Recurrent Clostridium Difficile
2006; Elsevier BV; Volume: 130; Issue: 4 Linguagem: Inglês
10.1053/j.gastro.2006.02.044
ISSN1528-0012
AutoresSeema Maroo, J. Thomas LaMont,
Tópico(s)Gastrointestinal motility and disorders
ResumoA 52-year-old woman recently was diagnosed with C difficile diarrhea after taking a course of antibiotics for an upper respiratory tract infection. She was treated with metronidazole, and her diarrhea resolved. However, 2 weeks later, she developed loose, nonbloody stools approximately 6 times a day. A stool toxin assay was again positive for C difficile and she was treated with metronidazole for 14 days with resolution of her diarrhea. However, 10 days later she again developed nonbloody diarrhea. She has no fevers. The patient has a history of hypertension for which she takes a diuretic. C difficile-associated diarrhea is a common nosocomial disease with substantial morbidity and mortality. Even though most patients respond initially to withdrawal of offending antibiotics and therapy with either metronidazole or vancomycin, about 15%–30% of patients will experience a recurrence of diarrhea in association with a positive stool test for C difficile toxin.1Kelly C.P. Pothoulakis C. LaMont J.T. Clostridium difficile colitis.N Engl J Med. 1994; 330: 257-262Crossref PubMed Scopus (1074) Google Scholar, 2Fekety R. American College of GastroenterologyPractice Parameters CommitteeGuidelines for the diagnosis and management of Clostridium difficile–associated diarrhea and colitis.Am J Gastroenterol. 1997; 92: 739-750PubMed Google Scholar, 3Tedesco F.J. Gordon D. Fortson W.C. Approach to patients with multiple relapses of antibiotic-associated pseudomembranous colitis.Am J Gastroenterol. 1985; 80: 867-868PubMed Google Scholar, 4Bartlett J.G. Tedesco F.J. Shull S. Lowe B. Chang T. Symptomatic relapse after oral vancomycin therapy of antibiotic-associated pseudomembranous colitis.Gastroenterology. 1980; 78: 431-434PubMed Scopus (127) Google Scholar, 5McFarland L.V. Surawicz C.M. Greenberg R.N. Fekety R. Elmer G.W. Moyer K.A. Melcher S.A. Bowen K.E. Cox J.L. Noorani Z. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease.JAMA. 1994; 271: 1913-1918Crossref PubMed Scopus (786) Google Scholar, 6Wenisch C. Parschalk B. Hasenhundle M. Hirschl A. Graninger W. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea.Clin Infect Dis. 1996; 22: 813-818Crossref PubMed Scopus (436) Google Scholar, 7McFarland L.V. Surawicz C.M. Rubin M. Fekety R. Elmer G.W. Greenberg R.N. Recurrent Clostridium difficile disease epidemiology and clinical characteristics.Infect Control Hosp Epidemiol. 1999; 20: 43-50Crossref PubMed Scopus (302) Google Scholar, 8Kyne L. Kelly C.P. Recurrent Clostridium difficile diarrhea.Gut. 2001; 49: 152-153Crossref PubMed Scopus (83) Google Scholar Some patients experience from 3 to even 10 or more relapses and may require repeat courses of vancomycin or metronidazole, anion-binding agents, probiotics, and immunotherapy or combinations of these measures. The large variety of management options for recurrent infection reflects the fact that no treatment scheme is universally successful, and that many of the recommendations are not strongly evidence based. The clinical manifestations of recurrent C difficile are the same as those of the initial episode: diarrhea, abdominal pain, and fever, and successive recurrences generally do not become more severe. As described in the case history, recurrences usually occur within 2–10 days after cessation of antibiotic therapy, but late recurrences from 2 weeks to as late as 2 months after discontinuation of antibiotics have been reported.9Fekety R. McFarland L.V. Surawicz C.M. Greenberg R.N. Elmer G.W. Mulligan M.E. Recurrent Clostridium difficile diarrhea characteristics of and risk factors for patients enrolled in a prospective, randomized, double-blinded trial.Clin Infect Dis. 1997; 24: 324-333Crossref PubMed Scopus (324) Google Scholar A firm diagnosis of recurrence implies that symptoms of the initial infection have completely resolved on appropriate therapy, and that other potential causes of diarrhea have been excluded. Diagnosis should be confirmed with a stool toxin assay; however, if symptoms are severe and typical, presumptive therapy with