Clostridium difficile

Authors: Hoonmo L. Koo, M.D., M.P.H. and Daniel M. Musher, M.D.


Clostridium difficile is an anaerobic, gram-positive spore-forming rod-shaped bacterium. Culture of C. difficile requires strict anaerobic conditions and pre-reduced media.  When cultivated on the selective CCFA (cycloserine-cefoxitin-fructose agar) media, colonies of C. difficile on CCFA are flat and yellow, with a ground-glass appearance and a surrounding yellow halo. Sporulation is important to the capacity of this organism to cause disease, as the spores persist on environmental surfaces, and are resistant to a number of disinfectants and antibiotics, thereby facilitating transmission.

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Several risk factors are known to predispose to C. difficile infection (CDI).  Prior antibiotic therapy is foremost and, until recent years, cases not associated with prior antibiotics were almost unheard of.  Advancing age, institutionalization and/or debilitation (e.g., hospitalization, significant comorbidities, a bed-ridden state, or residence in a long-term care or rehabilitation facility), and use of effective gastric antacids (H2 blockers and proton pump inhibitors) are other well-documented risk factors (48).  C. difficile is also emerging as an important cause of healthcare- and community-associated diarrhea in children (149).  In the past few years, cases of CDI have increasingly been documented in otherwise healthy outpatients who are not taking antibiotics (5).  A full explanation for this phenomenon has not been provided, but increased use of laboratory testing in outpatients has certainly contributed.

The association of CDI with healthcare facilities reflects the facts that: elderly and debilitated persons reside in them; a varying proportion of these residents are incontinent of feces; antibiotics are used frequently; C. difficile is transmissible; and hospitals and other chronic-care institutions are major reservoirs for toxigenic strains of this organism (50). CDI is endemic in most tertiary care hospitals, and large outbreaks continue to occur in these settings  (110). Surveillance of hospitalized patients indicates that C. difficile colonization is common, and careful epidemiological typing studies have demonstrated that the majority of these organisms are acquired exogenously  (67, 91, 119). In fact, the risk of being colonized by C. difficile is directly associated with the length of hospital stay (26). In one study, after three weeks of hospitalization, one-third of initially non-colonized patients were culture-positive, the majority of whom were asymptomatic (26). However, a recent epidemiological study using more sensitive genetic analysis of C. difficile isolates with whole genome sequencing observed that only one-third of isolates were related to C. difficile from a previously symptomatic patient (42).  Sources of the remaining two-thirds of acquired C. difficile were unclear but may reflect the importance of reservoirs in the community or asymptomatic hospitalized patients.

Clostridium difficile infections were originally recognized in patients who were treated with clindamycin and, for several decades thereafter, were almost exclusively associated with antimicrobial therapy (87). Disruption of indigenous bacterial flora in the intestinal tract by antimicrobial therapy (or, occasionally, by chemotherapy) is a critical element in the pathogenesis of infection  (145). With the understanding that this infection is a complication of antimicrobial therapy, an important therapeutic intervention is discontinuation of the offending drug when possible (52). Simply discontinuing the offending agent may be the only intervention necessary in a small proportion of patients, generally those with mild infection (130). More commonly, however, in the absence of specific therapy, C. difficile infection is prolonged. Clindamycin remains the most likely antibiotic to cause CDI.  The quinolones have also been implicated out of proportion to their use, followed by third-generation cephalosporins, but virtually all antibacterial drugs have been implicated. It is important to note, however, that increasing numbers of cases in recent years have occurred outside of health-care settings and have been unassociated with prior antibiotic use (3, 24).  Contagion within the community has been documented (24, 102).  Use of drugs that suppress gastric acid production has been particularly prominent in these subjects.  Contamination of food may also have a role in transmission of C. difficile for these community acquired cases (56). It is uncertain whether unique strains of C. difficile are responsible for community acquired CDI in persons traditionally considered at low risk for this disease (5).

Geographically dispersed outbreaks caused by a putatively more virulent and previously uncommon strain of C. difficile were reported to occur first in North America beginning in 2000, followed by northern Europe (33, 89)). The strain was characterized by several methods, leading to its characterization as restriction endonuclease (REA) type BI, pulsed field gel electrophoresis (PFGE) type NAP1, polymerase chain reaction (PCR) ribotype 027, and toxinotype III; it is commonly referred to as BI/NAP1/027(89).  Similar to other C. difficile, BI/NAP1 strains produce the two traditional toxins (A and B), but these strains produce much greater amounts of toxin, probably resulting from an 18-base pair deletion in a repressor tcdC gene (89).  Warny and colleagues (141) demonstrated that 16- and 23-times more toxin A and B, respectively, were produced in vitro compared with the common toxinotype 0 strain used as a laboratory control. In addition to the two traditional toxins, BI/NAP1strains also harbor a previously uncommon binary toxin gene (noted to be present in 6% of a historical sample of clinical isolates) (89).The structure and function of this toxin is similar to that of other binary toxins, such as iota toxin found in C. perfringens. Nearly all BI/NAP1strains are resistant to fluoroquinolones (82,89).

Incidence and Mortality

The incidence of CDI and the associated mortality have steadily increased (40).  Deaths associated with CDI in the United States rose from 5.7 per million persons in 1999 to 23.7 per million in 2004 (40, 117).  Epidemiologic surveillance data that might demonstrate the continuation of these trends after 2005 are currently unavailable.

