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Infectious Diseases in Clinical Practice:
doi: 10.1097/IPC.0b013e31820fc87d
Review Articles

The Most Effective Treatments for Clostridium difficile Diarrhea: An Evidence-Based Review

Griffin, Allen Thomas MD; Arnold, Forest Wayne DO

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Author Information

From the Division of Infectious Diseases, Department of Medicine, University of Louisville, School of Medicine, Louisville, KY.

Correspondence to: Allen Thomas Griffin, MD, Department of Medicine, University of Louisville, 627 S Preston St, Louisville, KY 40202. E-mail: atgrif01@louisville.edu.

The authors have no funding or conflicts of interest to disclose.

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Abstract

Clostridium difficile is more common, more virulent, and more difficult to treat than in past decades. Oral vancomycin and metronidazole have been the subject of the most rigorous study in this disease. Although these antibiotics have largely been viewed as equivalent, studies support vancomycin for severe disease, whereas metronidazole is noninferior in milder disease. Both antibiotics are superior to the toxin-binding agent tolevamer. No evidence supports probiotics for initial disease, but there may be utility in relapsing disease. There is an exiguous evidence base regarding antibiotic treatment of relapsing disease, but tapered and pulsed regimens of vancomycin remain possible options. Preliminary evidence supports the use of monoclonal antibodies against C. difficile toxins A and B for relapsing episodes. The studies concerning refractory disease are limited to a case series design, whereas it remains unclear how effective probiotics are in the prevention of C. difficile infection.

Clostridium difficile is an anaerobic, spore-forming bacillus that is an etiologic agent of antibiotic-associated colitis. This pathogen is becoming more common in the hospital setting with current estimates reaching 13.1 per 1000 inpatients in the United States.1 Since the year 2000, there have been reports of increasing virulence in lack of response to treatment,2 disease severity (presence of shock, megacolon, or perforation), and mortality, some of which have been attributed to the B1/NAP1/027 strain.3 Outbreaks of this virulent strain, for instance, have recently been reported in Canada,3 Europe,4 and the United States.5 With these facts in mind, clinicians are pressured to make a diagnosis and initiate effective therapy promptly. The following is a review of the medical therapy for this pathogen with a focus on antibiotics, probiotics, toxin-binding resins, immunotherapy, and fecal bacteriotherapy as they relate to initial C. difficile infection (CDI), relapsing CDI, and refractory CDI.

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SEARCH STRATEGY

PubMed, Ovid, and the Clinical Trials Registry were searched for relevant articles from 1966 to July of 2010. The terms "Clostridium difficile colitis," "Clostridium difficile infection," or "Clostridium difficile" were combined with "antibiotics," "probiotics," "toxin-binding agents," "tolevamer," "colestipol," "cholestyramine," "vancomycin," "metronidazole," "bacitracin," "fusidic acid," "immunotherapy," "fecal bacteriotherapy," "intravenous immunoglobulin," "monoclonal antibodies," "rectal vancomycin," or "intracolonic vancomycin." Criteria for inclusion were articles that addressed therapeutic strategies for CDI. Studies discussing the surgical treatment of CDI were excluded as were narrative reviews and systematic reviews. Although case reports and cases series were not excluded, preference was given to more rigorous analyses. A total of 74 articles were included in the final review.

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TREATMENT OPTIONS FOR INITIAL DISEASE

Antibiotics

Since the role of C. difficile in antibiotic-induced colitis was elucidated,6 a few basic antibiotics have been studied. These have included the glycopeptides vancomycin and teicoplanin in addition to metronidazole, bacitracin, and fusidic acid. Oral vancomycin and metronidazole have become the preferred agents. These antibiotics are the first-line agents recommended for CDI by the Infectious Diseases Society of America7 and the Centers for Disease Control and Prevention.8 Vancomycin and metronidazole failures, however, have prompted the study of alternative agents. The 21st century has brought with it 3 new antibiotics whose place in this illness remains uncertain. The initial focus of this review will be on therapy for illness not considered refractory or relapsing. Vancomycin and metronidazole will be discussed first in this context followed by alternative antibiotic options and, subsequently, novel antibiotic options for initial disease.