metronidazole or vancomycin can be initiated, while awaiting assay results. Colonoscopy with mucosal biopsy and abdominal CT scanning may provide additional information, but are seldom required except in atypical or urgent presentations. The pathogenesis of C difficile colitis involves disturbance of the normal colonic microflora from antibiotic exposure, intestinal colonization by a toxigenic strain of C difficile, release of toxins A and B into the colonic lumen, and toxin-mediated colitis and diarrhea.1Kelly C.P. Pothoulakis C. LaMont J.T. Clostridium difficile colitis.N Engl J Med. 1994; 330: 257-262Crossref PubMed Scopus (1074) Google Scholar Pathogenic strains of C difficile produce 2 structurally similar protein exotoxins, A and B, which cause all the signs and symptoms of this infection. Toxin A elicits an intense inflammatory diarrhea when injected into the intestinal lumen of animals and also possesses cytotoxic activity against cultured cells.10Triadafilopoulos G. Pothoulakis C. Weiss R. Giampaolo C. Lamont J.T. Comparative study of Clostridum difficile toxin A and cholera toxin in rabbit ileum. Role of prostaglandins and leukotrienes.Gastroenterology. 1989; 97: 1186-1192Abstract PubMed Scopus (78) Google Scholar Although toxin B has no enterotoxic activity in animals, it also causes intestinal injury in human colonic explants in vitro11Riegler M. Sedivy R. Pothoulakis C. Hamilton G. Zacherl J. Bischof G. Cosentini E. Feil W. Schiessel R. LaMont J.T. Clostridium difficile toxin B is more potent than toxin A in damaging human colonic epithelium in vitro.J Clin Invest. 1995; 95: 2004-2011Crossref PubMed Scopus (277) Google Scholar and in human intestinal xenografts transplanted into immunodeficient mice.12Savidge T.C. Pan W.H. Newman P. O'Brien M. Anton P.M. Pothoulakis C. Clostridium difficile toxin B is an inflammatory enterotoxin in human intestine.Gastroenterology. 2003; 125: 413-420Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar Recurrent C difficile infection is not related to microbial resistance to metronidazole or vancomycin. Bartlett et al found no evidence of vancomycin resistance in 20 patients with recurrence following successful oral vancomycin therapy4Bartlett J.G. Tedesco F.J. Shull S. Lowe B. Chang T. Symptomatic relapse after oral vancomycin therapy of antibiotic-associated pseudomembranous colitis.Gastroenterology. 1980; 78: 431-434PubMed Scopus (127) Google Scholar and to date no human strains have demonstrated significant in vitro resistance. Recurrence results from reinfection with the same or a different strain of C difficile from the environment.13Walters B.A. Roberts R. Stafford R. Seneviratne E. Relapse of antibiotic associated colitis endogenous persistence of Clostridium difficile during vancomycin therapy.Gut. 1983; 24: 206-212Crossref PubMed Scopus (94) Google Scholar, 14Young G. McDonald M. Antibiotic-associated colitis Why do patients relapse?.Gastroenterology. 1986; 90: 1098PubMed Google Scholar For example, using bacteriologic typing techniques, Wilcox et al reported that 56% of clinical recurrences were caused by a different strain of C difficile than the initial infecting strain.15Wilcox M.H. Fawley W.N. Settle C.D. Davidson A. Recurrence of symptoms in Clostridium difficile infection–relapse or reinfection?.J Hosp Infect. 1998; 38: 93-100Abstract Full Text PDF PubMed Scopus (164) Google Scholar Some investigators initially suggested that the persistence of C difficile in stools during successful vancomycin therapy may be associated with risk of recurrence,13Walters B.A. Roberts R. Stafford R. Seneviratne E. Relapse of antibiotic associated colitis endogenous persistence of Clostridium difficile during vancomycin therapy.Gut. 1983; 24: 206-212Crossref PubMed Scopus (94) Google Scholar but C difficile can also be cultured from stool of patients who have successfully completed antibiotic therapy and who do not relapse.16Issack M.I. Elliott T.S. Clostridium difficile carriage after infection.Lancet. 