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Exposure to C. difficile may lead to asymptomatic colonization or infection.   Infection is associated with a spectrum of clinical manifestations including non-specific watery diarrhea, severe diarrhea, fever, leukocytosis, pseudomembranous colitis and toxic megacolon (50). Asymptomatic colonization by toxin-producing C. difficile stimulates production of circulating antibody to C. difficile toxins that is thought to protect against clinical disease (74).  Typically, CDI presents as watery, non-bloody diarrhea in persons who, based on epidemiologic considerations noted above, are at risk for infection.  Fever, cramping abdominal pain, and leukocytosis are common. In the more severe manifestations of C. difficile disease, patients may also have abdominal distention and tenderness with or without ascites.  Imaging studies may show thickened colonic wall, ascites, or marked colonic dilatation consistent with toxic megacolon. Endoscopic visualization of pseudomembranes in this setting is diagnostic of C. difficile disease. Some patients with severe C. difficile disease may not have diarrhea due to ileus or toxic megacolon and may be misdiagnosed with ischemic bowel or some other intra-abdominal catastrophe. Blood cultures are rarely positive for C. difficile (77), although patients with CDI may have transient bacteremia due to translocation by other colonic bacteria (133).

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Laboratory diagnosis of CDI has evolved rapidly in the past few years.  Culture of feces to detect toxigenic C. difficile in a symptomatic patient was the original diagnostic technique and remains is the most sensitive one, but it is most labor intensive and takes 4-5 days to yield a final result.  Stool culture requires an additional toxin assay because both toxigenic and non-toxigenic C. difficile can be detected.

Soon after CDI was recognized, cytotoxicity assays were developed to detect C. difficile toxin in fecal samples.  These were regarded as extremely reliable – in fact, for years, they were called the “gold standard.”  This technique is also labor-intensive, requiring maintenance of tissue-cultured cells in vitro, a skilled technician and an inverted microscope, and the final reading can not be reported until 48 hours have elapsed.  Accordingly, an enzyme-linked immunosorbent assay (EIA) was developed to detect C. difficile toxins.  At first, several specimens had to be freshly obtained and sent for analysis, and the EIA was, at best, 75-80% sensitive compared to cytotoxicity.  In more recent years, commercial EIA tests have been 92-97% sensitive and specific when compared to cytotoxicity, and rapid EIA tests based on individual kits similar to those used in pregnancy tests yield similar results (100). Some laboratories have found it advantageous to screen fecal samples for glutamate dehydrogenase, since this enzyme is uniformly produced by toxigenic and non-toxigenic C. difficile. The absence of glutamate dehydrogenase detection is associated with a high negative predictive value and allows for laboratories to study only GDH-positive samples for the presence of toxin.

A polymerase chain reaction (PCR) technique to detect the C. difficile toxin genes has been commercially available since 2010.  Earlier studies reported greater sensitivity with PCR for detecting toxigenic C. difficile than ELISA and high specificity (123).  Musher et al showed that PCR increased the diagnostic sensitivity of ELISA by about 50% (101). The cost for each individual PCR test is substantially greater than each EIA, but this cost may be offset because repeat PCR tests do not have to be done on negative samples. Not surprisingly, as an increasing number of clinical microbiology laboratories in the US have switched from ELISA to PCR, the reported rates of CDI have significantly risen (57).  However, recent studies suggest that adverse clinical outcomes of CDI may be associated with the detection of toxin in feces rather than PCR or toxigenic culture identification of toxigenic C. difficile that have the potential to produce toxin (81, 116).  Multi-step algorithms utilizing PCR or glutamate dehydrogenase as a screening test, followed by a confirmatory test such as a toxin ELISA have been proposed to increase the specificity and positive predictive value of C. difficile testing (144). Further studies are necessary to ascertain the optimal CDI diagnostic method.

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C. difficile infection has been called a "three-hit" disease (Figure 1) (66). Patients are made susceptible by exposure to antimicrobials and/or other epidemiologic considerations (first hit).  If they are then exposed to, and become colonized with, toxigenic strains of C. difficile (second hit), they may or may not develop symptomatic illness depending on the presence of another factor (third hit) which may relate to host susceptibility factors such as the immune response to toxin A and B (74).

C. difficile infection is a toxin-mediated disease and two, large, single-unit exotoxins are produced by most pathogenic strains. Both toxin A, an enterotoxin, and toxin B, a potent cytotoxin, stimulate fluid secretion and cause mucosal damage and inflammation. More recent studies indicate that toxin B acts synergistically with toxin A to cause CDI (86).  These relatively homologous toxins probably have the same intra-cellular mode of action, but with different cell receptor specificity. Both toxins cause cell rounding and death as a consequence of glycosylation of small GTP-binding proteins of the Rho subfamily that are involved in the organization of the cell cytoskeleton (137). Subsequent pathogenic events may involve disruption of epithelial cell tight junctions and the pro-inflammatory effects of the toxins on leukocytes and monocytes.

