Recurrent Clostridium difficile infection: A review of risk factors, treatments, and outcomes

  • Stuart Johnson
    Infectious Disease Section, Loyola University Medical Center, 2160 South First Avenue, Fahey Center (Bldg. 54), Room 149, Maywood, IL 60153, USA. Tel.: +1 708 216 3232; fax: +1 708 216 8198.
    Infectious Disease Section, Loyola University Medical Center, Stritch School of Medicine, Maywood, IL 60153, USA

    Hines Veterans Affairs Hospital, Hines, IL, USA
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Published:April 27, 2009DOI:


      Episodes of recurrent Clostridium difficile infection (CDI) are difficult to treat for several reasons. Foremost, data are lacking to support any particular treatment strategy. In addition, treatment of recurrent episodes is not always successful, and repeated, prolonged treatment is often necessary. Identification of subgroups at risk for recurrent CDI may aid in diagnosing and treating these patients. Two likely mechanistic factors increasing the risk of recurrent CDI are an inadequate immune response to C. difficile toxins and persistent disruption of the normal colonic flora. Important epidemiologic risk factors include advanced age, continuation of other antibiotics, and prolonged hospital stays. Current guidelines recommend that the first recurrent episode be treated with the same agent (i.e., metronidazole or vancomycin) used for the index episode. However, if the first recurrence is characterized as severe, vancomycin should be used. A reasonable strategy for managing a subsequent episode involves tapering followed by pulsed doses of vancomycin. Other potentially effective strategies for recurrent CDI include vancomycin with adjunctive treatments, such as Saccharomyces boulardii, rifaximin “chaser” therapy after vancomycin, nitazoxanide, fecal transplantation, and intravenous immunoglobulin. New treatment agents that are active against C. difficile, but spare critical components of the normal flora, may decrease the incidence of recurrent CDI.


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        • Aslam S.
        • Hamill R.J.
        • Musher D.M.
        Treatment of Clostridium difficile-associated disease: old therapies and new strategies.
        Lancet Infect Dis. 2005; 5: 549-557
        • McFarland 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: 1769-1775
        • Barbut F.
        • Richard A.
        • Hamadi K.
        • Chomette V.
        • Burghoffer B.
        • Petit J.-C.
        Epidemiology of recurrence or reinfections of Clostridium difficile-associated diarrhea.
        J Clin Microbiol. 2000; 38: 2386-2388
        • Johnson S.
        • Adelmann A.
        • Clabots C.R.
        • Peterson L.R.
        • Gerding D.N.
        Recurrences of Clostridium difficile diarrhea not caused by the original infecting organism.
        J Infect Dis. 1989; 159: 340-343
        • O'Neill G.L.
        • Beaman M.H.
        • Riley T.V.
        Relapse versus reinfection with Clostridium difficile.
        Epidemiol Infect. 1991; 107: 627-635
        • Wilcox 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: 93-100
        • Tang-Feldman Y.
        • Mayo S.
        • Silva Jr., J.
        • Cohen S.H.
        Molecular analysis of Clostridium difficile strains isolated from 18 cases of recurrent Clostridium difficile-associated diarrhea.
        J Clin Microbiol. 2003 Jul; 41: 3413-3414
        • Spencer R.C.
        Clinical impact and associated costs of Clostridium difficile-associated disease.
        J Antimicrob Chemother. 1998; 41: 5-12
        • Pépin J.
        • Saheb N.
        • Coulombe M.A.
        • Alary M.E.
        • Corriveau M.P.
        • Authier S.
        • et al.
        Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec.
        Clin Infect Dis. 2005; 41: 1254-1260
        • McFarland L.V.
        Update on the changing epidemiology of Clostridium difficile-associated disease.
        Nat Clin Pract Gastroenterol Hepatol. 2008; 5: 40-48
        • Bartlett J.G.
        • Gerding D.N.
        Clinical recognition and diagnosis of Clostridium difficile infection.