1990; 335: 610-611Abstract PubMed Scopus (13) Google Scholar The mechanism of persistent carriage of the pathogen during and after successful therapy is incompletely understood, but one hypothesis is that C difficile forms antibiotic-resistant spores during antibiotic therapy. The finding of colonic diverticula in 18 of 22 patients with recurrence raised the possibility that spores might survive in diverticula and emerge after antibiotics were stopped.3Tedesco F.J. Gordon D. Fortson W.C. Approach to patients with multiple relapses of antibiotic-associated pseudomembranous colitis.Am J Gastroenterol. 1985; 80: 867-868PubMed Google Scholar However, recurrence is more likely a result of reinfection from the external environment through the fecal-oral route,15Wilcox M.H. Fawley W.N. Settle C.D. Davidson A. Recurrence of symptoms in Clostridium difficile infection–relapse or reinfection?.J Hosp Infect. 1998; 38: 93-100Abstract Full Text PDF PubMed Scopus (164) Google Scholar as occurs in intial infection with this organism. Recent evidence indicates that the host immune response to C difficile toxin A is a major determinant of clinical outcome following colonization.16Issack M.I. Elliott T.S. Clostridium difficile carriage after infection.Lancet. 1990; 335: 610-611Abstract PubMed Scopus (13) Google Scholar, 17Kyne L. Warny M. Qamar A. Kelly C.P. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A.N Engl J Med. 2000; 342: 390-397Crossref PubMed Scopus (800) Google Scholar, 18Leung D.Y. Kelly C.P. Boguniewicz M. Pothoulakis C. Lamont J.T. Flores A. Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin.J Pediatr. 1991; 118: 633-637Abstract Full Text PDF PubMed Scopus (255) Google Scholar, 19Warny M. Vaerman J.P. Avesani V. Delmee M. Human antibody response to Clostridium difficile toxin A in relation to clinical course of infection.Infect Immun. 1994; 62: 384-389Crossref PubMed Google Scholar, 20Kyne L. Warny M. Qamar A. Kelly C.P. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea.Lancet. 2001; 357: 189-193Abstract Full Text Full Text PDF PubMed Scopus (681) Google Scholar Although many infants are colonized with toxigenic C difficile during the first year of life, they rarely develop C difficile–associated diarrhea. One possible explanation for the infantile carrier state would be that the infant intestine lacks specific toxin-binding receptors, as has been demonstrated in rabbits.21Eglow R. Pothoulakis C. Itzkowitz S. Israel E.J. O'Keane C. Gong D. Gao N. Xu Y.L. Walker W.A. Lamont J.T. Diminished Clostridium difficile toxin A sensitivity in newborn rabbit ileum is associated with decreased toxin A receptor.J Clin Invest. 1992; 90: 822-829Crossref PubMed Scopus (151) Google Scholar Antibodies to C difficile toxins develop in the first year of life, and approximately 60% of the healthy, adult population will have detectable serum (IgG) and intestinal secretory (IgA) immunoglobulins to toxins A and B.22Viscidi R. Laughon B.E. Yolken R. Bo-Linn P. Moench T. Ryder R.W. Bartlett J.G. Serum antibody response to toxins A and B of Clostridium difficile.J Infect Dis. 1983; 148: 93-100Crossref PubMed Scopus (155) Google Scholar Kyne et al17Kyne L. Warny M. Qamar A. Kelly C.P. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A.N Engl J Med. 2000; 342: 390-397Crossref PubMed Scopus (800) Google Scholar observed that at the time of hospital admission patients with higher levels of serum IgG against toxin A, but not antibodies against toxin B or other C difficile antigens, were protected against diarrhea and colitis and usually became asymptomatic carriers (Figure 1). This suggests that prior exposure to C difficile during the infantile carrier state elicits a durable serum antitoxin response that protects against C difficile diarrhea later in life. Importantly, antitoxin antibodies protected against diarrhea but not against colonization by this pathogen, a process, which remains poorly understood. In a follow-up study of the same cohort of hospital patients, Kyne et al20Kyne L. Warny M. Qamar A. Kelly C.P. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea.Lancet. 