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The principal consideration in evaluation susceptibility of C. difficile to an antimicrobial agent is the achievable antimicrobial concentrations at the site of infection- the colonic mucosa. Nonabsorbable antibiotics such as vancomycin, rifaximin, and fidaxomicin are excellent examples.  In an in vitro study of the activities of 15 antimicrobial agents against 110 clinical isolates of toxigenic C. difficile collected from 1983 to 2004, Hecht et al (60) showed uniform susceptibility to achievable colonic concentrations of metronidazole, vancomycin, nitazoxanide, fidaxomicin, tigecycline and ramoplanin.   However, reports of resistance to metronidazole have appeared in Spain and the United Kingdom (12, 49, 111, 112).   In the study by Hecht et al, 3 isolates were highly resistant to rifaximin; resistance has appeared during treatment with this drug when it was studied in a small numbers of patients (64, 106).    Other studies have shown fusidic acid, bacitracin, linezolid, daptomycin, and tigecycline to be active against C. difficile in vitro (11, 105).  It remains poorly understood why certain antibiotics to which C. difficile is susceptible in vitro, such as ampicillin, imipenem or doripenem, do not cure CDI and actually predispose to it.

Vancomycin inhibits and kills C. difficile at concentrations of <4 ug/mL (60).  With oral therapy, fecal vancomycin concentrations are typically in the 100 - 1000 µg/gm range (68), at which concentration this drug is bacteriostatic but not bactericidal for C. difficile (79).  This observation may partially explain the failure to eradicate C. difficile following initially effective therapy and may justify the use of tapered doses in treating CDI.  In contrast, metronidazole is fully absorbed in the small intestine (10,61, 68) and is thought to appear in the lumen of the colon only through exudation during inflammation.  This finding may explain the high relapse rate that is observed when patients are treated with this drug; as soon as inflammation comes under control, metronidazole no longer appears in the colon in a concentration sufficient to continue to act against the infecting organisms (17).

General Considerations and Treatment for First and Second Episodes

Treatment of a First Infection


Vancomycin was the first effective therapy for C. difficile diarrhea and has been the drug to which all subsequent therapies have been compared (44). Cure rates of >90% have consistently been reported when vancomycin is used at a dosage of >125 mg given orally 3-4 times daily for >10 days (Table 1) (36, 39, 85, 97, 130, 142, 146).   Until the very recent approval of fidaxomicin (see below), this drug remained the only FDA-approved one for treating CDI.


Soon after vancomycin was shown to be effective, the possibility of treating with metronidazole was investigated; initial results suggested that this drug was just as effective (107, 130, 142).  Throughout the 1980’s and 1990’s metronidazole was used extensively to treat CDI, even without an FDA indication.  In fact, this drug was generally preferred because it was far less expensive and because its use was believed to reduce the risk that vancomycin-resistant bacteria would emerge in hospital settings (2, 43, 50)).

In the 1990’s, it became apparent that metronidazole therapy was associated with a substantial number of treatment failures, probably because hospitalized patients were older, more likely to be bedridden, and suffered from more severe comorbid conditions than in previous decades. In separate studies, Musher et al (96) and Pepin et al (113) presented remarkably similar results, showing that about 25% of patients treated with metronidazole failed therapy and another 25% relapsed within 1-2 months.

Vancomycin vs. Metronidazole: Current Recommendations

The Infectious Diseases Society of America (IDSA) currently recommends metronidazole as the therapeutic agent of choice for mild CDI and vancomycin for severe CDI (29). These recommendations are based upon two recent prospective randomized controlled trials, which demonstrated significantly greater cure rates with vancomycin compared to metronidazole for severe CDI. Zar et al demonstrated that patients who had mild disease responded equally well with >90% cure rate, whereas those with severe illness were more likely to fail metronidazole than vancomycin treatment.  The severity of CDI was determined by age, height of fever, serum albumin, white blood cell (WBC) count, requirement for ICU care and the presence of pseudomembranes on endoscopy (148).  Louie et al (83) showed that vancomycin provided a significantly higher treatment response rate compared to metronidazole (85% vs. 65%, respectively) for severe CDI. Severity for this second trial was defined by the number of bowel movements passed in 24 hours, WBC count and severity of abdominal pain. Although a validated classification system for CDI severity is lacking, the IDSA recommends considering patients with a white blood cell count of >15,000 cells/mm3 or a rise in serum creatinine level equal to or greater than 1.5 times the baseline level to have severe CDI (29). In the absence of an established severity scoring scheme, it is incumbent for each physician to use clinical judgment in evaluating the severity of an episode of CDI. The authors of this chapter recommend that factors considered by Zar et al (148) and Louie et al (83) be considered in determining the severity of CDI.


Fidaxomicin (DIFICID®, formerly referred to as OPT-80) is a newly released, poorly absorbed macrolide that is highly active against C. difficile but has limited activity against other intestinal organisms. Two randomized, double-blind clinical trials (4,84) have compared fidaxomicin 200 mg twice daily to vancomycin 4 times daily for 10 days in patients with CDI. Similar cure rates were demonstrated for fidaxomicin and vancomycin in both studies (88% vs 86% and 88% vs 87%, respectively). However, the recurrence rate was significantly lower in fidaxomicin-treated patients (30% vs. 43%, respectively) over 25 days of followup. This lower recurrence rate was only observed in patients infected with non-BI/NAP1 strains. Lower recurrence with fidaxomicin may be associated with less disruption of the intestinal microbiome compared to vancomycin (129). Fidaxomicin is approved by the Food and Drug Administration of the United States for the treatment of CDI. The high cost of this antibiotic (the estimated cost of a 10-day course of therapy is $2,800) limits its use in clinical practice (1).

