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Disclosures: Ciarán P Kelly, MD Grant/Research/Clinical Trial Support: Claremont BioSolutions, CSL Behring, GSK, Merck, Optimer, Sanofi-Pasteur (Clostridium difficile infection); Alba (Celiac disease). Speaker's Bureau: Astellas (Clostridium difficile infection). Consultant/Advisory Board: Astellas, CSL Behring, Cubist, Optimer, Regeneron, Sanofi-Pasteur, VHSquared (Clostridium difficile infection); Alba, Alvine, ImmunosanT (Celiac disease). Equity Ownership/Stock Options: Alvine, ImmunosanT (Celiac disease). J Thomas LaMont, MD Nothing to disclose. Stephen B Calderwood, MD Consultant/Advisory Boards: Pulmatrix (Inhaled antimicrobial products). Patent Holder: Vaccine Technologies (Cholera vaccines). Equity Ownership/Stock Options: PharmAthene (Anthrax). Elinor L Baron, MD, DTMH Employee of UpToDate, Inc.

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Literature review current through: Mar 2014. | This topic last updated: Feb 21, 2014.

INTRODUCTION — Clostridium difficile infection (CDI) is one of the most common hospital-acquired (nosocomial) infections and is an increasingly frequent cause of morbidity and mortality among elderly hospitalized patients [1]. C. difficile colonizes the human intestinal tract after the normal gut flora has been altered by antibiotic therapy and is the causative organism of antibiotic-associated pseudomembranous colitis.

The treatment of CDI, including initial management, management of relapse, and management of severe disease, will be reviewed here [2]. The pathophysiology, epidemiology, clinical manifestations, and diagnosis are discussed separately. (See "Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology" and "Clostridium difficile in adults: Clinical manifestations and diagnosis".)

GENERAL MANAGEMENT PRINCIPLES — An important initial step in the treatment of C. difficile infection (CDI) is cessation of the inciting antibiotic as soon as possible. Treatment with concomitant antibiotics (ie, antibiotics other than those given to treat C. difficile infection) is associated both with significant prolongation of diarrhea and with increased risk of recurrent C. difficile infection [3,4]. If ongoing antibiotics are essential for treatment of the primary infection, it may be prudent, if possible, to select antibiotic therapy that is less frequently implicated in antibiotic-associated CDI, such as parenteral aminoglycosides, sulfonamides, macrolides, vancomycin, or tetracycline.

Management must also include implementation of infection control policies. Patients with suspected or proven C. difficile infection should be placed on contact precautions, and healthcare 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. Therefore, use of soap and water is favored over alcohol-based hand sanitization in the setting of a CDI outbreak, although thus far no studies have demonstrated superiority of soap and water in non-outbreak settings [1]. (See "Clostridium difficile infection: Prevention and control".)

In addition, antimotility agents such as loperamide and opiates have traditionally been avoided in CDI, but the evidence that they cause harm is equivocal [5,6]. Supportive care with attention to correction of fluid losses and electrolyte imbalances is also important. Patients may have regular diet as tolerated, unless surgery or other procedure is planned.

INDICATIONS FOR TREATMENT — Patients with typical manifestations of C. difficile (eg, diarrhea, abdominal pain, or nausea and vomiting) and a positive diagnostic assay should receive antibiotics for treatment for C. difficile [7,8]. Empiric therapy is appropriate pending results of diagnostic testing if the clinical suspicion is high. Treatment of C. difficile is not indicated in patients who have a positive toxin assay but are asymptomatic. (See "Clostridium difficile in adults: Clinical manifestations and diagnosis".)


Initial therapy — Therapy for non-severe C. difficile infection (CDI) consists of oral metronidazole or oral vancomycin (table 1) [1,9,10]. Several randomized trials have demonstrated equivalent efficacy of metronidazole and vancomycin for the treatment of nonsevere CDI [11-13]. In one prospective, randomized double-blind trial including 81 patients with mild or moderately severe CDI, metronidazole and vancomycin produced similar rates of clinical cure (90 versus 98 percent) [11].

Guidelines published in the 1990s advocated metronidazole over vancomycin as first-line therapy [14-17]. Reasons included the lower cost of metronidazole relative to vancomycin and the comparable clinical effectiveness in non-severe disease. In addition, use of metronidazole has been favored over vancomycin to limit the spread of vancomycin-resistant enterococci (VRE), although subsequent data have suggested that the risk of bowel VRE colonization is equivalent with these drugs [18,19].