2001; 357: 189-193Abstract Full Text Full Text PDF PubMed Scopus (681) Google Scholar also observed that those with an acute infection who developed an appropriate serum immune response to toxin A were much less likely to develop recurrent C difficile when antibiotics were stopped. Conversely, those who failed to mount a primary immune response were likely to relapse after discontinuation of metronidazole or vancomycin. In a univariate analysis of potential factors associated with relapsing infection, the authors also identified age, disease comorbidity, and additional exposure to antibiotics during the follow up period. In summary, the serum immune response to toxin A, established either in infancy or following acute infection later in life, is a major determinant of recurrence following acute C difficile colitis. It is not yet clear why some patients are plagued with multiple recurrences of C difficile infection, but the most likely explanation, based on the data outlined above, is that they fail to mount a serum IgG antitoxin A response. This lack of response is not related to a specific immune deficiency syndrome but is more likely attributed to age, impaired nutrition, or multiple comorbidities, all of which can impair immune responses to infection. As with an initial episode of C difficile diarrhea, the first step in managing suspected recurrence is to discontinue, if possible, any inciting antibiotics and to confirm the diagnosis with a stool toxin assay. If symptoms are mild and the patient is otherwise healthy, an attempt can be made to manage symptoms conservatively with supportive management and without antibiotics. This simple approach allows the colonic microflora to recover and restores its normal barrier function that prevents C difficile colonization. One might consider this conservative management approach in a patient who is not elderly or infirm and has no significant comorbidity that would put her at high risk. However, most elderly or debilitated patients with moderate or severe symptoms require antibiotic treatment for recurrent infection. Recurrences are treated with a second course of the same antibiotic used to treat the initial episode, usually for 14 days (Table 1). After one recurrence, patients appear to be at significant risk for subsequent recurrences. For example, patients with at least one prior recurrence had a subsequent recurrence rate of greater than 65% after discontinuation of standard antibiotic therapy with vancomycin or metronidazole.23McFarland L.V. Elmer G.W. Surawicz C.M. Breaking the cycle treatment strategies for 163 cases of recurrent Clostridium difficile disease.Am J Gastroenterol. 2002; 97: 1769-1775Crossref PubMed Google ScholarTable 1Management of Recurrent Clostridium difficileInitial recurrenceConfirm diagnosis with stool toxin essayWithhold antibiotics if symptoms are mild14 day course of metronidazole 250 tid or vancomycin 250 tidSecond recurrenceTapered-pulsed Vancomycin125 mg qid for 1 week125 mg tid for 1 week125 mg qd for 1 week125 mg qod for 2 weeks125 mg q3d for 2 weeksThird or subsequent recurrencesTapered-pulsed VancomycinPlusSaccharomyces boulardii (Florastor)500 mg (2 × 250 mg caps) bid for 30 days started during the last 2 weeks of the tapered-pulsed vancomycin regimen (above).orCholestyramine 4 g daily started during the last 2 weeks of tapered-pulsed vancomycin regimen (above).tid, 3 times daily; qid, 4 times daily; qd, every day; qod, every other day; q3d, every 3rd day; bid, twice daily Open table in a new tab tid, 3 times daily; qid, 4 times daily; qd, every day; qod, every other day; q3d, every 3rd day; bid, twice daily The rationale for a tapered-pulsed antibiotic regimen in recurrent infection is that antibiotic-resistant spores convert to antibiotic-sensitive vegetative forms when antibiotics are withdrawn slowly (tapered) and given on alternate days (pulsed). Pulsed antibiotic therapy allows C difficile spores to vegetate on days when antibiotics are held and then be killed when the antibiotics are taken again on the second or third day. Tedesco et al3Tedesco F.J. Gordon D. Fortson W.C. Approach to patients with multiple relapses of antibiotic-associated pseudomembranous colitis.Am J Gastroenterol. 1985; 80: 867-868PubMed Google Scholar successfully treated 22 patients with recurrent C difficile with tapering doses of oral vancomycin for 3 weeks, followed by pulsed doses over the next 3 weeks (Table 1). All patients remained symptom-free during a mean follow-up period of 6 months. Tapered or pulsed vancomycin regimens in combination with cholestyramine24Tedesco F.J. Treatment of recurrent antibiotic-associated pseudomembrane colitis.Am J Gastroenterol. 