Other Options

Teicoplanin has demonstrated efficacy similar to that achieved with vancomycin and metronidazole in two prospective clinical studies when studied at two different doses given twice a day for 10 days (36, 142). Fusidic acid has been studied prospectively and although similar, high cure rates were demonstrated, the clinical recurrence rate was higher than for those treated with teicoplanin (142). Fusidic acid was also associated with at higher rate of side effects (gastrointestinal discomfort) compared with vancomycin and teicoplanin therapy. Clinical cure rates and C. difficile eradication rates with bacitracin are somewhat lower than with vancomycin (39, 146), and bacitracin should be considered as a second line agent in the treatment of C. difficile diarrhea. Nitazoxanide, an antiparasitic drug that blocks anaerobic metabolism, has also been shown to treat CDI, comparing favorably to metronidazole and vancomycin (Table 3) (97, 98) and even curing patients who fail with metronidazole or vancomycin (92). Rifaximin has been effective in the treatment of small series of patients with recurrent CDI but, even in these few cases, resistant organisms have appeared(47, 70).

Miscellaneous Considerations

The optimal dosage of most effective treatments for C. difficile diarrhea has not been determined, but duration of therapy for at least 10 days appears necessary to achieve cure rates of 90%. Based on the available data we recommend the following dosages; metronidazole 500 mg three times daily and vancomycin 125 mg orally four times daily. Patients who respond slowly or who have had relapsing disease should receive at least 14 days of treatment. Further studies will be necessary before teicoplanin (6, 142) and fusidic acid (31,142) dosage recommendations can be made. Nitazoxanide and fidaxomicin have been studied only at a single, twice-daily dosage. The efficacy of anion-exchange binding resins, such as cholestyramine and colestipol, in the treatment of primary C. difficile diarrhea has been poor, and these drugs are not recommended.

In general, because treatment of CDI relies on nonabsorbable antimicrobial agents, such treatment is given orally. For patients who cannot take oral therapy, intravenous metronidazole should be as effective based on the above comments relating to complete absorption of this drug in the small bowel after oral administration and the appearance of the drug in inflammatory secretions in the bowel. Based on a small number of anecdotal reports, many authorities have stated that antiperistaltic agents should not be administered to patients with CDI (29, 51), although Koo et al (73) have questioned the basis for, and the relevance of this conclusion when effective anti-C. difficile treatment is co-administered. Carefully designed prospective studies need to be conducted before general recommendations can be made regarding the use of antimotility agents for C. difficile induced diarrhea (73).

Treatment of a Relapsing Infection

Historically, patients whose first episode of CDI has responded to therapy but who develop a 2nd episode have been retreated with the same therapy, an approach also endorsed by IDSA guidelines (29). A recent study conducted in the era of BI/NAP1 confirmed that 1st and 2nd episodes of CDI can be effectively treated with metronidazole (114). However in this study, regardless of choice of therapy (metronidazole or vancomycin), complication rates were higher than previously reported for either drug. Caveats to the general principle of utilizing the same therapy to manage 1st and 2nd episodes of CDI, which may influence the clinician’s decision to use a different agent for the 2nd episode, include the presence of markers for severe disease and whether or not the gastrointestinal tract is functioning (e.g., presence of ileus, toxic megacolon). As with the primary infection, metronidazole can be used for recurrent CDI when the episode is mild, but vancomycin is recommended when the recurrence meets criteria for severe disease.

Treatment of Multiply Relapsing Infections ≥3rd Episode

Recurrent disease remains a challenge for clinicians, researchers, and particularly for the patients themselves. The majority of patients with CDI respond to a first or second course of treatment. Recurrence, however, can be seen in up to 25% of cases.

The mechanism for recurrent disease is uncertain and probably varies from case to case. As mentioned above, recurrence may be a result of decreasing metronidazole fecal levels during initial resolution of diarrhea or the bacteriostatic (rather than bactericidal) effect of vancomycin on C. difficile at the high concentrations achieved during therapy (79). Alteration of the colonic flora by the initial insult that led to CDI may be perpetuated by therapy given for this disease. Metronidazole is broadly active against anaerobic bacteria. Although vancomycin is often considered as being restricted in activity to Gram positive organisms, in concentrations achieved in the colon during oral therapy, this drug suppresses Bacteriodes species, as well. Of available drugs, fidaxomicin has the most limited antimicrobial spectrum, and preliminary studies have shown relatively little disruption of the microbial flora of the colon by treatment with this drug. Persistent diarrhea may also reflect a chronic abnormality of the bowel mucosa that has been triggered by CDI. Finally, diarrhea recurrence may be due to regrowth of the original infecting strain or exogenous reinfection with a new strain (65). There is no evidence that recurrence or failure of initial treatment in the case of metronidazole is due to acquisition of resistance to the initial therapeutic agent (120). An underlying host factor responsible for relapsing disease may be the failure to develop antibody to C. difficile toxins (76).

Several strategies have been explored for managing patients who have multiple recurrences (Table 2). When interpreting the efficacy of these strategies, one must consider a number of pitfalls that cloud the interpretation of the efficacy of the intervention and limits the widespread extrapolation of the results to a broader population. Chief among these are the introduction of type 2 error and investigator bias due in part to small sample sizes and the open-label nature of the treatments in these reports.