Observational study of C. difficile disease in Canada from 1991 to 2003 preliminarily suggested that patients treated with metronidazole for an initial episode of CDI may be at increased risk for relapse [20,21]. However, review of the data through 2006 demonstrated a similar trend in the frequency of recurrences for both metronidazole and vancomycin, suggesting that the rise in recurrence rate during 2003 to 2004 for patients treated with either drug may have corresponded to reinfection during a period when in-hospital exposure to C. difficile spores was very high [22,23].

Limitations of metronidazole include dose-dependent peripheral neuropathy and side effects of nausea and metallic taste. Although the above studies are limited because of their observational methodologies, the findings raise the possibility that metronidazole may be less effective than oral vancomycin [24].

The treatment of severe disease is discussed below. (See 'Treatment' below.)

Antibiotic dosing — Metronidazole can be used for initial treatment of nonsevere CDI. The recommended regimen is 500 mg three times daily or 250 mg four times daily for 10 to 14 days. As discussed below, intravenous metronidazole at a dose of 500 mg every eight hours may also be used for treatment of CDI in patients in whom oral therapy is not feasible. Fecal concentrations in the therapeutic range are achievable with this regimen because of the drug's biliary excretion and increased exudation across the intestinal mucosa during CDI [25-27].

If oral vancomycin is used, the recommended dose is 125 mg four times daily. Oral vancomycin is not absorbed systemically and achieves predictably high levels in the colon. Dosing regimens of 125 mg four times daily and 500 mg four times daily are equally effective for the treatment of nonsevere CDI (figure 1) [28]. Intravenous vancomycin has no effect on C. difficile colitis since the antibiotic is not excreted appreciably into the colon.

Duration of therapy — The recommended duration of initial antibiotic therapy for non-severe C. difficile diarrhea is 10 to 14 days [1]. Patients with an underlying infection requiring prolonged duration of antibiotics are at increased risk for recurrence [4]. Therefore, it may be reasonable to continue CDI treatment throughout the antibiotic course plus an additional week after its completion.

Repeat stool assays are NOT warranted during or following treatment in patients who are recovering or are symptom free. Up to 50 percent of patients have positive stool assays for as long as six weeks after the completion of therapy [28,29].

Recurrent disease — Recurrence is defined by complete abatement of CDI symptoms while on appropriate therapy, followed by subsequent reappearance of diarrhea and other symptoms after treatment has been stopped. Recurrence should be distinguished from persistent diarrhea without resolution during initial therapy, which should prompt an evaluation for other causes. In the absence of an alternative diagnosis, such patients should be considered to have refractory illness.

Recurrent CDI can result from reinfection with the same or a different strain of C. difficile [30-32]. Studies using molecular methods have shown that up to one-half of recurrent episodes are reinfections rather than relapses of infection with the original strain [33,34].

Recurrence occurs in approximately 25 percent of cases treated with metronidazole or vancomycin, and patients may experience several episodes of recurrent colitis [12,17,35-38]. Most recurrences present within one to three weeks after discontinuing antibiotic therapy, although recurrences rarely can occur as late as two to three months. Recurrences may be mild or severe and may result from an impaired host immune response to C. difficile. (See "Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology".)

Risk factors for recurrence include age >65 years, severe underlying medical disorders, and the need for ongoing therapy with concomitant antibiotics during treatment for CDI [3,36,39,40]. Patients with at least one episode of recurrent C. difficile have a 45 to 65 percent chance of additional episodes [41].

Pathophysiology — The mechanism of CDI recurrence following initial infection is not fully understood. It may be due to persistent spores from the initial infection. C. difficile spores in colonic diverticula, for example, may escape mechanical clearance by peristalsis [36].

Impairment of the host immune response to C. difficile toxins may also be an important mechanism for recurrence. Asymptomatic carriers of C. difficile tend to have high serum antibody levels against C. difficile toxins [42], while patients with recurrent CDI tend to have lower anti-toxin antibody levels than patients with a single, brief episode of diarrhea [39,43-45].

Antibiotic resistance does not appear to be a factor in recurrence. However, treatment with metronidazole or vancomycin for an initial episode of CDI may alter the colonic microenvironment (with regard to flora or other factors), potentially increasing susceptibility to reinfection and recurrence. (See 'Metronidazole failure' below.)

