunodeficiency

Criteria for response, failure and recurrence in the treatment of CDI

Treatment response is present when either stool frequency decreases or stool consistency improves, and parameters of disease severity (clinical, laboratory, radiological) improve, and no new signs of severe disease develop. In all other cases, treatment is considered a failure. It is only reasonable to evaluate treatment response after at least 3 days, assuming that the patient is not worsening on treatment. Treatment with metronidazole, in particular, may result in a clinical response only after 3–5 days [1,16]. After clinical response, it may take weeks for stool consistency and frequency to become entirely normal [17]. Recurrence is present when, after an initial response, stool frequency increases for two consecutive days and stools become looser, or new signs of severe disease develop and microbiological evidence of toxin-producing C. difficile in stool is present without evidence of another cause. It is impossible to distinguish recurrence due to relapse (renewed symptoms from already present CDI) from recurrence due to reinfection in daily practice.

Overview of Medical Treatment Options Available for CDI

  1. Top of page
  2. Abstract
  3. Summary of definitions and recommendations
  4. Introduction
  5. Objective
  6. Update Methodology
  7. Definitions
  8. Overview of Medical Treatment Options Available for CDI
  9. Recommendations for the Treatment of CDI
  10. On behalf of the Committee
  11. Authorship
  12. Transparency Declaration
  13. References

There is an increasing body of evidence concerning treatment of CDI, both initial (Table 2 [6,18–32], Table 3 [17,33–36] and Table 4 [9,11,13,15,37–48]) and recurrent episodes (Table 5 [33,49–52] and Table 6 [7,53–68]). Tables 2, 3 and 5 report the evidence from randomized trials, with comments on methodology. It is difficult to compare these studies because of differences in diagnostic criteria, exclusion of co-pathogens, severity of CDI, co-morbidity, inciting antibiotics and concomitant use of antibiotics. Moreover, these studies usually have endpoints of clinical cure or microbiological cure. However, the definition of clinical cure and recurrence is highly variable. Patients seldom have normal stools directly after treatment of CDI. With respect to microbiological cure, the significance of persistently or recurrently positive stool toxin tests or cultures is not clear. Furthermore, it is not possible to distinguish relapse from reinfection. Lastly, the number of participants in most trials is small. In conclusion, we need more randomized controlled trials on CDI treatment.