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Vancomycin and Metronidazole

Shortly after C. difficile was found to be a cause of antibiotic-induced colitis, a small series suggested the effectiveness of vancomycin.9 After this work, the first controlled trial was performed.10 This trial was a randomized placebo-controlled study of surgical patients with postoperative diarrhea. The primary analysis focused on patients who had CDI confirmed by toxin assay or stool culture. At 125 mg 4 times daily, vancomycin restored normal bowel function in 7 of 9 postsurgical patients with CDI compared with 1 of 7 placebo postsurgical patients with CDI (P = 0.02). Generalizability was severely limited secondary to the small number of patients and the narrow population surveyed. Furthermore, eligible patients for the study (anyone with postoperative diarrhea) who were later found not to have CDI were then excluded from the primary analysis after initial randomization to vancomycin or placebo had taken place, therby invalidating the initial randomization procedure. However, this trial sets the stage for further controlled study. Two small case series followed reporting the utility of metronidazole.11,12

Vancomycin and metronidazole were originally compared in a randomized study of 94 patients.13 Metronidazole at 250 mg 4 times daily was compared with vancomycin at 500 mg 4 times daily. Treatment failures and relapses were not different between groups (P = 0.20 and P = 0.17, respectively), although higher doses of vancomycin were used in this study compared with studies that followed. A subsequent nonrandomized study compared vancomycin, metronidazole, teicoplanin, and fusidic acid.14 No differences were found among the antibiotics in clinical response (including vancomycin vs. metronidazole), although there was a trend for the teicoplanin group to have less relapses. In addition, a study by Wilcox and Howe15 documented similar treatment success with vancomycin or metronidazole in initial resolution and relapse; however, vancomycin resolved the disease more rapidly (3 vs. 4.6 days, P < 0.01). A later report by Al-Nassir et al,2 like the study by Wilcox and Howe,15 found that vancomycin and metronidazole were equivalent in response, yet vancomycin again resolved the disease faster, leading to cure more commonly in the first 5 days than metronidazole (P = 0.005). It must be noted that these latter 3 comparative studies had significant problems with design, including lack of blinding and randomization. Aggregating the results of these studies is difficult, furthermore, because varying definitions of cure were used. On the basis of the single study with superior design,13 vancomycin and metronidazole seem largely equivalent for CDI when no stratification for illness severity is used.

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Severity of Illness

Three subsequent studies with a randomized double-blinded design offer the best evidence of vancomycin and metronidazole efficacy while comparing effectiveness in illness severity. In the first study,16 participants were stratified by severity based on the presence of pseudomembranes on endoscopy, intensive care unit treatment, leukocytosis (≥15,000 cells/μL), temperature (>38.3°C), albumin level (<2.5 mg/dL), and age older than 60 years. A score of 2 and higher was considered severe. All parameters were assigned 1 point with the exception of intensive care unit treatment and pseudomembranes that were assigned 2 points. Patients with refractory disease were excluded from the analysis. Vancomycin was administered at 125 mg 4 times daily, whereas metronidazole was administered at 250 mg 4 times daily. The number of patients treated successfully was 97% for vancomycin and 84% for metronidazole (P = 0.006). However, when stratified by severity, vancomycin and metronidazole were equivalent for milder disease, but vancomycin was superior in severe disease (Fig. 1).

Figure 1
Figure 1
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The second such study17 was a phase 3 study evaluating tolevamer, a novel agent capable of binding C. difficile toxin. Patients received this agent, vancomycin, or metronidazole. Disease severity was defined in terms of severe abdominal pain, leukocytosis (≥20,000 cells/μL), or 10 or more loose stools per day. Vancomycin outperformed metronidazole in severe disease but was equivalent in milder disease, whereas tolevamer was inferior to both antibiotics.

