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Clostridioides difficile infection in adults: Treatment and prevention

Clostridioides difficile infection in adults: Treatment and prevention
Authors:
Ciarán P Kelly, MD
J Thomas Lamont, MD
Johan S Bakken, MD, PhD
Section Editor:
Stephen B Calderwood, MD
Deputy Editor:
Milana Bogorodskaya, MD
Literature review current through: Apr 2025. | This topic last updated: May 05, 2025.

INTRODUCTION — 

Clostridioides difficile infection (CDI) is one of the most common hospital-acquired (nosocomial) infections and is a frequent cause of morbidity and mortality among older adult hospitalized patients [1-3]. CDI is now recognized to cause colitis in younger patients and in the community. C. difficile colonizes the human intestinal tract after the normal gut microbiota has been disrupted (frequently in association with antibiotic therapy) and is the causative organism of antibiotic-associated colitis including pseudomembranous colitis.

The treatment of CDI in adults, including management of initial disease, recurrent disease, severe disease, and fulminant disease (previously referred to as severe, complicated CDI) will be reviewed here [4].

Issues related to surgical management of CDI are discussed separately. (See "Surgical management of Clostridioides difficile colitis in adults".)

The epidemiology, pathophysiology, clinical manifestations, and diagnosis of CDI in adults are discussed separately. (See "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology" and "Clostridioides difficile infection in adults: Clinical manifestations and diagnosis".)

Issues related to prevention of CDI in individual patients are discussed here; issues related to prevention of CDI in health care and community settings are discussed separately. (See "Clostridioides difficile infection: Prevention and control".)

Issues related to CDI in children are discussed separately. (See "Clostridioides difficile infection in children: Clinical features and diagnosis" and "Clostridioides difficile infection in children: Treatment and outcome" and "Clostridioides difficile infection in children: Microbiology, pathogenesis, and epidemiology".)

GENERAL PRINCIPLES

Infection control — Patients with suspected or proven CDI should be placed on contact precautions, and health care workers should wash hands before and after patient contact. Hand hygiene with soap and water may be more effective than alcohol-based hand sanitizers in removing C. difficile spores, since C. difficile spores are resistant to killing by alcohol, although thus far, no studies have demonstrated superiority of soap and water in infection control [2,3]. Therefore, use of soap and water is favored when contact with feces is likely over (or in addition to) alcohol-based hand sanitization and should be considered in outbreak settings. (See "Clostridioides difficile infection: Prevention and control".)

Discontinue inciting antibiotic agent(s) — An important initial step in the treatment of CDI is discontinuation of the inciting antibiotic agent(s) as soon as possible [2,3]. Treatment with concomitant antibiotics (ie, antibiotics other than those given to treat CDI) is associated with prolongation of diarrhea, increased likelihood of treatment failure, and increased risk of recurrent CDI [5-7]. If ongoing antibiotics are essential for treatment of the primary infection, if possible, it may be prudent to select antibiotic agents that are less frequently implicated in antibiotic-associated CDI (table 1). (See 'Duration of antibiotic therapy' below.)

Management of fluids, nutrition, and diarrhea — Supportive care with attention to correction of fluid losses and electrolyte imbalances is important.

Patients may have a regular diet as tolerated (to reduce stool frequency and volume). Since the diarrhea is due to a colonic process, instituting measures such as a lactose-free diet is not required.

Antimotility agents (eg, loperamide, diphenoxylate-atropine) have traditionally been avoided in CDI, but there is no evidence that they cause harm [3,8,9]. In the absence of ileus or colonic distention we reserve use of these agents for patients in whom there is difficulty keeping up with fluid losses, and treatment with CDI has already been initiated.

CLINICAL APPROACH TO TREATMENT

Indications for treatment — Treatment is indicated for anyone with a positive diagnostic laboratory assay with symptoms of CDI (eg, acute diarrhea with no obvious alternative explanation, colonic distention with ileus) or in setting of very high clinical suspicion for CDI (algorithm 1 and table 2).

●Empiric treatment – Empiric treatment is reasonable in the setting of very high clinical suspicion for CDI (particularly for patients with symptoms of severe or fulminant colitis), pending results of diagnostic testing [3]. (See "Clostridioides difficile infection in adults: Clinical manifestations and diagnosis", section on 'When to suspect C. difficile infection'.)

●Positive C. difficile test – Treatment is warranted for patients with typical manifestations of CDI (eg, acute diarrhea [≥3 loose stools in 24 hours] with no obvious alternative explanation) and a positive diagnostic laboratory assay [10,11]. (See "Clostridioides difficile infection in adults: Clinical manifestations and diagnosis", section on 'Establishing the diagnosis'.)

Treatment is not indicated in patients who have a positive diagnostic laboratory assay but do not have diarrhea or other CDI disease manifestations, as asymptomatic carriage is common.

Assessing disease severity — Treatment decisions for CDI are based on severity of infection. There is no consensus definition for severe or fulminant CDI nor is there agreement as to the most important clinical indicators that should be used to differentiate severity; prospectively validated severity scores for CDI are needed [2,3,12-17].

Proposed criteria for disease severity (based on expert opinion) include [2]:

●Non-fulminant disease:

•Nonsevere CDI – White blood cell count ≤15,000 cells/microL and serum creatinine <1.5 mg/dL (or <50 percent rise from baseline creatinine level)

•Severe CDI – White blood cell count >15,000 cells/microL and/or serum creatinine ≥1.5 mg/dL (or ≥50 percent rise from baseline creatinine level) (see 'Role of surgery in severe or fulminant disease' below)

●Fulminant colitis (previously referred to as severe, complicated CDI) – Presence of hypotension or shock, ileus, or megacolon (see 'Role of surgery in severe or fulminant disease' below)

For the purposes of the treatment decisions in the following discussion, determination of disease severity is left to clinician judgment and may include any or all of the above criteria. Age ≥65 years confers increased risk for severe CDI; this and other risk factors are discussed further separately. (See "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology", section on 'Risk factors'.)

When to admit to the hospital — All patients with fulminant CDI should be admitted immediately to the hospital for stabilization, intravenous (IV) hydration, and antibiotic administration. Hospitalization should also be considered in patients with severe CDI or in any patient who is frail, shows signs and symptoms of dehydration (eg, low blood pressure, orthostasis, poor urinary output), or who have poor social support and may not be able to call for help if symptoms worsen. Other patients with mild CDI can be managed in the outpatient setting.

Antibiotic therapy

Non-fulminant disease

Initial episode — For patients presenting with an initial episode of CDI, we suggest oral fidaxomicin (table 2 and algorithm 1). For patients with severe CDI, we also consider the need for surgery. (See 'Role of surgery in severe or fulminant disease' below.)

