Therapy for Clostridium difficile infection – any news beyond Metronidazole and Vancomycin?

References

• Peery AF, Dellon ES, Lund J, et al. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology. 2012;143(1179–87):e1–3.
   Google Scholar
• Wiegand PN, Nathwani D, Wilcox MH, et al. Clinical and economic burden of Clostridium difficile infection in Europe: a systematic review of healthcare-facility-acquired infection. J Hosp Infect. 2012;81:1–14.
   PubMed Web of Science ®Google Scholar
• Elliott B, Androga GO, Knight DR, et al. Clostridium difficile infection: evolution, phylogeny and molecular epidemiology. Infect Genet Evol. 2017;49:1–11.
   PubMed Web of Science ®Google Scholar
• Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364:422–431.
   PubMed Web of Science ®Google Scholar
• Wilcox MH, Gerding DN, Poxton IR, et al. Bezlotoxumab for prevention of recurrent clostridium difficile infection. N Engl J Med. 2017;376:305–317.
   PubMed Web of Science ®Google Scholar
• Brown KA, Khanafer N, Daneman N, et al. Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection. Antimicrob Agents Chemother. 2013;57:2326–2332.
   PubMed Web of Science ®Google Scholar
• Slimings C, Riley TV. Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis. J Antimicrob Chemother. 2014;69:881–891.
   PubMed Web of Science ®Google Scholar
• Theriot CM, Bowman AA, Young VB. Antibiotic-induced alterations of the gut microbiota alter secondary bile acid production and allow for clostridium difficile spore germination and outgrowth in the large intestine. mSphere. 2016;1:e00045-15.
   Web of Science ®Google Scholar
• Swann JR, Want EJ, Geier FM, et al. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc Natl Acad Sci U S A. 2011;108(Suppl 1):4523–4530.
   PubMed Web of Science ®Google Scholar
• Theriot CM, Koenigsknecht MJ, Carlson PE Jr., et al. Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection. Nat Commun. 2014;5:3114.
   PubMed Web of Science ®Google Scholar
• Vrieze A, Out C, Fuentes S, et al. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. J Hepatol. 2014;60:824–831.
   PubMed Web of Science ®Google Scholar
• Abt MC, McKenney PT, Pamer EG. Clostridium difficile colitis: pathogenesis and host defence. Nat Rev Microbiol. 2016;14:609–620.
   PubMed Web of Science ®Google Scholar
• Pruitt RN, Chambers MG, Ng KK, et al. Structural organization of the functional domains of Clostridium difficile toxins A and B. Proc Natl Acad Sci U S A. 2010;107:13467–13472.
   PubMed Web of Science ®Google Scholar
• Sun X, Savidge T, Feng H. The enterotoxicity of Clostridium difficile toxins. Toxins (Basel). 2010;2:1848–1880.
   PubMed Web of Science ®Google Scholar
• Gerding DN, Johnson S, Rupnik M, et al. Clostridium difficile binary toxin CDT: mechanism, epidemiology, and potential clinical importance. Gut Microbes. 2014;5:15–27.
   PubMed Web of Science ®Google Scholar
• Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108:478–498, quiz 99
   PubMed Web of Science ®Google Scholar
• Hagel S, Epple HJ, Feurle GE, et al. [S2k-guideline gastrointestinal infectious diseases and Whipple’s disease]. Z Gastroenterol. 2015;53:418–459.
   PubMed Web of Science ®Google Scholar
• Debast SB, Bauer MP, Kuijper EJ, et al. European society of clinical microbiology and infectious diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2014;20(Suppl 2):1–26.
   PubMed Web of Science ®Google Scholar
• Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31:431–455.
   PubMed Web of Science ®Google Scholar
• Ofosu A. Clostridium difficile infection: a review of current and emerging therapies. Ann Gastroenterol. 2016;29:147–154.
   PubMed Web of Science ®Google Scholar
• Hemminger J, Balada-Llasat JM, Raczkowski M, et al. Two case reports of Clostridium difficile bacteremia, one with the epidemic NAP-1 strain. Infection. 2011;39:371–373.
   PubMed Web of Science ®Google Scholar
• Binning M, John MA, Schieven BC, et al. Comparison of culture, cytotoxin assay and two EIA tests with clinical diagnosis of Clostridium difficile-associated diarrhea. Can J Infect Dis. 1994;5:163–167.
   PubMedGoogle Scholar
• Crobach MJ, Dekkers OM, Wilcox MH, et al. European Society of Clinical Microbiology and Infectious Diseases (ESCMID): data review and recommendations for diagnosing Clostridium difficile-infection (CDI). Clin Microbiol Infect. 2009;15:1053–1066.