If disruption of bowel flora is the principal explanation for relapsing CDI, it would be reasonable to replace the normal bacterial flora of the colon to the extent possible. Bacteria administered in this fashion are called probiotics. Of the biotherapeutic approaches, treatment with the yeast Saccharomyces boulardii is probably the most widely studied. In the initial report of 13 patients with multiple diarrhea recurrences who received vancomycin for 10 days and S. boulardii for 28 days, 11 patients had no further recurrences (127). A subsequent randomized, placebo-controlled study showed that S. boulardii in combination with standard therapy was more effective than standard therapy alone in preventing recurrences in patients who had a history of more than one C. difficile diarrhea episode (92). In a  more recent study, however, S. boulardii failed to decrease CDI recurrence compared to placebo, but a subanalysis in which the standard therapy and therapeutic dose were stratified showed a significant decrease in recurrent episodes among patients treated with high-dose vancomycin (2 gm/day) and S. boulardii compared with to high-dose vancomycin and placebo (128). Neither low-dose vancomycin nor metronidazole with or without S. boulardii was effective. Overall, the data to support the use of Lactobacillus-containing and S. boulardii-containing regimens are poor and conflicting. The best study supporting the use of S. boulardii (92) did not convince the Food and Drug Administration to approve it for this use (14). With the heterogeneity of study methodologies and patient populations, it remains exceedingly difficult to reach conclusions from the probiotic literature. Critical examinations of an earlier meta-analysis (32) of probiotic use cast doubt upon the authors’ conclusions for related reasons (15). A systematic review of probiotic efficacy indicated that the current literature does not support the use of probiotics for CDI (38). Significant discrepancies from the reported probiotic contents, including probiotic concentrations, viability, and identification of the actual probiotic strains contained exist because of the current lack of regulation of probiotic manufacturing. Moreover, so-called non-pathogenic strains of the various fungi and bacteria used in the currently marketed probiotics have caused infectious complications both in immunocompetent and immunocompromised hosts; S. boulardii  has especially been implicated (23, 41, 80, 118). As a result, there is currently insufficient evidence to recommend the use of probiotics for primary or recurrent CDI treatment or prevention.

The most specific biotherapy might be the administration of a non-toxigenic strain of C. difficile. Colonization with such an organism might fill an ecologic niche that would prevent relapse of CDI. Anecdotal reports showed some success with this approach (110, 114, 121), and Merrigan et al. have reported good results in preventing relapsing CDI in the hamster model (94). Trials in human subjects are currently underway.

Infusion of Normal Feces

Infusion of feces from healthy donors via enema, colonoscope, duodenoscope or nasogastric tube has been reported to be highly effective in treating CDI.  In a review of all reported cases (55) the overall cure rate exceeded 90%.  Importantly, the great majority of patients who received this treatment had already failed numerous courses of therapy with available antimicrobial agents.  In an open-label, randomized trial, van Nood et al administered a filtrate of feces from normal subjects via nasoduodenal tube after a course of therapy with vancomycin, which was significantly more effective in resolving recurrent CDI than a 14-day course of vancomycin  or vancomycin with bowel lavage (81% vs. 31% and 23%, respectively) (136). A second infusion of normal feces may cure recurrent CDI patients who fail to respond to the initial donor feces (136, 46). Although logistic and aesthetic considerations remain obstacles to widespread use of this treatment, the growing body of literature supporting the efficacy of this therapeutic intervention is mobilizing the medical community to adopt and provide this treatment. Given the potential for transmission of infections or other diseases from donors to recipients of fecal transplantation, development of specific bacterial microbiota therapy is a necessity.

Repeated Courses of Anti-C. difficile Antibiotics

The simplest approach to managing repeated relapses of CDI is to retreat with a different drug or prolonged therapy with a single agent with either metronidazole or vancomycin. Patients often have control of symptoms, but the disease may relapse promptly once therapy is discontinued. This sequence of events is consistent with persistence of C. difficile due to disruption in the microbiome or that C. difficile spores resistant to antibiotics persist in the colon rather than with the concept that CDI somehow alters the colonic mucosa. Two weeks of rifaximin therapy have been given to a total of 8 patients with relapsing disease after symptoms were brought under control by conventional antibiotics; 7 of the 8 appeared to be cured by this therapy. One patient required a second course of rifaximin before becoming asymptomatic but developed high-level resistance to rifaximin during therapy (70).

Tapering and Pulsed Doses of Antibiotics

In observational studies, a regimen of tapering doses of vancomycin has been said to be effective in treating relapsing CDI (90). After the initial 10-14 day course of therapy with 125 mg vancomycin four times daily, 125 mg may be given twice daily for a week, then once daily for a week, and finally every other day for 2- 8 weeks (29). A study of 163 patients evaluated a variety of strategies including treatment with different vancomycin doses for 10 days, treatment which was followed by tapering doses for a mean of 21 days, or treatment with vancomycin (or no treatment) immediately followed by pulsed dosed vancomycin (a single dose of 125, 250, or 500 mg given every 3 days) for a mean of 27 days (90).  Treatment followed by tapered vancomycin and treatment followed by pulsed vancomycin resulted in a significantly reduced rate of recurrence when compared with treatment alone, with the latter regimen being associated with the least amount of recurrences. Tedesco and colleagues (131) also studied vancomycin tapered regimens in 22 patients. The regimen consisted of: week 1 (500 mg/d), week 2 (250 mg/d), week 3 (125 mg/d), weeks 4-6 (pulsed dosed vancomycin 125 mg every 3 days). Collectively, these descriptive studies demonstrate that tapered and pulsed dosed vancomycin regimens seem to be effective in reducing recurrences, and prospective controlled studies are warranted. Metronidazole has also been studied in a pulsed and tapered regimen but too few patients were evaluable to draw any conclusions. In addition, prolonged metronidazole administration should be avoided due to concerns of potential neurotoxicity. In one very small case series, a rifaximin taper was used with apparent success in a 5 of 6 cases (47). The basis for pulsed and tapered regimens is that current treatments (e.g., vancomycin, metronidazole) are only effective against vegetative forms (but not spore forms) of C. difficile. By allowing for a relatively antibiotic-free period in the gastrointestinal tract, it is theorized that spore forms will germinate into vegetative forms rendering them susceptible to subsequent therapy. The other theory for the success of pulsed or tapered dosing is to allow recovery the normal intestinal microbiome by decreasing antibiotic exposure.