We favor fidaxomicin over vancomycin given a benefit with respect to recurrence rates and sustained clinical response, especially in patients with severe disease or at higher risk for recurrence (eg, age ≥65 years, compromised immunity, severe CDI, or ribotype 027/078/244 infections) [1]. For many patients, fidaxomicin may be unattainable, due to cost restraints. In such cases, oral vancomycin is a reasonable alternative (see 'Cost considerations' below). Intravenous vancomycin has no effect on C. difficile colitis since vancomycin is not excreted into the colon in sufficient concentrations to treat CDI.

For patients with nonsevere CDI, metronidazole is another alternative agent if oral vancomycin and oral fidaxomicin are not available; however, metronidazole is less effective than fidaxomicin or vancomycin; it should be avoided in patients who are frail, ≥65 years old, or who develop CDI in association with inflammatory bowel disease [1,18-20].

Evidence and rationale behind the choice of regimen for an initial episode of CDI is discussed separately. (See 'Regimens for initial episodes' below.)

Recurrent episodes — Recurrent CDI is defined by resolution of CDI symptoms while on appropriate therapy, followed by reappearance of symptoms within two months of discontinuing treatment [2]. Approach to recurrent CDI caused by relapse or by reinfection are the same. (See "Clostridioides difficile infection in adults: Clinical manifestations and diagnosis", section on 'Recurrent disease'.)

The approach to antibiotic management of nonfulminant recurrent CDI is the same regardless of severity, but varies depending on the number of recurrences, as discussed below (table 2 and algorithm 1). For patients with a severe recurrent episode of CDI, we also consider the need for surgery. (See 'Role of surgery in severe or fulminant disease' below.)

Evidence and rationale behind the choice of regimen for recurrent episodes of CDI is discussed separately. (See 'Regimens for recurrent episodes' below.)

First recurrence (2nd CDI episode) — For patients with their first recurrence, we administer either a fidaxomicin or a vancomycin regimen [1].

●Prior treatment with vancomycin – For patients presenting with their first recurrence of CDI who received vancomycin for their initial CDI episode, we suggest one of the fidaxomicin regimens outlined in the table (table 2 and algorithm 1) [1].

●Prior treatment with fidaxomicin – For patients presenting with their first recurrence of CDI who received fidaxomicin for their initial CDI episode, we suggest a pulsed vancomycin regimen (table 2 and algorithm 1) [1,21]. For patients who prefer not to take a prolonged tapered and pulsed vancomycin regimen, the standard 10-day vancomycin regimen is an alternative. A fidaxomicin regimen is also a reasonable alternative if oral vancomycin cannot be used. There are limited data on the optimal regimen to use in CDI recurrences and the preference for using a vancomycin-based regimen in patients who have previously received prior treatment with fidaxomicin is largely based on expert opinion. Some experts prefer to use fidaxomicin-based regimens in all patients with recurrent CDI episodes due to the increased disruption of gut microbiota with vancomycin compared with fidaxomicin.

Evidence and rationale behind the choice of regimen for recurrent episodes of CDI is discussed separately. (See 'Regimens for recurrent episodes' below.)

Second recurrence (3rd CDI episode) — Treatment of patients with a second recurrence consists of a fidaxomicin or vancomycin regimen with adjunctive fecal microbiota product (FMP).

●Clinical approach – For patients with their second recurrence, we suggest one of the fidaxomicin regimens outlined in the table (table 2 and algorithm 1), although the vancomycin or vancomycin plus rifaximin regimens are reasonable alternatives. Additionally, we suggest administering an FMP (eg, rectal suspension [Rebyota], oral capsule [Vowst]) after completion of CDI therapy to help prevent further recurrences.

If FMP is not available due to cost constraints, some physicians may consider referral for traditional fecal microbiota therapy (FMT; in regions where available) to help prevent further recurrences. (See 'Role of traditional FMT' below.)

●Fecal microbiota products – Commercial live fecal microbiota products (FMP) are now available in both rectal suspension (Rebyota) and oral capsule (Vowst) form [22,23]. Although they are United States Food & Drug Administration (FDA) approved for use in patients with first recurrence of CDI, because of cost considerations and concern for transmission of infectious agents, we prefer to use them for patients who have had two prior CDI episodes and are now experiencing their second recurrence (third episode). Additionally, the majority of patients with a first recurrence do not go on to have a second recurrence [24] so the benefit of FMPs in patients with first recurrence is small. In contrast, FMPs have shown a much more substantial reduction in recurrence rates in patients who have had ≥2 recurrences [25,26].

The selection of the FMP depends on availability, cost considerations, and patient preferences. We avoid using FMPs in patients who are severely immunocompromised (CD4 cell count ≤200 cells/microL and/or absolute neutrophil count ≤500 cells/microL) given the scarcity of safety data for this patient population.

•Fecal microbiota rectal suspension (Rebyota) – The rectal suspension consists of a wide variety of microbes (including Bacteroides spp) derived from human stool. The rectal enema is administered as a one-time dose of 150 mL via the rectum using the provided administration set and can be administered at home; refer to labeling for specific instructions. It should be administered 24 to 72 hours after the last dose of antibiotics for CDI treatment. Prior to being given, the enema needs to be thawed in the refrigerator for approximately 24 hours. Adverse effects are similar to those of any retention enema and include mild abdominal pain, distension, diarrhea, flatulence, and nausea.

•Fecal microbiota oral capsule (Vowst) – The oral capsules are composed of live purified Firmicutes spores. The oral capsules are administered as four capsules once daily on an empty stomach for three consecutive days. It should be administered two to four days after the last dose of antibiotics for CDI treatment. Administer 296 mL (10 oz) of magnesium citrate solution containing 17.45 g magnesium citrate on the day before and at least 8 hours prior to taking the first dose of oral capsules. Patients should not eat or drink, except for small amounts of water, for at least 8 hours before the first dose. Subsequent doses on days 2 and 3 are taken on an empty stomach before the first meal of the day. Participants with impaired kidney function can receive polyethylene glycol electrolyte solution (250 mL GoLYTELY) instead of magnesium citrate. Adverse effects are generally mild and include mild abdominal distension, fatigue, constipation, chills, and diarrhea.

Evidence and rationale behind the choice of regimen for recurrent episodes of CDI is discussed separately. (See 'Regimens for recurrent episodes' below and 'Adjunctive fecal microbiota products' below.)

Third and subsequent recurrences (4th and subsequent CDI episodes) — Treatment of third and subsequent recurrences consists of an extended fidaxomicin or vancomycin regimen along with either traditional FMT or a FMP (table 2 and algorithm 1).

●For most patients – For patients who have received appropriate antibiotic treatment for at least three CDI episodes (ie, initial episode plus two recurrences), who subsequently present with a fourth or further episode (third or subsequent recurrence), we suggest repeating one of the prolonged duration fidaxomicin or vancomycin regimens listed in the table (table 2) as well as traditional FMT in regions where available (algorithm 1) [1,2].

