Clostridium difficile is an anaerobic, gram-positive, Treatment of Clostridium difficile-associated Disease. Epidemiology and Pathogenesis

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1 GASTROENTEROLOGY 2009;136: Treatment of Clostridium difficile-associated Disease Daniel A. Leffler J. Thomas Lamont Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts Clostridium difficile infection is an increasing burden to the health care system, totaling more than $1 billion/year in the United States. Treatment of patients with C difficile infection with metronidazole or vancomycin reduces morbidity and mortality, although the number of patients that do not respond to metronidazole is increasing. Despite initial response rates of greater than 90%, 15% 30% of patients have a relapse in symptoms after successful initial therapy, usually in the first few weeks after treatment is discontinued. Failure to develop specific antibody response has recently been identified as a critical factor in recurrence. The review discusses the different management strategies for initial and recurrent symptomatic C difficile infections. Clostridium difficile is an anaerobic, gram-positive, spore-forming, toxin-producing bacillus transmitted between human beings by the fecal oral route. This pathogen infects 20% of hospitalized patients taking antibiotics 1 and is an increasing burden to the health care system. Nosocomial C difficile infection has been estimated to more than quadruple the cost of otherwise matched hospitalizations, 2 totaling $1 billion/year in the United States. 3,4 The most important control measures are proper hand hygiene with the use of soap, water, and disposable gloves; isolation of infected patients; and limitation of unnecessary antibiotic use. Specific treatment of C difficile infection with metronidazole or vancomycin reduces morbidity and mortality. In general, metronidazole s high level of efficacy and low cost make it the initial treatment choice for nonpregnant adults. Vancomycin is reserved for individuals with severe infection and those who have failed or cannot take metronidazole therapy. C difficile is highly sensitive to both antibiotics in vitro, but treatment failures with metronidazole appear to be increasing. Despite initial response rates of 90%, 15% 30% of patients will experience a relapse in symptoms after successful initial therapy, usually in the first few weeks after treatment is discontinued. Recurrence may involve reinfection with the initial strain or a new strain. Failure to develop specific antibody response has recently been identified as a critical factor in recurrence. Management strategies for initial and recurrent symptomatic C difficile infection are described in detail below. Epidemiology and Pathogenesis Infection occurs when a susceptible host ingests C difficile spores, which then colonize the large bowel (Figure 1) and release 2 protein exotoxins that cause colitis and diarrhea. Healthy adults are protected from C difficile colonization and disease by normal bacterial flora and by antibody to toxin A. 1 Antibiotic therapy, bowel surgery, and rarely cancer chemotherapy change the indigenous colonic microflora, allowing C difficile to colonize in some patients. C difficile infection is most common in elderly hospitalized adults receiving either antibiotics or cancer chemotherapy. C difficile also colonizes 60% 70% of healthy newborns and infants up to months of age who lack the adult microflora. 5,6 However, infants rarely develop colitis even with large amounts of toxins in their stool. The infantile carrier state disappears at months of age, at about the same time that the normal adult flora becomes established. The lack of clinical response to toxin A in newborn animals was attributed to the lack of toxin-binding receptors. 7 The actual incidence of clinical C difficile infection in hospitalized patients varies widely with time and between locations; one recent study estimated an incidence of 1.5% in adults receiving perioperative antibiotic prophylaxis from 2003 to In the external environment, C difficile survives as heat-, acid-, and antibiotic-resistant spores. After ingestion and Abbreviations used in this paper: Ig, immunoglobulin; IVIG, intravenous immunoglobulin; MIC, minimal inhibitory concentration; VRE, vancomycin-resistant enterococci by the AGA Institute /09/$36.00 doi: /j.gastro