   PubMed Web of Science ®Google Scholar
• Kelly MT, Champagne SG, Sherlock CH, et al. Commercial latex agglutination test for detection of Clostridium difficile-associated diarrhea. J Clin Microbiol. 1987;25:1244–1247.
   PubMed Web of Science ®Google Scholar
• Shetty N, Wren MW, Coen PG. The role of glutamate dehydrogenase for the detection of Clostridium difficile in faecal samples: a meta-analysis. J Hosp Infect. 2011;77:1–6.
   PubMed Web of Science ®Google Scholar
• O’Horo JC, Jones A, Sternke M, et al. Molecular techniques for diagnosis of Clostridium difficile infection: systematic review and meta-analysis. Mayo Clin Proc. 2012;87:643–651.
   PubMed Web of Science ®Google Scholar
• Barbut F, Surgers L, Eckert C, et al. Does a rapid diagnosis of Clostridium difficile infection impact on quality of patient management? Clin Microbiol Infect. 2014;20:136–144.
   PubMed Web of Science ®Google Scholar
• Tenover FC, Baron EJ, Peterson LR, et al. Laboratory diagnosis of Clostridium difficile infection can molecular amplification methods move us out of uncertainty? J Mol Diagn. 2011;13:573–582.
   PubMed Web of Science ®Google Scholar
• Bagdasarian N, Rao K, Malani PN. Diagnosis and treatment of Clostridium difficile in adults: a systematic review. JAMA. 2015;313:398–408.
   PubMed Web of Science ®Google Scholar
• Surawicz CM, McFarland LV, Greenberg RN, 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.
   PubMed Web of Science ®Google Scholar
• Fujitani S, George WL, Murthy AR. Comparison of clinical severity score indices for Clostridium difficile infection. Infect Control Hosp Epidemiol. 2011;32:220–228.
   PubMed Web of Science ®Google Scholar
• Hensgens MP, Dekkers OM, Goorhuis A, et al. Predicting a complicated course of Clostridium difficile infection at the bedside. Clin Microbiol Infect. 2014;20:O301–8.
   PubMed Web of Science ®Google Scholar
• Cruz MP. Fidaxomicin (Dificid), a novel oral macrocyclic antibacterial agent for the treatment of Clostridium difficile-associated diarrhea in adults. P T. 2012;37:278–281.
   PubMedGoogle Scholar
• Al-Nassir WN, Sethi AK, Nerandzic MM, et al. Comparison of clinical and microbiological response to treatment of Clostridium difficile-associated disease with metronidazole and vancomycin. Clin Infect Dis. 2008;47:56–62.
   PubMed Web of Science ®Google Scholar
• Johnson S, Louie TJ, Gerding DN, et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014;59:345–354.
   PubMed Web of Science ®Google Scholar
• Zar FA, Bakkanagari SR, Moorthi KM, et al. 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.
   PubMed Web of Science ®Google Scholar
• Rokas KE, Johnson JW, Beardsley JR, et al. The addition of intravenous metronidazole to oral vancomycin is associated with improved mortality in critically ill patients with Clostridium difficile infection. Clin Infect Dis. 2015;61:934–941.
   PubMed Web of Science ®Google Scholar
• Pasic M, Jost R, Carrel T, et al. Intracolonic vancomycin for pseudomembranous colitis. N Engl J Med. 1993;329:583.
   PubMed Web of Science ®Google Scholar
• Malamood M, Nellis E, Ehrlich AC, et al. Vancomycin enemas as adjunctive therapy for Clostridium difficile infection. J Clin Med Res. 2015;7:422–427.
   PubMedGoogle Scholar
• Baines SD, O’Connor R, Freeman J, et al. Emergence of reduced susceptibility to metronidazole in Clostridium difficile. J Antimicrob Chemother. 2008;62:1046–1052.
   PubMed Web of Science ®Google Scholar
• Brazier JS, Fawley W, Freeman J, et al. Reduced susceptibility of Clostridium difficile to metronidazole. J Antimicrob Chemother. 2001;48:741–742.
   PubMed Web of Science ®Google Scholar
• Baines SD, Wilcox MH. Antimicrobial resistance and reduced susceptibility in Clostridium difficile: potential consequences for induction, treatment, and recurrence of C. difficile infection. Antibiotics (Basel). 2015;4:267–298.
   PubMed Web of Science ®Google Scholar
• Cornely OA, Crook DW, Esposito R, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis. 2012;12:281–289.