Monoclonal Antibody to C. difficile Toxins

A single double-blind randomized control trial appeared to show benefit from treatment of CDI in humans with monoclonal antibody to toxins A and B. The stated primary outcome of the study was the prevention of recurrence of infection. A significant and meaningful difference was demonstrated for recipients of the monoclonal antibody, but only in outpatient subjects who were less ill and had a history of multiple previous CDI episodes. Secondary endpoints of the study were the rate of resolution of symptoms, the persistence of severe symptoms, and the initial response to therapy. For these endpoints, infusion of monoclonal antibody was not beneficial. In the opinion of the authors of this chapter, the initial response rate should have been used to determine the primary outcome. It is unclear why monoclonal antibodies should fail to help bring the disease under control, yet should help to prevent a recurrence 2-3 weeks later. These concerns, in addition to the anticipated high cost of the monoclonal antibodies, will likely narrow prospective recipients of this therapy to include CDI subjects who experience multiple recurrences who fail other treatment options if phase 3 clinical trials are similarly successful (Table 3).

Intravenous Immunoglobulins

Based on anecdotal reports and observational studies, intravenous administration of “immune globulin” (IVIG), a preparation of IgG isolated from healthy controls but not specifically containing antibody to C. difficile toxins, may benefit a subgroup of patients with multiple recurrences of CDI (59, 78, 140). In two of the published studies involving a total of 7 patients, patients had low levels of serum anti-toxin A IgG (78, 140) and the patient in the third study had selective IgG1 deficiency (59). In one observational study of 14 patients (93), 6 responded clinically with no further relapse reported. The doses used ranged from 150-400 mg/kg administered as a single-dose (one patient received a second dose). The median response time was 10 days. In another study, 3 of 5 patients treated with doses of IVIG between 300 to 500 mg/kg (usually 400 mg/kg), were deemed successes, with resolution occurring within 11 days (131). However, an equally large retrospective analysis at one institution, (71) found no benefit to this therapeutic approach. In summary, IVIG has been said by some investigators to possibly provide a therapeutic option for patients with severe/relapsing disease where no other therapeutic options are available. Unfortunately, marginal efficacy, lack of data regarding the optimal dose, cost (~$U.S. 1,500/dose for a 70kg patient) (145) and frequent shortages of the preparation are significant disadvantages (134).

Toxoid Vaccine

Toxoid vaccine (Acambis Pharmaceuticals) is currently in early developmental stages (Table 3). In a very small study of three patients with recurrent CDI who had received 7-22 months of continuous vancomycin therapy, a parenterally administered C. difficile vaccine containing toxoids A and B enabled discontinuation of the vancomycin without further recurrence (125). Two of the 3 patients demonstrated increased IgG antitoxin A antibodies (3- and 4-fold increases) and an increased IgG antitoxin B antibody response (20- and 50-fold).

When Oral Therapy Is Not Possible

Although several options exist for the treatment of C. difficile diarrhea (Table 1), all well-studied regimens employ oral therapy. When the oral route is compromised, intravenous therapy may be considered. After intravenous administration of vancomycin, colonic concentrations of vancomycin are insufficient to be active against C. difficile, and there is little support for this option. Metronidazole is fully absorbed in the small intestine and gets into the colon along with inflammatory exudates; therefore, fecal concentrations of metronidazole are similar whether metronidazole is given orally or intravenously (17). Clinical experience is supported by limited reports in the literature supporting the use of intravenous metronidazole therapy for CDI (17, 45, 54, 72). This therapy alone may be inadequate in patients with severe adynamic ileus, but that may relate to the advanced state of the disease, not the available concentration of metronidazole in the colonic lumen (58). Vancomycin, 500 mg every 6 hours in a volume of 100 ml saline, has been administered by enema, with success being reported in a few cases (8, 104). The 2013 Guidelines from the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) (35) recommend intravenous metronidazole for 10 days for nonsevere CDI. For severe, complicated or refractory CDI, ESCMID recommends adding intracolonic vancomycin with or without vancomycin by nasogastric tube, while the IDSA recommends adding vancomycin orally or by nasogastric tube with or without intracolonic vancomycin (29).  Unfortunately, the data supporting these recommendations are sparse.

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Fulminant CDI

Many C. difficile strains have been shown to be responsible for fulminant CDI.  Some studies have found that the so-called hypervirulent C. difficile strain (BI/NAP1) has caused more severe disease, without regard to which treatment is used (5, 33, 88, 113, 115) although others dispute that finding, particularly in non-epidemic settings (28, 138). In cases of severe CDI, patients should be monitored daily for response to therapy, including the number and consistency of bowel movements as well as for markers that might indicate a need for surgical intervention.