2 1900 LEFFLER AND LAMONT GASTROENTEROLOGY Vol. 136, No. 6 however, because spores are generally acid resistant, the importance of this is unclear. Although some studies have shown an increased risk of C difficile infection with acid suppression, 13,14 others have not confirmed this finding. 9,15 It has been suggested that acid suppression is associated with infection only as a marker of increased comorbidity. 16 Other important emerging risk factors for C difficile infection include white race 17 and inflammatory bowel disease in which C difficile is the most common superimposed infection Figure 1. Pathogenesis of C difficile infection. colonization, spores convert to vegetative forms in the large intestine which divide and produce toxins. Spores remain viable for months or longer in the hospital where they can be detected on bedding, hospital furniture, and equipment and on the skin, fingernails, and rings of patients and their caregivers. Risk Factors The most important risk factor for the development of C difficile infection is antibiotic use. Ampicillin or amoxicillin, cephalosporins, clindamycin, and fluoroquinolones are most frequently associated with disease, but almost all antibiotics, including metronidazole, have been associated with infection, although many show at least some in vitro activity against C difficile (Table 1). Hospitalization or residence in nursing homes or rehabilitation facilities are also main predisposing factors, 9 probably because of the increased concentration of spores from caregivers and infected patients. Advanced age also predisposes to risk of acquisition as well as severity of infection. 8 In one study individuals older than 65 years had a 10-fold higher risk of contracting C difficile during an outbreak than did younger patients. 10 The increasing incidence of hospital-acquired infection has been accompanied by increased reports of communityacquired infection. 11,12 The role of acid suppression in C difficile infection is unclear. In theory, reduction of gastric acid should allow more viable spores to reach the colon; Clinical Spectrum of C difficile Infection Two factors appear to influence clinical expression of disease: virulence of the infecting strain and the host immune response. In particular, infection with the highly virulent NAP1/027 strain characterized by fluoroquinolone resistance and higher levels of toxin production than conventional strains causes a 3-fold higher mortality rate than matched controls infected with less virulent strains. 10,22,23 Outbreaks with this and other epidemic strains in North America, Europe, and Asia are accompanied by dramatic increases in incidence and severity of infection. This has public health implications, because surveillance for epidemic strains may allow control measures to limit the spread and morbidity associated with these outbreaks. Although all strains show adequate in vitro sensitivity to metronidazole and vancomycin, reduced clinical response to metronidazole is emerging, perhaps relating to increasing minimal inhibitory concentration (MIC). The host immune response appears to develop in infancy. Infants that are asymptomatic carriers of toxigenic C difficile develop a lasting serum immune response to toxins A and B 6 (Figure 2). Moreover, mice infected with Table 1. Susceptibility of C difficile Isolates to Various Antibiotics Agent Median MIC 90 ( g/ml) Range ( g/ml) % Resistant Metronidazole Vancomycin Bacitracin NA Fusidic acid Rifampin Cefotaxime to Ceftriaxone to Meropenem Piperacillintazobactam 8 4 to Clarithromycin to Clindamycin to Ciprofloxacin to Levofloxacin Gatifloxacin to NOTE. Data from reference 27. NA, not applicable.

3 May 2009 TREATMENT OF CLOSTRIDIUM DIFFICILE INFECTION 1901 is suspected. However, they are not recommended for diagnosis because perforation may occur, and pseudomembranes may occur in only half of infected patients. 36 Colonoscopy is recommended because pseudomembranes may be limited to the right colon only. 37 Figure 2. Age-related prevalence of antibody to C difficile toxin A and B. Modified from Viscidi et al. 6 C difficile or vaccinated against the toxins are protected against subsequent infection. 28 In adult human beings, higher titers of serum immunoglobulin (Ig) G against toxin A appear to protect against C difficile induced diarrhea and promote the development of the asymptomatic carrier state. 1 Conversely, low levels of toxin A antibody, specifically, antitoxin A IgM and posttreatment antitoxin A IgG2 and IgG3, increase the risk of symptomatic C difficile recurrence Overview of Therapy Permanent cure of C difficile requires restoration of normal colonic microflora, resulting in the elimination of C difficile. Therefore, patients with mild symptoms can occasionally be managed conservatively by stopping administration of the inciting antibiotic and following them to confirm clinical improvement. In one early study of clindamycin-associated colitis, which in retrospect was probably C difficile colitis, all patients recovered after cessation of clindamycin administration, followed by supportive care. 32 Antibiotic treatment of C difficile aims to ameliorate symptoms while allowing gradual restoration of the normal gut flora (Table 2). It is also important to note that symptoms of C difficile infection are not specific and that confirmation of the diagnosis should be made with the use of assays for fecal toxin before specific therapy. Nonspecific antibiotic-associated diarrhea, postinfectious irritable bowel syndrome, new onset celiac disease or inflammatory bowel disease, or other infections, including Klebsiella oxytoca, Clostridium perfringens, and Staphylococcus aureus 33 all may be confused with C difficile associated disease. 