   PubMed Web of Science ®Google Scholar
• De Lalla F, Nicolin R, Rinaldi E, et al. Prospective study of oral teicoplanin versus oral vancomycin for therapy of pseudomembranous colitis and Clostridium difficile-associated diarrhea. Antimicrob Agents Chemother. 1992;36:2192–2196.
   PubMed Web of Science ®Google Scholar
• Lagrotteria D, Holmes S, Smieja M, et al. 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.
   PubMed Web of Science ®Google Scholar
• Teasley DG, Gerding DN, Olson MM, et al. Prospective randomised trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis. Lancet. 1983;2:1043–1046.
   PubMed Web of Science ®Google Scholar
• Musher DM, Logan N, Bressler AM, et al. Nitazoxanide versus vancomycin in Clostridium difficile infection: a randomized, double-blind study. Clin Infect Dis. 2009;48:e41–6.
   PubMed Web of Science ®Google Scholar
• Fekety R, Silva J, Kauffman C, et al. Treatment of antibiotic-associated Clostridium difficile colitis with oral vancomycin: comparison of two dosage regimens. Am J Med. 1989;86:15–19.
   PubMed Web of Science ®Google Scholar
• Wenisch C, Parschalk B, Hasenhundl M, et al. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis. 1996;22:813–818.
   PubMed Web of Science ®Google Scholar
• Shue YK, Sears PS, Shangle S, et al. Safety, tolerance, and pharmacokinetic studies of OPT-80 in healthy volunteers following single and multiple oral doses. Antimicrob Agents Chemother. 2008;52:1391–1395.
   PubMed Web of Science ®Google Scholar
• Tannock GW, Munro K, Taylor C, et al. A new macrocyclic antibiotic, fidaxomicin (OPT-80), causes less alteration to the bowel microbiota of Clostridium difficile-infected patients than does vancomycin. Microbiology. 2010;156:3354–3359.
   PubMed Web of Science ®Google Scholar
• Feher C, Munez Rubio E, Merino Amador P, et al. The efficacy of fidaxomicin in the treatment of Clostridium difficile infection in a real-world clinical setting: a Spanish multi-centre retrospective cohort. Eur J Clin Microbiol Infect Dis. 2017;36:295–303.
   PubMed Web of Science ®Google Scholar
• Petrella LA, Sambol SP, Cheknis A, et al. Decreased cure and increased recurrence rates for Clostridium difficile infection caused by the epidemic C. difficile BI strain. Clin Infect Dis. 2012;55:351–357.
   PubMed Web of Science ®Google Scholar
• Bartsch SM, Umscheid CA, Fishman N, et al. Is fidaxomicin worth the cost? An economic analysis. Clin Infect Dis. 2013;57:555–561.
   PubMed Web of Science ®Google Scholar
• Nathwani D, Cornely OA, Van Engen AK, et al. Cost-effectiveness analysis of fidaxomicin versus vancomycin in Clostridium difficile infection. J Antimicrob Chemother. 2014;69:2901–2912.
   PubMed Web of Science ®Google Scholar
• Stranges PM, Hutton DW, Collins CD. Cost-effectiveness analysis evaluating fidaxomicin versus oral vancomycin for the treatment of Clostridium difficile infection in the United States. Value Health. 2013;16:297–304.
   PubMed Web of Science ®Google Scholar
• Bhangu A, Nepogodiev D, Gupta A, et al. West midlands research C. Systematic review and meta-analysis of outcomes following emergency surgery for Clostridium difficile colitis. Br J Surg. 2012;99:1501–1513.
   PubMed Web of Science ®Google Scholar
• Koss K, Clark MA, Sanders DS, et al. The outcome of surgery in fulminant Clostridium difficile colitis. Colorectal Dis. 2006;8:149–154.
   PubMed Web of Science ®Google Scholar
• Lee DY, Chung EL, Guend H, et al. Predictors of mortality after emergency colectomy for Clostridium difficile colitis: an analysis of ACS-NSQIP. Ann Surg. 2014;259:148–156.
   PubMed Web of Science ®Google Scholar
• Halaweish I, Alam HB. Surgical management of severe colitis in the intensive care unit. J Intensive Care Med. 2015;30:451–461.
   PubMed Web of Science ®Google Scholar
• Kautza B, Zuckerbraun BS. The surgical management of complicated clostridium difficile infection: alternatives to colectomy. Surg Infect (Larchmt). 2016;17:337–342.
   PubMed Web of Science ®Google Scholar
• McDonald LC, Coignard B, Dubberke E, et al. Recommendations for surveillance of Clostridium difficile-associated disease. Infect Control Hosp Epidemiol. 2007;28:140–145.