If an FMP is available and was not administered during prior recurrences, it is reasonable to administer an FMP (eg, rectal suspension, oral capsules) instead of traditional FMT after completion of CDI therapy. Information on selection and administration of FMPs is discussed separately (see 'Second recurrence (3rd CDI episode)' above). Further recurrence after use of an FMP should prompt referral for traditional FMT. (See 'Role of traditional FMT' below and "Fecal microbiota transplantation for treatment of Clostridioides difficile infection".)

●For patients who cannot undergo FMT or relapse post-FMT

•For patients with a third or subsequent CDI recurrence who are unable to undergo FMT (eg, severely immunocompromised patients), we suggest suppressive oral vancomycin (125 mg orally once daily) following completion of a treatment regimen in some circumstances [3]. Patients most likely to benefit are those at greatest risk for CDI recurrence (eg patients ≥65 years, patients with history of severe CDI, or immunosuppressed patients). We administer vancomycin (125 mg orally once daily) for six to eight weeks with close follow-up. Some patients continue to experience loose stools at this dose; in such cases, twice daily or three-times daily dosing is reasonable. Suppressive vancomycin may be continued indefinitely for patients in whom recurrent CDI may be life threatening. (See 'Secondary prevention' below.)

•For patients with further recurrence despite two FMTs (at least one of which was via colonoscopy), we administer an antibiotic treatment regimen (table 2) followed by suppressive oral vancomycin (125 mg orally once daily) indefinitely to reduce the risk of further recurrence [3].

The use of suppressive oral vancomycin is supported by a small retrospective study including 20 patients with recurrent CDI who were not FMT candidates or who relapsed after FMT [27]. Patients were treated with oral vancomycin for a minimum of eight weeks; during 200 patient-months of follow-up, one case of relapse occurred; among those who stopped suppressive vancomycin, 31 percent relapsed within six weeks. Fidaxomicin might be useful for long-term suppressive use; however, thus far, data are not available.

Evidence and rationale behind the choice of regimen for recurrent episodes of CDI is discussed separately. (See 'Regimens for recurrent episodes' below.)

Fulminant disease — Management of fulminant colitis (see 'Assessing disease severity' above) consists of antibiotic therapy, supportive care, and close monitoring; in addition, patients should be assessed for indications for surgery. (See 'Management of fluids, nutrition, and diarrhea' above and 'Role of surgery in severe or fulminant disease' below.)

Initial management — For treatment of patients with fulminant colitis, we suggest oral (or per nasogastric tube) vancomycin (500 mg four times daily) plus parenteral metronidazole (500 mg every 8 hours) (table 2 and algorithm 1) [2,3,15,28]. We do not use fidaxomicin in fulminant disease given lack of evidence and experience with these agents in this setting.

For patients with ileus, we also administer vancomycin rectally to optimize the concentration of vancomycin in the colon [3,29-31]. The optimal dosing of rectal vancomycin has not been established by clinical trials, and case descriptions vary widely. It is often given as a retention enema (500 mg in 100 mL of normal saline; retained for as long as possible and readministered every six hours). Rectal vancomycin can be stopped once ileus has resolved.

Evidence and rationale behind the choice of regimen for fulminant episodes of CDI is discussed separately. (See 'Regimens for fulminant disease' below.)

Reassessment in 24 to 48 hours — Response to treatment should be reassessed in 24 to 48 hours. Patients who have no sustained improvement in vital signs after 24 to 48 hours should be considered for further intervention.

●For patients improving on therapy – For patients improving on therapy, we continue therapy for the usual duration of therapy (10 days). Once the patient clinically improves, the metronidazole can be stopped and the vancomycin dose reduced to the standard dose used in non-fulminant disease. If recovery is slow, the duration of treatment can be extended to 14 days.

●No improvement/worsening on therapy – If the patient is worsening on therapy, surgical re-assessment is warranted (see 'Role of surgery in severe or fulminant disease' below). For patients who are not surgical candidates, traditional FMT (administered retrograde via enema or antegrade via loop colostomy) may be considered if benefits appear to outweigh the risks.

●Since FMT is associated with risk of colonic perforation, it should be restricted to patients who are unresponsive to standard therapy and the procedure should be performed by personnel with appropriate expertise [3]. (See 'Role of traditional FMT' below.)

Duration of antibiotic therapy — The duration of initial antibiotic therapy for treatment of CDI is 10 days [2]. For patients with severe/fulminant CDI who have a slow recovery, treatment can be extended to 14 days. Duration of antibiotic therapy for recurrent disease depends on the regimen selected, as summarized in the table (table 2).

Patients with CDI in the setting of another underlying infection requiring prolonged duration of antibiotic therapy are at increased risk for recurrent CDI [7]. In such cases, we typically continue CDI treatment throughout the antibiotic course plus an additional tail of one week after completion of the antibiotic course [32-34]. Experts differ on which dosing to use. If using vancomycin, some continue the full treatment dose of vancomycin (125 mg orally four times a day) while others feel comfortable transitioning to the preventive dose (125 mg orally once daily). Data to support this practice are limited to retrospective observational studies and may reflect a delay in recurrences rather than in preventing them. (See 'Prevention' below.)

Monitoring vancomycin levels during therapy — Patients with severe or fulminant colitis have mucosal disruption and systemic absorption of enteral vancomycin can occur [2,35,36]. In patients with severe or fulminant colitis and renal insufficiency (creatinine clearance <10 mL/minute) who are receiving a prolonged course (>10 days) of enteral vancomycin therapy, we suggest monitoring serum vancomycin levels unless the patient is on dialysis. (See "Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults", section on 'Approach to dosing and monitoring'.)

Cost considerations — In the setting of cost constraints, we prioritize use of fidaxomicin and suppressive oral vancomycin for patients at greatest risk for CDI recurrence (eg, age ≥65 years, history of severe CDI, or immunosuppression) [1]. In the United States, there is an increasing acceptance among commercial and governmental payers to pay for the cost of fidaxomicin [37,38]. Detailed discussion of cost considerations for each agent is out of the scope of this topic. (See "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology", section on 'Risk factors'.)

Effect on microbiome — Thus far, minimal alteration of the microbiome has been observed with fidaxomicin [39,40]. The risk of bowel colonization with vancomycin-resistant enterococci associated with vancomycin and metronidazole use is comparable and likely higher than with fidaxomicin use [41-44].