34 The reported sensitivity and specificity of C difficile toxin assays varies from 0.83 to 0.95 and from 0.93 to 1.00, respectively. 35 In acutely ill patients with probable C difficile infection, treatment should be initiated while test results are pending and, in select cases, continued despite negative toxin assays. Sigmoidoscopy or colonoscopy may be helpful when another cause such as inflammatory bowel disease Antibiotic Treatment of Initial C difficile Infection Most patients with acute C difficile associated disease require antibiotic therapy and, whenever possible, discontinuation of the predisposing antibiotics. It is vital to assess disease severity based on clinical and demographic information, to determine the most appropriate treatment for each individual. Markers of severity include severe diarrhea, pseudomembranous colitis, ileus, fever because of C difficile, age older than 60 years, and acute renal failure (Table 2). In younger patients with mild symptoms, a reasonable approach is to stop the predisposing antibiotic and provide supportive care with hydration and close monitoring for deterioration. This approach is supported by data showing faster elimination of spores in carriers not given antibiotics, a finding that could have important consequences in limiting spread and recurrence. 38 For individuals with comorbidities and those with moderate-to-severe infection, specific antibiotic therapy aimed at C difficile is warranted. Although toxin-binding resins and probiotics are currently being studied, the only therapies confirmed to be effective are antibiotics and colectomy for patients with fulminant disease not responding to antibiotic therapy. Primarily because of its low cost, metronidazole is currently recommended as first-line therapy. The value of limiting vancomycin use to slow the emergence of vancomycin-resistant enterococci (VRE) is unclear because metronidazole has also been shown to select for VRE, 39,40 and VRE colonization rates appear similar in patients treated with vancomycin and metronidazole. 41 The standard initial therapy is 500 mg orally ( mg/kg in children) 3 times daily for 14 days, which successfully resolves symptoms in 90% of patients within 1 week. 42,43 Oral vancomycin is preferred if metronidazole has failed or is contraindicated. This approach is supported by professional society guidelines 44 and a recent Cochrane review. 45 However, metronidazole s apparent decreasing efficacy 46,47 (Figure 3) and slower response, compared with vancomycin, 43 has led to controversy about this recommendation. Moreover, recent data support the use of vancomycin as a first-line treatment in individuals with severe C difficile infection. 48,49 Although data are lacking, antidiarrheal agents and narcotics should be avoided in patients with symptomatic C difficile infection because of concerns about toxin retention and possible precipitation of toxic megacolon.

4 1902 LEFFLER AND LAMONT GASTROENTEROLOGY Vol. 136, No. 6 Table 2. Classification and Treatment of Initial C difficile Infection Severity Clinical manifestations Treatment Carrier No discernible clinical symptoms or signs No treatment is indicated Mild to moderate Mild diarrhea 12 stools/day Afebrile Mild-to-moderate abdominal discomfort or tenderness Nausea with rare or absent vomiting With or with hospitalization Not in intensive care unit Dehydration Leukocytosis 20,000 BUN or creatinine above baseline Discontinuation of predisposing antibiotics Hydration Monitor clinical status Isolation Consider probiotics Oral metronidazole 500 mg 3 times daily or intravenous metronidazole 500 mg 3 times daily if not tolerating oral intake Oral vancomycin 125 mg 4 times daily if intolerant of metronidazole Severe Fulminant BUN, blood urea nitrogen. Severe or bloody diarrhea 12 stools/day Pseudomembranous colitis Severe abdominal pain Nausea or vomiting Ileus Temperature 38.9 C Age 60 years in intensive care unit Leukocytosis 20,000 Albumin 2.5mg/dL Renal failure Toxic megacolon Peritonitis Albumin 2.5mg/dL Renal failure Respiratory distress Hemodynamic instability As above plus: Oral vancomycin 125 mg 4 times daily Consider addition of intravenous metronidazole 500 mg 3 times daily As above plus: Surgical consultation Oral vancomycin 125 mg 3 times daily and intravenous metronidazole 500 mg 3 times daily Consider IVIG Metronidazole Metronidazole is generally recommended as the first-line treatment of C difficile. Parenteral, oral, or rectal administration can be used in patients unable to take oral doses and leads to similar systemic and colonic tissue drug levels. Metronidazole, a nitroimidazole-class antibiotic and antiprotozoal, is administered and taken up in an inactive state by anaerobic organisms then reduced to its active form. It induces microbial cell death by DNA disruption and subsequent inhibition of nucleic acid synthesis. Metronidazole is most effective in anaerobic sites such as the human colonic lumen. In addition to its antimicrobial properties, metronidazole also appears to have anti-inflammatory, antioxidant, and immunomodulatory effects. 50,51 Oral absorption of metronidazole is highly efficient, with a serum half-life of 8 hours and bioavailability of Figure 3. Recent increase in reported treatment failures for metronidazole. Modified from Aslam et al. 46