   PubMed Web of Science ®Google Scholar
• McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol. 2002;97:1769–1775.
   PubMed Web of Science ®Google Scholar
• Abdelfatah M, Nayfe R, Nijim A, et al. Factors predicting recurrence of Clostridium difficile Infection (CDI) in hospitalized patients: retrospective study of more than 2000 patients. J Investig Med. 2015;63:747–751.
   PubMed Web of Science ®Google Scholar
• Cornely OA, Miller MA, Louie TJ, et al. Treatment of first recurrence of Clostridium difficile infection: fidaxomicin versus vancomycin. Clin Infect Dis. 2012;55(Suppl 2):S154–61.
   PubMed Web of Science ®Google Scholar
• Halloran TJ. Convulsions associated with high cumulative doses of metronidazole. Drug Intell Clin Pharm. 1982;16:409.
   PubMedGoogle Scholar
• D’Agostino RB Sr., Collins SH, Pencina KM, et al. Risk estimation for recurrent Clostridium difficile infection based on clinical factors. Clin Infect Dis. 2014;58:1386–1393.
   PubMed Web of Science ®Google Scholar
• Garey KW, Ghantoji SS, Shah DN, et al. A randomized, double-blind, placebo-controlled pilot study to assess the ability of rifaximin to prevent recurrent diarrhoea in patients with Clostridium difficile infection. J Antimicrob Chemother. 2011;66:2850–2855.
   PubMed Web of Science ®Google Scholar
• Chopra T, Goldstein EJ, Gorbach SL. Rethinking strategies to select antibiotic therapy in Clostridium difficile infection. Pharmacotherapy. 2016;36:1281–1289.
   PubMed Web of Science ®Google Scholar
• Kelly CR, Kahn S, Kashyap P, et al. Update on fecal microbiota transplantation 2015: indications, methodologies, mechanisms, and outlook. Gastroenterology. 2015;149:223–237.
   PubMed Web of Science ®Google Scholar
• Trubiano JA, Gardiner B, Kwong JC, et al. Faecal microbiota transplantation for severe Clostridium difficile infection in the intensive care unit. Eur J Gastroenterol Hepatol. 2013;25:255–257.
   PubMed Web of Science ®Google Scholar
• van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407–415.
   PubMed Web of Science ®Google Scholar
• Hota SS, Sales V, Tomlinson G, et al. Oral vancomycin followed by fecal transplantation versus tapering oral vancomycin treatment for recurrent Clostridium difficile infection: an open-label, randomized controlled trial. Clin Infect Dis. 2017;64:265–271.
   PubMed Web of Science ®Google Scholar
• Cammarota G, Ianiro G, Gasbarrini A. Fecal microbiota transplantation for the treatment of Clostridium difficile infection: a systematic review. J Clin Gastroenterol. 2014;48:693–702.
   PubMed Web of Science ®Google Scholar
• Youngster I, Russell GH, Pindar C, et al. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA. 2014;312:1772–1778.
   PubMed Web of Science ®Google Scholar
• Dutta SK, Girotra M, Garg S, et al. Efficacy of combined jejunal and colonic fecal microbiota transplantation for recurrent Clostridium difficile Infection. Clin Gastroenterol Hepatol. 2014;12:1572–1576.
   PubMed Web of Science ®Google Scholar
• Kelly CR, Ihunnah C, Fischer M, et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol. 2014;109:1065–1071.
   PubMed Web of Science ®Google Scholar
• Orenstein R, Dubberke E, Hardi R, et al. Safety and durability of RBX2660 (Microbiota Suspension) for recurrent clostridium difficile infection: results of the PUNCH CD study. Clin Infect Dis. 2016;62:596–602.
   PubMed Web of Science ®Google Scholar
• Bakken JS, Borody T, Brandt LJ, et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol. 2011;9:1044–1049.
   PubMed Web of Science ®Google Scholar
• Konijeti GG, Sauk J, Shrime MG, et al. Cost-effectiveness of competing strategies for management of recurrent Clostridium difficile infection: a decision analysis. Clin Infect Dis. 2014;58:1507–1514.
   PubMed Web of Science ®Google Scholar
• Shim JK, Johnson S, Samore MH, et al. Primary symptomless colonisation by Clostridium difficile and decreased risk of subsequent diarrhoea. Lancet. 1998;351:633–636.
   PubMed Web of Science ®Google Scholar
• Sambol SP, Merrigan MM, Tang JK, et al. Colonization for the prevention of Clostridium difficile disease in hamsters. J Infect Dis. 2002;186:1781–1789.