Role of surgery in severe or fulminant disease — Early surgical consultation is warranted for patients with CDI who meet one or more of the following clinical indicators that have been associated with poor prognosis (table 3) [45-50]:

•Hypotension

•Fever ≥38.5°C

•Ileus or significant abdominal distention

•Peritonitis or significant abdominal tenderness

•Altered mental status

•White blood cell count ≥20,000 cells/microL

•Serum lactate levels >2.2 mmol/L

•Admission to intensive care unit

•End organ failure (eg, requiring mechanical ventilation, renal failure)

•Failure to improve after three to five days of maximal medical therapy

Toxic megacolon should be suspected if the patient develops abdominal distention with diminution of diarrhea; this may reflect paralytic ileus resulting from loss of colonic muscular tone [51]. (See "Toxic megacolon".)

Earlier surgical consultation facilitates timely operative management if a patient's clinical course worsens. Several studies have demonstrated or implied that in patients who undergo surgery for C. difficile colitis, timely surgical management improves outcomes [45-48]. Early surgical consultation for severe or complicated CDI has been advocated by multiple society guidelines [3,49,52-54].

Issues related to surgical management of CDI are discussed further separately. (See "Surgical management of Clostridioides difficile colitis in adults".)

Role of traditional FMT — Traditional FMT has been used in fulminant colitis as an alternative to colectomy as well as a preventive measure against further recurrent CDI episodes. However, traditional FMT is likely to be utilized less often with the advent of FMPs that do not require an endoscopy for administration. (See 'Adjunctive fecal microbiota products' below.)

●Indications – FMT should be considered for patients presenting with fulminant colitis or in patients presenting with their third or subsequent recurrence (fourth or subsequent episode) of CDI. Among patients with fulminant disease, situations in which we consider FMT include patients with a recurrent fulminant infection and those who are not improving after three to five days of medical therapy and are not candidates for surgery [55]. (See 'Initial episode' above and 'Fulminant disease' above and 'Recurrent episodes' above.)

●Administration – FMT consists of administrating a fecal slurry into the intestinal tract of a patient with severe, fulminant, or recurrent CDI. However, we avoid FMT in severely immunocompromised patients and patients with inflammatory bowel disease [55]. FMT instillations should be administered via colonoscope, since a larger volume of stool can be instilled into the colon than via oral capsule administration [3,55]. In addition, the possibility of a concomitant atonic colon or ileus may prevent orally administered fecal material from reaching the colon. Multiple stool infusions may be more effective than a single infusion [55,56]. For patients with fulminant disease, we favor administration of FMT in a reduced volume via enema (100 mL every six hours) (table 2). Risks associated with FMT include procedural complications and transmission of new infectious agents. Issues related to pretreatment evaluation and administration of FMT are discussed separately. (See "Fecal microbiota transplantation for treatment of Clostridioides difficile infection".)

Evidence supporting the use of traditional FMT in fulminant or recurrent disease is discussed separately. (See 'Adjunctive FMT' below.)

Follow up — In patients who are recovering or whose symptoms have resolved, repeat stool assays are not warranted during or following treatment, as up to 50 percent of patients have positive stool assays for as long as six weeks after the completion of therapy [57,58].

RATIONALE FOR TREATMENT

Regimens for initial episodes — Treatment regimens for initial non-fulminant episodes of CDI consist of fidaxomicin and vancomycin.

●Fidaxomicin versus vancomycin

•Mild to moderate disease – Preference for fidaxomicin is supported by four randomized trials including 1673 patients with CDI treated with fidaxomicin or vancomycin [59-62]. In a pooled analysis of these studies, initial clinical cure was comparable between the groups (risk ratio 1.00, 95% CI 0.96-1.04) while clinical cure at four weeks following completion of therapy was observed more frequently among patients treated with fidaxomicin (risk ratio 1.16, 95% CI 1.09-1.24) [1]. There was no difference in mortality (risk ratio 0.90, 95% CI 0.66-1.23) or drug-related adverse events. In one of the studies, patients in the fidaxomicin arm received an extended-pulsed regimen rather than a standard regimen [61].

Similarly, in an earlier 2017 meta-analysis of 22 randomized trials including 3215 patients with nonsevere CDI treated with oral vancomycin, oral fidaxomicin, and oral metronidazole, fidaxomicin was modestly more effective at achieving a sustained symptomatic cure than vancomycin (71 versus 61 percent; relative risk 1.17, 95% CI 1.04-1.31) [11]. Observational studies have demonstrated similar findings [63].

•Severe disease – Fidaxomicin and vancomycin appear to be comparable in efficacy for severe CDI, albeit efficacy rates appear to be lower than in non-severe CDI. As an example, in a subgroup analysis of participants with severe CDI from a double-blinded, randomized study, clinical cure rates were similar with fidaxomicin and vancomycin (82 versus 88 percent) [59]. Other trials and observational studies have shown similar results [60,62,64]. However, in one observational study, fidaxomicin appeared to have better outcomes compared with vancomycin. In a retrospective study of more than 500 patients with CDI (around half of whom had severe CDI), fidaxomicin was associated with a lower 30-day relapse rate compared with vancomycin (2.4 versus 13.6 percent, aHR 0.16, 95% CI 0.04-0.66) [63].

●Metronidazole associated with higher rates of treatment failure

•Mild to moderate disease – Use of metronidazole has been associated with higher rates of treatment failure in observational and retrospective studies [65,66]. The reasons for metronidazole failure are poorly understood [67,68]. One factor may be that stool drug levels in patients taking oral metronidazole (which is well absorbed) decrease as colonic inflammation subsides, whereas stool drug levels in patients taking oral vancomycin or fidaxomicin (which are poorly absorbed or not absorbed) remain high throughout the course of therapy [69,70]. Age ≥65 years may be another factor associated with risk for metronidazole failure [71].

•Severe disease – Metronidazole is not recommended for severe CDI. Studies in patients with severe disease are more limited than in patients with mild to moderate disease but support the use of fidaxomicin or vancomycin over metronidazole [12,72,73].

Regimens for recurrent episodes — Agents used in regimens for recurrent episodes are fidaxomicin, vancomycin, rifaximin, and the addition of traditional FMT. Some of these agents may be administered with standard dosing or in an extended-pulsed regimen, as summarized in the table (table 2). The rationale for use of a pulsed regimen is based on the hypothesis that this approach may facilitate a gradual return of the normal colonic microbiome and/or allow treatment of vegetative C. difficile released by persistent fecal spores.

●Fidaxomicin – Use of fidaxomicin for treatment of recurrent CDI is supported by subgroup analysis from three randomized trials including 253 patients with recurrent CDI treated with fidaxomicin or vancomycin [59-61,74]. In a pooled subgroup analysis, initial clinical cure was comparable between the groups (risk ratio 1.03, 95% CI 0.94-1.14); clinical cure at 30 days following completion of therapy was observed more frequently among patients treated with fidaxomicin (risk ratio 1.27, 95% CI 1.05-1.54) [1]. There was no difference in mortality (risk ratio 0.81, 95% CI 0.20-3.38) or drug-related adverse events.