Management of initial recurrence — The signs and symptoms of recurrence are similar to those in the initial episode, usually without progression in severity [46]. Because a positive stool toxin assay does not exclude asymptomatic carriage, other causes for diarrhea should be considered, including other infections, inflammatory bowel disease, or irritable bowel syndrome. Colonoscopy should be considered in atypical cases to evaluate for evidence of CDI and to exclude other etiologies.

For treatment of an initial episode of CDI, fidaxomicin has been associated with a lower incidence of recurrent CDI than vancomycin (15 versus 25 percent) [47]. For treatment of initial recurrence of CDI, the initial response to therapy with fidaxomicin and vancomycin has been observed to be comparable, although the likelihood of recurrence four weeks later is lower with fidaxomicin than vancomycin (20 versus 36 percent) [48].

Patients with mild symptoms of recurrence who are otherwise well may be managed conservatively, without further antibiotic therapy. Nonsevere initial recurrence following therapy for CDI can be treated with metronidazole. The decision to administer vancomycin as treatment for a first recurrence should be based upon the presence of markers of severe disease at the time of first recurrence, rather than on previous drug exposure.

Fidaxomicin is an alternative agent for treatment of an initial recurrence of CDI (table 1). In one study including 128 patients with a first CDI recurrence, the recurrence rate was lower among patients treated with fidaxomicin than among patients treated with vancomycin (19 versus 35 percent) (95% CI 30-0.3%; p = 0.045) [48]. (See 'Fidaxomicin' below.)

Management of subsequent recurrences — Patients with one recurrence have a substantial risk of subsequent CDI episodes after the second course of antibiotic therapy is discontinued. In one study, for example, patients with one or more previous recurrences had a subsequent recurrence rate of 65 percent following standard therapy with metronidazole or vancomycin [38].

Antibiotic therapy — There are no rigorous studies of management for multiple recurrences of CDI. Patients with multiple recurrences may benefit from vancomycin (administered in a pulse tapered fashion), fidaxomicin, or rifaximin, with or without the use of probiotics (table 1).

Vancomycin — Administration of vancomycin in a pulse tapered fashion may be effective for management of recurrent C. difficile infection (table 1). The use of intermittent antibiotic therapy is based upon a theory that relapse may be due to the presence of persistent spores that survive antibiotic therapy. Intermittent therapy may allow the spores to germinate on the days when no antibiotics are administered. Once the spores have converted to the fully functional vegetative, toxin-producing forms, they are susceptible to killing when the antibiotics are readministered.

A tapered oral vancomycin regimen consists of a stepwise decrease in dose over a period of time. Intermittent (or pulsed) vancomycin therapy consists of administering the drug every few days. Prolonged antibiotic therapy, with or without tapered or intermittent dosing, may also be important for definitive treatment.

Intermittent and tapered vancomycin regimens have been evaluated in observational studies [29,36]. In one study of 163 CDI cases, for example, 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 [29].

Fidaxomicin — Fidaxomicin is a macrocyclic antibiotic that is bactericidal against C. difficile (in contrast to metronidazole and vancomycin, which are bacteriostatic) [49]. It has a narrower antimicrobial spectrum than metronidazole or vancomycin, leading to less disruption of the normal colonic anaerobic microflora [50-54].

In a phase 3 randomized trial including 629 patients with nonsevere C. difficile infection, clinical cure rates with fidaxomicin (200 mg orally twice daily) and vancomycin (125 mg orally four times daily) were similar, but recurrence of C. difficile infection occurred significantly less often with fidaxomicin than with vancomycin among patients with non-NAP1 strains (10 versus 28 percent in the modified intention-to-treat population) [47]. Lower recurrence rates were not seen among patients with the NAP1 strain. (See "Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology", section on 'Hypervirulent strain: NAP1/BI/027'.)

Fidaxomicin may be an appropriate therapy in patients with recurrent CDI or perhaps as initial therapy in patients at high risk of developing recurrent disease, although parameters for its most appropriate use are still being defined.

Rifaximin — Small case series have suggested that sequential therapy with vancomycin followed by rifaximin may be effective for the treatment of recurrent CDI [55,56]. 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 [55].

Exposure to rifamycins prior the development of CDI is a risk factor for rifampin resistant C. difficile infection. In such cases, the use of rifaximin for treatment of CDI may be limited [57].