   PubMed Web of Science ®Google Scholar
• Villano SA, Seiberling M, Tatarowicz W, et al. Evaluation of an oral suspension of VP20621, spores of nontoxigenic Clostridium difficile strain M3, in healthy subjects. Antimicrob Agents Chemother. 2012;56:5224–5229.
   PubMed Web of Science ®Google Scholar
• Gerding DN, Meyer T, Lee C, et al. Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial. JAMA. 2015;313:1719–1727.
   PubMed Web of Science ®Google Scholar
• Gergely Szabo B, Kadar B, Szidonia Lenart K, et al. Use of intravenous tigecycline in patients with severe Clostridium difficile infection: a retrospective observational cohort study. Clin Microbiol Infect. 2016;22:990–995.
   PubMed Web of Science ®Google Scholar
• Thomas A, Khan F, Uddin N, et al. Tigecycline for severe Clostridium difficile infection. Int J Infect Dis. 2014;26:171–172.
   PubMed Web of Science ®Google Scholar
• Alfandari S, Bonenfant C, Depretere L, et al., Group AHPS. Use of 27 parenteral antimicrobial agents in north of France hospitals. Med Mal Infect. 2007;37:103–107.
   PubMed Web of Science ®Google Scholar
• Martin J, Wilcox M. New and emerging therapies for Clostridium difficile infection. Curr Opin Infect Dis. 2016;29:546–554.
   PubMed Web of Science ®Google Scholar
• Gerding DN, Hecht DW, Louie T, et al. Susceptibility of Clostridium difficile isolates from a phase 2 clinical trial of cadazolid and vancomycin in C. Difficile Infection J Antimicrob Chemother. 2016;71:213–219.
   PubMed Web of Science ®Google Scholar
• Locher HH, Seiler P, Chen X, et al. In vitro and in vivo antibacterial evaluation of cadazolid, a new antibiotic for treatment of Clostridium difficile infections. Antimicrob Agents Chemother. 2014;58:892–900.
   PubMed Web of Science ®Google Scholar
• Louie T, Nord CE, Talbot GH, et al. Multicenter, double-blind, randomized, phase 2 study evaluating the novel antibiotic cadazolid in patients with clostridium difficile infection. Antimicrob Agents Chemother. 2015;59:6266–6273.
   PubMed Web of Science ®Google Scholar
• Basseres E, Endres BT, Khaleduzzaman M, et al. Impact on toxin production and cell morphology in Clostridium difficile by ridinilazole (SMT19969), a novel treatment for C. difficile infection. J Antimicrob Chemother. 2016;71:1245–1251.
   PubMed Web of Science ®Google Scholar
• Chang JY, Antonopoulos DA, Kalra A, et al. Decreased diversity of the fecal microbiome in recurrent Clostridium difficile-associated diarrhea. J Infect Dis. 2008;197:435–438.
   PubMed Web of Science ®Google Scholar
• Kyne L, Warny M, Qamar A, et al. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med. 2000;342:390–397.
   PubMed Web of Science ®Google Scholar
• Kyne L, Warny M, Qamar A, et al. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet. 2001;357:189–193.
   PubMed Web of Science ®Google Scholar
• Maynard-Smith M, Ahern H, McGlashan J, et al. Recombinant antigens based on toxins A and B of Clostridium difficile that evoke a potent toxin-neutralising immune response. Vaccine. 2014;32:700–705.
   PubMed Web of Science ®Google Scholar
• Pechine S, Gleizes A, Janoir C, et al. Immunological properties of surface proteins of Clostridium difficile. J Med Microbiol. 2005;54:193–196.
   PubMed Web of Science ®Google Scholar
• De Bruyn G, Saleh J, Workman D, et al. Defining the optimal formulation and schedule of a candidate toxoid vaccine against Clostridium difficile infection: a randomized phase 2 clinical trial. Vaccine. 2016;34:2170–2178.
   PubMed Web of Science ®Google Scholar
• Foglia G, Shah S, Luxemburger C, et al. Clostridium difficile: development of a novel candidate vaccine. Vaccine. 2012;30:4307–4309.
   PubMed Web of Science ®Google Scholar
• Sheldon E, Kitchin N, Peng Y, et al. A phase 1, placebo-controlled, randomized study of the safety, tolerability, and immunogenicity of a Clostridium difficile vaccine administered with or without aluminum hydroxide in healthy adults. Vaccine. 2016;34:2082–2091.
   PubMed Web of Science ®Google Scholar
• Kociolek LK, Gerding DN. Breakthroughs in the treatment and prevention of Clostridium difficile infection. Nat Rev Gastroenterol Hepatol. 2016;13:150–160.
   PubMed Web of Science ®Google Scholar