1982; 77: 220-221PubMed Google Scholar or rifampin25Buggy B.P. Fekety R. Silva J. Therapy of relapsing Clostridium difficile-associated diarrhea and colitis with the combination of vancomycin and rifampin.J Clin Gastroenterol. 1987; 9: 155-159Crossref PubMed Scopus (106) Google Scholar have also been successful for recurrent infection in small, uncontrolled studies. C difficile is an "opportunistic infection" in that it can colonize the bowel only after the normal colonic flora has been reduced by antibiotics. The use of beneficial microorganisms or probiotics is an attractive therapeutic approach for recurrent C difficile because it allows restoration of the normal flora, in contrast to metronidazole or vancomycin, which further perturb this protective barrier. A variety of probiotics have been tried in patients with recurrent C difficile, including nonpathogenic yeast, intestinal bacteria such as Lactobacillus species, and "stool transplant" with normal human feces. The most widely studied probiotic agent for recurrent C difficile is Saccharomyces boulardii, a nonpathogenic yeast used extensively in Europe for various forms of diarrhea and now available in capsule form in the United States without a prescription. S boulardii interferes with the ability of C difficile to colonize the large bowel, and does not inhibit the reestablishment of the normal bowel flora.26Elmer G.W. Surawicz C.M. McFarland L.V. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections.JAMA. 1996; 275: 870-876Crossref PubMed Google Scholar In a prospective, double-blind, controlled prevention trial,27Surawicz C.M. Elmer G.W. Speelman P. McFarland L.V. Chinn J. van Belle G. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardiia prospective study.Gastroenterology. 1989; 96: 981-988Abstract PubMed Google Scholar patients treated with both S boulardii and antibiotics had significantly fewer episodes of antibiotic-associated diarrhea than those on antibiotics alone (22% on placebo vs 9.5% on S boulardii, P = .04). Among the 48 patients who became C difficile positive, a trend toward a lower incidence of diarrhea (9.4% vs 31%, P = .07) was observed. In a subsequent randomized, double-blind, placebo-controlled trial5McFarland L.V. Surawicz C.M. Greenberg R.N. Fekety R. Elmer G.W. Moyer K.A. Melcher S.A. Bowen K.E. Cox J.L. Noorani Z. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease.JAMA. 1994; 271: 1913-1918Crossref PubMed Scopus (786) Google Scholar involving 124 patients with C difficile diarrhea, co-administration of S boulardii (1 g/day) with antibiotics (either vancomycin or metronidazole) did not improve outcome of those with an initial episode of C difficile compared with placebo plus antibiotics (recurrence rate, 19% versus 24%; P = .86). However, patients with a history of recurrent C difficile who received antibiotics plus S boulardii had significantly fewer recurrences compared with those who received antibiotics alone (recurrence rate 35% vs 65%; P = .04). In contrast, a later study28Surawicz C.M. McFarland L.V. Greenberg R.N. Rubin M. Fekety R. Mulligan M.E. Garcia R.J. Brandmarker S. Bowen K. Borjal D. Elmer G.W. The search for a better treatment for recurrent Clostridium difficile disease use of high-dose vancomycin combined with Saccharomyces boulardii.Clin Infect Dis. 2000; 31: 1012-1017Crossref PubMed Scopus (495) Google Scholar showed reduced recurrence rates (from 50% to 17%, P = .05) only in patients co-treated with S boulardii (1 g/day × 28 days) and high doses of vancomycin (500 mg by mouth 4 times daily × 10 days) but not in patients receiving either lower doses of vancomycin (500 mg per day) or metronidazole (1 g/day). S boulardii is relatively well tolerated but fatal cases of fungemia during therapy with this organism have been reported.29Cherifi S. Robberecht J. Miendje Y. Saccharomyces cerevisiae fungemia in an elderly patient with Clostridium difficile colitis.Acta Clin Belg. 2004; 59: 223-224Crossref PubMed Scopus (44) Google Scholar, 30Lestin F. Pertschy A. Rimek D. [Fungemia after oral treatment with Saccharomyces boulardii in a patient with multiple comorbidities].Dtsch Med Wochenschr. 