5 May 2009 TREATMENT OF CLOSTRIDIUM DIFFICILE INFECTION %. Food may slow the rate, but not the overall extent, of absorption. Intravenous and oral administration results in distribution to all tissues and fluids, including the placenta and breast milk. Sixty to eighty percent of metronidazole is metabolized by the liver and subsequently cleared by the kidneys; the remaining unmetabolized metronidazole is excreted in feces, with similar amounts reaching the colon after oral and parenteral administration. Metronidazole preferentially diffuses from the serum and interstitial compartment of the inflamed colon into the lumen, a property that can increase its efficacy against C difficile. 52 Impaired renal function does not alter metronidazole pharmacokinetics, although the dose should be reduced in patients with severe liver disease. Side effects and toxicity. The most common side effects of metronidazole are metallic taste, headache, nausea, and a disulfiram-like effect with alcohol, although these symptoms rarely require cessation of treatment. The neurotoxic effects of metronidazole include peripheral neuropathy, vertigo, and, rarely, ataxia or encephalopathy. Fortunately, neuropathy is seldom observed in patients who receive 2 weeks of therapy, and most cases have occurred after exposure to standard doses for 1 month Treatment with metronidazole should be immediately discontinued if there is concern about neurotoxicity, which may not be reversible. Metronidazole is rated pregnancy class B, but it should not be given in the first trimester, because of concerns of teratogenicity based on animal data. Activity. Metronidazole is highly active against most strains of pathogenic C difficile with only rare reports of antibiotic resistance Although MIC was shown to differ between strains, MIC remains below in vivo therapeutic levels in nearly all isolates. 26,59,60 Increasing evidence suggests, that prolonged exposure to metronidazole can lead to resistance 61 and that susceptibility decreases over time. 48,62,63 For this reason, surveillance of antibiotic resistance in C difficile is ongoing and resistance could limit the use of this antibiotic in the future. Vancomycin Vancomycin, a tricyclic glycopeptide that inhibits bacterial cell wall synthesis, 64 has broad activity against gram-positive bacteria, but it essentially has no effect on gram-negative bacteria or fungi. Vancomycin is orally administered in its active form and, because o f its large molecular weight, is not absorbed and reaches the colon intact, an advantage for the treatment of C difficile. Conversely, parenteral vancomycin is not excreted into the colonic lumen and, for this reason, is not effective for treatment of C difficile. However, ileus may result in unpredictable delivery of vancomycin to the colon. In these patients the drug may be delivered by rectal or colonic tube or by enemas. Although the initially recommended dose used to treat C difficile was 500 mg 4 times daily, 125 Figure 4. Equivalent response of low and high dose vancomycin. (Modified with permission from Fekety et al. 42 ) mg 4 times daily also results in concentrations in the colon well above the MIC for C difficile, with identical clinical outcomes (Figure 4). 42 Side effects and toxicity. Because vancomycin is not absorbed systemically from the gastrointestinal tract, reported side effects observed during parenteral administration, including ototoxicity, nephrotoxicity, and Red- Man syndrome, are avoided. 64 Mild upset stomach and nausea are the most common side effects of oral vancomycin and rarely limit treatment. Although systemic vancomycin is classified as pregnancy class C, oral vancomycin is the agent of choice for C difficile infection during pregnancy. Activity. Vancomycin is highly active against all strains of pathogenic C difficile, and resistance has been reported in only a single study 65 (Table 1). Vancomycin is recommended as first-line therapy in pregnant women, in children younger than 10 years of age, and for severe infections. Regimen. Initial treatment and treatment of a first recurrence should be for days. Although there does not appear to be any benefit of vancomycin compared with metronidazole in treating mild-to-moderate C difficile infection, some evidence suggests that outcomes are improved with the use of vancomycin for severe disease 48 (Figure 5). Vancomycin enemas can be given when oral administration is not possible; colonoscopic decompression with vancomycin lavage was described in one report. 66