Nonantibiotic therapy

Fecal bacteriotherapy — Fecal bacteriotherapy may be useful for treatment of patients with recurrent CDI. This issue is discussed further separately. (See "Fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection".)

Probiotic therapy — Studies of probiotics are inconclusive regarding treatment benefit. This issue is discussed further separately. (See "Clostridium difficile and probiotics" and "Probiotics for gastrointestinal diseases", section on 'Antibiotic-associated diarrhea'.)

Monoclonal antibodies — Adjunctive use of monoclonal antibodies against C. difficile toxins A and B (in addition to antibiotic therapy) appears to reduce the recurrence rate of C. difficile infection; they are not yet available for routine clinical use. In a study of 200 patients with C. difficile treated with antibiotics (metronidazole or vancomycin) in addition to monoclonal antibodies or placebo, recurrence rates were 7 versus 25 percent, respectively [58]. Studies are needed to confirm these results for recurrent disease, as well as to determine whether monoclonal antibodies are useful in the management of severe disease or whether there is a role for prophylactic passive immunization for patients at highest risk.


Definition — Patients with acute C. difficile infection (CDI) may develop signs of systemic toxicity with or without profuse diarrhea warranting admission to an intensive care unit or emergency surgery.

There is no consensus definition for severe CDI nor is there agreement as to the most important clinical indicators that should be used to differentiate severity [11,21,59]. The following illustrate some definitions that have been described in the literature:

Guideline parameters for severe CDI include white blood cell count of >15,000 cells/microL or a serum creatinine level ≥1.5 times the premorbid level [1,10].

Clinicians in the setting of the Quebec outbreak identified a white blood cell count >20,000 cells/microL and an elevated serum creatinine as potential indicators of complicated disease [21]. Significantly elevated white blood cell counts in the absence of any other evident cause should raise suspicion for C. difficile infection.

As part of a randomized trial comparing metronidazole with vancomycin, a scoring system was devised to identify patients with severe infection [11]. One point each was given for age >60 years, temperature >38.3ºC, serum albumin <2.5 mg/dL (25 g/L), or peripheral white blood cell count >15,000 cells/microL within 48 hours of enrollment. Two points were given for endoscopic evidence of pseudomembranous colitis or treatment in the intensive care unit. Patients with two or more points were considered to have severe disease.

In a phase 3 trial of tolevamer versus vancomycin and metronidazole, severe disease was defined as ≥10 bowel movements per day, a peripheral white blood cell count ≥20,000 cells/microL, or severe abdominal pain [60].

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 criteria mentioned above.

Incidence — Data on the incidence of severe CDI are limited, especially given the lack of a consensus definition. The risk of complications during first CDI recurrence in the Quebec outbreak caused by the hypervirulent North American Pulsed Field type 1 (NAP1) strain was 11 percent [40]. Complications included shock, need for colectomy, megacolon, perforation, or death within 30 days. Older age, high leukocyte count, and acute renal failure were strongly associated with a complicated course. (See "Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology".)

Treatment — Patients with severe CDI (by clinician judgment) should receive antibiotic therapy, supportive care, and close monitoring. Surgery should be considered if the patient's clinical status fails to improve and the serum lactate is above 2.2 [61]. 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 [35]. (See "Toxic megacolon" and 'Surgery' below.)

Antibiotics — We are in agreement with guidelines issued after 2010 that recommend oral vancomycin as first-line therapy for severe CDI [1,10]. This is in contrast to previous guidelines published in the 1990s that recommended oral metronidazole as initial therapy for both mild and severe C. difficile–associated diarrhea (CDAD) [14-17]. This change reflects reports of frequent metronidazole failures in CDI and studies showing the superiority of oral vancomycin in severe disease [11-13,21,60].

The major pharmacologic advantage of vancomycin over metronidazole is that vancomycin is not absorbed, so maximal concentrations of the drug can act intracolonically at the site of infection. The major advantage of metronidazole over vancomycin is that the cost of metronidazole is substantially lower. With respect to in vitro activity, risk of relapse, and potential for emergence of vancomycin-resistant enterococci, the drugs appear to be relatively similar [18,23,50,62,63].

Oral vancomycin is the preferred therapy for severe or refractory cases [1,11,40,60,64]. This issue was directly addressed in a prospective, randomized double-blind trial that included 69 patients with severe CDI as defined above [11]. The cure rate was significantly higher with vancomycin (97 versus 76 percent with metronidazole). (See 'Definition' above.)