2003; 128: 2531-2533Crossref PubMed Scopus (46) Google Scholar Nontoxigenic strains of C difficile can prevent C difficile diarrhea in both animals and humans.31Sambol S.P. Merrigan M.M. Tang J.K. Johnson S. Gerding D.N. Colonization for the prevention of Clostridium difficile disease in hamsters.J Infect Dis. 2002; 186: 1781-1789Crossref PubMed Scopus (140) Google Scholar, 32Shim J.K. Johnson S. Samore M.H. Bliss D.Z. Gerding D.N. Primary symptomless colonization by Clostridium difficile and decreased risk of subsequent diarrhoea.Lancet. 1998; 351: 633-636Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar Oral administration of a nontoxigenic strain of C difficile was found to be effective in 2 patients with recurrent C difficile.33Seal D. Borriello S.P. Barclay F. Welch A. Piper M. Bonnycastle M. Treatment of relapsing Clostridium difficile diarrhoea by administration of a non-toxigenic strain.Eur J Clin Microbiol. 1987; 6: 51-53Crossref PubMed Scopus (125) Google Scholar Further controlled clinical studies are necessary to determine if nontoxigenic strains can be used prophylactically to prevent nosocomial infection with toxigenic strains of C difficile. Lactobacillus strains have been used for decades to prevent or treat various forms of diarrhea including antibiotic-associated diarrhea. In an uncontrolled, open-label study, Lactobacillus strain GG was found to be effective in preventing recurrent C difficile34Gorbach S.L. Chang T.W. Goldin B. Successful treatment of relapsing Clostridium difficile colitis with Lactobacillus GG.Lancet. 1987; 2: 1519Abstract PubMed Scopus (398) Google Scholar; however, in a subsequent controlled trial, this agent was not effective in protecting against antibiotic-associated diarrhea.35Thomas M.R. Litin S.C. Osmon D.R. Corr A.P. Weaver A.L. Lohse C.M. Lack of effect of Lactobacillus GG on antibiotic-associated diarrhea a randomized, placebo-controlled trial.Mayo Clin Proc. 2001; 76: 883-889Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar Fecal bacteriotherapy is based on the concept the colonic microflora in patients with relapsing infection can be more quickly restored by administrating normal human feces by enema or colonoscopy, or as the more esthetically acceptable freeze-dried fecal flora. Enemas of fresh feces from a healthy relative or rectal infusions of freeze-dried cultures of 10 different aerobic and anaerobic bacteria were administered to 6 patients with recurrent C difficile.36Tvede M. Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients.Lancet. 1989; 1: 1156-1160Abstract PubMed Scopus (406) Google Scholar The bacterial mixture led to bowel colonization with Bacteroides species, which was accompanied by prompt loss of C difficile and its toxin from stool samples, suggesting that Bacteriodes may be a critical component of the barrier flora that normally prevents colonization by C difficile. Aas et al treated 18 patients with multiply recurrent C difficile infection with a nasogastric infusion of donor stool provided by a healthy family member.37Aas J. Gessert C. Bakken J. Recurrent Clostridium difficile colitis case series involving 18 patients treated with donor stool administered via a nasogastric tube.Clin Infect Dis. 2003; 36: 580-585Crossref PubMed Scopus (435) Google Scholar Ninety days after receipt of the "stool transplant," 15 of 18 patients remained relapse-free. The use of passive immunotherapy with immune serum for relapsing C difficile infection is supported by several experimental and clinical observations. Relatively low serum anti-toxin antibody concentrations have been associated with recurrent C difficile diarrhea in both children18Leung D.Y. Kelly C.P. Boguniewicz M. Pothoulakis C. Lamont J.T. Flores A. Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin.J Pediatr. 1991; 118: 633-637Abstract Full Text PDF PubMed Scopus (255) Google Scholar and adults.20Kyne L. Warny M. Qamar A. Kelly C.P. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea.Lancet. 2001; 357: 189-193Abstract Full Text Full Text PDF PubMed Scopus (681) Google Scholar Low serum IgG antibody levels against toxin A were observed in 6 children with relapsing C difficile colitis who had previously failed multiple courses of antibiotics.18Leung D.Y. Kelly C.P. Boguniewicz M. Pothoulakis C. Lamont J.T. Flores A. Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin.J Pediatr. 