        Clin Infect Dis. 2008; 46: S12-S18
        • Centers for Disease Control
        Severe Clostridium difficile-associated disease in populations previously at low risk—four states, 2005.
        MMWR Morb Mortal Wkly Rep. 2005; 54: 1201-1205
        • McFarland L.V.
        • Brandmarker S.A.
        • Guandalini S.
        Pediatric Clostridium difficile: a phantom menace or clinical reality?.
        J Pediatr Gastroenterol Nutr. 2000; 31: 220-231
        • Gogate A.
        • De A.
        • Nanivadekar R.
        • Mathur M.
        • Saraswathi K.
        • Jog A.
        • et al.
        Diagnostic role of stool culture & toxin detection in antibiotic associated diarrhoea due to Clostridium difficile in children.
        Indian J Med Res. 2005; 122: 518-524
        • Garey K.W.
        • Jiang Z.-D.
        • Yadav Y.
        • Mullins B.
        • Wong K.
        • Dupont H.L.
        Peripartum Clostridium difficile infection: case series and review of the literature.
        Am J Obstet Gynecol. 2008; 199: 322-327
        • Rouphael N.G.
        • O'Donnell J.A.
        • Bhatnagar J.
        • Lewis F.
        • Polgreen P.M.
        • Beekmann S.
        • et al.
        Clostridium difficile-associated diarrhea: an emerging threat to pregnant women.
        Am J Obstet Gynecol. 2008; 198 (e1–635.e6): 635
        • Klein E.J.
        • Boster D.R.
        • Stapp J.R.
        • Wells J.G.
        • Qin X.
        • Clausen C.R.
        • et al.
        Diarrhea etiology in a children's hospital emergency department: a prospective cohort study.
        Clin Infect Dis. 2006; 43: 807-813
        • Kyne 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: 390-397
        • Kyne 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: 189-193
        • Warny M.
        • Vaerman J.P.
        • Avesani V.
        • Delmeé M.
        Human antibody response to Clostridium difficile toxin A in relation to clinical course of infection.
        Infect Immun. 1994; 62: 384-389
        • Chang J.Y.
        • Antonopoulos D.A.
        • Kalra A.
        • Tonelli A.
        • Khalife W.T.
        • Schmidt T.M.
        • et al.
        Decreased diversity of the fecal Mircobiome in recurrent Clostridum difficile-associated diarrhea.
        J Infect Dis. 2008; 197: 435-438
        • Pepin J.
        • Alary M.-E.
        • Valiquette L.
        Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada.
        Clin Infect Dis. 2005; 40: 1591-1597
        • McFarland 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: 43-50
        • Garey K.W.
        • Sethi S.
        • Yadav Y.
        • DuPont H.L.
        Meta-analysis to assess risk factors for recurrent Clostridium difficile infection.
        J Hosp Infect. 2008; 70: 298-304
        • Mayfield J.L.
        • Leet T.
        • Miller J.
        • Mundy L.M.
        Environmental control to reduce transmission of Clostridium difficile.
        Clin Infect Dis. 2000; 31: 995-1000
        • Muto C.A.
        • Blank M.K.
        • Marsh J.W.
        • Vergis E.N.
        • O'Leary M.M.
        • Shutt K.A.
        • et al.
        Control of an outbreak of infection with the hypervirulent Clostridium difficile BI strain in a university hospital using a comprehensive “bundle” approach.
        Clin Infect Dis. 2007; 45: 1266-1273
        • Scheurer D.
        Diagnostic and treatment delays in recurrent Clostridium difficile-associated disease.
        J Hosp Med. 2008; 3: 156-159
        • Pepin J.
        • Routhier S.
        • Gagnon S.
        • Brazeau I.
        Management and outcomes of a first recurrence of Clostridium difficile-associated disease in Quebec, Canada.
        Clin Infect Dis. 2006; 42: 758-764
        • Teasley D.G.
        • Gerding D.N.
        • Olson M.M.
        • Peterson L.R.
        • Gebhard R.L.