Although the data are limited, clinical practice is shifting toward using oral vancomycin as initial therapy for severe CDI [65]. Many have endorsed vancomycin as the preferred therapy for moderate or severe disease caused by the epidemic strain, and most favor its use for all patients with severe and/or complicated disease [1,23,62,66].

Intracolonic administration of vancomycin via enema (given in combination with intravenous metronidazole) is an option for patients who do not tolerate oral medication, but there is risk of colonic perforation. Therefore, use of intracolonic vancomycin should be restricted to patients who are unresponsive to standard therapies, and the procedure should be performed by personnel with expertise in administering enemas. (See 'Intracolonic antibiotics' below.)

Clinical approach — We recommend that patients with severe disease be treated with oral vancomycin (125 mg four times daily). For patients with severe disease who do not demonstrate clinical improvement, we suggest increasing the dose of oral vancomycin to 500 mg four times daily. Fidaxomicin may be considered in patients who cannot tolerate vancomycin, although more data are needed. In the setting of ileus, addition of intravenous metronidazole (500 mg every eight hours) is appropriate. Intracolonic vancomycin may be considered in patients with profound ileus.

The standard duration of antibiotic therapy for C. difficile diarrhea is 10 to 14 days; the antibiotic course should be tailored to clinical circumstances for patients with severe disease. Those with an underlying infection requiring prolonged duration of antibiotics should continue CDI treatment throughout the antibiotic course plus one additional week after its completion.

Oral antibiotics — Oral vancomycin (125 mg four times daily) should be initiated promptly for severely ill patients. Some data suggest that levels achieved with higher dosing of vancomycin (500 mg four times daily) may be equivalent to levels with standard dosing [28]. Nevertheless, many clinicians favor higher dosing for severe disease although there is no supportive evidence [1].

For patients with severe disease who do not demonstrate clinical improvement with oral vancomycin, administration of therapy with fidaxomicin (200 mg orally twice daily) is reasonable. Additional data are needed on the efficacy of fidaxomicin in the setting of severe disease. (See 'Fidaxomicin' above.)

For circumstances in which neither vancomycin nor fidaxomicin is available, oral metronidazole (500 mg three times daily or 250 mg four times daily for 14 days) may be administered, although it is less effective than vancomycin [11].

Intravenous antibiotics — Severely ill patients with ileus may have markedly delayed passage of oral antibiotics from the stomach to the colon. These individuals may benefit from the addition of intravenous metronidazole (500 mg every eight hours). Fecal concentrations in the therapeutic range can be achieved with this regimen because of biliary and intestinal excretion of the drug [25-27]. However, it is uncertain whether intravenous therapy alone is as effective as oral therapy, so oral therapy should be administered whenever feasible [67].

Intravenous vancomycin has no effect on C. difficile colitis since vancomycin is not excreted into the colon.

Intravenous tigecycline has been used in a small number of patients with severe CDI that was refractory to standard therapy [68].

Intracolonic antibiotics — Intracolonic vancomycin (vancomycin enema) may be an effective adjunctive therapy for patients who cannot tolerate the oral preparation, or patients who have megacolon or ileus which would prevent oral vancomycin from reaching the colon [69-71]. In a case series of nine patients with refractory symptoms, toxic megacolon, or fulminant colitis, rectal vancomycin was administered in addition to standard antibiotics [69]. Eight patients had complete resolution of symptoms and one patient died from multisystem organ failure.

Intracolonic vancomycin may be useful in the setting of profound ileus that impairs the distal delivery of orally administered drugs. Although the optimal dosing and volume has not been established by clinical trials and case descriptions vary widely, rectal vancomycin is often given as a retention enema containing 500 mg in 100 mL of normal saline every six hours [1,69,70,72-76]. One report suggests that patients with megacolon may benefit from colonoscopic decompression and placement of a tube in the right colon which can be perfused with a 1 mg/mL solution of vancomycin in normal saline to deliver a total dose of 1 to 2 g per day [70]; however, this requires further confirmation. Dose adjustments may be required depending on individual circumstances including extent of colonic disease and patient weight. It is important to note that vancomycin can be absorbed through inflamed colonic mucosa and cause toxicity if it accumulates in patients with renal failure. (See "Vancomycin dosing and serum concentration monitoring in adults".)