Table 2.   Randomized controlled trials of antibiotic treatment of initial CDI. Initial cure rate as a percentage of all patients and relapse rate as a percentage of initially cured patients
TrialTreatmentNumber of patientsCure (%)Relapse (%)
Keighley et al. [18]Vancomycin 125 mg qid, 5 days9780
Placebo714
No clear case definition. No description of allocation of treatment. Only data of patients with toxin-positive stool shown. Unclear length of follow-up and incidence or relapse in placebo group. p <0.02 for comparison of cure rates
Teasley et al. [19]Vancomycin 500 mg qid, 10 days3210019
Metronidazole 250 mg qid, 10 days32976
Only data of patients with toxin-positive stools or pseudomembranous colitis shown. Per-protocol analysis. Follow-up 21 days. Differences not statistically significant
Young et al. [20]Vancomycin 125 mg qid, 7 days218633
Bacitracin 20 000 U qid, 7 days217642
Double-blind. 25% drop-out during follow-up of bacitracin group. Follow-up 5 weeks. Differences not statistically significant
Dudley et al. [21]Vancomycin 500 mg qid, 10 days1510020
Bacitracin 25 000 U qid, 10 days158042
Double-blind. Patients had leukocytosis, fever or abdominal pain. 29% drop-out in vancomycin group, 12% in bacitracin group. Per-protocol analysis. Unclear definition of failure (‘worsening during treatment’). Failing patients crossed over to alternate drug. Interruption of study drug in vancomycin group for a mean of 2.8 days and in bacitracin group for a mean of 1.8 days. Unclear length of follow-up. Differences not statistically significant
Fekety et al. [22]Vancomycin 125 mg qid, mean 10.6 days2410021
Vancomycin 500 mg qid, mean 10.1 days2210018
Variable duration of therapy. 18% dropout rate. Per-protocol analysis. Unclear length of follow-up. Differences not statistically significant
Boero et al. [23]Vancomycin 500 mg bid, 10 days10100
Rifaximin 200 mg tid, 10 days1090
Article in Italian. Patients had diarrhoea, abdominal pain and fever. No description of allocation of treatment. Unclear definition of cure. Differences not statistically significant
de Lalla et al. [24]Vancomycin 500 mg qid, 10 days2010020
Teicoplanin 100 mg bid, 10 days26968
No description of allocation of treatment. Per-protocol analysis. Unclear length of follow-up. Differences not statistically significant
Wiström [25]Teicoplanin 100 mg qid, 3 days, followed by 100 mg bid, 4 days249635
Teicoplanin 100 mg bid, 7 days237050
Double-blind. Outcome of ‘improvement, but not cure’ (2 loose stools per day or 1 loose stool per day with fever or cramps) was counted as failure. Three patients with improvement in bid group; 1 in qid group. Follow-up 5 weeks. p 0.02 for comparison of cure rates. Relapse rates not statistically different
Wenisch et al. [26]Vancomycin 500 mg tid, 10 days319417
Metronidazole 500 mg tid, 10 days319417
Teicoplanin 400 mg bid, 10 days28967
Fusidic acid 500 mg tid, 10 days299330
Follow-up 30 days. Only statistically significant difference was relapse rate of fusidic acid vs. teicoplanin (p 0.042)
Wullt [27]Metronidazole 400 mg tid, 7 days559330
Fusidic acid 250 mg tid, 7 days598330
Double-blind. 13% drop-out during treatment; 15% further drop-out during follow-up. Per-protocol analysis. Follow-up 35 days. Differences not statistically significant
Musher et al. [28]Metronidazole 250 mg qid, 10 days348230
Nitazoxanide 500 mg bid, 7 days409026
Nitazoxanide 500 mg bid, 10 days368916
No definition of relapse. Double-blind. 23% drop-out during treatment. Per-protocol analysis. Follow-up 31 days. Differences not statistically significant
Lagrotteria et al. [29]Metronidazole 500 mg tid, 10 days206538
Metronidazole 500 mg tid + rifampicin 300 mg bid, 10 days196342
Intention-to-treat analysis. Follow-up 40 days. Differences not statistically significant
Zar et al. [6]Vancomycin 125 mg qid, 10 days71977
Metronidazole 250 mg qid, 10 days798414
Double-blind. 13% drop-out during treatment. Per-protocol analysis. Follow-up 21 days. p 0.006 for comparison of cure rates. p 0.27 for comparison of relapse rates. The original protocol was stratified in a group with mild and a group with severe disease (based on age, fever, albumin level and leukocyte count), which resulted in a larger difference between cure rates in the group with severe disease and a statistically non-significant difference between cure rates in the group with mild disease
Louie et al. [30]Fidaxomicin 50 mg bid, 10 days14718
Fidaxomicin 100 mg bid, 10 days15800
Fidaxomicin 200 mg bid, 10 days16946
Open-label. Patients with signs of highly severe CDI (>12 bowel movements per day, vomiting, severe abdominal tenderness, ileus, WBC > 30, toxic megacolon) were excluded. Cure = complete resolution of diarrhoea. Follow-up 6 weeks after end of treatment
Musher et al. [31]Vancomycin 125 mg qid, 10 days27747
Nitazoxanide 500 mg bid, 10 days22775
CDI = stool EIA for toxin A or B positive AND (temperature > 38.3°C OR abdominal pain OR leukocytosis). Patients with >1 episode in preceding 6 months. 12% dropout rate during treatment. Double-blind, placebo-controlled. Modified intention-to-treat analysis. Industry-sponsored. Cure = complete resolution of symptoms during 3 days after completion of therapy. Per-protocol analysis: 87% vs. 94% cure. Follow-up 31 days after start of treatment. No differences in severity subgroups. Differences not statistically significant
Louie et al. [32]Vancomycin 125 mg qid, 10 days2849024
Fidaxomicin 200 mg bid, 10 days2659213
Unpublished trial
Table 3.   Randomized controlled trials of non-antibiotic treatment of initial CDI. Initial cure rate as a percentage of all patients and relapse rate as a percentage of initially cured patients
TrialTreatmentNumber of patientsCure (%)Relapse (%)
Probiotics
 McFarland et al. [33]Vancomycin or metronidazole + Saccharomyces boulardii 2 × 1010 CFU/day, 4 weeks3119
Vancomycin or metronidazole + placebo3324
Double-blind. No control for type, duration or dose of antibiotic. Unclear definition of relapse. Follow-up 8 weeks after start of treatment. p 0.86 for comparison of relapse rates
Toxin-binding resins and polymers
 Louie et al. [17]Tolevamer 1 g tid, 14 days + placebo946016
Tolevamer 2 g tid, 14 days + placebo91797
Vancomycin 125 mg qid, 10 days + placebo949119
Non-inferiority trial. Patients with stool frequency >12 per day or abdominal pain were excluded. Tolevamer could be prolonged when inciting antibiotic could not be stopped. Double-blind. 23% drop-out. Per-protocol analysis. Cure rate of tolevamer 2 g non-inferior in comparison with vancomycin (Chow-test p 0.03). Non-inferiority of tolevamer 1 g compared with vancomycin could not be demonstrated. p 0.05 for comparison of relapse rates of tolevamer 2 g with vancomycin. Relapse rates of tolevamer 1 g and vancomycin not statistically different. Follow-up 6–8 weeks
 Louie et al. [34]Tolevamer 3 g tid, 14 days266473
Vancomycin 125 mg qid, 10 days1348123
Metronidazole 375 mg qid, 10 days1437227
Unpublished trial
 Bouza et al. [35]Tolevamer 3 g tid, 14 days268426
Vancomycin 125 mg qid, 10 days1258118
Metronidazole 375 mg qid, 10 days1357319
Unpublished trial
Immunotherapy
 Lowy [36]MDX-066 and MDX-1388 (intravenously administered monoclonal antibodies against TcdA and TcdB) after standard antimicrobial therapy1017
Placebo after standard antimicrobial therapy9925
Unpublished trial. Follow-up 12 weeks
Table 4.   Observational studies of treatment of initial CDI.
TrialTreatmentNumber of patientsCure (%)Relapse (%)
Antibiotics
 Bartlett et al. [37]Vancomycin799614
 Silva et al. [38]Vancomycin1610013
 Cherry et al. [39]Metronidazole1310015
 Bartlett [40]Vancomycin1899724
 de Lalla et al. [41]Vancomycin 500 mg qid, 10 days2310013
Teicoplanin 200 mg bid, 10 days221000
 Olson et al. [42]Metronidazole632986
Vancomycin1229910
 Kyne et al. [15]Metronidazole44?50
 Fernandez et al. [11]Metronidazole9962?
 Musher et al. [43]Metronidazole2077828
 Pépin et al. [9]Metronidazole11238429
Vancomycin112?28
 Louie [44]Difimicin varying dose45915
 Musher et al. [45]Nitazoxanide 500 mg bid, 10 days357427
Patients first failed metronidazole
 Al Nassir et al. [16]Metronidazole34>9012
Ten patients switched to vancomycin
Vancomcyin18>9011
 Herpers et al. [46]Tigecycline varying duration41000
Severe CDI. Follow-up at least 3 months
Toxin-binding resins and polymers
 Mogg et al. [47]Colestipol 10 g qid, 5 days1225
Originally set up as a randomized placebo-controlled trial. Placebo group was merged with historical control, however. Only six patients had toxin-positive stool
Passive immunotherapy with immune whey
 van Dissel et al. [48]Metronidazole or vancomycin followed by immune whey protein concentrate, 14 days161000
 56% of patients had recurrent CDI; mean follow-up 333 days
 Numan et al. [13]Metronidazole or vancomycin followed by immune whey protein concentrate, 14 days10910010
 109 episodes; 101 patients; 40% of patients had recurrent CDI
Table 5.   Randomized controlled studies of treatment of recurrent CDI
TrialTreatmentNumber of patientsFailurea (%)
  1. aNon-response or relapse.