Use of extended-pulsed fidaxomicin dosing is supported by a randomized trial including 364 patients hospitalized with CDI who were randomly assigned to receive extended-pulsed fidaxomicin (200 mg oral tablets, twice daily on days 1 to 5, then once daily on alternate days on days 7 to 25) or vancomycin (125 mg oral capsules, four times daily for 10 days) [61]. Clinical cure at 30 days following completion of therapy was observed more frequently among patients treated with extended-pulsed fidaxomicin (70 versus 59 percent; odds ratio 1.62, 95% CI 1.04-2.54). Recurrent CDI rates were 2 percent in patients receiving extended-pulsed fidaxomicin and 17 percent in those treated with vancomycin. In a separate investigation, tapered-pulsed fidaxomicin was used to treat 46 patients who had failed prior treatment by tapered-pulsed vancomycin [75]. Sustained clinical response rates at 30 and 90 days were 74 percent and 61 percent, respectively.

●Pulse-tapered oral vancomycin – Use of pulse-tapered oral vancomycin for treatment of recurrent CDI is supported by small retrospective studies [58,76-79]. In one nonrandomized study of 163 patients with recurrent CDI, 29 patients were treated with a vancomycin-tapered regimen and 7 were treated with a vancomycin-pulsed regimen; recurrence rates were 31 and 14 percent, respectively, compared with a recurrence rate of 45 percent for other regimens [58]. In another study, 12 patients with recurrent CDI were treated with a vancomycin-tapered regimen; the recurrence rate was 41 percent [77].

●Vancomycin followed by rifaximin – Use of vancomycin followed by rifaximin has been evaluated in two small studies [80,81]. In one series, eight women with recurrent CDI received a two-week course of rifaximin when they were asymptomatic, immediately after completing their last course of vancomycin. Seven patients had no further recurrence of infection [80].

Regimens for fulminant disease — The rationale for the use of higher dose vancomycin and parenteral metronidazole in fulminant CDI relies on data in severe disease and concern for poor absorption in the setting of poor motility.

●Oral vancomycin – Data supporting use of oral vancomycin for fulminant colitis is based on evidence in severe disease. (See 'Regimens for initial episodes' above.)

There are no data comparing vancomycin dosing in the setting of fulminant disease. In this life-threatening situation, with concern about intestinal motility and delivery to the site of infection, higher doses of vancomycin are conventional [1]. (See 'Initial management' above.)

●Parenteral metronidazole – The rationale for use of parenteral metronidazole is that there may be delayed passage of oral vancomycin from the stomach to the colon. Therapeutic stool metronidazole concentrations can be achieved with intravenous metronidazole because of biliary and intestinal excretion of the drug [69,82,83]. Use of parenteral metronidazole is supported by a retrospective study including 88 critically ill patients (of whom 44 received parenteral metronidazole in addition to oral vancomycin, and the remainder received oral vancomycin monotherapy); a lower mortality rate was observed among those who received dual therapy (36 versus 16 percent) [82]. However, in a subsequent retrospective study including 525 patients with fulminant CDI, there was no association between dual therapy and death, colectomy within 90 days, or CDI recurrence [84]. (See 'Initial management' above.)

●Rectal vancomycin – Reports in the literature of the use of rectal vancomycin for CDI are limited [2,29,30,85,86]. In one case series including nine patients with refractory symptoms, toxic megacolon, or fulminant colitis, rectal vancomycin was administered in addition to standard antibiotics; eight patients had complete resolution of symptoms and one patient died from multisystem organ failure [29]. (See 'Reassessment in 24 to 48 hours' above.)

Adjunctive fecal microbiota products — Microbiota-based fecal microbiota products (FMPs) appear to be effective in reducing the risk of CDI recurrence by reinstating healthy gut bacteria post-CDI. Two commercial products are available, one administered via enema and the other via an oral capsule. Decision on which one to use is primarily determined by availability, cost, and patient preference. Information on administration is discussed elsewhere. (See 'Second recurrence (3rd CDI episode)' above.)

●Fecal microbiota rectal suspension (Rebyota) – A commercial fecal microbiota rectal suspension (fecal microbiota live-jslm; Rebyota) has been approved by the FDA to prevent recurrence in patients with ≥2 episodes (first recurrence) of CDI [22,87]. The rectal suspension is an FMP that consists of a wide variety of microbes (including Bacteroides spp) retrieved from human stool.

The rectal suspension has been shown to reduce the risk of recurrence in CDI in adults [24,88,89]. In a double-blinded randomized controlled trial of 267 adults with ≥1 recurrent treated CDI, those who received the stool-based rectal enema had a lower rate of recurrence at eight-week follow-up (29 versus 42 percent) [24]. More than 90 percent of participants (in both the placebo and treatment group) who did not have a recurrence at eight weeks remained so by six months of follow-up. Another randomized trial of adults with ≥2 CDI recurrences that administered two doses of the rectal enema one week apart showed similar results [88].

●Fecal microbiota oral capsule (Vowst) – A commercial fecal microbiota oral capsule (SER-109; fecal microbiota spore live-BRPK; Vowst) has been approved by the FDA to prevent recurrence in patients with ≥2 episodes (first recurrence) of CDI [90]. The oral capsules are composed of live purified Firmicutes spores.

The oral capsules have shown to reduce the risk of recurrence of CDI in adults. As an example, in a phase III trial, 182 patients with recurrent (three or more episodes) CDI who had resolution of symptoms after treatment with standard-of-care antibiotics were assigned an oral capsule composed of live purified Firmicutes spores (SER-109) or placebo [91]. Administration of SER-109 significantly decreased recurrence rates relative to placebo (21 versus 47 percent; RR 0.46, 95% CI 0.30-0.73) up to 24 weeks after treatment [25].

Adjunctive FMT — Traditional FMT has a role in recurrent CDI as well as fulminant CDI. Indications and information on administration of FMT is discussed separately. (See 'Third and subsequent recurrences (4th and subsequent CDI episodes)' above and 'Role of traditional FMT' above.)

●Recurrent CDI – The efficacy of traditional FMT for management of recurrent CDI has been evaluated in randomized controlled and open-label trials; cure rates range from 70 to 90 percent with a follow-up period ranging from 10 to 18 weeks [77,92-96]. In one meta-analysis of 320 participants from six randomized trials comparing FMT with placebo or antibiotics, the weighted pooled cure rate was higher for FMT compared with the control (77 versus 40 percent; RR 1.92, 95% CI 1.36-2.71) [97]. Another meta-analysis of randomized trials showed similar findings (68 cure rate for FMT versus 44 percent cure rate for the comparator) [98]. (See "Fecal microbiota transplantation for treatment of Clostridioides difficile infection".)