        • Schwartz M.J.
        • et al.
        Prospective randomized trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhea and colitis.
        Lancet. 1983; 2: 1043-1046
        • Wenisch C.
        • Parschalk B.
        • Hasenhündl M.
        • Hirschl A.M.
        • Graninger W.
        Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea.
        Clin Infect Dis. 1996; 22: 813-818
        • Musher D.
        • Aslam S.
        • Logan N.
        • Nallacheru S.
        • Bhaila I.
        • Borchert F.
        • et al.
        Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole.
        Clin Infect Dis. 2005; 40: 1586-1590
        • Lagrotteria D.
        • Holmes S.
        • Smieja M.
        • Smaill F.
        • Lee C.
        Prospective, randomized inpatient study of oral metronidazole versus oral metronidazole and rifampin for treatment of primary episode of Clostridium difficile-associated diarrhea.
        Clin Infect Dis. 2006; 43: 547-552
        • Sanchez J.L.
        • Gerding D.N.
        • Olson M.M.
        • Johnson S.
        Metronidazole susceptibility in Clostridium difficile isolates recovered from cases of C. difficile-associated disease treatment failures and successes.
        Anaerobe. 1999; 5: 201-204
        • Zar F.A.
        • Bakkanagari S.R.
        • Moorthi K.M.
        • Davis M.B.
        A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity.
        Clin Infect Dis. 2007; 45: 302-307
      1. Louie T, Gerson M, Grimard D, Johnson S, Poirier S, Weiss K. Results of a phase III trial comparing tolevamer, vancomycin and metronidazole in patients with Clostridium difficile-associated diarrhea. In: Presented at the 47th interscience conference on antimicrobial agents and chemotherapy (ICAAC), September 17 to 20, 2007, Chicago, IL.

      2. European Society for Clinical Microbiology and Infectious Diseases. Guidance document of Clostridium difficile infection (CDI) diagnosis and treatment: treatment guideline. Clin Microbiol Infect, in press.

        • Gerding D.N.
        Treatment of Clostridium difficile-associated diarrhea and colitis.
        Curr Top Microbiol Immunol. 2000; 250: 127-139
        • Kokkotou E.
        • Moss A.C.
        • Michos A.
        • Espinoza D.
        • Cloud J.W.
        • Mustafa N.
        • et al.
        Comparative efficacies of rifaximin and vancomycin for treatment of Clostridium difficile-associated diarrhea and prevention of disease recurrence in hamsters.
        Antimicrob Agents Chemother. 2008; 52: 1121-1126
        • Johnson S.
        • Schriever C.
        • Galang M.
        • Kelly C.P.
        • Gerding D.N.
        Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin.
        Clin Infect Dis. 2007; 44: 846-848
        • Jiang Z.D.
        • Ke S.
        • Palazzini E.
        • Riopel L.
        • Dupont H.
        In vitro activity and fecal concentration of rifaximin after oral administration.
        Antimicrob Agents Chemother. 2000; 44: 2205-2206
        • O'Connor J.
        • Galang M.
        • Sambol S.P.
        • Hecht D.W.
        • Vedantam G.
        • Gerding D.N.
        • et al.
        Rifampin and rifaximin resistance in clinical isolates of Clostridium difficile.
        Antimicrob Agents Chemother. 2008; 52: 2813-2817
        • Curry S.R.
        • Marsh J.W.
        • Shutt K.A.
        • Muto C.A.
        • O'Leary M.M.
        • Saul M.I.
        • et al.
        High frequency of rifampin resistance identified in an epidemic Clostridium difficile clone from a large teaching hospital.
        Clin Infect Dis. 2009; 48: 425-429
        • Musher D.M.
        • Logan N.
        • Mehendiratta V.
        • Melgarejo N.A.
        • Garud S.
        • Hamill R.J.
        Clostridium difficile colitis that fails conventional metronidazole therapy: response to nitazoxanide.
        J Antimicrob Chemother. 2007; 59: 705-710
        • Buggy B.P.