Probiotics
 McFarland et al. [33]Vancomycin or metronidazole + Saccharomyces boulardii 2 × 1010 CFU/day, 4 weeks2635
Vancomycin or metronidazole + placebo3465
Double-blind. No control for type, duration or dose of antibiotic. Unclear definition of relapse. Follow-up 8 weeks after start of treatment. p 0.04 for comparison of failure rates
 Surawicz et al. [49]Vancomycin 500 mg qid, 10 days, followed by Saccharomyces boulardii 2 × 1010 CFU/day, 4 weeks1817
Vancomycin 500 mg qid, 10 days, followed by placebo1450
Vancomycin 125 mg qid, 10 days, followed by Saccharomyces boulardii 2 × 1010 CFU/day, 4 weeks4551
Vancomycin 125 mg qid, 10 days, followed by placebo3845
Metronidazole 1 g/day, 10 days, followed by Saccharomyces boulardii 2 × 1010 CFU/day, 4 weeks2748
Metronidazole 1 g/day, 10 days, followed by placebo2650
Follow-up 5 months after completion of study drug. p 0.05 for the comparison of failure rates in patients who received 500 mg of vancomycin qid. Drop-out was 22%. No further statistically significant differences
 Wullt et al. [50]Metronidazole 400 mg tid, 10 days + Lactobacillus plantarum 299v 5 × 1010 CFU/day, 38 days1242
Metronidazole 400 mg tid, 10 days + placebo967
Double-blind. 28% cent drop-out. Follow-up 70 days. Difference not statistically significant
 Lawrence et al. [51]Vancomycin or metronidazole followed by Lactobacillus GG 6 × 1011 CFU/day, 21 days838
Vancomycin or metronidazole followed by placebo714
Patients blinded. No control for type, duration or dose of antibiotic. Follow-up 60 days after completion of antibiotic. Difference not statistically significant
Passive immunotherapy with immune whey
 Mattila et al. [52]Colostral immune whey 200 mL tid + placebo, 14 days1844
Metronidazole 400 mg tid + placebo, 14 days2045
Double-blind. Multi-centre trial. Follow-up 70 days. Difference not statistically significant.
Table 6.   Observational studies of treatment of recurrent CDI
TrialTreatmentNumber of patientsFailurea (%)Mean follow-up
  1. aNon-response or relapse.

  2. bAs reported by Bakken [69].

Antibiotics
 Buggy et al. [53]Vancomycin 125 mg qid + rifampicin 600 mg bid, 7 days7012 months
 McFarland et al. [7]Vancomycin 1–2 g/day147159 days
Vancomycin <1 g/day485459 days
Vancomycin ≥2 g/day214359 days
Vancomycin taper293180 days
Vancomycin pulse71480 days
Metronidazole <1 g/day294559 days
Metronidazole 1.5 g/day54059 days
Metronidazole 2 g/day2059 days
 Johnson et al. [54]Vancomycin, 14 days, followed by rifaximin varying dose, 14 days813233 days
 Garey et al. [55]Rifaximin 400 mg tid, 14 days, followed by rifaximin 200 mg tid, 14 days50310 days
Rifaximin 400 mg tid, 36 days1100
Probiotics
 Gorbach et al. [56]Metronidazole or bacitracin, 10 days, followed by Lactobacillus GG 1010 CFU/day, 7–10 days520
 Biller et al. [57]Lactobacillus GG 6 × 108 CFU/day, 14 days4011 months
Faecal or bacterial instillation
 Bowden et al. [58]Faecal enema1619
 Tvede and Rask-Madsen [59]Faecal or bacterial enema60
 Lund-Tønnesen et al. [60]Faecal instillation through coloscope or gastrostoma1817
 Aas et al. [61]Faecal instillation through nasogastric tube, median 3 courses16690 days
 Jorup-Rönström et al. [62]Faecal enema50
 Nieuwdorp et al. [63]Vancomycin 500 mg qid, followed by faecal instillation by nasoduodenal tube or colonoscopy729150 days
 BorodybFaecal enema6110
 Lund-TønnesenbFaecal instillation through nasojejunal tube2017
 MoorebFaecal enema653
 AasbFaecal instillation through nasogastric tube90
 Macconnachie et al. [64]Faecal instillation through nasogastric tube1527
Immunotherapy
 Leung et al. [65]iv gammaglobulin 400 mg/kg every 3 weeks, 4–6 months505 months
 Beales [66]iv gammaglobulin 400 mg/kg day 1 and 21407.5 months
iv gammaglobulin, varying dose5402.8 months
 Wilcox [67]iv gammaglobulin 300–500 mg/kg, 1–6 doses54086 days
 McPherson et al. [68]iv gammaglobulin 150–400 mg/kg14716.6 months

It is important to realize that several experimental treatment options are not widely available, such as toxin-binding resins and polymers and specific immunotherapy.

Discontinuing the inciting antibiotic without antibiotic treatment

The rate of spontaneous resolution is unknown in patients with mild CDI. In one study [40], the spontaneous recovery rate in hospitalized patients with diarrhoea and a positive toxin assay who did not undergo endoscopy or had no pseudomembranous colitis on colonoscopy was 33%. More antibiotics after discontinuing the inciting antibiotic might increase the chance of subsequent recurrence, since gut flora will be exposed to a second antibiotic with a different spectrum (i.e. metronidazole). It may therefore be prudent to discontinue the inciting antibiotic only in the case of mild CDI, while closely monitoring the patient.