The third study18 was a repeat phase 3 study investigating tolevamer with a similar design to the aforementioned studies. This analysis documented the equivalency of vancomycin and metronidazole with cure rates of 81% and 73%, respectively, when no stratification for severity was undertaken (P = 0.153). However, in the subset of patients with severe disease, vancomycin was again superior to metronidazole.

As a result, these 3 randomized double-blinded studies, although suggesting similar efficacy of vancomycin and metronidazole, emphasize the importance of vancomycin in severe disease. A caveat is that disease severity was not a uniform criterion in these studies (Table 1).

Table 1
Table 1
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In addition to disease severity, a few studies have specifically looked at other predictors of metronidazole failure. In 1 study,19 it was found that an albumin level less than 2.5 mg/dL or intensive care was linked to failure of metronidazole. Another study uncovered cephalosporin use as a marker of failure.20 Although the NAP-1 strain was associated with more severe disease in previous reports, paradoxically, this strain was not shown to be more responsive to vancomycin than metronidazole in 1 study.21

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Dosing and Route of Administration

Although metronidazole was dosed at 250 mg 4 times daily in most of these studies, varying dosages of vancomycin were used. The 3 randomized controlled trials16-18 comparing vancomycin and metronidazole used vancomycin at 125 mg 4 times daily. One study has specifically compared high-dose versus low-dose vancomycin (500 mg 4 times daily vs. 125 mg 4 times daily). After randomizing patients to one of the regimens, researchers found no difference in resolution of illness or relapse.22 There was no stratification for severity in this analysis.

The method of administration of vancomycin was oral in all of these previously mentioned studies because of the low intracolonic levels achieved by intravenous dosing. Although the above studies used oral metronidazole, 1 series of severely afflicted patients with an ileus documented the safety and efficacy of 500 mg of metronidazole administered intravenously 3 times daily.23 Another found similar colonic levels for intravenous and oral dosing in patients without an ileus.24 A paucity of evidence supports intracolonic regimens of vancomycin, but such regimens may be useful in instances of severe ileus resulting from CDI. Successful use of such a regimen was reported in a case series of 9 patients.25 A similar series had previously documented the success of intracolonic vancomycin combined with decompression to treat a group of severely afflicted patients with CDI and ileus.26 Failures with both agents have prompted researchers to look elsewhere.

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Alternative Antibiotic Options

Other antibiotics active against C. difficile, in addition to vancomycin and metronidazole, have also been studied for initial disease. One prospective randomized study27 compared teicoplanin to vancomycin. Resolution of disease was documented in 100% of the vancomycin-treated patients and 96.2% of the teicoplanin-treated patients (P = 0.56); however, there was a trend for fewer recurrence with teicoplanin. This suggestion of a lower recurrence rate with teicoplanin was mirrored in a study by Wenisch et al14 discussed previously. Vancomycin has also been compared in 2 studies against bacitracin alone. These analyses both showed similar cure rates, but persistence of toxin in the stool was more common with bacitracin.28,29 However, because a test of cure is not usually performed, the significance of this finding is not known. Metronidazole has been compared separately against fusidic acid in a double-blinded randomized study.30 Initial cures and recurrences were not statistically different, but a subsequent study documented a high degree of emergence of resistance to fusidic acid.31 A final partially blinded study evaluated the combination of metronidazole and rifampin for initial illness.32 The combination was no more effective than metronidazole alone. A caveat is that these studies, looking at alternative antibiotics, were plagued by small samples, limiting power and generalizability, and some of the analyses used end points (toxin eradication) that are difficult to interpret clinically (Table 2).