        • Fekety R.
        • Silva Jr., J.
        Therapy of relapsing Clostridium difficile-associated diarrhea and colitis with the combination of vancomycin and rifampin.
        J Clin Gastroenterol. 1987; 9: 155-159
        • Surawicz C.M.
        • McFarland L.V.
        • Greenberg R.N.
        • Rubin M.
        • Fekety R.
        • Mulligan M.E.
        • et al.
        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: 1012-1017
        • McDonald L.C.
        • Owings M.
        • Jernigan D.B.
        Clostridium difficile infection in patients discharged from US short-stay hospitals, 1996–2003.
        Emerg Infect Dis. 2006; 12: 409-415
        • McFarland L.V.
        • Surawicz C.M.
        • Greenberg R.N.
        • Fekety R.
        • Elmer G.W.
        • Moyer K.A.
        • et al.
        A randomized placebo controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease.
        JAMA. 1994; 271: 1913-1918
        • Graf C.
        • Gavazzi G.
        Saccharomyces cerevisiae fungemia in an immunocompromised patient not treated with Saccharomyces boulardii preparation.
        J Infect. 2007; 54: 310-311
        • Wullt M.
        • Hagslätt M.L.
        • Odenholt I.
        Lactobacillus plantarum 299v for the treatment of recurrent Clostridium difficile-associated diarrhoea: a double-blind, placebo-controlled trial.
        Scand J Infect Dis. 2003; 35: 365-367
        • Wilcox W.H.
        Descriptive study of intravenous immunoglobulin for the treatment of recurrent Clostridium difficile diarrhoea.
        J Antimicrobial Chemother. 2004; 53: 882-884
        • Beales I.L.P.
        Intravenous immunoglobulin for recurrent Clostridium difficile diarrhoea.
        Gut. 2002; 51: 456
        • Sougioultzis S.
        • Kyne L.
        • Drudy D.
        • Keates S.
        • Maroo S.
        • Pothoulakis C.
        • et al.
        Clostridium difficile toxoid vaccine in recurrent C. difficile-associated diarrhea.
        Gastroenterology. 2005; 128: 764-770
        • Aas J.
        • Gessert C.E.
        • Bakken J.S.
        Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube.
        Clin Infect Dis. 2003; 36: 580-585
        • Moncino M.D.
        • Falletta J.M.
        Multiple relapses of Clostridium difficile-associated diarrhea in a cancer patient: successful control with long-term cholestyramine therapy.
        Am J Pediatr Hematol Oncol. 1992; 14: 361-364
        • Pruksananonda P.
        • Powell K.R.
        Multiple relapses of Clostridium difficile-associated diarrhea responding to an extended course of cholestyramine.
        Pediatr Infect Dis J. 1989; 8: 175-178
        • Kurtz C.B.
        • Cannon E.P.
        • Brezzani A.
        • Pitruzzello M.
        • Dinardo C.
        • Rinard E.
        • et al.
        GT160-246, a toxin-binding polymer for treatment of Clostridium difficile colitis.
        Antimicrob Agents Chemother. 2001; 45: 2340-2347
        • Ackermann G.
        • Löffler B.
        • Adler D.
        • Rodloff A.C.
        In vitro activity of OPT-80 against Clostridium difficile.
        Antimicrob Agents Chemother. 2004; 48: 2280-2282
        • Louie T.
        • Miller M.
        • Donskey C.
        • Mullane K.
        • Goldstein E.J.
        Clinical outcomes, safety and pharmacokinetics of OPT-80 in a phase 2 trial of patients with Clostridium difficile infection.
        Antimicrob Agents Chemother. 2009; 53: 223-228
        • Louie T.J.
        • Emery J.
        • Krulicki W.
        • Byrne B.
        • Mah M.
        OPT-80 eliminates Clostridium difficile and is sparing of Bacteroides species during treatment of C. difficile infection.
        Antimicrob Agents Chemother. 2009; 53: 261-263