Oral antibiotics

There is only one placebo-controlled trial investigating the effectiveness of antibiotics for CDI and it had very few participants. Several antibiotics have been compared to each other. Oral administration of the glycopeptides vancomycin and teicoplanin appears most effective in inducing both clinical cure and microbiological cure, especially in severe CDI. The difficulty is how to define severe CDI. In one prospective, randomized, and blinded study [6], which evaluated the efficacy of vancomycin vs. metronidazole according to disease severity, the diagnosis of severe CDI was based on age, body temperature, albumin level and leukocyte count. Vancomycin proved to be superior to metronidazole in cases of severe CDI. Two trials investigating the efficacy of the toxin-binding polymer, tolevamer [34,35], also showed the superiority of oral vancomycin over metronidazole in severe cases. A recent Cochrane systematic review [70] has examined the available literature on antibiotic treatment options for CDI and concluded that teicoplanin is the most effective antibiotic treatment for moderate to severe CDI and vancomycin has no superiority over metronidazole. However, this review did not include the above-mentioned recent studies. It seems likely that the effectiveness of teicoplanin and vancomycin is in the same range.

Oral metronidazole is also very effective in inducing a response and has the advantage of low cost and the fact that it may contribute less to the emergence of vancomycin-resistant enterococci.

If metronidazole is indeed less effective than glycopeptides, this may be explained by the low levels metronidazole reaches in the colon, since it is absorbed in the small intestine and then excreted again in the bile and in the inflamed colon, whereas glycopeptides are not absorbed. Different doses of oral vancomycin have been used, but only one small randomized trial [22] has compared high- vs. low-dose vancomycin and found no statistically significant difference. Since low doses of oral vancomycin result in high concentrations in stool, there is no need to treat with high doses, except in an attempt to reach sufficient concentrations in the colon when administering vancomycin by nasogastric tube in a patient with ileus. Given the poor faecal concentrations of metronidazole achieved following a 500 mg 8-hourly dose, lower doses (e.g. 250 mg at a 6–8 hourly dose) should be less effective. Several studies, however, have used lower doses, usually with good results [6,7,19,27,28,34,35]. Even a modest increase in the MIC of metronidazole for C. difficile might result in insufficient faecal antibiotic concentrations to inhibit (vegetative) bacteria. Metronidazole resistance is to be regarded as exceedingly rare. However, the emergence of reduced susceptibility to metronidazole has recently been reported in UK C. difficile strains [1,71,72]. No reduced susceptibility to vancomycin was observed. The exact mechanism of reduced susceptibility to metronidazole remains to be determined. Notably, there is also evidence that inactivation of metronidazole occurs in the presence of gut contents, possibly due to metabolism by enterococci [73].

Oral bacitracin and fusidic acid seem to be less effective than vancomycin and metronidazole, respectively, although this has not convincingly been demonstrated. Currently, there is insufficient evidence to advocate the use of the rifamycin derivative rifaximin, to which resistance has been noted, and the antiprotozoal/anthelminthic nitazoxanide, which has been shown to be statistically similar to metronidazole in a small prospective randomized trial [28], but whose non-inferiority to vancomycin could not be shown in another trial due to lack of power [31]. As yet, there is also insufficient evidence to justify routine use of fidaxomicin (OPT-80), an inhibitor of RNA polymerase of gram-positive bacteria, although preliminary results of a recently presented study are very promising [32].

Duration of antibiotic therapy

The duration of antibiotics has been 10 days in most studies. Occasionally, a shorter duration (e.g. 7 days) has been reported. We feel that there is insufficient evidence of success with a shorter duration of therapy with any antibiotic to consider shorter regimens a treatment option.

There is no definitive evidence that taper or pulse regimens with vancomycin are effective in reducing the incidence of relapses. This strategy is mainly based on favourable experience and the theoretical rationale that spores can still germinate long after the clinical symptoms have resolved. McFarland et al. [7] retrospectively compared a standard course of antibiotics, vancomycin taper strategies (gradually decreasing the daily dose of vancomycin by 125–750 mg per day from varying starting doses) and vancomycin pulse strategies (125–500 mg of vancomycin every 2–3 days during a period of usually 3 weeks). They found the recurrence rate to be lowest in pulse regimens (14%), followed by taper regimens (31%) and the standard regimen of vancomycin (54%; average for all dose groups). No other studies investigating taper or pulse regimens have been published. Further studies are needed.

Probiotics

Probiotics may be of value when added to antibiotics, but the studies that have investigated this have major drawbacks such as small numbers, non-randomized allocation of antibiotics to which the probiotics were added, and lack of homogeneity among study groups. This is also the conclusion reached by a recent Cochrane systematic review [74]. Therefore, there is insufficient evidence to recommend the addition of probiotics to antibiotics. In addition, several studies of invasive disease have been reported, resulting from the use of probiotics such as Saccharomyces boulardii in debilitated or immunocompromised patients [75,76]. Moreover, probiotics were associated with increased mortality, partly due to nonocclusive mesenterial ischemia, in a randomized controlled trial in acute pancreatitis [77].

Treatment when oral administration is not possible

The only parenteral antibiotic therapy for CDI, supported by case series, is metronidazole [78]. Several case reports regarding the use of intravenous immunoglobulin have been published, but the data do not provide sufficient evidence to support its use. Thus, it is unknown how to best treat patients with ileus due to CDI. There are some anecdotal reports on delivery of vancomycin to the gut by means other than orally, mainly through intracolonic delivery. Questions regarding the efficacy, optimal dosing and duration of treatment with intracolonic vancomycin are unanswered. The introduction of faecal collector drainage systems has facilitated the use of glycopeptide retention enemas in ICUs, but they are very expensive. Tigecycline appeared useful as salvage therapy, as reported in a recent case series of patients with severe CDI complicated by ileus, but these promising findings require confirmation in prospective clinical trials [46]. Faecal transplantation has been performed through instillation with a colonoscope or enemas, but there is insufficient evidence to recommend this.

There are no prospective studies assessing which CDI patients benefit from surgical intervention. One study found that colectomy was most successful at a relatively early stage of the disease, i.e. before lactate exceeds 5.0 mmol/L [79].