●Fulminant CDI – Traditional FMT has been used in patients with severe and fulminant colitis as an alternative to colectomy and has been associated with reductions in mortality in retrospective and observational studies; however, prospective randomized studies comparing FMT with colectomy are needed to determine whether there is a role for routine use of FMT in treatment of severe and fulminant CDI [2,3,99-101].

In a retrospective study including 111 hospitalized patients with CDI (of whom 66 underwent FMT), use of FMT was associated with improved survival among patients with severe disease (odds ratio [OR] 0.08, 95% CI 0.016-0.34) [102]. In a cohort study including 57 patients with severe or fulminant CDI treated with FMT, the cure rate among 19 patients with severe CDI was 100 percent; cure rates among 33 patients with fulminant CDI were 87 percent [103]. Similarly, in a retrospective study including 48 patients hospitalized in the ICU with severe or fulminant CDI, use of FMT was associated with a mortality benefit over standard of care (OR 0.23, 95% CI 0.06-0.97) [104]. In another study including 199 patients with severe or fulminant CDI, implementation of an FMT program was associated with a reduction in mortality rate (10.2 to 4.4 percent) and colectomy rate (6.8 to 2.7 percent) [105].

THERAPIES OF LIMITED USE — 

Other therapeutic options for CDI are discussed below; based on available data, none warrants routine use for management of CDI [106].

●Probiotics – We suggest against adjunctive administration of probiotics for treatment of CDI, in agreement with society guidelines [3]. Limitations of the available data include differences in probiotic formulations studied, duration of probiotic administration, definitions of CDI, duration of study follow-up, and inclusion of patients not typically considered at high risk for CDI [107-109].

●Alternative antibiotics – A meta-analysis of 22 studies including more than 3200 participants evaluated several alternative antibiotics for treatment of CDI, including fusidic acid, nitazoxanide, teicoplanin, rifampin, rifaximin, bacitracin, or ridinilazole; no single agent was clearly superior [11]. Combination therapy has been tried without success [110]. Nitazoxanide may be as effective as vancomycin (as suggested by a randomized trial of 50 CDI patients), although the small sample precluded conclusions about noninferiority of nitazoxanide to vancomycin [111]. Teicoplanin may be at least as effective as vancomycin or metronidazole, although it is costly and is not available in the United States [112,113].

Ridinilazole is an investigational antimicrobial agent restricted to the gastrointestinal tract. In a phase 3 randomized, double-blinded trial that included over 700 adults with CDI, oral ridinilazole (200 mg twice a day for 10 days) achieved a similar sustained clinical response rate (defined as clinical cure at the end of treatment and no recurrence within 30 days) as vancomycin (73 versus 71 percent) and a lower rate of recurrent CDI (8 versus 17 percent, 95% CI -14% to -4.5%) [114]. It is unknown how ridinilazole compares to fidaxomicin.

●Intravenous immune globulin (IVIG) – IVIG contains anti-C. difficile antibodies and has been used in some patients with relapsing or severe C. difficile colitis. Although there are case reports suggesting IVIG may be a useful addition to antibiotic therapy for refractory CDI [115-117], a retrospective review of 18 patients who received IVIG demonstrated no significant difference in clinical outcomes compared with 18 matched control cases [118].

●Anion-binding resins – Tolevamer is a C. difficile toxin-binding resin developed specifically for CDI [119]. Preliminary studies with tolevamer showed promising results, although subsequent large trials have found it to be inferior to both vancomycin and metronidazole as primary therapy for CDI [72]. Similarly, the anion-binding resins colestipol and cholestyramine are not effective as primary therapy for C. difficile colitis [120,121].

PREVENTION — 

Issues related to prevention of CDI in individual patients are discussed below; issues related to prevention of CDI in health care and community settings are discussed separately. (See "Clostridioides difficile infection: Prevention and control".)

Primary prevention — Evidence-supported strategies for preventing an initial episode of CDI include:

●Minimizing antibiotic use (see "Clostridioides difficile infection: Prevention and control", section on 'Antibiotic stewardship' and "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology", section on 'Antibiotic use')

●Avoiding gastric acid suppression (see "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology", section on 'Gastric acid suppression')

Secondary prevention — For patients at high risk for future CDI (patients ≥65 years of age or with significant immunocompromise who were hospitalized for severe CDI within the past three months) who require ongoing (longer than a week) treatment with systemic antibiotics for a separate infection, some experts administer oral vancomycin (125 mg orally once daily) prophylactically for the duration of antibiotic treatment plus an additional tail of one week [3].

Data on the utility of oral vancomycin in reducing risk of further CDI episodes in patients on systemic antibiotic therapy are conflicting. This approach is supported by a retrospective study that included 172 patients with at least two prior CDI episodes who subsequently started on other antibiotics and showed that prophylactic oral vancomycin was associated with a lower likelihood of yet another recurrence (54 versus 70 percent); prophylaxis made no difference in recurrence rates among 379 patients with only one prior CDI episode [32]. In a subsequent retrospective study of over 750 patients who had at least one prior episode of CDI and received courses of systemic antibiotics, prophylactic oral vancomycin was not associated with an overall difference in further instances of CDI [122]. However, among the subset of patients with only one prior episode of CDI, relapses were less frequent at 90 days with prophylactic vancomycin.

Metronidazole should not be used for secondary prophylaxis because of its dose-dependent association with peripheral neuropathy. Data on fidaxomicin use in secondary prophylaxis are not yet available.

Strategies for preventing further episodes of CDI also include those summarized above for preventing an initial episode of CDI (eg, minimizing antibiotic use and avoiding unnecessary gastric acid suppression). (See 'Primary prevention' above.).

Potential future strategies — Efficacy in preventing CDI for the following strategies remains unknown, although promising. There is not enough evidence to support routine use of these strategies.

●Primary prophylaxis with oral vancomycin in certain patient populations – Primary prophylaxis with oral vancomycin may be of benefit in patients at high risk for CDI. In a randomized open-label trial of 100 hospitalized patients determined to be at high risk for a first episode of CDI (age ≥60 years who had received systemic antibiotics during a prior hospitalization within 30 days and were receiving antibiotics during the current hospitalization), vancomycin (125 mg daily) reduced the rate of CDI during the hospitalization compared with no prophylaxis (zero versus six cases) [123]. Two patients in the no-prophylaxis group developed recurrent CDI after discharge from the hospital; no cases occurred after discharge in the vancomycin prophylaxis group. No new vancomycin-resistant Enterococcus colonization was found in those patients receiving prophylaxis. Prophylaxis (with oral vancomycin or fidaxomicin) may also be useful for prevention of CDI in patients undergoing hematopoietic cell transplantation with concomitant antibiotic administration [124-127]. Larger prospective studies are warranted prior to determining the role of primary prophylaxis in CDI.