Table 2
Table 2
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Novel Antibiotic Options

Newer agents have emerged in the armamentarium against this pathogen. The best studied for first-episode CDI, nitazoxanide, is effective against protozoan causes of diarrhea. In a double-blinded study,33 nitazoxanide 500 mg twice daily was compared with metronidazole. No difference was found between the 2 agents in initial response. With a similar design, nitazoxanide was pitted against vancomycin.34 Similarly, there was no difference in initial response, maintenance of remission, or time to recovery. Both of these studies excluded some of the most severely affected patients, limiting generalizations to this population. Currently, however, the high cost of nitazoxanide is likely to limit use. Ramoplanin, a glycolipodepsipeptide, is currently being studied in in vitro models. It has shown efficacy in hamster models similar to vancomycin.35 Finally, fidaxomicin (OPT-80), a poorly absorbed macrocyclic antibiotic, has been studied in an open-label trial of CDI and has shown efficacy in response and minimal lack of recurrence.36

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Summary of Antibiotics for Initial Disease

Taken together, these antibiotic studies for initial CDI suggest that vancomycin, metronidazole, bacitracin, fusidic acid, and nitazoxanide have similar efficacy in the initial therapy for mild or moderate CDI. Most high-quality studies have been performed on vancomycin and metronidazole. There is a paucity of research on combination therapy for an initial episode, but 1 study suggests no benefit.32 Nitazoxanide is a promising alternative to vancomycin and metronidazole. Although only 3 randomized controlled trials16-18 have stratified patients by severity, these studies were rigorous enough to conclude the superiority of vancomycin in severe CDI, although severity was defined differently in each analysis. Conclusions drawn from most of these antibiotic studies must be tempered with the fact that varying definitions of disease response were used, some of which may not be clinically relevant. Furthermore, all but one of the studies were not placebo-controlled, and at least in milder illness, patients with C. difficile may improve without treatment.

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Probiotics

Owing to antibiotic failures, research has looked beyond antibiotics for initial CDI therapy. With the goal of restoring balance to the colonic microbiota, researchers have investigated probiotics as options in initial and recurrent disease. The study of probiotics has largely been limited to the prevention of relapses in recurrent disease, but at least 1 trial provides information on the efficacy of probiotics in initial episodes of CDI.

In a study of 164 patients with recurrent or first-episode CDI, patients were randomized to metronidazole or vancomycin plus placebo or one of the antibiotics plus 1 g daily of Saccharomyces boulardii for 4 weeks.37 For initial disease, the addition of the probiotic did not decrease recurrence; however, for recurrent disease, S. boulardii reduced relapses (Fig. 2). Although the study was randomized, a serious flaw is that the concomitant antibiotic administered throughout the study was not controlled, and outcomes in the study addressed only relapse, not resolution of the presenting episode. As a result, this evidence suggests no benefit to probiotics in initial CDI, although there may be a benefit in recurrent disease.

Figure 2
Figure 2
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Toxin-Binding Agents

Various in vitro reports have described the ability of anion exchange resins to bind toxin produced by C. difficile. These agents are appealing owing to a lack of selection for antibiotic resistant bacteria. Therefore, these medications have been the subject of treatment studies. Although this area is largely limited to case reports,38 there are some relevant studies with regard to the treatment of first-episode CDI.

A randomized trial39 compared the ability of colestipol to bind C. difficile toxin to placebo. The primary outcome of continued fecal excretion of C. difficile toxin did not differ between groups. Definite end points, such as remission of symptoms, were not evaluated. In a phase 2 trial,40 tolevamer was compared with vancomycin. In this study, patients were randomized to vancomycin, 3 g daily of tolevamer, or 6 g daily of tolevamer. The major end point was time to cessation of illness. Although the 6-g tolevamer group was equivalent to vancomycin, the 3-g group was inferior to both higher-dose tolevamer and vancomycin (Fig. 3). Those with severe CDI were excluded. Two subsequent phase 3 trials17,18 found tolevamer to be inferior to vancomycin and metronidazole. For those who did improve with tolevamer, however, there was a low recurrence. Currently, tolevamer is not available in the United States, and work on the agent has largely ceased since the results of the above trials.