Recommendations for the Treatment of CDI

  1. Top of page
  2. Abstract
  3. Summary of definitions and recommendations
  4. Introduction
  5. Objective
  6. Update Methodology
  7. Definitions
  8. Overview of Medical Treatment Options Available for CDI
  9. Recommendations for the Treatment of CDI
  10. On behalf of the Committee
  11. Authorship
  12. Transparency Declaration
  13. References

Recommendations for medical treatment of initial CDI

In the case of mild CDI (stool frequency < 4 times daily; no signs of severe colitis), clearly induced by the use of antibiotics, it is acceptable to discontinue the inducing antibiotic and observe the clinical response, but patients must be followed very closely for any signs of clinical deterioration and placed on therapy immediately if this occurs. Theoretic rationale, anecdotic evidence, and one case-control study suggest that antiperistaltic and opiate agents should be avoided, especially in the acute setting [80]. There is no evidence that switching to ‘low-risk’ antibiotics when the antibiotic treatment that cited the episode of CDI cannot be discontinued, nor its spectrum narrowed, is effective. It seems rational, however, to always strive to use antibiotics covering a spectrum no broader than necessary. When the inciting antibiotic cannot be discontinued, antibiotic treatment for CDI should be initiated. Furthermore, there is no proof that discontinuing gastric acid suppressants is effective, either.

In all cases other than mild CDI medical treatment for CDI should be started. Antibiotics may be started while awaiting diagnostics when there is sufficient clinical suspicion. We recommend treatment of an initial episode of CDI with the following antibiotics, according to disease severity (implementation category between brackets), when oral therapy is possible:

  • non-severe: metronidazole 500 mg tid orally for 10 days (A-I)
  • severe: vancomycin 125 mg qid* orally for 10 days (A-I)

 *Oral vancomycin may be replaced by teicoplanin 100 mg bid, if available.

CDI is judged to be severe when one or more of the markers of severe colitis mentioned under ‘definitions’ is present. It is unclear whether moderate disease in a patient with other unfavourable prognostic factors, such as advanced age and comorbidity, should be regarded as severe. This is left to the judgment of the treating physician. There is no evidence that various genotypes of C. difficile should be treated differently if disease severity does not differ.

When oral therapy is impossible, we recommend the following antibiotics, according to disease severity (implementation category between brackets):

  • non-severe: metronidazole 500 mg tid intravenously for 10 days (A-III)
  • severe: metronidazole 500 mg tid intravenously for 10 days (A-III) + intracolonic vancomycin 500 mg in 100 mL of normal saline every 4–12 h (C-III) and/or vancomycin 500 mg qid by nasogastric tube (C-III)

Recommendations for surgical treatment of CDI

Colectomy should be performed to treat CDI in any of the following situations:

  • • 
    perforation of the colon
  • systemic inflammation and deteriorating clinical condition not responding to antibiotic therapy; this includes the clinical diagnoses of toxic megacolon and severe ileus.

Since mortality following colectomy in patients with advanced disease is high, it is recommended to operate at a less severe stage. No definite recommendations on the timing of colectomy can be given. Serum lactate may, inter alia, serve as a marker for severity, and one should attempt to operate before the threshold of 5.0 mmol/L [79].

Recommendations for medical treatment of recurrent CDI

Observational data [12] suggest that the incidence of a second recurrence after treatment of a first recurrence with oral metronidazole or vancomycin is similar. Therefore, we recommend treating a first recurrence of CDI as a first episode, unless disease has progressed from non-severe to severe.

We recommend treatment of recurrent CDI with the following antibiotics (implementation category between brackets):

First recurrence:

See Recommendations for medical treatment of initial CDI.

Second recurrence and subsequent recurrences:

If oral therapy is possible:

  • vancomycin 125 mg qid* orally for at least 10 days (B-II) and consider a taper/pulse strategy (B-II)

 *Oral vancomycin may be replaced by teicoplanin 100 mg bid, if available.

If oral therapy is impossible:

  • metronidazole 500 mg tid intravenously for 10–14 days (A-III) + retention enema of vancomycin 500 mg in 100 mL of normal saline every 4–12 h (C-III) and/or vancomycin 500 mg qid by nasogastric tube (C-III)

Recommendation for prophylaxis of CDI

Currently, there is no evidence that medical prophylaxis for CDI is efficacious and therefore we do not recommend prophylactic antibiotics. Of course, other preventive measures should be taken, such as hand hygiene of hospital personnel, prompt isolation of patients suspected of having CDI, and prudent use of antibiotics [81].

On behalf of the Committee

  1. Top of page
  2. Abstract
  3. Summary of definitions and recommendations
  4. Introduction
  5. Objective
  6. Update Methodology
  7. Definitions
  8. Overview of Medical Treatment Options Available for CDI
  9. Recommendations for the Treatment of CDI
  10. On behalf of the Committee
  11. Authorship
  12. Transparency Declaration
  13. References

UK: M. Wilcox, Department of Microbiology, Old Medical School Leeds General Infirmary, Leeds Teaching Hospitals & University of Leeds, Leeds, UK.

Sweden: L. Burman, Swedish Institute for Infectious Disease Control, Stockholm.

Belgium: M. Delmée, Université Catholique de Louvain, Bruxelles.

Germany: T. Welte, Department of Infectious Diseases, Hannover Medical School, Hannover.

France: B. Guery – Hopital Calmette – Pavillon Christiaens, Lille Cedex, France.

Spain: E. Bouza, Servicio de Microbiología Clínica y E. Infecciosas Madrid, Spain.

Hungary: Z. Maszárovics, Department of Hygiene, Department of Infectious Diseases Markhot Ferenc County Hospital, Eger, Hungary.

Switzerland: A. F. Widmer. Facharzt für Innere Medizin und Infektiologie Universitätsspital, Basel, Switzerland.