6 1904 LEFFLER AND LAMONT GASTROENTEROLOGY Vol. 136, No. 6 Figure 5. Vancomycin is more effective than metronidazole for severe C difficile infection. Modified with permission from Zar et al. 48 Other Treatments Although metronidazole and vancomycin are the mainstays of therapy for symptomatic infection, several other agents (Table 4) are used or under investigation for C difficile, either as stand-alone treatments or as adjunctive agents. Alternative Antibiotics Rifaximin is a nonabsorbed antibiotic similar to rifampin that inhibits bacterial RNA synthesis. The lack of systemic absorption gives rifaximin a favorable safety profile, especially in cases requiring prolonged treatment. Animal data 67 and human studies suggest efficacy in both initial and recurrent C difficile infection, but widespread use of this agent for C difficile is likely to be limited by the appearance of resistant strains. 68,72 Rifaximin is designated pregnancy class C. Nitazoxanide is a synthetic antiparasitic and antibiotic that appears to interfere with enzyme-dependent electron transfer and has activity against many anaerobic and microaerophilic bacteria. Side effects are mild and are similar to placebo. Studies have shown in vitro and clinical efficacy of nitazoxanide against C difficile, 25,73 76 and recent studies have reported non-inferiority compared with both metronidazole 74 and vancomycin. 77 Nitazoxanide is currently approved only for use in Giardia intestinalis and cryptosporidium infection in children. Nitazoxanide is designated pregnancy class B. Bacitracin is an inhibitor of cell wall synthesis derived from Bacillus subtilis. In general, this agent is less effective than vancomycin, and clearance of viable spores from the stool occurs in a significantly lower percentage of individuals treated with bacitracin Bacitracin is more expensive than metronidazole and currently only available in topical formulations; it is not recommended for treatment of C difficile infections. Ramoplanin is a novel glycolipodepsipeptide antibiotic with broad activity against C difficile, S. aureus, and vancomycin-resistant enterococci, by inhibiting peptidoglycan synthesis. A phase 2 study reported similar efficacy to vancomycin in patients with mild-to-moderate C difficile infection. 82 Ramoplanin is currently being tested in phase 3 trials for VRE, and further studies are planned for C difficile. Teicoplanin is similar to vancomycin in structure, mode of action, and antibacterial activity. Small studies of teicoplanin report a benefit compared with vancomycin, 45 although it is not yet approved for use in the United States. Oritavancin is another vancomycin analog currently under review by the Food and Drug Administration. Early data suggest that, unlike vancomycin, oritavancin has activity against C difficile spores, a trait which may be important in preventing relapse. 83 Rifampin has also been studied for treatment of C difficile infection either alone or with metronidazole. Use of rifampin has fallen from favor after a recent study reported increased mortality in patients treated with metronidazole and rifampin compared with metronidazole alone. 84 Treatment of Acute Fulminant Infection Despite the efficacy of antibiotic treatment, acute C difficile infection remains a disease that has a high rate of morbidity with an estimated case fatality rate of 2%. 85 Severe C difficile colitis tends to occur during the initial infection or first recurrence. Patients with risk factors such as advanced age, significant comorbidities, high peak white blood cell count, and lactate acidemia are at increased risk of death and should be followed closely. Importantly, diarrhea may be absent in cases of severe C difficile infection with toxic megacolon, and a high index of suspicion must be kept in these situations to prevent delay in therapy. Hemodynamic instability is consistently associated with high rates of mortality. 86,87 Unfortunately, the interval between presentation and hemodynamic collapse can be short and unpredictable, with a mean of 9 days in one study 88 but a range of 0 to 30 days. Patients with fulminant disease should be treated with both oral vancomycin and intravenous metronidazole despite a lack of evidence from clinical trials about combination therapy. If oral administration of medications is