Figure 3
Figure 3
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Summary of Toxin-Binding Agents for Initial Disease

As a result, there is a paucity of controlled research with toxin-binding agents in initial disease other than tolevamer. In addition, some research suggests toxin-binding agents as a group may bind vancomycin when used together with the antibiotic, limiting bioavailable vancomycin.41

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Immunotherapy

Armed with the idea that those who become ill from C. difficile compared with those who merely remain colonized have inadequate immune responses, researchers have begun to focus on immunotherapy. From the use of nonspecific intravenous immunoglobulin (IVIG) to administering antibodies manufactured against C. difficile toxins, several ideas have emerged.

One of the first case reports of IVIG suggested it to be effective in resolving 2 instances of severe initial CDI.42 One case series that considered a mixed population of patients with relapsing or severe initial disease also found positive responses using IVIG.43 However, a related observational study, limited predominantly to first-episode, severely affected patients, demonstrated disappointing results with more than half of the cohort treated with IVIG died of illness.44 Likewise, in a study by Juang et al,45 a retrospective comparison was made between 18 patients with severe initial CDI who received 200 to 300 mg/kg of IVIG and 18 matched controls who received antibiotics for CDI. No differences or trends were found based on mortality (P = 1.00), need for surgery (P = 1.00), or duration of hospitalization (P = 0.570).

The most robust positive evidence for immunotherapy, in contrast, comes from a randomized, double-blinded, placebo-controlled study on monoclonal antibodies manufactured against toxins A and B.46 Unlike most studies on immunotherapy, this analysis was not limited solely to refractory, relapsing, or severe cases and included many patients presenting with CDI for the first time. Two hundred patients were randomized to vancomycin or metronidazole alone or combined with the antibodies. The major end point of disease relapse was less in the antibody group (7%) than the antibiotic group (25%, P < 0.001). This finding held true even in cases of the virulent NAP1 strain (Fig. 4). Major modifying variables, such as the severity of CDI, past number of relapses, and the number of patients on vancomycin or metronidazole, did not differ in the 2 treatment groups. However, it must be remembered that the primary end point of preventing relapse in this analysis is quite different from the negative IVIG studies that addressed resolution of a severe presenting episode.

Figure 4
Figure 4
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Summary of Immunotherapy for Initial Disease

Therefore, although monoclonal antibodies seem to be a promising adjunct to prevent relapses in both initial and relapsing disease, there is little positive evidence for the use of pooled immunoglobulin in resolving initial episodes of CDI. However, pooled immunoglobulin has not been studied under more rigorous conditions controlling for severity as monoclonal antibodies have, placing pooled immunoglobulin at a disadvantage. Furthermore, it is difficult to aggregate these studies because the end points, preventing relapse after the initial episode of CDI or resolving the presenting episode of initial CDI, were quite different. A problem with extrapolating any of the results of immunotherapy to initial disease is that these analyses considered a mixed population of patients with relapsing and first-episode CDI.

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TREATMENT OPTIONS FOR RELAPSING DISEASE

Antibiotics

Unlike the large amount of evidence available to guide antibiotic therapy for initial disease, few studies are available for relapsing disease, despite the ubiquitous nature of relapse in this illness. The largest study involving recurrent CDI and antibiotics enrolled patients relapsing on vancomycin or metronidazole.47 Those relapsing were treated with tapered dosing of vancomycin or pulsed dosing of vancomycin (125-500 mg every 2-3 days). Tapered vancomycin resulted in 31% fewer recurrences than treatment as usual (P = 0.01), whereas pulsed dosing resulted in 14.3% fewer recurrences (P = 0.02). The tapered regimen with the best efficacy involved starting vancomycin at 500 to 1000 mg daily in divided doses and tapering to 125 mg daily for 19 to 25 days. Despite its findings, this study suffered a lack of randomization and blinding; furthermore, the study did not control for the initial antibiotic used to treat patients. Similar positive results were found in a series of 22 patients with recurrent disease who were given tapered vancomycin.48

Two small case series on recurrent disease suggest some efficacy for preventing relapses by adding rifampin to vancomycin49 or adding rifaximin at the completion of oral vancomycin therapy.50 However, resistance rates to rifamycins as high as 40% and 80% for non-NAP1 and NAP1 isolates, respectively, have emerged in some institutions.51 Finally, in an analysis of 35 patients who failed metronidazole therapy or relapsed, nitazoxanide resolved the episode of diarrhea or prevented relapse in 66% of the sample.52 Again, lack of blinding and randomization limits inferences.