1991; 118: 633-637Abstract Full Text PDF PubMed Scopus (255) Google Scholar Treatment with normal pooled intravenous gamma globulin (400 mg/kg every 3 weeks) containing high levels of IgG antitoxin A led to elevated serum anti-toxin A IgG levels, as well as resolution of infection. Similar results have been reported in adults.38Wilcox M.H. Descriptive study of intravenous immunoglobulin for the treatment of recurrent Clostridium difficile diarrhoea.J Antimicrob Chemother. 2004; 53: 882-884Crossref PubMed Scopus (173) Google Scholar In a small, open-label pilot study, 9 adults with relapsing C difficile diarrhea were treated orally with immune cow's milk whey protein concentrate prepared by immunizing cows with C difficile toxoids.39van Dissel J.T. de Groot N. Hensgens C.M. Numan S. Kuijper E.J. Veldkamp P. van't Wout J. Bovine antibody-enriched whey to aid in the prevention of a relapse of Clostridium difficile-associated diarrhoea preclinical and preliminary clinical data.J Med Microbiol. 2005; 54: 197-205Crossref PubMed Scopus (107) Google Scholar Resolution of symptoms was observed in all patients during a median follow up period of 333 days. The anion-binding resins cholestyramine and colestipol have been used therapeutically for both intial C difficile infection and for recurrence. These agents bind C difficile toxins in the lumen and prevent their access to membrane receptors on the apical surface of colonocytes. When used as single agents for initial C difficile infection, the efficacy of anion binding resins has been disappointing40Tedesco F.J. Napier J. Gamble W. Chang T.W. Bartlett J.G. Therapy of antibiotic-associated colitis.J Clin Gastroenterol. 1979; 1: 51-54Crossref PubMed Scopus (30) Google Scholar but cholestyramine and other binding agents in combination with antibiotics have been used successfully in recurrent disease.3Tedesco F.J. Gordon D. Fortson W.C. Approach to patients with multiple relapses of antibiotic-associated pseudomembranous colitis.Am J Gastroenterol. 1985; 80: 867-868PubMed Google Scholar, 41Tedesco F.J. Treatment of antibiotic-associated colitis.Am J Gastroenterol. 1982; 77: 220-221PubMed Google Scholar, 42Tedesco F.J. Pseudomembranous colitis pathogenesis and therapy.Med Clin North Am. 1982; 66: 655-664PubMed Google Scholar, 43Kunimoto D. Thompson A.B. Recurrent Clostridium difficile-associated colitis responding to cholestyramine.Digestion. 1986; 33: 225-228Crossref PubMed Scopus (27) Google Scholar Tedesco24Tedesco F.J. Treatment of recurrent antibiotic-associated pseudomembrane colitis.Am J Gastroenterol. 1982; 77: 220-221PubMed Google Scholar treated 11 patients with recurrent C difficile with tapering doses of vancomycin (125 mg every 6 hours initially down to 125 mg daily over 2–3 weeks) and colestipol hydrochloride (Colestid) 5 g every 12 hours beginning during the second week of vancomycin therapy and continuing at that dosage for 2 additional weeks after vancomycin was stopped. All patients responded and were free of diarrhea after 6 weeks of follow-up. Our practice is to recommend chloestyramine 4 g 4 times daily as ancillary therapy to metronidazole or vancomycin, particulary after these antibiotics are stopped. Anion binding agents have an important advantage over antibiotics in that they do not interfere with recovery of the colonic flora. In order to cause inflammation and diarrhea, C. difficile toxins must first bind to specific plasma membrane receptors expressed on the apical surface of human colonocytes. Like anion binding resins, receptor decoys mimic a part of the toxin receptor molecule, causing the toxin to bind firmly, remain sequestered in the colonic lumen and thus unable to bind biologic receptors on the colonocyte. Tolevamer, a soluble anionic polymer that binds C difficile toxins in the gut lumen, strongly inhibits the cytotoxicity and enterotoxicity of C difficile toxins, and was superior to metronidazole in protecting hamsters from death caused by C difficile cecitis.44Kurtz C.B. Cannon E.P. Brezzani A. Pitruzzello M. Dinardo C. Rinard E. Acheson D.W. Fitzpatrick R. Kelly P. Shackett K. Papoulis A.T. Goddard P.J. Barker Jr, R.H. Palace G.P. Klinger J.D. GT160-246, a toxin binding polymer for treatment of Clostridium difficile colitis.Antimicrob Agents Chemother. 