●Immunization – Vaccination is an area of investigation for prevention of CDI. Several studies have shown that the host humoral immune response to C. difficile toxins A and B influences the clinical course of CDI as well as the risk of relapse [115,128-132].

●Probiotics – We suggest against administration of probiotics for prevention of CDI, in agreement with society guidelines [2,3]. There are multiple studies of various probiotics for CDI prevention; the data are highly inconsistent [108,109,133-139]. An important flaw of the meta-analyses is that they erroneously refer to "probiotics" as a single entity; however, no single probiotic agent has shown reliable or reproducible efficacy for prevention of CDI (even Saccharomyces boulardii or Lactobacillus GG, which are the best studied).

●Gastrointestinal colonization by nontoxigenic C. difficile strains – Gastrointestinal colonization by nontoxigenic C. difficile strains has been shown to prevent CDI with exposure to a toxigenic strain [140-142]; further study of this approach is needed. In a randomized trial including 173 patients who recovered following treatment of CDI with metronidazole or vancomycin, administration of nontoxigenic C. difficile strain M3 was associated with a lower rate of recurrent CDI (recurrence rate 11 versus 30 percent; odds ratio 0.28, 95% CI 0.11-0.69) [142].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Clostridioides difficile infection".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: C. difficile infection (The Basics)")

●Beyond the Basics topic (see "Patient education: Antibiotic-associated diarrhea caused by Clostridioides difficile (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●General principles – General principles in the treatment of Clostridioides difficile infection (CDI) include discontinuation of the inciting antibiotic agent(s), and implementation of infection control practices including contact precautions and hand hygiene. Use of soap and water may be more effective than alcohol-based hand sanitizers in removing C. difficile spores, which are resistant to killing by alcohol. (See 'General principles' above.)

●Assessing disease severity – There are no consensus definitions for severe CDI. Determination of disease severity may include the following criteria (see 'Assessing disease severity' above):

•Nonfulminant disease:

-Nonsevere CDI – White blood cell count ≤15,000 cells/microL and serum creatinine <1.5 mg/dL (or <50 percent rise from baseline creatinine level)

-Severe CDI – White blood cell count >15,000 cells/microL and/or serum creatinine ≥1.5 mg/dL (or ≥50 percent rise from baseline creatinine level)

•Fulminant colitis – Presence of hypotension or shock, ileus, or megacolon

●Treatment of nonfulminant disease

•Initial episode – For patients with an initial episode of CDI (regardless of severity), we suggest fidaxomicin over vancomycin (table 2 and algorithm 1) (Grade 2C), given the benefit with respect to recurrence rates. (See 'Initial episode' above.)

Patients with severe CDI also warrant assessment for indications for surgery (table 3). (See 'Role of surgery in severe or fulminant disease' above.)

•Recurrent episodes – Recurrent CDI is defined by resolution of CDI symptoms while on appropriate therapy, followed by reappearance of symptoms within two months of discontinuing treatment. The management approach varies depending on the number of recurrences (See 'Recurrent episodes' above.):

-For patients presenting with their first recurrence of CDI who received vancomycin for their initial CDI episode, we suggest one of the fidaxomicin regimens outlined in the table rather than a vancomycin regimen (table 2 and algorithm 1) (Grade 2C). (See 'First recurrence (2nd CDI episode)' above.)

-For patients presenting with their first recurrence of CDI who received fidaxomicin for their initial CDI episode, we suggest a pulsed vancomycin regimen rather than a standard vancomycin or fidaxomicin regimen (table 2 and algorithm 1) (Grade 2C). (See 'First recurrence (2nd CDI episode)' above.)

-For patients with their second recurrence, we suggest one of the fidaxomicin regimens outlined in the table (table 2 and algorithm 1) (Grade 2C), although the vancomycin or vancomycin plus rifaximin regimens are reasonable alternatives. Additionally, we suggest administering a fecal microbiota product (FMP; eg, rectal suspension, oral capsule) after completion of CDI therapy to help prevent further recurrences (Grade 2C). (See 'Second recurrence (3rd CDI episode)' above.)

-For patients who have received appropriate antibiotic treatment for at least three CDI episodes (ie, initial episode plus two recurrences), who subsequently present with a fourth or further episode (third or subsequent recurrence), we suggest repeating one of the prolonged duration fidaxomicin or vancomycin regimens listed in the table (table 2) followed by traditional FMT in regions where available (algorithm 1) (Grade 2C). If an FMP is available and was not administered during the second recurrence, it is reasonable to administer an FMP (eg, oral capsule, rectal suspension) instead of traditional FMT after completion of CDI therapy. Further recurrence after use of an FMP should prompt referral for traditional FMT. (See 'Third and subsequent recurrences (4th and subsequent CDI episodes)' above.)

●Treatment of fulminant colitis – For treatment of patients with fulminant colitis, we suggest oral (or per nasogastric tube) vancomycin (500 mg four times daily) plus parenteral metronidazole (500 mg every 8 hours) (table 2 and algorithm 1) (Grade 2C) (see 'Initial management' above). For patients with ileus, we also administer vancomycin rectally.

●Response to treatment should be reassessed in 24 to 48 hours. Patients who have no sustained improvement in vital signs should be considered for further intervention. (See 'Reassessment in 24 to 48 hours' above.)

●Prevention

•For patients with a history of CDI who are at increased risk for recurrent CDI (patients ≥65 years of age or with significant immunocompromise who were hospitalized for severe CDI within the past three months) and require ongoing (longer than a week) treatment with systemic antibiotics for a separate infection, some experts administer secondary prophylaxis with oral vancomycin for the duration of antibiotic treatment plus an additional tail of one week. (See 'Secondary prevention' above.)

•We suggest not using probiotics for treatment or prevention of CDI (Grade 2C). (See 'Therapies of limited use' above and 'Prevention' above.)

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Topic 2698 Version 118.0

References

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51 : Clostridium difficile colitis.

52 : WSES guidelines for management of Clostridium difficile infection in surgical patients.

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54 : Practice parameters for the management of Clostridium difficile infection.

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57 : Treatment of antibiotic-associated Clostridium difficile colitis with oral vancomycin: comparison of two dosage regimens.

58 : Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease.

59 : Fidaxomicin versus vancomycin for Clostridium difficile infection.

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63 : The Clinical Effectiveness of Fidaxomicin Compared to Vancomycin in the Treatment of Clostridioides difficile Infection, A Single-Center Real-World Experience.

64 : Fidaxomicin versus oral vancomycin for severe Clostridium difficile infection: a retrospective cohort study.

65 : Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole.

66 : Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada.

67 : Metronidazole for Clostridium difficile-associated disease: is it okay for Mom?

68 : A prospective study of risk factors and historical trends in metronidazole failure for Clostridium difficile infection.