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Summary of Antibiotics for Relapsing Disease

To summarize, there are no methodologically robust studies to guide antibiotic therapy for relapsing disease. Although 2 series suggest some efficacy in preventing recurrence with vancomycin combined with rifampin49 or rifaximin,50 the largest study on relapsing disease supports tapered or pulsed dosings of vancomycin for preventing relapse.47 Nitazoxanide could be considered. Although these studies considered prevention of relapse as the major end point, only the nitazoxanide study had the added benefit of using a combined end point looking at prevention of relapse and resolution of a repeat episode.

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Probiotics

Probiotics have also been tried with some success in preventing relapse in recurrent CDI. A pilot trial53 provided preliminary evidence for the effectiveness of S. boulardii in the treatment of recurrent CDI. Subsequent to these results, another randomized analysis54 compared vancomycin and placebo to vancomycin and 1 g daily of S. boulardii in patients experiencing a recurrent episode of CDI. Treatment group patients had less recurrences by 16.7% (P = 0.05). Likewise, the study of McFarland et al37 using S. boulardii in those with initial or recurrent CDI found a benefit in reduction of recurrences only for those with relapsing CDI. Two other controlled trials55,56 revealed no difference between the treatment and placebo groups in recurrence of CDI when a Lactobacillus cocktail was administered to patients with relapsing CDI. Each study, however, suffered small sample sizes (n = 20 and n = 15, respectively). None of these studies offered the benefit of studying a probiotic without an adjunctive antibiotic.

A novel approach was taken in a study by Lewis et al.57 As an alternative to administering probiotics, these researchers administered oligofructose to stimulate growth of bowel flora to eliminate C. difficile. Antibiotics against C. difficile were administered concomitantly. In a randomized fashion, 142 patients with relapsing CDI received the "prebiotic" or placebo for 30 days. The study found that 34.3% of placebo patients relapsed compared with 8% of treated patients (P < 0.001).

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Summary of Probiotics for Relapsing Disease

Thus, the evidence for the use of probiotics in the treatment of recurrent CDI is limited to concomitant use of an antibiotic against C. difficile. Furthermore, these agents have only been studied as an adjunct to prevent relapse in recurrent CDI, not to treat an acute episode of recurrent CDI. Although the evidence for treatment with S. boulardii in relapsing disease is moderate, the concomitant antibiotic used varied among studies and within the same study. The utility of other probiotic agents in the treatment of recurrent CDI remains to be demonstrated, and replication is needed to discern the usefulness of oligofructose or similar preparations in stimulating the growth of normal bowel flora. Studies on probiotics and treatment were combined in a meta-analysis by McFarland.58 The analysis demonstrated the beneficial effects of S. boulardii, not alternative probiotics, and only for prevention of further episodes in relapsing cases, as the individual data suggested. Caution should be embraced in using yeast-based agents in immunodeficient patients because case reports of fungemia have been noted with S. boulardii59,60 (Table 3).

Table 3
Table 3
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Immunotherapy

Three case series support the effectiveness of IVIG in resolving severe initial or relapsing episodes of CDI.43,61,62 In one of the more intriguing studies on immunotherapy in a relapsing population,63 immunoglobulins active against C. difficile toxins were prepared. Using an inactivated toxin, these researchers injected cows and harvested the antibody-rich colostrum subsequently produced by the cows ("immune whey"). The colostrum was tested for the presence of antibodies to C. difficile toxins before administration. Subjects with relapsing CDI were randomized to the colostrum (administered per os) or metronidazole. Similar improvement rates were noted in both groups (100% metronidazole and 89% for the immune whey). Relapse rates after treatment were not assessed, unlike most studies that consider recurrent CDI. The best support for immunotherapy in relapsing disease, however, comes from the study of Lowy et al46 discussed previously. This study demonstrated significantly less relapses of CDI in a mixed group of patients with relapsing and initial CDI who were administered intravenous infusions of monoclonal antibodies against C. difficile toxins.