Severe Ileus and Toxic Megacolon

The most serious manifestation of C. difficile disease is toxic megacolon which, paradoxically, may present without diarrhea (95, 107)). Treatment of patients with toxic megacolon or severe ileus is difficult and controversial, and the mortality remains high.  Various attempts have been made to achieve effective antimicrobial concentrations at the site of infection when the oral route is compromised. Although clinical data are insufficient to evaluate optimal therapy for severe CDI complicated by ileus or toxic megacolon, expert opinion advocates treatment with intravenous metronidazole combined with vancomycin by nasogastric tube and rectal enema both at dosages of 2 grams per day (53, 107, 109, 124). This strategy was used successfully at one institution in six patients with severe ileus and included vancomycin administered by nasogastric tube and by retention enema plus intravenous metronidazole(53, 107).

When Medical Therapy Fails

Further intervention is indicated in patients with toxic megacolon who are not responding to medical treatment or when colonic perforation is suspected (95). The more conservative approach is decompressive colonoscopy (123). After decompression of the colon in 8 patients with ileus and toxic megacolon, a fenestrated tube was positioned over a guidewire and the tube was perfused with a vancomycin solution. This treatment was effective in treating the colitis in several patients, and complications such as perforation were not seen. Colonic diversions and partial colectomies have been performed but mortality is high (95). Although efficacy has been difficult to assess, subtotal colectomy with sparing of the rectal stump (total abdominal colectomy) appears to be the preferred surgical option (30, 95). At one medical center during a 12-year period, 64 patients died or underwent colectomy for complicated CDI (33). The mortality in patients who underwent colectomy in this series was 57%, and the authors state that early colectomy was associated with a better outcome. Clues to the need for surgical intervention include very high WBC counts, hypotension and lactate levels of >5 mmol/L (75).

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The principal endpoint for monitoring the success of therapy for CDIis clinical evaluation of patient symptoms. In first treatment for uncomplicated cases, an anti-C. difficile drug (Table 1) should be given for 10 days and discontinued. Although some clinicians will continue specific therapy for longer than 10 days if the precipitating antimicrobial cannot be discontinued, there are no studies to support this practice. In addition, it is unclear how long C. difficile therapy would need to be continued in this situation because antibiotic disturbances of the intestinal microbiome can persist for weeks after the discontinuation of the offending antibiotic (147).  More prolonged therapy in patients who have responded to treatment has potential disadvantages, because the treatments themselves (metronidazole and vancomycin) are not active against spore forms of C. difficile and are destructive to normal commensal flora; in rare instances, these treatments have been implicated as causes of CDI (108). CDI should be treated episodically and there is no role for “prophylaxis” by continuation of metronidazole or vancomycin once the patient has experienced clinical resolution (65). Clinical resolution of CDI has not been shown to correlate with clearance of C. difficile bacteria or toxins. Positive stool cultures for C. difficile at the completion of therapy is moderately predictive of recurrence (139), but it is strongly recommended that stool cultures and toxin assays not be performed if the patient’s symptoms have resolved (29) because repeat positive test results often lead clinicians to inappropriately prolong therapy or switch therapy to a different agent. Patients who have previously relapsed or who respond slowly to therapy should probably be treated for 14 days, although there are no data specifically to support this practice, and most guidelines recommend 10-14 days of therapy.

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Strategies employed to control and prevent C. difficile diarrhea can be classified into those that reduce the risk transmission of C. difficile and those that reduce the risk of clinical illness if the patient is exposed.

Infection Control Measures

Numerous methods have been employed in attempts to prevent transmission including barrier precautions, gloving, handwashing, environmental disinfection, replacement of electronic rectal thermometers and treatment of asymptomatic carriers of C. difficile. Although handwashing and especially barrier precautions are probably effective, decreased rates of C. difficile diarrhea have only been demonstrated to date with glove use (20, 67), replacement of electronic thermometers with single use disposables (20), and replacement of quaternary ammonium solution with unbuffered 1:10 hypochlorite solution for environmental disinfection (9, 88). C. difficile spores are resistant to alcohol. Handwashing with soap and water is believed to physically remove spores from contaminated hands. Differences in hand-to-hand transmission of C. difficile were noted between the two methods favoring the use of handwashing with soap and water over alcohol hand rubs (63)). As a result, handwashing with soap and water is preferred over alcohol hand rubs, as recommended by the CDC and the IDSA, when caring for patients with CDI during outbreaks. It is important to note that alcohol hand sanitizers have improved compliance with hand hygiene policies in healthcare settings and should continue to be encouraged when caring for patients without C. difficile. Isolation of patients in private rooms or cohorting of patients is also recommended to decrease transmission of C. difficile spores (22, 29, 126).

Complete prevention of transmission may be impossible because of compliance with barrier methods, practical issues with hypochlorite disinfectants, and other unidentified factors. Since many patients are either treated as outpatients or are initially treated in an acute care facility and then discharged when clinically improved, patients should be advised regarding proper hand hygiene and environmental cleaning (with regard to their bathrooms at home).