2001; 45: 2340-2347Crossref PubMed Scopus (83) Google Scholar A large multicenter trial of efficacy and safety of tolevamer in humans with acute C difficile infection is underway.45Louie T. Peppe J. Watt C.K. Johnson D. Mohammed R.A. Dow G. Weiss K. Somon S. Davidson D. A phase 2 study of the toxin binding polymer Tolevamer in patients with C. difficile-associated diarrhea.Gastroenterology. 2004; 126: A511PubMed Google Scholar This agent is not currently available for clinical use. A parenteral C difficile toxoid vaccine has been shown to induce a vigorous serum anti-toxin A antibody response in the sera of healthy volunteers in early clinical studies.46Kotloff K.L. Wasserman S.S. Losonsky G.A. Thomas Jr, W. Nichols R. Edelman R. Bridwell M. Monath T.P. Safety and immunogenicity of increasing doses of a Clostridium difficile toxoid vaccine administered to healthy adults.Infect Immun. 2001; 69: 988-995Crossref PubMed Scopus (142) Google Scholar, 47Aboudola S. Kotloff K.L. Kyne L. Warny M. Kelly E.C. Sougioultzis S. Giannasca P.J. Monath T.P. Kelly C.P. Clostridium difficilevaccine and serum immunoglobulin G antibody response to toxin A.Infect Immun. 2003; 71: 1608-1610Crossref PubMed Scopus (121) Google Scholar A small, open-label study48Sougioultzis S. Kyne L. Drudy D. Maroo S. Pothoulakis C. Giannasca P.J. Lee C.K. Warny M. Monath T.P. Kelly C.P. Clostridium difficile toxoid vaccine in recurrent C. difficile-associated diarrhea.Gastroenterology. 2005; 128: 764-770Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar involving 3 subjects with recurrent C difficile colitis reported that vaccination with intramuscular injections over an 8-week period led to resolution of C difficile diarrhea. Although only 2 subjects developed a robust IgG response, all 3 were able to discontinue treatment with oral vancomycin and remained symptom-free in a 6-month follow-up period. Larger, randomized trials are needed to establish the efficacy of vaccination in adults and to apply for FDA approval. For the first relapse in our patient, we agree with confirming the diagnosis of recurrent C difficile infection with a stool toxin assay. While awaiting the result we would have encouraged her to stay well hydrated. Given her nontoxic appearance and minimal risk, she might have been managed conservatively without antibiotics. However, if a patient develops fever or abdominal pain we would recommend a repeat 14-day course of metronidazole at 500 mg 3 times daily. For a second recurrence after successful resolution of symptoms on metronidazole, the diagnosis should again be confirmed with a stool toxin assay. Then we would recommend a tapered-pulsed course of vancomycin, as outlined in Table 1. For third or subsequent recurrences we would consider therapy with a combination of vancomycin and either S boulardii or cholestyramine, and if that were unsuccessful we would attempt to passively immunize her with intravenous immunoglobulin. If all therapeutic maneuvers fail, some patients with multiple recurrent C difficile may require prolonged oral therapy with 125 or 250 mg vancomycin daily or every other day to prevent acute recurrence. We avoid long-term use of metronidazole for such patients as it may cause peripheral sensory neuropathy that may be permanent. C difficle has emerged over the past decade as the most common nosocomial infection, with a heavy burden of morbidity, mortality, and hospital cost, particularly in the elderly. Recurrent infection occurs in approximately 20% of patients, and in about half of this group recurs a second or third time after cessation of metronidazole or vancomycin therapy. Recurrence requires re-ingestion of spores from the environment, or persistence of spores in the GI tract following antibiotic therapy. A variety of management strategies may be required to treat multiple recurrences including repeated courses of metronidazole or vancomycin, the use of probiotics or toxin-binding agents, or passive immunization with pooled immunoglobulins (IgG). Vaccination, currently under development, will likely provide future control of this infection, as host IgG antitoxins appear to provide protection against diarrhea and colitis.
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