Advisors: P. Carling (USA), J. Coia (Scotland), A. Collignon (France), J. O’Driscoll (UK), A. Eastaway (Scotland), D. Gerding (USA), A. Guleri (UK), M. Hell (Austria), J. Keller (Nl), M.-L. Lambert (Belgium), E. van Nood (Nl), C. E. Nord (Sweden), M. Orfanidou (Greece), B. Patel (UK), P. Speelman (Nl), R.-P. Vonberg (Germany), C. Wiuff (Scotland).

Authorship

  1. Top of page
  2. Abstract
  3. Summary of definitions and recommendations
  4. Introduction
  5. Objective
  6. Update Methodology
  7. Definitions
  8. Overview of Medical Treatment Options Available for CDI
  9. Recommendations for the Treatment of CDI
  10. On behalf of the Committee
  11. Authorship
  12. Transparency Declaration
  13. References

Three draft versions of this guideline document were written by three authors (MB, EK, JvD) and critiqued by the Committee and Advisors. A consensus was reached, resulting in the final version.

References

  1. Top of page
  2. Abstract
  3. Summary of definitions and recommendations
  4. Introduction
  5. Objective
  6. Update Methodology
  7. Definitions
  8. Overview of Medical Treatment Options Available for CDI
  9. Recommendations for the Treatment of CDI
  10. On behalf of the Committee
  11. Authorship
  12. Transparency Declaration
  13. References
  • 1
    Kuijper EJ, Wilcox MW. Decreased effectiveness of metronidazole for the treatment of Clostridium difficile infection? Clin Infect Dis 2008; 47: 6365.
  • 2
    O’Donnell LJD, Virjee J, Heaton KW. Detection of pseudodiarrhoea by simple clinical assessment of intestinal transit rate. BMJ 1990; 300: 439440.
  • 3
    McDonald LC, Coignard B, Dubberke E, Song X, Horan T, Kutty PK. Recommendations for surveillance of Clostridium difficile-associated disease. Infect Control Hosp Epidemiol 2007; 28: 140145.
  • 4
    Kuijper EJ, Coignard B, Tull P. Emergence of Clostridium difficile-associated disease in North America and Europe. Clin Microbiol Infect 2006; 12 (suppl 6): 218.
  • 5
    Tal S, Gurevich A, Guller V, Gurevich I, Berger D, Levi S. Risk factors for recurrence for Clostridium difficile-associated diarrhea in the elderly. Scand J Infect Dis 2002; 34: 594597.
  • 6
    Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile–associated diarrhea, stratified by disease severity. Clin Infect Dis 2007; 45: 302307.
  • 7
    McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol 2002; 97: 17691775.
    Direct Link:
  • 8
    Moshkowitz M, Ben-Baruch E, Kline Z, Shimoni Z, Niven M, Konikoff F. Risk factors for severity and relapse of pseudomembranous colitis in an elderly population. Colorectal Dis 2007; 9: 173177.
  • 9
    Pépin J, Alary ME, Valiquette L et al. Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. Clin Infect Dis 2005; 40: 15911597.
  • 10
    Nair S, Yadav D, Corpuz M, Pitchumoni CS. Clostridium difficile colitis: factors influencing treatment failure and relapse – a prospective evaluation. Am J Gastroenterol 1998; 93: 18731876.
  • 11
    Fernandez A, Anand G, Friedenberg F. Factors asscoiated with failure of metronidazole in Clostridium difficile-associated disease. J Clin Gastroenterol 2004; 38: 414418.
  • 12
    Pépin J, Routhier S, Gagnon S, Brazeau I. Management and outcomes of a first recurrence of Clostridium difficile-associated disease in Quebec, Canada. Clin Infect Dis 2006; 42: 758764.
  • 13
    Numan S, Veldkamp P, Kuijper EJ et al. Clostridium difficile-associated diarrhea: bovine anti-Clostridium difficile whey protein to help aid the prevention of relapses. Gut 2007; 56: 888889.
  • 14
    Warny M, Vaerman J-P, Avesani V, Delmée M. Human antibody response to Clostridium difficile toxin A in relation to clinical course of infection. Infect Immun 1994; 62: 384389.
  • 15
    Kyne L, Warny M, Qamar A, Kelly CP. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhea. Lancet 2001; 357: 189193.
  • 16
    Al-Nassir WN, Sethi AK, Riggs MM, Bobulsky GS, Jump RLP, Donskey CJ. A comparison of clinical and microbiologic response to treatment of Clostridium difficile-associated disease with metronidazole and vancomycin. Clin Infect Dis 2008; 47: 5662.
  • 17
    Louie TJ, Peppe J, Watt CK et al. Tolevamer, a novel nonantibiotic polymer, compared with vancomycin in the treatment of mild to moderately severe Clostridium difficile-associated diarrhea. Clin Infect Dis 2006; 43: 411420.
  • 18
    Keighly MRB, Burdon DW, Arabi Y et al. Randomised controlled trial of vancomycin for pseudomembranous colitis and postoperative diarrhoea. BMJ 1978; 2: 16671679.
  • 19
    Teasley DG, Gerding DN, Olson MM et al. Prospective randomised trial of metronidazole versus vancomycin for Clostridium difficile-associated diarrhoea and colitis. Lancet 1983; 2: 10431046.
  • 20
    Young GP, Ward PB, Bayley N et al. Antibiotic-associated colitis due to Clostridium difficile: double-blind comparison of vancomycin with bacitracin. Gastroenterology 1985; 89: 10381045.
  • 21
    Dudley MN, McLaughlin JC, Carrington G et al. Oral bacitracin vs vancomycin therapy for Clostridium difficile-associated diarrhoea. A randomized double-blind trial. Arch Intern Med 1986; 146: 11011104.
  • 22
    Fekety R, Silva J, Kauffman C et al. Treatment of antibiotic-associated Clostridium difficile colitis with oral vancomycin: comparison of two dosage regimens. Am J Med 1989; 86: 1519.
  • 23