7 May 2009 TREATMENT OF CLOSTRIDIUM DIFFICILE INFECTION 1905 not possible because of ileus, parenteral metronidazole can be supplemented with vancomycin enemas. Close monitoring of clinical status is vital, and, for patients who fail to respond to antibiotics or who have deteriorating hemodynamics, respiratory status or renal function, urgent surgical intervention may be required. Patients who are not good candidates for surgery can be given doses of pooled human immunoglobulin ( mg/kg/day) until they improve, although evidence to support efficacy of this therapy is anecdotal. For patients with fulminant disease and severe ileus, toxic megacolon, or localizing peritoneal signs, emergent subtotal colectomy and ileostomy is generally required; postoperative mortality rates range from 35% to 80%. Randomized trials evaluating the timing or type of surgical procedure for severe C difficile infection are unavailable; however, observational studies suggest that survival is improved with prompt surgical intervention in patients with severe or fulminant infection. 86,87,89 93 Subtotal colectomy is the procedure of choice because reports of hemicolectomy suggest increased mortality. 91 Treatment of Recurrent C difficile Infection After successful initial therapy, approximately 15% 30% of patients experience a symptomatic recurrence after discontinuation of antibiotics. 30, Older patients and those with a history of prior C difficile recurrence are at an even higher risk ( 50%) for recurrent disease. 47,101 Most recurrences happen within 2 weeks of stopping therapy, but delayed recurrences have been documented. 95,100 Approximately half of recurrent C difficile infections are caused by repeated ingestion of bacteria (reinfection) before the normal intestinal flora recovers, and half are attributed to incomplete eradication of the original strain during antibiotic treatment (relapse) The first recurrence can be treated with the same antibiotic, for example a 14-day course of metronidazole (if tolerated) or with supportive care alone, if symptoms are mild. Unfortunately, a significant rate of further episodes follows a first recurrence ( 65%, in one study 96 ). Management strategies for recurrent C difficile infection include repeat courses of metronidazole or vancomycin, tapered and pulsed dosing of vancomycin, toxin-binding agents such as cholestyramine, probiotics such as Saccharomyces boulardii, and immunotherapy, but none are supported by randomized large clinical trials 4,34,95,96,100, (Tables 3 and 4). For patients who experience 2 recurrences of symptomatic C difficile infection, a change in strategy is warranted. Before starting antibiotic therapy, the diagnosis of recurrent C difficile infection should be confirmed by stool assay, because other causes, including postinfectious irritable bowel syndrome, have similar presentations. For confirmed recurrent C difficile infection, we recommend a 6-week pulsed-tapered course of oral vancomycin therapy (Table 3). During continuous antibiotic Table 3. Treatment of Recurrent C difficile Infection Initial recurrence 14-day course of oral metronidazole or vancomycin Consider probiotics Second Recurrence Tapered pulse dose oral vancomycin 125 mg 4 times daily for 1 week 125 mg twice daily for 1 week 125 mg daily for 1 week 125 mg every other day for 1 week 125 mg every third day for 2 weeks Consider 1-month course of probiotics starting in the final 2 weeks of antibiotic therapy Third or subsequent recurrence Tapered pulse dose oral vancomycin (see above) Followed by 14-day course of rifaximin, nitazoxanide, or toxin-binding resins Consider 1-month course of probiotics starting in the final 2 weeks of antibiotic therapy Consider intravenous immunoglobulin or fecal bacteriotherapy Consider chronic low-dose suppressive therapy with oral vancomycin for elderly patients and those with multiple comorbidities therapy C difficile persists in the bowel lumen as antibiotic-resistant spores. 106,107 Pulsed doses of antibiotics may allow spores to germinate into antibiotic-sensitive vegetative forms, which are then killed on the next day of antibiotic therapy. Pulsing may also allow restoration of normal colonic flora while conferring adequate protection against C difficile. Metronidazole is generally not recommended for long-term therapy, because of the risk of peripheral neuropathy, particularly in older patients. Probiotics or toxin-binding resins 107 may provide additional benefit when added in the later weeks of the antibiotic taper and continued for 4 6 weeks after antibiotic therapy is stopped. A more recent strategy reported for treatment of multiply-recurrent C difficile infections is the addition of a 2-week course of rifaximin ( mg daily) in 2 or 3 divided doses for 2 weeks, immediately after days of vancomycin therapy while the patient is still in clinical remission. 68 Seven of 8 patients with a minimum of 4 prior recurrent episodes treated in this manner had no further recurrences. Despite these treatment strategies, some patients still have repeat bouts of C difficile infection, after multiple attempts at eradication. For infirm or elderly patients, we sometimes recommend chronic vancomycin therapy at the lowest effective dose, usually 125 mg daily or every other day for an indefinite period. Immunotherapy or fecal bacteriotherapy, described below, are other options in younger patients or if recurrences are particularly severe. Toxin-Binding Resins C difficile toxins in the colonic lumen lead to clinical disease, but the bacteria itself is not invasive and does not cause tissue damage. This observation prompted