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Summary of Immunotherapy for Relapsing Disease

Thus, the evidence for the use of IVIG in relapsing CDI, although positive, is limited to a case series design. Although the use of an oral immunoglobulin preparation sounds intriguing, such a product needs further study. Currently, the most robust evidence for immunotherapy for relapsing disease is with the use of monoclonal antibodies against C. difficile toxins, although this study considered a mixed population of relapsing and initial CDI.

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Fecal Bacteriotherapy

As an extension from the use of probiotics to replenish depleted flora that seems to make one susceptible to C. difficile, researchers have turned to transplanting feces to rejuvenate the intestinal microbiota in relapsing cases of CDI. Methods of administration and preparation have varied but have typically involved donor feces administered by nasogastric tube or via another enteric route into the small bowel or the colon.

Aas et al64 reviewed the charts of 18 recurrent CDI cases and noted little recurrence after administration of donor feces through a nasogastric tube. In the case series by Nieuwdorp et al,65 7 patients were administered a suspension of feces from donor relatives or volunteers. Inclusion criteria required patients to have failed 2 antibiotic courses, one of which had to be tapered dosing of vancomycin. Patients were initially retreated with vancomycin for 4 days proceeded by intestinal lavage. Subsequently, 150 g of donor feces was mixed with 300 to 400 mL of normal saline and was administered into the jejunum by duodenal catheter or into the colon via a colonoscope. Five of the patients had a rapid return of normal bowel movements, whereas the remaining 2 required repeat treatment before responding.

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Summary of Fecal Bacteriotherapy for Relapsing Disease

Although the study by Nieuwdorp et al65 was limited by being merely a case series, the logistics of the analysis could be used as a guide for further study in patients with multiple recurrences of CDI. It must be remembered that the repeat administration of vancomycin could have confounded the positive response found. Given the lack of appeal of this treatment, however, the likelihood of a controlled trial is less likely.

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TREATMENT OPTIONS FOR REFRACTORY DISEASE

Antibiotics

As is the case with antibiotic studies for relapsing disease, little evidence exists to guide clinicians in disease that never responds to traditional therapy. A few case series and case reports are available. Herpers et al66 report 4 patients with severe CDI complicated by septic shock who responded to tigecycline. Three of the patients did not respond to initial treatment with metronidazole or vancomycin, but all 4 patients responded to treatment with tigecycline within a week of starting the antibiotic. Vancomycin was continued in one of the patients in combination with tigecycline. Another report boasts a similar outcome with tigecycline in a patient severely affected by CDI who also failed metronidazole and vancomycin.67 Metronidazole, like vancomycin in the previous report, was continued in this case with tigecycline.

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Immunotherapy

In contrast, preliminary evidence for pooled immunoglobulin does not seem as promising as the reports on tigecycline. A case series42 and a case report68 show mixed results with the use of IVIG after failure to respond to standard antibiotics.

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Summary of Treatment Options for Refractory Disease

As a result, although a case series design provides preliminary evidence for tigecycline in refractory CDI, similar quality evidence is inconclusive with regard to the use of IVIG. Firm conclusions on the treatment of refractory CDI await systematic study.

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PREVENTION OF INITIAL EPISODES OF CDI

Probiotics

For the prevention of CDI, researchers have turned to methods to bolster the normal flora presumed to be depleted by antibiotics. Although the end points in many of these trials have considered only prevention of antibiotic-associated diarrhea, some have specifically considered prevention of CDI.