    Boero M, Berti E, Morgando A et al. Terapia della colite da Clostridium difficile: Risultati di uno studio randomizzato aperto rifaximina vs. vancomicina. Microbiologia Medica 1990; 5: 7477.
  • 24
    De Lalla F, Nicolin R, Rinaldi E et al. Prospective study of oral teicoplanin versus oral vancomycin for therapy of pseudomembranous colitis and Clostridium difficile-associated diarrhea. Antimicrob Agents Chemother 1992; 36: 21922196.
  • 25
    Wiström J, on behalf of the Swedish CDAD study group. Treatment of Clostridium difficile associated diarrhea and colitis with an oral preparation of teicoplanin; a dose finding study. Scand J Infect Dis 1994; 26: 309316.
  • 26
    Wenisch C, Parschalk B, Hasenhündl M et al. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis 1996; 22: 813818.
  • 27
    Wullt M, Odenholt I. A double-blind randomized controlled trial of fusidic acid and metronidazole for treatment of an initial episode of Clostridium difficile-associated diarrhoea. J Antimicrob Chemother 2004; 54: 211216.
  • 28
    Musher DM, Logan N, Hamill RJ et al. Nitazoxanide for the treatment of Clostridium difficile colitis. Clin Infect Dis 2006; 43: 421427.
  • 29
    Lagrotteria D, Holmes S, Smieja M et al. Prospective, randomized inpatient study of oral metronidazole versus oral metronidazole and rifampin for treatment of primary episode of Clostridium difficile-associated diarrhea. Clin Infect Dis 2006; 43: 547552.
  • 30
    Louie T, Miller M, Donskey C, Mullane K, Goldstein EJ. Clinical outcomes, safety and pharmacokinetics of OPT-80 in a phase 2 trial of patients with Clostridium difficile infection. Antimicrob Agents Chemother 2009; 53: 223228.
  • 31
    Musher DM, Logan N, Bressler AM, Johnson DP, Rossignol JF. Nitazoxanide versus vancomycin in Clostridium difficile infection: a randomized, double-blind study. Clin Infect Dis 2009; 48: e41e46.
  • 32
    Louie T, Mullane KM, Weiss K et al. A randomized, double-blind clinical trial of OPT-80 versus vancomycin in Clostridium difficile infection (abstract #O148). European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 2009 in Helsinki, Finland; 2009.
  • 33
    McFarland LV, Surawicz CM, Greenberg RN et al. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA 1994; 271: 19131918.
  • 34
    Louie TJ, Gerson M, Grimard D et al. Results of a phase III trial comparing tolevamer, vancomycin and metronidazole in patients with Clostridium difficile-associated diarrhea (CDAD). In: Program and abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, 17 20 September 2007, Chicago, USA. Abstract K-425a.
  • 35
    Bouza E, Dryden M, Mohammed R et al. Results of a phase III trial comparing tolevamer, vancomycin and metronidazole in patients with Clostridium difficile-associated diarrhoea. In: Program and abstracts of the 18th European Congress of Clinical Microbiology and Infectious Diseases, 19 22 April 2008, Barcelona, Spain. Abstract O464.
  • 36
    Lowy I. Phase II Efficacy of Human Monoclonal Antibody Treatment to Prevent C. difficile Recurrence. Oral presentation at Digestive Disease Week in Chicago on June 2, 2009; Abstract 751b.
  • 37
    Bartlett JG, Tedesco FJ, Shull S et al. Symptomatic relapse after oral vancomycin therapy of antibiotic-associated pseudomembranous colitis. Gastroenterology 1980; 78: 431434.
  • 38
    Silva J Jr, Batts DH, Fekety R et al. Treatment of Clostridium difficile colitis and diarrhea with vancomycin. Am J Med 1981; 71: 815822.
  • 39
    Cherry RD, Portnoy D, Jabbari M et al. Metronidazole: an alternate therapy for antibiotic-associated colitis. Gastroenterology 1982; 82: 849851.
  • 40
    Bartlett JG. Treatment of antibiotic-associated pseudomembranous colitis. Rev Infect Dis 1984; 6 (suppl 1): S235S241.
  • 41
    De Lalla F, Privitera G, Rinaldi E et al. Treatment of Clostridium difficile-associated disease with teicoplanin. Antimicrob Agents Chemother 1989; 33: 11251127.
  • 42
    Olson MM, Shanholtzer CJ, Lee JT Jr, Gerding DN. Ten years of prospective Clostridium difficile-associated disease surveillance and treatment at the Minneapolis VA Medical Center, 1982–1991. Infect Control Hosp Epidemiol 1994; 15: 371381.
  • 43
    Musher DM, Aslam S, Logan N et al. Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis 2005; 40: 15861590.
  • 44
    Louie TJ. Treating Clostridium difficile in the future: what’s coming? Program and abstracts of the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16–19, 2005; Washington, DC. Abstract 1774.
  • 45
    Musher DM, Logan N, Mehendiratta V et al. Clostridium difficile colitis that fails conventional metronidazole therapy: response to nitazoxanide. J Antimicrob Chemother 2007; 59: 705710.
  • 46
    Herpers BL, Vlaminckx B, Burkhardt O et al. Tigecycline for severe refractory Clostridium difficile infection. Clin Infect Dis 2009; 48: 17321735.
  • 47
    Mogg GA, George RH, Youngs D et al. Randomised controlled trial of colestipol in antibiotic-associated colitis. Br J Surg 1982; 69: 137139.
  • 48
    Van Dissel JT, De Groot N, Hensgens CM et al. Bovine antibody-enriched whey to aid in the prevention of a relapse of Clostridium difficile associated diarrhoea: preclinical and preliminary clinical data. J Med Microbiol 2005; 54: 197205.
  • 49
    Surawicz CM, McFarland LV, Greenberg RN et al. The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis 2000; 31: 10121017.
  • 50