8 1906 LEFFLER AND LAMONT GASTROENTEROLOGY Vol. 136, No. 6 Table 4. Treatment Options for C difficile Infection Treatment Regimen Comments Metronidazole mg 3 times daily or 4 times daily by mouth or intravenously First-line therapy or in combination with vancomycin in severe disease Vancomycin mg 3 times daily or 4 times daily First-line therapy for severe disease by mouth Rifaximin mg twice daily or 3 times daily by Adjunctive in recurrent C difficile infection mouth Binding resins; cholestyramine preferred over colestipol 4 g 3 times daily or 4 times daily Adjunctive with antibiotics; must be taken 2 hours apart from vancomycin Nitazoxanide 500 mg twice daily by mouth Adjunctive in recurrent C difficile infection Immunoglobulin mg/kg daily until resolution or maximum of 6 doses Adjunctive with antibiotics in severe refractory or recurrent C difficile infection Probiotics Variable oral dosing Adjunctive with antibiotics for treatment or prevention of recurrent C difficile infection Surgery Subtotal colectomy with ileostomy Early surgical consultation recommended in severe disease research into the efficacy of compounds that bind and sequester C difficile toxin but do not alter the intestinal flora or lead to antibiotic resistance. Unfortunately, initial studies with the bile acid binding resins colestipol and cholestyramine were disappointing, with response rates in patients with acute infection of 36% and 68%, respectively These findings largely relegated the use of binding resins to adjunct therapy of patients who fail to respond to antibiotics or those with mild disease that do not tolerate or need antibiotics. Later studies determined that the binding affinity of cholestyramine to C difficile toxin was substantially greater than that of colestipol 119 ; these findings suggest that higher affinity binding agents might be more effective. Tolevamer, a nonabsorbed anionic polymer, was developed specifically as a high-affinity binder of C difficile toxins. Studies in animals showed that tolevamer was superior to metronidazole in reducing acute C difficile infection. 120 A phase 2 study reported efficacy in patients with mild-to-moderate C difficile infections that was similar to that of vancomycin with a trend toward lower rates of recurrence in the group given tolevamer. 121 However a larger phase 3 study suggested that tolevamer was inferior to vancomycin. 49 Investigations into other formulations of tolevamer are underway. 122 Immunotherapy The association between low serum levels of IgG antitoxin A and increased disease severity 1,30,31 suggests that bolstering the immune response to C difficile toxins might prevent or ameliorate disease in patients. Animal models support this concept; passive immunization has been shown to substantially improve outcome 123,124 and to reduce C difficile colonization rates. 125 Currently intravenous immunoglobulin (IVIG) is the only available therapeutic option. Randomized clinical trials are not available, but case reports suggest efficacy of IVIG in patients with either recurrent or severe acute disease Two small studies reported IVIG treatment for recurrent C difficile infection with response rates of 100% in children 114 and 60% in adults. 115 In the typical regimen, patients were given mg IVIG/kg/day (1 and 5 total doses); a clinical response occurred in most patients within 1 week. In another small series, IVIG provided no benefit in acute disease. 126 In addition to issues of expense and availability, side effects of IVIG are common and include infusion reactions, hemolytic anemia, neutropenia, anaphylaxis, renal toxicity, and aseptic meningitis. We reserve the use of IVIG for patients with multiple moderate-to-severe recurrences of C difficile who have failed vancomycin taper therapy at least twice, in combination with probiotics and toxin-binding resins or rifaximin. Active vaccination of animals against C difficile toxins has been successful in preventing infection and death from C difficile. 127,128 Phase 1 trials have shown that intramuscular injection of C difficile toxoid vaccine is safe and immunogenic in healthy volunteers, inducing robust serum IgG antitoxin and fecal IgA antitoxin production. 129,130 A small case series suggested efficacy of therapeutic vaccination in adults with multiply recurrent disease. 131 Microbiologic Therapy The critical factor in C difficile pathogenesis is antibiotic-induced reduction of colonization resistance, provided by the normal colonic microflora, which allows C difficile to have a selective advantage. For this reason, active reconstitution of the normal colonic flora is theoretically attractive for prevention and treatment. Several reports have documented the efficacy of stool transplants, delivered by enema or gastric tube, from a healthy donor to patients with recurrent 132,133 or acute 134 C difficile infection. Inadvertent spread of pathogenic microorganisms from donor to host as well as distaste by patients and physicians have limited the use of this technique.