Surgery — Some severely ill patients with CDI require surgical intervention as a result of toxic megacolon, perforation or impending perforation, necrotizing colitis or rapidly progressive and/or refractory disease with systemic inflammatory response syndrome leading to multiorgan system failure [77,78]. The optimal timing of surgery remains uncertain.

Timing — Literature written prior to the emergence of the hypervirulent strain suggested surgery for CDI patients with severe disease unresponsive to medical therapy within 48 hours, bowel perforation, or multiorgan system failure [79].

However, in the setting of CDI due to the hypervirulent strain, some patients progressed from severe disease to death in less than 48 hours. Furthermore, some patients with severe disease cannot receive enteral therapy due to ileus or severe nausea and vomiting. Data from the Canadian outbreak with the hypervirulent strain have been used to try to standardize criteria for surgical intervention. In a retrospective review, colectomy was most beneficial for immunocompetent patients aged ≥65 years with a white blood cell count ≥20,000 cells/microL and/or a plasma lactate between 2.2 and 4.9 meq/L [61].

We favor early surgery for patients with the above criteria. In addition, surgical intervention is advisable in the setting of peritoneal signs, severe ileus, or toxic megacolon.

Procedure — Two surgical approaches for management of CDI have been described: subtotal colectomy (removal of the entire colon with ileostomy, without removal of the rectum), and diverting loop ileostomy with colonic lavage.

Subtotal colectomy — Subtotal colectomy is the procedure for which there is greatest experience in the setting of emergency surgical intervention for CDI [61,80-82]. In a retrospective review of 14 patients who underwent surgery for severe CDI, nine patients survived, of whom eight had subtotal colectomy and one had a right hemicolectomy [80]. Four of the five patients who died had undergone left hemicolectomy.

Primary anastomosis is not feasible acutely due to the pancolitis associated with severe disease. However, after colonic inflammation has subsided, closure of the ileostomy and ileorectal anastomosis can be created.

Diverting loop ileostomy and colonic lavage — Diverting loop ileostomy and colonic lavage may be a potential alternative procedure to colectomy in the treatment of severe, complicated CDI. In one study including 42 patients with severe CDI, reduced mortality was observed among patients who underwent loop ileostomy and colonic lavage, compared with the historical controls who underwent colectomy (19 versus 50 percent; odds ratio, 0.24; P = 0.006) [83]. The surgical approach involved creation of a loop ileostomy, intraoperative colonic lavage with warmed polyethylene glycol solution via the ileostomy, and postoperative antegrade instillation of vancomycin flushes via the ileostomy. Preservation of the colon was achieved in 93 percent of patients. This surgical approach is potentially promising, but further data from prospective, randomized controlled trials are needed to validate this preliminary study.

METRONIDAZOLE FAILURE — The reasons for metronidazole failure are poorly understood [84]. Stool metronidazole concentrations in patients receiving the drug orally are higher in watery stools at the beginning of C. difficile infection (CDI) treatment than in semiformed stools a few days later [25]. Thus, stool metronidazole levels decrease as colonic inflammation subsides. In contrast, oral vancomycin maintains high stool concentrations (1000 to 3000 mcg/mL throughout the course of therapy) [25,85].

Given these observations, even a modest increase in an organism's minimum inhibitory concentration for metronidazole might lead to insufficient stool levels after a few days of treatment. Although some metronidazole resistance in C. difficile has been described [86-90], resistance rates are low and do not appear to be increasing in the setting of the rising rates of treatment failure [37,91-93].

Risk factors associated with metronidazole failure include recent cephalosporin use, C. difficile on admission and transfer from another hospital [94].

ALTERNATIVE THERAPIES — Other therapeutic options for C. difficile infection (CDI) are being developed, and drugs used for other infections are being studied as alternatives to metronidazole and vancomycin [95].

Probiotics — Studies of probiotics are inconclusive regarding benefit. The data are presented separately. (See "Clostridium difficile and probiotics".)

Fecal bacteriotherapy — Fecal bacteriotherapy may be useful for treatment of patients with recurrent CDI. This issue is discussed further separately. (See "Fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection".)

Alternative antibiotics — A meta-analysis of 12 studies including 1157 participants evaluated eight different antibiotics for the treatment of CDI: vancomycin, metronidazole, fusidic acid, nitazoxanide, teicoplanin, rifampin, rifaximin, and bacitracin [7]. In paired comparisons, no single antibiotic was clearly superior to others. Combination therapy has been tried without success [96].