In an analysis focusing on a mixed probiotic cocktail,69 a 100-g probiotic mixture of Lactobacillus casei, Lactobacillus bulgaricus, and Streptococcus thermophilus was administered orally to patients receiving antibiotics. Fewer patients in the cocktail group developed CDI than those in the placebo group (0% vs. 17%, P < 0.001). Criticisms of the trial are that it was limited to older adults (mean age = 74 years) and excluded patients taking antibiotics highly associated with CDI, such as clindamycin, cephalosporins, and aminopenicillins. In a similar analysis,70 a Lactobacillus species and a Bifidiobacterium species resulted in a trend for less CDI; however, this trial did not control for the inciting antibiotic. Another study using the same probiotic combination, however, found no benefit above placebo.71 In one of the best-designed studies on this topic,72 255 hospitalized patients on antibiotics were randomized in a double-blinded fashion to placebo, 100 billion colony-forming units (CFUs) of a combined Lactobacillus acidophilus and L. casei cocktail, or 50 CFUs of this cocktail. Both dosages of this cocktail resulted in significantly less episodes of CDI compared with placebo with the 100-billion-CFU dose outperforming the 50-billion-CFU dose. This analysis represents the first systematic attempt to evaluate probiotics as a function of the dose administered in the prevention of CDI.

Other studies have focused on using yeasts. Two small studies73,74 revealed disconcordant results for S. boulardii in the prophylaxis of CDI. The negative study suffered inadequate power, whereas the other demonstrated that S. boulardii was effective for prevention. These analyses, like some of the previous ones on lactobacilli, did not control for the inciting antibiotic.

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Summary of Probiotic Prevention Studies

To summarize, these studies on prevention showed mixed results and were difficult to compare because the probiotic used varied and dosages were not always specified. Furthermore, some were limited to elderly, and the inciting antibiotics given to the placebo and treatment groups were not always controlled. Most of the studies suffered inadequate power. The one study with adequate power and superior design both found a beneficial effect of a mixed probiotic cocktail in prevention of CDI and suggested the importance of dose as a moderating factor. Future study with trials with this degree of power and control for dose are needed to form conclusions (Table 4).

Table 4
Table 4
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CONCLUSIONS

C. difficile is becoming more common and more complicated to treat. Vancomycin and metronidazole remain the 2 antibiotics with the best evidence for successful treatment in initial episodes of CDI. Vancomycin seems to be a better choice for severely afflicted patients. Studies have identified markers, such as leukocytosis, albumin levels, and temperature elevation as indicators of severe disease and hence for potentially better response to vancomycin. However, disease severity and need for vancomycin remain clinical judgments. Although severe cases were not studied, higher doses of vancomycin seem no more effective than conventional doses. Newer antibiotics, such as nitazoxanide, are amassing positive findings as alternatives to vancomycin or metronidazole, whereas alternatives to antibiotics for initial CDI, such as probiotics and toxin-binding agents, seem inferior to antibiotics.

Although no antibiotic regimen seems to be optimal for relapsing disease, it seems that tapered and pulsed dosings of vancomycin are possibilities for preventing further relapse in this poorly studied area. Monoclonal antibodies offer a promising alternative to antibiotics for relapsing disease, although more research is needed to determine the role of probiotics in stopping relapses, particularly with better standardization of dosages and type of probiotic. Intravenous immunoglobulin seems largely ineffective for both initial and relapsing CDI. Fecal bacteriotherapy remains a nonpalatable treatment of relapses that will make performing a controlled study difficult. A case series design is the only evidence currently available for guiding the treatment of refractory CDI. As a result, more study is clearly needed to define the role of probiotics and immunotherapy in CDI and to further elucidate the appropriate treatment of relapsing and refractory CDI.

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ACKNOWLEDGMENTS

The authors thank Elizabeth Smigielski, MSEd, MSLS, Medical Librarian at Kornhauser Health Sciences Library, Louisville, KY, and Gene Haynes, MLS, Medical Librarian at Veterans Administration Medical Center, Louisville, KY, for assistance.

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Keywords:

Clostridium difficile; antibiotics; probiotics; toxin-binding agents; immunotherapy; fecal bacteriotherapy

© 2011 Lippincott Williams & Wilkins, Inc.

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