9 May 2009 TREATMENT OF CLOSTRIDIUM DIFFICILE INFECTION 1907 Oral administration of nontoxigenic strains of C difficile to compete with and limit the growth of toxin-producing strains was reported to lead to remission of recurrent C difficile infection in 2 patients, 135 and studies are underway to characterize a strain that is suitable for larger trials. 136 Probiotic Therapy Probiotics are commonly used for prevention and treatment of infectious diarrhea. 137,138 Organisms studied in C difficile include Saccharomyces boulardii, Lactobacillus rhamnosus GG, Lactobacillus plantarum, Lactobacillus acidophilus, and Bifidobacterium bifidum. Most studies to date have focused on the prevention of antibiotic-associated diarrhea and C difficile infection. A recent meta-analysis reviewed 31 studies of various probiotics for C difficile diarrhea (25 studied prevention of disease). 139 This analysis found that prophylactic probiotics significantly reduced the subsequent incidence of acute C difficile diarrhea (relative risk [RR], 0.43; P.001). A smaller number of studies have evaluated the efficacy of probiotics for treatment of C difficile diarrhea and prevention of recurrence. Although no individual study reduced recurrence, in aggregate, a significant therapeutic benefit of probiotics was reported (RR, 0.59; P.005). 139 In contrast, a recent Cochrane Review found only 4 studies of sufficient quality for inclusion and suggested a modest benefit of Saccharomyces boulardii in both prevention of recurrence and cessation of diarrhea as an adjunct to antibiotics. Lactobacillus rhamnosus GG and Lactobacillus plantarum did not appear to provide any benefit. This Cochrane Review concluded that evidence is insufficient to recommend probiotic therapy as an adjunct to antibiotic therapy and that no evidence supports the use of probiotics alone in the treatment of C difficile diarrhea. 140 Other studies not included in this meta-analysis have been published, 141,142 with some studies reporting benefit, while others found no difference. Despite these discrepant results, probiotics remain a safe and reasonable option for prevention of initial infections and possibly for treatment of recurrent infections. Animal studies are underway to optimize the type and dose of organisms and to explore the mechanisms of action. 136, Prevention As with any disease, C difficile is better managed by prevention than by cure (Table 5). Appropriate use of antibiotics, especially broad-spectrum agents and those shown to have a particular predisposition to cause C difficile infections, will continue to be the cornerstone of disease control for the foreseeable future. Several studies have shown that antibiotic prescription guidelines reduce C difficile infection rates by approximately 50% Although community-acquired C difficile infection has been increasingly reported, 11,153 the main nidus of C Table 5. Guidelines for the Prevention of C difficile Infection Individual patient Limit antibiotics Institution Hand washing after all patient contact Isolation for patients known to be infected with C difficile Use of gloves and gowns when in contact with patients known or suspected to be infected with C difficile Disinfect contaminated objects with appropriate agents, including sodium hypochlorite, glutaraldehyde, or ethylene oxide Regional Educate medical staff and at-risk populations about C difficile difficile remains hospitals and nursing facilities. 34, Viable C difficile spores are widespread in the hospital environment 155,156, and are spread by asymptomatic carriers and hospital personnel, giving rise to hospital outbreaks and geographic clustering in specific wards. 155,156,161 The use of alcohol wipes or solutions to clean hands and equipment after patient contact is ineffective against C difficile spores. Only the use of disposable gloves, gowns, and hand washing with chlorhexidine gluconate containing soap have been documented to reduce the spread of C difficile by health care workers. 164,165 Decontamination of rooms and equipment with the use of sporicidal agents such as sodium hypochlorite, ethylene oxide, and alkaline glutaraldehyde is recommended. 34 Treatment of known carriers with vancomycin is not effective. 38 Combination of tactics that include education, increased case finding, expanded infection-control measures, a C difficile infection management team, and stringent antimicrobial guidelines has been shown to reduce the spread of C difficile and to improve outcomes. 166 Conclusions C difficile prevention requires avoidance of inappropriate antibiotic use, combined with proper hand hygiene by medical staff and surveillance and prompt isolation of new cases of C difficile infection. For infected individuals, treatment should be individualized and based on severity of symptoms and whether symptomatic disease is primary or recurrent. For most patients with active symptoms, metronidazole is the treatment of choice for initial infection and first or second recurrence, because of cost concerns. For patients with severe disease or multiple recurrences, vancomycin is recommended. Surgical consultation is warranted early in the course of suspected fulminant disease. The roles of other antibiotics, probiotics, binding resins, and vaccination hold great promise for future management. References 1. Kyne L, Warny M, Qamar A, Kelly CP. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med 2000;342:

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