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 [97].

Teicoplanin may be at least as effective as vancomycin or metronidazole, although it is costly and is not available in the United States [12,98].

Fidaxomicin was approved by the United States Food and Drug Administration (FDA) in 2011. (See 'Fidaxomicin' above.)

Anion-binding resins — The importance of toxin production in the pathophysiology of C. difficile diarrhea has prompted consideration of anion-binding resins as a possible alternative to antimicrobial therapy [99]. An advantage of resin therapy is that the bowel flora is not altered, as occurs with vancomycin or metronidazole. This may allow more rapid reconstitution of the normal colonic flora.

The anion-binding resins colestipol and cholestyramine are not effective as primary therapy for C. difficile colitis [100,101], although they may be beneficial as adjunctive therapy for relapsing infection [102]. In a series of 11 patients with relapsing CDI, the administration of colestipol with tapered vancomycin led to sustained resolution in all patients [102].

Anion-exchange resins bind vancomycin as well as toxins; thus, the resin must be taken at least two or three hours apart from the vancomycin [99]. Suggested regimens are colestipol (5 g every 12 hours) or cholestyramine (4 g three or four times daily) for one to two weeks, usually with vancomycin.

Tolevamer is a C. difficile toxin binding resin developed specifically for CDI [60,103]. Preliminary studies with tolevamer showed promising results. However, two large multicenter trials found that it was inferior to both vancomycin and metronidazole as primary therapy for CDI [60].

Intravenous immunoglobulin — Intravenous immunoglobulin (IVIG) contains C. difficile antitoxin 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 [43,104,105], a retrospective review of 18 patients who received IVIG demonstrated no significant difference in clinical outcomes compared with 18 matched control cases [106].

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Beyond the Basics topics (see "Patient information: Antibiotic-associated diarrhea caused by Clostridium difficile (Beyond the Basics)")


The initial step in the treatment of Clostridium difficile infection (CDI) is cessation of the inciting antibiotic as soon as possible. Infection control practices must be implemented, including contact precautions and hand hygiene. 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. Therefore, use of soap and water is favored over alcohol-based hand sanitization in the setting of a CDI outbreak, although thus far no studies have demonstrated superiority of soap and water in non-outbreak settings. (See 'General management principles' above.)

For initial treatment of nonsevere CDI, we suggest oral metronidazole (Grade 2B). (See 'Initial therapy' above.)

For treatment of severe CDI, we recommend vancomycin 125 mg four times daily for 10 to 14 days (Grade 1B). For patients with severe disease who do not demonstrate clinical improvement, we suggest treatment with oral vancomycin 500 mg four times daily (Grade 2C); fidaxomicin may be considered in patients who cannot tolerate vancomycin, although more data are needed. In critically ill patients with fulminant or refractory disease, we suggest oral vancomycin 500 mg four times daily and intravenous metronidazole 500 mg every eight hours (Grade 2C); fidaxomicin may be considered in patients who cannot tolerate vancomycin, although more data are needed. (See 'Treatment' above.)

For treatment of severe disease in patients with profound ileus, we suggest addition of intracolonic vancomycin (Grade 2C), but there is risk of colonic perforation. Therefore, use of intracolonic vancomycin should be restricted to patients who are not responsive to oral therapy, and the procedure should be performed by personnel with expertise in administering enemas. (See 'Treatment' above.)

For treatment of a nonsevere initial recurrence of CDI, we suggest oral metronidazole (Grade 2A). Alternatives include oral vancomycin or fidaxomicin. (See 'Management of initial recurrence' above.)

For treatment of a second recurrence of CDI, we suggest intermittent and tapering vancomycin therapy or fidaxomicin (table 1) (Grade 2B). For treatment of subsequent recurrences of CDI, we suggest administering either fidaxomicin or vancomycin followed by rifaximin (Grade 2C). (See 'Management of subsequent recurrences' above.)

We recommend urgent surgical evaluation for patients with a white blood cell count ≥20,000 cells/microL and/or a plasma lactate between 2.2 and 4.9 meq/L (Grade 1B). In addition, surgical intervention should be strongly considered in the setting of peritoneal signs, severe ileus, or toxic megacolon. (See 'Surgery' above.)

Potential alternative therapies requiring further investigation prior to routine use include new antibiotic agents, binding resins, intravenous immunoglobulin, and fecal bacteriotherapy. (See 'Alternative therapies' above.)

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