    Wullt M, Hagslätt ML, Odenholt I. Lactobacillus plantarum 299v for the treatment of recurrent Clostridium difficile-associated diarrhoea: a double-blind, placebo-controlled trial. Scand J Infect Dis 2003; 35: 365367.
  • 51
    Lawrence SJ, Korzenik JR, Mundy LM. Probiotics for recurrent Clostridium difficile disease. J Med Microbiol 2005; 54: 905906.
  • 52
    Mattila E, Veli-Jukka A, Broas M et al. A randomized, double-blind study comparing Clostridium difficile immune whey and metronidazole for recurrent Clostridium difficile-associated diarrhoea: efficacy and safety data of a prematurely interrupted trial. Scand J Infect Dis 2008; 40: 702708.
  • 53
    Buggy BP, Fekety R, Silva J Jr. Therapy of relapsing Clostridium difficile-associated diarrhea and colitis with the combination of vancomycin and rifampin. J Clin Gastroenterol 1987; 9: 155159.
  • 54
    Johnson S, Schriever C, Galang M et al. Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin Infect Dis 2007; 44: 846848.
  • 55
    Garey KW, Jiang ZD, Bellard A, DuPont HL. Rifaximin in treatment of recurrent Clostridium difficile-associated diarrhea, an uncontrolled pilot study. J Clin Gastroenterol 2009; 43: 9192.
  • 56
    Gorbach SL, Chang TW, Goldin B. Successful treatment of relapsing Clostridium difficile colitis with Lactobacillus GG. Lancet 1987; 2: 1519.
  • 57
    Biller JA, Katz AJ, Flores AF et al. Treatment of recurrent Clostridium difficile colitis with Lactobacillus GG. J Pediatr Gastroenterol Nutr 1995; 21: 224226.
  • 58
    Bowden TA Jr, Mansberger AR Jr, Lykins LE. Pseudomembraneous enterocolitis: mechanism for restoring floral homeostasis. Am Surg 1981; 47: 178183.
  • 59
    Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet 1989; 1: 11561160.
  • 60
    Lund-Tønnesen S, Berstad A, Schreiner A, Midtvedt T. Clostridium difficile-associated diarrhea treated with homologous feces. Tidsskr Nor Laegeforen 1998; 118: 10271030.
  • 61
    Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis 2003; 36: 580585.
  • 62
    Jorup-Rönström C, Håkanson A, Persson AK et al. Feces culture successful therapy in Clostridium difficile diarrhea. Lakartidningen 2006; 103: 36033605.
  • 63
    Nieuwdorp M, Van Nood E, Speelman P et al. Behandeling van recidiverende Clostridium difficile-geassocieerde diarree met een suspensie van donorfeces. Ned Tijdschr Geneeskd 2008; 152: 19271932.
  • 64
    Macconnachie AA, Fox R, Kennedy DR, Seaton RA. Faecal transplant for recurrent Clostridium difficile-associated diarrhoea: a UK case series. QJM 2009; 102: 781784.
  • 65
    Leung DAY, Kelly CP, Boguniewicz M et al. Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin. J Pediatr 1991; 118: 633637.
  • 66
    Beales IL. Intravenous immunoglobulin for recurrent Clostridium difficile diarrhoea. Gut 2002; 51: 456.
  • 67
    Wilcox MH. Descriptive study of intravenous immunoglobulin for the treatment of recurrent Clostridium difficile diarrhoea. J Antimicrob Chemother 2004; 53: 882884.
  • 68
    McPherson S, Rees CJ, Ellis R, Soo S, Panter SJ. Intravenous immunoglobulin for the treatment of severe, refractory, and recurrent Clostridium difficile diarrhea. Dis Colon Rectum 2006; 49: 640645.
  • 69
    Bakken S. Novel therapies for Clostridium difficile disease. In: Program and abstracts of the 45th Annual Meeting of the Infectious Disease Society of America, 4 7 October 2007, San Diego, USA. Oral session 611.
  • 70
    Nelson R. Antibiotic treatment for Clostridium difficile-associated diarrhea in adults. Cochrane Database Syst Rev 2007; CD004610. DOI: 10.1002/14651858.CD004610.pub3.
  • 71
    Anonymous. Emergence of reduced susceptibility to metronidazole in Clostridium difficile. Health Protection report, 2008: 2: January 18th. Available at: http://www.hpa.org.uk/hpr/archives/2008/news0308.htm#cdiff1.
  • 72
    Baines SD, O’Connor R, Freeman J et al. Emergence of reduced susceptibility to metronidazole in Clostridium difficile. J Antimicrob Chemother 2008; 62: 10461052.
  • 73
    Nagy E, Földes J. Inactivation of metronidazole by Enterococcus faecalis. J Antimicrob Chemother 1991; 27: 6370.
  • 74
    Pillai A, Nelson R. Probiotics for treatment of Clostridium difficile-associated colitis in adults. Cochrane Database Syst Rev 2008; CD004611. DOI: DOI: 10.1002/14651858.CD004611.pub2.
  • 75
    Bassetti S, Frei R, Zimmerli W. Fungemia with Saccharomyces cerevisiae after treatment with Saccharomyces boulardii. Am J Med 1998; 105: 7172.
  • 76
    Muñoz P, Bouza E, Cuenca-Estrella M et al. Saccharomyces cerevisiae fungemia: an emerging infectious disease. Clin Infect Dis 2005; 40: 16251634.
  • 77
    Besselink MG, Van Santvoort HC, Buskens E et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 2008; 371: 651659.
  • 78
    Friedenberg F, Fernandez A, Kaul V et al. Intravenous metronidazole for the treatment of Clostridium difficile colitis. Dis Colon Rectum 2001; 44: 11761180.
  • 79
    Lamontage F, Labbe AC, Kaeck O 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: 267272.
  • 80
    Kato H, Kato H, Iwashima Y, Nakamura M, Nakamura A, Ueda R. Inappropriate use of loperamide worsens Clostridium difficile-associated diarrhoea. J Hosp Infect 2008; 70: 194195.
  • 81
    Vonberg R-P, Kuijper EJ, Wilcox MH et al. Infection control measures to limit the spread of Clostridium difficile. Clin Microbiol Infect 2008; 14 (suppl 5): 220.