Antimicrobial Stewardship

Even if prevention of transmission is incomplete, methods that reduce risk of disease should also be implemented and are potentially effective. Control of antimicrobial use has successfully reduced rates of CDI and interrupted local epidemics caused by C. difficile. Restriction of clindamycin was repeatedly shown to be effective (27, 110) in settings characterized by heavy clindamycin use and the presence of highly clindamycin-resistant strains (69). Control of second and third generation cephalosporins was also effective, particularly when these drugs were replaced with apparently less-predisposing antimicrobials, such as piperacillin-tazobactam (122). Programs that encourage diversity in antimicrobial use, and reduce unnecessary use (by eliminating redundant antimicrobials, promoting shorter courses of therapy, using a “careful watch and wait” approach to outpatient upper respiratory tract infections, as examples) may be part of a “bundled” strategy for healthcare facilities or clinics to adopt. A recent Cochrane Review emphasized that reduction in the incidence of CDI was one of the major benefits of an antimicrobial stewardship program (34). Guidelines for establishing a programmatic approach to enhance antimicrobial stewardship were recently published jointly by the IDSA and SHEA (37).

Other measures. Several studies have implicated proton pump inhibitors as predisposing to CDI (25,60), although one recent case control series has questioned this association (103). In the majority of patients, there has been no recorded indication in the medical record for the proton pump inhibitors. Cadle et al found that the incidence of recurrent CDI was 4 times greater in patients receiving a proton pump inhibitor (21). It seems prudent to avoid unnecessary usage of proton pump inhibitors in hospitalized patients.

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In summary, diarrhea and colitis due to C. difficile are, most often, complications of antimicrobial therapy. Unnecessary antibiotics should be avoided, especially in hospitalized persons. Once CDI is suspected, it may be helpful, if possible to discontinue the offending antibiotic (50). In hospitalized patients who have diarrheal disease and in whom CDI is suspected, empiric therapy should be started while awaiting the results of toxin assay results. This approach will decrease the degree of debilitation produced by the infection and decrease the likelihood of spread of infectious organisms. Barrier precautions and contact isolation, with handwashing with soap and water before and after patient contact, should be meticulously observed if the diagnosis is established. Metronidazole is recommended for mild CDI, but vancomycin should be used to treat severe cases. The expected time to response is 3-4 days, but many patients may respond more slowly. The usual duration of treatment is 10 days, but one might consider a longer course of therapy – e.g., 14 days – in patients who have slowly responded or who have previous relapsed. No test of cure assay is indicated in patients who have responded to therapy. In patients who fail to respond, less traditional therapeutic agents, biotherapeutic approaches, and even immunotherapy should be considered. Extensive experience with fecal replacement favors that approach when it is practicable.

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Table 1: Randomized, Comparative Trials of Oral Therapy for Clostridium difficile Diarrhea

Agent Regimen Patients Studied Cure Rate (%) Time to Resolution Relapse Rate (%) References
Vancomycin 125 mg qid x 7d 21 86 4.2 d NS Young  1985 (133)
  125 mg qid x 10d 80 91 2.0 d 19 Louie 2006 (78)
  125 mg qid x 10d 134 81 5.0 d 23 Louie 2007 (76)
  125 mg qid x 10d 71 97   7 Zar 2007 (135)
  125 mg qid x 10d 27 74   7 Musher 2009 (90)
  125 mg qid x 10d 309 86 3.3 d 25 Louie 2011 (77)
Metronidazole 500 mg tid x 10d 31 94 3.2 d 16 Wenisch 1996 (130)
  250 mg qid x 10d 76 87.95 2.4 d, NS 42 Teasley 1983 (121)
Musher 2006 (91)
  375 mg qid x 10d 143 72 5.0 d 27 Louie 2007 (76)
  250 mg qid x 10d 79 84   14 Zar 2007 (135)
Fidaxomicin 200 mg bid x 10d 287 88 2.4 d 15 Louie 2011 (77)
Teicoplanin 400 mg x bid x 10d 28 96 2.8 d 8 Wenisch 1996 (130)
  100 mg bid x 10d 26 96 3.4 d 28 daLalla 1992 (33)
Fusidic acid 500 mg tid x 10 d 29 93 3.8 d 28 Wenisch 1996 (130)
Bacitracin 20k-25k U qid x 7-10 d 36 78 2.5-4.1 d 23 Dudley 1986, Young 1985 (36, 133)
Nitazoxanide 500 mg bid x 7 d 40 90 NS 23 Musher 2006 (91)
  500 mg bid x 10 d 36 89 NS 10 Musher 2006 (91)
Rifaximin 200 mg tid x 10 d 10 90 NS NS Boero 1990 (16)

Table 2.  Empirical Treatment Strategies for Patients with Multiple Recurrences of C. difficile Diarrhea


Repeated courses of antimicrobial agents (metronidazole, vancomycin, nitazoxanide, rifaximin)

Tapering doses of antimicrobial agents (vancomycin, rifaximin)

Infusion of normal feces (fecal transplantation)
            Ingestion of bacteria that normally inhabit the bowel (probiotics)
            Ingestion of non-toxigenic C. difficile

Monoclonal antibody to C. difficile toxins

Intravenous immunoglobulin

Table 3. Potential Future Treatment Options

Product Type Stage of Development Company
C. difficile vaccine
Phase I
Monoclonal Antibody Antibody Phase III Merck
Nitazoxanide Antibiotic Phase III Romark
Ramoplanin Antibiotic Phase III Oscient
Rifaximin Antibiotic Phase III Salix

 Figure 1: Three Hit Disease

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