69 : Faecal metronidazole concentrations during oral and intravenous therapy for antibiotic associated colitis due to Clostridium difficile.

70 : Treatment of asymptomatic Clostridium difficile carriers (fecal excretors) with vancomycin or metronidazole. A randomized, placebo-controlled trial.

71 : What Is the Role for Metronidazole in the Treatment of Clostridium difficile Infection? Results From a National Cohort Study of Veterans With Initial Mild Disease.

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80 : Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin.

81 : A randomized, double-blind, placebo-controlled pilot study to assess the ability of rifaximin to prevent recurrent diarrhoea in patients with Clostridium difficile infection.

82 : The Addition of Intravenous Metronidazole to Oral Vancomycin is Associated With Improved Mortality in Critically Ill Patients With Clostridium difficile Infection.

83 : Intravenous metronidazole for the treatment of Clostridium difficile colitis.

84 : Does Addition of Intravenous Metronidazole to Oral Vancomycin Improve Outcomes in Clostridioides difficile Infection?

85 : Current and future treatment modalities for Clostridium difficile-associated disease.

86 : Severe Clostridium difficile colitis: the role of intracolonic vancomycin?

87 : Severe Clostridium difficile colitis: the role of intracolonic vancomycin?

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91 : SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection.

92 : Duodenal infusion of donor feces for recurrent Clostridium difficile.

93 : Frozen vs Fresh Fecal Microbiota Transplantation and Clinical Resolution of Diarrhea in Patients With Recurrent Clostridium difficile Infection: A Randomized Clinical Trial.

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95 : Fecal Microbiota Transplantation for Clostridium difficile Infection: A Systematic Review.

96 : Fecal Microbiota Transplantation Is Superior to Fidaxomicin for Treatment of Recurrent Clostridium difficile Infection.

97 : Fecal microbiota transplantation for the treatment of recurrent Clostridioides difficile (Clostridium difficile).

98 : Low Cure Rates in Controlled Trials of Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection: A Systematic Review and Meta-analysis.

99 : European consensus conference on faecal microbiota transplantation in clinical practice.

100 : The 5D framework: a clinical primer for fecal microbiota transplantation to treat Clostridium difficile infection.

101 : Fecal Microbiota Transplantation Is Highly Effective in Real-World Practice: Initial Results From the FMT National Registry.

102 : Early Fecal Microbiota Transplantation Improves Survival in Severe Clostridium difficile Infections.

103 : Fecal microbiota transplant in severe and severe-complicated Clostridium difficile: A promising treatment approach.

104 : Faecal microbiota transplant decreases mortality in severe and fulminant Clostridioides difficile infection in critically ill patients.

105 : Fecal Microbiota Transplant Decreases Mortality in Patients with Refractory Severe or Fulminant Clostridioides difficile Infection.

106 : Treatment of Clostridium difficile-associated disease (CDAD).

107 : Probiotics for treatment of Clostridium difficile-associated colitis in adults.

108 : Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis.

109 : A meta-analysis of probiotic efficacy for gastrointestinal diseases.

110 : Prospective, randomized inpatient study of oral metronidazole versus oral metronidazole and rifampin for treatment of primary episode of Clostridium difficile-associated diarrhea.

111 : Nitazoxanide versus vancomycin in Clostridium difficile infection: a randomized, double-blind study.

112 : Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea.

113 : Prospective study of oral teicoplanin versus oral vancomycin for therapy of pseudomembranous colitis and Clostridium difficile-associated diarrhea.

114 : A Randomized, Double-Blind, Phase 3 Safety and Efficacy Study of Ridinilazole Versus Vancomycin for Treatment of Clostridioides difficile Infection: Clinical Outcomes With Microbiome and Metabolome Correlates of Response.

115 : Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin.

116 : Intravenous immunoglobulin therapy for severe Clostridium difficile colitis.

117 : Gamma globulin administration in relapsing Clostridium difficile-induced pseudomembranous colitis with a defective antibody response to toxin A.

118 : Clinical outcomes of intravenous immune globulin in severe clostridium difficile-associated diarrhea.

119 : Tolevamer, a novel nonantibiotic polymer, compared with vancomycin in the treatment of mild to moderately severe Clostridium difficile-associated diarrhea.

120 : Therapeutic trials of antibiotic associated colitis.

121 : Treatment of antibiotic-associated pseudomembranous colitis with cholestyramine resin.

122 : Oral vancomycin prophylaxis during systemic antibiotic exposure to prevent Clostridiodes difficile infection relapses.

123 : Effectiveness of Oral Vancomycin for Prevention of Healthcare Facility-Onset Clostridioides difficile Infection in Targeted Patients During Systemic Antibiotic Exposure.

124 : A Randomized, Placebo-controlled Trial of Fidaxomicin for Prophylaxis of Clostridium difficile-associated Diarrhea in Adults Undergoing Hematopoietic Stem Cell Transplantation.

125 : Oral Vancomycin Prophylaxis Is Highly Effective in Preventing Clostridium difficile Infection in Allogeneic Hematopoietic Cell Transplant Recipients.

126 : Evaluation of Primary Oral Vancomycin Prophylaxis Against Clostridioides difficile Infection During Autologous Stem Cell Transplantation.

127 : Prophylactic Vancomycin in the Primary Prevention of Clostridium difficile in Allogeneic Stem Cell Transplant.

128 : Human antibody response to Clostridium difficile toxin A in relation to clinical course of infection.

129 : Clostridium difficile vaccine and serum immunoglobulin G antibody response to toxin A.

130 : Safety and immunogenicity of increasing doses of a Clostridium difficile toxoid vaccine administered to healthy adults.

131 : Clostridium difficile toxoid vaccine in recurrent C. difficile-associated diarrhea.

132 : Treatment with monoclonal antibodies against Clostridium difficile toxins.

133 : Probiotics are effective at preventing Clostridium difficile-associated diarrhea: a systematic review and meta-analysis.

134 : Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis.

135 : Timely Use of Probiotics in Hospitalized Adults Prevents Clostridium difficile Infection: A Systematic Review With Meta-Regression Analysis.

136 : Lactobacillus probiotics in the prevention of diarrhea associated with Clostridium difficile: a systematic review and Bayesian hierarchical meta-analysis.

137 : Systematic review with meta-analysis: Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea.

138 : Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children.

139 : Microbial Preparations (Probiotics) for the Prevention of Clostridium difficile Infection in Adults and Children: An Individual Patient Data Meta-analysis of 6,851 Participants.

140 : Primary symptomless colonisation by Clostridium difficile and decreased risk of subsequent diarrhoea.

141 : Evaluation of an oral suspension of VP20621, spores of nontoxigenic Clostridium difficile strain M3, in healthy subjects.

142 : Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial.