Advanced search
Publication Cover
Expert Review of Anti-infective Therapy Volume 12, 2014 - Issue 1
Submit an article Journal homepage
682
Views
64
CrossRef citations to date
0
Altmetric
Reviews

Clostridium difficile infection: molecular pathogenesis and novel therapeutics

Ardeshir RinehThe Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA;School of Chemistry, University of Wollongong, NSW 2522, Australia
,
Michael J KelsoSchool of Chemistry, University of Wollongong, NSW 2522, Australia
,
Fatma VatanseverThe Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA;Department of Dermatology, Harvard Medical School, Boston, MA, USA
,
George P TegosThe Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA;;Center for Molecular Discovery, University of New Mexico, Albuquerque, NM, USA
&
Michael R HamblinThe Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA;Department of Dermatology, Harvard Medical School, Boston, MA, USA;Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USACorrespondence[email protected]
Pages 131-150 | Published online: 10 Jan 2014

References

  • Bartlett JG. Narrative review: the new epidemic of Clostridium difficile-associated enteric disease. Ann. Intern. Med. 145, 758–764 (2006).
  • Brazier JS. Clostridium difficile: from obscurity to superbug. Br. J. Biomed. Sci. 65, 39–44 (2008).
  • Ozaki E, Kato H, Kita H et al. Clostridium difficile colonization in healthy adults: transient colonization and correlation with enterococcal colonization. J. Med. Microbiol. 53, 167–172 (2004).
  • Hurley BW, Nguyen CC. The spectrum of pseudomembranous enterocolitis and antibiotic-associated diarrhea. Arch. Intern. Med. 162, 2177–2184 (2002).
  • Bartlett JG. Antibiotic-associated diarrhea. Clin. Infect. Dis. 15, 573–581 (1992).
  • Bean NH, Griffin PM, Goulding JS, Ivey CB. Foodborne disease outbreaks, 5-year summary, 1983–1987. MMWR CDC Surveill. Summ. 39, 15–57 (1990).
  • Johnson S, Clabots CR, Linn FV, Olson MM, Peterson LR, Gerding DN. Nosocomial Clostridium difficile colonisation and disease. Lancet 336, 97–100 (1990).
  • Mcfarland LV, Mulligan ME, Kwok RY, Stamm WE. Nosocomial acquisition of Clostridium difficile infection. N. Engl. J. Med. 320, 204–210 (1989).
  • Adams SD, Mercer DW. Fulminant Clostridium difficile colitis. Curr. Opin. Crit. Care 13, 450–455 (2007).
  • Bartlett JG, Chang TW, Gurwith M, Gorbach SL, Onderdonk AB. Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N. Engl. J. Med. 298, 531–534 (1978).
  • Mcdonald LC, Killgore GE, Thompson A et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N. Engl. J. Med. 353, 2433–2441 (2005).
  • Warny M, Pepin J, Fang A et al. Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet 366, 1079–1084 (2005).
  • Sullivan NM, Pellett S, Wilkins TD. Purification and characterization of toxins A and B of Clostridium difficile. Infect. Immun. 35, 1032–1040 (1982).
  • Rifkin GD, Fekety FR, Silva J Jr. Antibiotic-induced colitis implication of a toxin neutralised by Clostridium sordellii antitoxin. Lancet 2, 1103–1106 (1977).
  • Bartlett JG, Onderdonk AB, Cisneros RL, Kasper DL. Clindamycin-associated colitis due to a toxin-producing species of Clostridium in hamsters. J. Infect. Dis. 136, 701–705 (1977).
  • Voth DE, Ballard JD. Clostridium difficile toxins: mechanism of action and role in disease. Clin. Microbiol. Rev. 18, 247–263 (2005).
  • Von E-SC, Boquet P, Sauerborn M, Thelestam M. Large clostridial cytotoxins--a family of glycosyltransferases modifying small GTP-binding proteins. Trends Microbiol. 4, 375–382 (1996).
  • Dove CH, Wang SZ, Price SB et al. Molecular characterization of the Clostridium difficile toxin A gene. Infect. Immun. 58, 480–488 (1990).
  • Von E-SC, Laufenberg-Feldmann R, Sartingen S, Schulze J, Sauerborn M. Comparative sequence analysis of the Clostridium difficile toxins A and B. Mol. Gen. Genet. 233, 260–268 (1992).
  • Triadafilopoulos G, Pothoulakis C, O’brien MJ, Lamont JT. Differential effects of Clostridium difficile toxins A and B on rabbit ileum. Gastroenterology 93, 273–279 (1987).
  • Jump RLP, Pultz MJ, Donskey CJ. Vegetative Clostridium difficile survives in room air on moist surfaces and in gastric contents with reduced acidity: a potential mechanism to explain the association between proton pump inhibitors and C. difficile-associated diarrhea? Antimicrob. Agents Chemother. 51, 2883–2887 (2007).
  • Wilcox MH. Gastrointestinal disorders and the critically ill. Clostridium difficile infection and pseudomembranous colitis. Best Pract. Res. Clin. Gastroenterol. 17, 475–493 (2003).
  • Gerding DN, Muto CA, Owens RC Jr. Measures to control and prevent Clostridium difficile infection. Clin. Infect. Dis. 46( Suppl. 1), S43–S49 (2008).
  • Riggs MM, Sethi AK, Zabarsky TF, Eckstein EC, Jump RLP, Donskey CJ. Asymptomatic carriers are a potential source for transmission of epidemic and nonepidemic Clostridium difficile strains among long-term care facility residents. Clin. Infect. Dis. 45, 992–998 (2007).
  • Bartlett JG. Clostridium difficile: old and new observations. J. Clin. Gastroenterol. 41( Suppl. 1), S24–S29 (2007).
  • Bartlett JG. Clinical practice. Antibiotic-associated diarrhea. N. Engl. J. Med. 346, 334–339 (2002).
  • Gorbach SL. Antibiotics and Clostridium difficile. N. Engl. J. Med. 341, 1690–1691 (1999).
  • Rupnik M, Braun V, Soehn F et al. Characterization of polymorphisms in the toxin A and B genes of Clostridium difficile. FEMS Microbiol. Lett. 148, 197–202 (1997).
  • Torres JF. Purification and characterisation of toxin B from a strain of Clostridium difficile that does not produce toxin A. J. Med. Microbiol. 35, 40–44 (1991).
  • Hammond GA, Johnson JL. The toxigenic element of Clostridium difficile strain VPI 10463. Microb. Pathol. 19, 203–213 (1995).
  • Hundsberger T, Braun V, Weidmann M, Leukel P, Sauerborn M, Von E-SC. Transcription analysis of the genes tcdA-E of the pathogenicity locus of Clostridium difficile. Eur. J. Biochem. 244, 735–742 (1997).
  • Mani N, Dupuy B. Regulation of toxin synthesis in Clostridium difficile by an alternative RNA polymerase sigma factor. Proc. Natl Acad. Sci. USA 98, 5844–5849 (2001).
  • Braun V, Hundsberger T, Leukel P, Sauerborn M, Von E-SC. Definition of the single integration site of the pathogenicity locus in Clostridium difficile. Gene 181, 29–38 (1996).
  • Rupnik M, Avesani V, Janc M, Von E-SC, Delmee M. A novel toxinotyping scheme and correlation of toxinotypes with serogroups of Clostridium difficile isolates. J. Clin. Microbiol. 36, 2240–2247 (1998).
  • Rupnik M. Heterogeneity of large clostridial toxins: importance of Clostridium difficile toxinotypes. FEMS Microbiol. Rev. 32, 541–555 (2008).
  • Geric B, Carman RJ, Rupnik M et al. Binary toxin-producing, large clostridial toxin-negative Clostridium difficile strains are enterotoxic but do not cause disease in hamsters. J. Infect. Dis. 193, 1143–1150 (2006).
  • Avbersek J, Janezic S, Pate M et al. Diversity of Clostridium difficile in pigs and other animals in Slovenia. Anaerobe 15, 252–255 (2009).
  • Geric SB, Rupnik M. Clostridium difficile toxinotype XI (A-B-) exhibits unique arrangement of PaLoc and its upstream region. Anaerobe 16, 393–395 (2010).
  • Akerlund T, Persson I, Unemo M et al. Increased sporulation rate of epidemic Clostridium difficile Type 027/NAP1. J. Clin. Microbiol. 46, 1530–1533 (2008).
  • Maccannell DR, Louie TJ, Gregson DB et al. Molecular analysis of Clostridium difficile PCR ribotype 027 isolates from Eastern and Western Canada. J. Clin. Microbiol. 44, 2147–2152 (2006).
  • Schwan C, Stecher B, Tzivelekidis T et al. Clostridium difficile toxin CDT induces formation of microtubule-based protrusions and increases adherence of bacteria. PLoS Pathol. 5(10), e1000626 (2009).
  • Bourgault A-M, Lamothe F, Loo VG, Poirier L. In vitro susceptibility of Clostridium difficile clinical isolates from a multi-institutional outbreak in southern Quebec, Canada. Antimicrob. Agents Chemother. 50, 3473–3475 (2006).
  • Drudy D, Quinn T, O’mahony R, Kyne L, O’Gaora P, Fanning S. High-level resistance to moxifloxacin and gatifloxacin associated with a novel mutation in gyrB in toxin-A-negative, toxin-B-positive Clostridium difficile. J. Antimicrob. Chemother. 58, 1264–1267 (2006).
  • Drudy D, Kyne L, O’Mahony R, Fanning S. gyrA mutations in fluoroquinolone-resistant Clostridium difficile PCR-027. Emerging Infect. Dis. 13, 504–505 (2007).
  • Carter GP, Lyras D, Allen DL et al. Binary toxin production in Clostridium difficile is regulated by CdtR, a LytTR family response regulator. J. Bacteriol. 189, 7290–7301 (2007).
  • Mcmaster-Baxter NL, Musher DM. Clostridium difficile: recent epidemiologic findings and advances in therapy. Pharmacotherapy 27, 1029–1039 (2007).
  • Blossom DB, Mcdonald LC. The challenges posed by reemerging Clostridium difficile infection. Clin. Infec. Dis. 45, 222–227 (2007).
  • Cohen SH, Tang YJ, Silva J Jr. Analysis of the pathogenicity locus in Clostridium difficile strains. J. Infect. Dis. 181, 659–663 (2000).
  • Donelli G, Fiorentini C. Bacterial protein toxins acting on the cell cytoskeleton. New Microbiol. 17(4), 345–362 (1994).
  • Just I, Hofmann F, Genth H, Gerhard R. Bacterial protein toxins inhibiting low-molecular-mass GTP-binding proteins. Int. J. Med. Microbiol. 291(4), 243–250 (2001).
  • Halabi-Cabezon I, Huelsenbeck J, May M et al. Prevention of the cytopathic effect induced by Clostridium difficile Toxin B by active Rac1. FEBS Lett. 582(27), 3751–3756 (2008).
  • Hamm EE, Voth DE, Ballard JD. Identification of Clostridium difficile toxin B cardiotoxicity using a zebrafish embryo model of intoxication. Proc. Natl Acad. Sci. USA 103(38), 14176–14181 (2006).
  • Pavliakova D, Moncrief JS, Lyerly DM et al. Clostridium difficile recombinant toxin A repeating units as a carrier protein for conjugate vaccines: Studies of pneumococcal type 14, Escherichia coli K1, and Shigella flexneri type 2a polysaccharides in mice. Infect. Immun. 68(4), 2161–2166 (2000).
  • Lyras D, O’Connor JR, Howarth PM et al. Toxin B is essential for virulence of Clostridium difficile. Nature 458(7242), 1176–1179 (2009).
  • Shin BM, Kuak EY, Yoo SJ, Shin WC, Yoo HM. Emerging toxin A-B+ variant strain of Clostridium difficile responsible for pseudomembranous colitis at a tertiary care hospital in Korea. Diagn. Microbiol. Infect. Dis. 60(4), 333–337 (2008).
  • He X, Wang J, Steele J et al. An ultrasensitive rapid immunocytotoxicity assay for detecting Clostridium difficile toxins. J. Microbiol. Methods 78(1), 97–100 (2009).
  • Steele J, Feng H, Parry N, Tzipori S. Piglet models of acute or chronic Clostridium difficile illness. J. Infect. Dis. 201(3), 428–434 (2010).
  • Dubberke ER, Reske KA, Noble-Wang J et al. Prevalence of Clostridium difficile environmental contamination and strain variability in multiple health care facilities. Am. J. Infec. Control 35(5), 315–318 (2007).
  • Roberts K, Smith CF, Snelling AM et al. Aerial dissemination of Clostridium difficile spores. BMC Infect. Dis. 8, 7 (2008).
  • Johnson S, Kent SA, O’Leary KJ et al. Fatal pseudomembranous colitis associated with a variant Clostridium difficile strain not detected by toxin A immunoassay. Ann. Intern. Med. 135(6), 434–438 (2001).
  • Jacob SS, Sebastian JC, Hiorns D, Jacob S, Mukerjee PK. Clostridium difficile and acute respiratory distress syndrome. Heart Lung 33(4), 265–268 (2004).
  • Dobson G, Hickey C, Trinder J. Clostridium difficile colitis causing toxic megacolon, severe sepsis and multiple organ dysfunction syndrome. Intensive Care Med. 29(6), 1030 (2003).
  • Cunney RJ, Magee C, Mcnamara E, Smyth EG, Walshe J. Clostridium difficile colitis associated with chronic renal failure. Nephrol. Dial. Transplant. 13(11), 2842–2846 (1998).
  • Sakurai T, Hajiro K, Takakuwa H, Nishio A, Aihara M, Chiba T. Liver abscess caused by Clostridium difficile. Scand. J. Infect. Dis. 33(1), 69–70 (2001).
  • Just I, Selzer J, Wilm M, Mann M, Aktories K. Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 375(6531), 500–503 (1995).
  • Egerer M, Giesemann T, Jank T, Fullner Satchell KJ, Aktories K. Auto-catalytic cleavage of Clostridium difficile toxins A and B depends on cysteine protease activity. J. Biol. Chem. 282(35), 25314–25321 (2007).
  • Pfeifer G, Schirmer J, Leemhuis J et al. Cellular uptake of Clostridium difficile toxin B. Translocation of the N-terminal catalytic domain into the cytosol of eukaryotic cells. J. Biol. Chem. 278(45), 44535–44541 (2003).
  • Jank T, Giesemann T, Aktories K. Rho-glucosylating Clostridium difficile toxins A and B: new insights into structure and function. Glycobiology 17(4), 15R–19R (2007).
  • Hofmann F, Busch C, Prepens U, Just I, Aktories K. Localization of the glucosyltransferase activity of Clostridium difficile toxin B to the N-terminal part of the holotoxin. J. Biol. Chem. 272(17), 11074–11078 (1997).
  • Faust C, Ye B, Song KP. The enzymatic domain of Clostridium difficile toxin A is located within its N-terminal region. Biochem. Biophys. Res. Commun. 251(1), 100–105 (1998).
  • Tucker KD, Wilkins TD. Toxin A of Clostridium difficile binds to the human carbohydrate antigens I, X, and Y. Infect. Immun. 59(1), 73–78 (1991).
  • Wren BW. A family of clostridial and streptococcal ligand-binding proteins with conserved C-terminal repeat sequences. Mol. Microbiol. 5(4), 797–803 (1991).
  • Frisch C, Gerhard R, Aktories K, Hofmann F, Just I. The complete receptor-binding domain of Clostridium difficile toxin A is required for endocytosis. Biochem. Biophys. Res. Commun. 300(3), 706–711 (2003).
  • Ho JGS, Greco A, Rupnik M, Ng KKS. Crystal structure of receptor-binding C-terminal repeats from Clostridium difficile toxin A. Proc. Natl Acad Sci USA 102(51), 18373–18378 (2005).
  • Kai Soo T, Boon Yu W, Keang Peng S. Evidence for holin function of tcdE gene in the pathogenicity of Clostridium difficile. J. Med. Microbiol. 50(7), 613–619 (2001).
  • Ferretti JJ, Gilpin ML, Russell RRB. Nucleotide sequence of a glucosyltransferase gene from Streptococcus sobrinus MFe28. J. Bacteriol. 169(9), 4271–4278 (1987).
  • Reineke J, Tenzer S, Rupnik M et al. Autocatalytic cleavage of Clostridium difficile toxin B. Nature 446(7134), 415–419 (2007).
  • Lanis JM, Barua S, Ballard JD. Variations in Tcdb activity and the hypervirulence of emerging strains of Clostridium difficile. PLoS Pathogens 6(8), 65–66 (2010).
  • Demarest SJ, Salbato J, Elia M et al. Structural characterization of the cell wall binding domains of Clostridium difficile toxins A and B; evidence that Ca2+ plays a role in toxin A cell surface association. J. Mol. Biol. 346(5), 1197–1206 (2005).
  • Elliott B, Squire MM, Thean S et al. New types of toxin A-negative, toxin B-positive strains among clinical isolates of Clostridium difficile in Australia. J. Med. Microbiol. 60(Pt 8), 1108–1111 (2011).
  • Lemee L, Dhalluin A, Pestel-Caron M, Lemeland JF, Pons JL. Multilocus sequence typing analysis of human and animal Clostridium difficile isolates of various toxigenic types. J. Clin. Microbiol. 42(6), 2609–2617 (2004).
  • Johnson S, Sambol SP, Brazier JS et al. International typing study of toxin A-negative, toxin B-positive Clostridium difficile variants. J. Clin. Microbiol. 41(4), 1543–1547 (2003).
  • Limaye AP, Turgeon DK, Cookson BT, Fritsche TR. Pseudomembranous colitis caused by a toxin A-B+ strain of Clostridium difficile. J. Clin. Microbiol. 38(4), 1696–1697 (2000).
  • Depitre C, Delmee M, Avesani V et al. Serogroup F strains of Clostridium difficile produce toxin B but not toxin A. J. Med. Microbiol. 38(6), 434–441 (1993).
  • Delmee M, Avesani V. Virulence of ten serogroups of Clostridium difficile in hamsters. J. Med. Microbiol. 33(2), 85–90 (1990).
  • Rupnik M, Kato N, Grabnar M, Kato H. New types of toxin A-negative, toxin B-positive strains among Clostridium difficile isolates from Asia. J. Clin. Microbiol. 41(3), 1118–1125 (2003).
  • Pothoulakis C, Gilbert RJ, Cladaras C et al. Rabbit sucrase-isomaltase contains a functional intestinal receptor for Clostridium difficile toxin A. J. Clin. Invest. 98(3), 641–649 (1996).
  • Pothoulakis C, Galili U, Castagliuolo I et al. A human antibody binds to α-galactose receptors and mimics the effects of Clostridium difficile toxin A in rat colon. Gastroenterology 110(6), 1704–1712 (1996).
  • Aktories K, Barbieri JT. Bacterial cytotoxins: targeting eukaryotic switches. Nat. Rev. Microbiol. 3(5), 397–410 (2005).
  • Cho W. Membrane Targeting by C1 and C2 Domains. J. Biol. Chem. 276(35), 32407–32410 (2001).
  • Dodd RB, Drickamer K. Lectin-like proteins in model organisms: Implications for evolution of carbohydrate-binding activity. Glycobiology 11(5), 71R–79R (2001).
  • Ciesla WP, Bobak DA. Clostridium difficile toxins A and B are cation-dependent UDP-glucose hydrolases with differing catalytic activities. J. Biol. Chem. 273(26), 16021–16026 (1998).
  • Fiorentini C, Donelli G, Nicotera P, Thelestam M. Clostridium difficile toxin A elicits Ca2+-independent cytotoxic effects in cultured normal rat intestinal crypt cells. Infect. Immun. 61(9), 3988–3993 (1993).
  • Gilbert RJ, Pothoulakis C, Lamont JT, Yakubovich M. Clostridium difficile toxin B activates calcium influx required for actin disassembly during cytotoxicity. Am. J. Physiol. 268(3 Pt 1), G487–G495 (1995).
  • Pruitt RN, Chagot B, Cover M, Chazin WJ, Spiller B, Lacy DB. Structure-function analysis of inositol hexakisphosphate-induced autoprocessing in Clostridium difficile toxin A. J. Biol. Chem. 284(33), 21934–21940 (2009).
  • Pruitt RN, Chambers MG, Ng KKS, Ohi MD, Lacy DB. Structural organization of the functional domains of Clostridium difficile toxins A and B. Proc. Natl Acad. Sci. USA 107(30), 13467–13472 (2010).
  • Florin I, Thelestam M. Lysosomal involvement in cellular intoxication with Clostridium difficile toxin B. Microb. Pathog. 1(4), 373–385 (1986).
  • Giesemann T, Jank T, Gerhard R et al. Cholesterol-dependent pore formation of Clostridium difficile toxin A. J. Biol. Chem. 281(16), 10808–10815 (2006).
  • Qa’dan M, Spyres LM, Ballard JD. pH-induced conformational changes in Clostridium difficile toxin B. Infect. Immun. 68(5), 2470–2474 (2000).
  • Barth H, Pfeifer G, Hofmann F, Maier E, Benz R, Aktories K. Low pH-induced formation of ion channels by Clostridium difficile toxin B in target cells. J. Biol. Chem. 276(14), 10670–10676 (2001).
  • Sandvig K, Spilsberg B, Lauvrak SU, Torgersen ML, Iversen TG, Van Deurs B. Pathways followed by protein toxins into cells. Int. J. Med. Microbiol. 293(7–8), 483–490 (2004).
  • Florin I, Thelestam M. Internalization of Clostridium difficile cytotoxin into cultured human lung fibroblasts. Biochim. Biophys. Acta 763(4), 383–392 (1983).
  • Matte I, Lane D, Côté É et al. Antiapoptotic proteins Bcl-2 and Bcl-XL inhibit Clostridium difficile toxin A-induced cell death in human epithelial cells. Infect. Immun. 77(12), 5400–5410 (2009).
  • Reed JC. Bcl-2 family proteins. Oncogene 17(25), 3225–3236 (1998).
  • Tait SWG, Green DR. Caspase-independent cell death: Leaving the set without the final cut. Oncogene 27(50), 6452–6461 (2008).
  • Taylor RC, Cullen SP, Martin SJ. Apoptosis: controlled demolition at the cellular level. Nat. Rev. Mol. Cell Biol. 9(3), 231–241 (2008).
  • Bodmer JL, Holler N, Reynard S et al. TRAIL receptor-2 signals apoptosis through FADD and caspase-8. Nature Cell Biol. 2(4), 241–243 (2000).
  • Kischkel FC, Hellbardt S, Behrmann I et al. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO 14(22), 5579–5588 (1995).
  • Muzio M, Stockwell BR, Stennicke HR, Salvesen GS, Dixit VM. An induced proximity model for caspase-8 activation. J. Biol. Chem. 273(5), 2926–2930 (1998).
  • Gonçalves C, Decré D, Barbut F, Burghoffer B, Petit JC. Prevalence and Characterization of a Binary Toxin (Actin-Specific ADP-Ribosyltransferase) from Clostridium difficile. J. Clin. Microbiol. 42(5), 1933–1939 (2004).
  • Geric B, Johnson S, Gerding DN, Grabnar M, Rupnik M. Frequency of binary toxin genes among Clostridium difficile strains that do not produce large clostridial toxins. J. Clin. Microbiol. 41(11), 5227–5232 (2003).
  • Sorg JA, Sonenshein AL. Bile salts and glycine as cogerminants for Clostridium difficile spores. J. Bacteriol. 190(7), 2505–2512 (2008).
  • Henriques AO, Moran CP, Jr. Structure, assembly, and function of the spore surface layers. Annu. Rev. Microbiol. 61, 555–588 (2007).
  • Jarvis WR, Schlosser J, Jarvis AA, Chinn RY. National point prevalence of Clostridium difficile in US health care facility inpatients, 2008. Am. J. Infect. Control 37(4), 263–270 (2009).
  • Vollaard EJ, Clasener HaL. Colonization resistance. Antimicrob. Agents Chemother. 38(3), 409–414 (1994).
  • Drudy D, Harnedy N, Fanning S, O’Mahony R, Kyne L. Isolation and characterisation of toxin A-negative, toxin B-positive Clostridium difficile in Dublin, Ireland. Clin. Microbiol. Infec. 13(3), 298–304 (2007).
  • Stecher B, Hardt WD. The role of microbiota in infectious disease. Trends Microbiol. 16(3), 107–114 (2008).
  • Stecher B, Robbiani R, Walker AW et al. Salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS Biol. 5(10), 2177–2189 (2007).
  • Kuipers EJ, Surawicz CM. Clostridium difficile infection. Lancet 371(9623), 1486–1488 (2008).
  • Powell RC, Nunes WT, Harding RS, Vacca JB. The influence of nonabsorbable antibiotics on serum lipids and the excretion of neutral sterols and bile acids. Am. J. Clin. Nutr. 11, 156–168 (1962).
  • Rolfe RD, Helebian S, Finegold SM. Bacterial interference between Clostridium difficile and normal fecal flora. J. Infect. Dis. 143(3), 470–475 (1981).
  • Giel JL, Sorg JA, Sonenshein AL, Zhu J. Metabolism of bile salts in mice influences spore germination in Clostridium difficile. PLoS ONE 5(1), e8740 (2010).
  • Cloud J, Kelly CP. Update on Clostridium difficile associated disease. Curr. Opp. Gastroenterol. 23(1), 4–9 (2007).
  • Setlow P. Spore germination. Curr. Opp. Microbiol. 6(6), 550–556 (2003).
  • Wax R, Freese E, Cashel M. Separation of two functional roles of L-alanine in the initiation of Bacillus subtilis spore germination. J. Bacteriol. 94(3), 522–529 (1967).
  • Corzo G, Gilliland SE. Bile salt hydrolase activity of three strains of Lactobacillus acidophilus. J. Dairy Sci. 82(3), 472–480 (1999).
  • Carey Jr JB, Watson CJ. Isolation of deoxycholic acid from normal human feces. J. Biol. Chem. 216(2), 847–850 (1955).
  • Makita M, Wells WW. Quantitative analysis of fecal bile acids by gas-liquid chromatography. Anal. Biochem. 5(6), 523–530 (1963).
  • Thomas LA, Veysey MJ, French G, Hylemon PB, Murphy GM, Dowling RH. Bile acid metabolism by fresh human colonic contents: a comparison of caecal versus faecal samples. Gut 49(6), 835–842 (2001).
  • Kamiya S, Yamakawa K, Ogura H, Nakamura S. Recovery of spores of Clostridium difficile altered by heat or alkali. J. Med. Microbiol. 28(3), 217–221 (1989).
  • Weese JS, Staempfli HR, Prescott JF. Isolation of environmental Clostridium difficile from a veterinary teaching hospital. J. Vet. Diagnost. Investig. 12(5), 449–452 (2000).
  • Wilson KH, Kennedy MJ, Fekety FR. Use of sodium taurocholate to enhance spore recovery on a medium selective for Clostridium difficile. J. Clin. Microbiol. 15(3), 443–446 (1982).
  • Fisher N, Hanna P. Characterization of Bacillus anthracis germinant receptors in vitro. J. Bacteriol. 187(23), 8055–8062 (2005).
  • Hornstra LM, De Vries YP, Wells-Bennik MHJ, De Vos WM, Abee T. Characterization of germination receptors of Bacillus cereus ATCC 14579. Appl. Environmen. Microbiol. 72(1), 44–53 (2006).
  • Ramirez N, Liggins M, Abel-Santos E. Kinetic evidence for the presence of putative germination receptors in Clostridium difficile spores. J. Bacteriol. 192(16), 4215–4222 (2010).
  • Freeman J, Wilcox MH. Antibiotics and Clostridium difficile. Microb. Infect. 1(5), 377–384 (1999).
  • Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J. Lipid Res. 47(2), 241–259 (2006).
  • Edenharder R. Dehydroxylation of cholic acid at C12 and epimerization at C5 and C7 by Bacteroides species. J. Steroid Biochem. 21(4), 413–420 (1984).
  • Hashimoto S, Igimi H, Uchida K, Satoh T, Benno Y, Takeuchi N. Effects of β-lactam antibiotics on intestinal microflora and bile acid metabolism in rats. Lipids 31(6), 601–609 (1996).
  • Lancaster JW, Matthews SJ. Fidaxomicin: the newest addition to the armamentarium against Clostridium difficile infections. Clin. Ther. 34, 1–13 (2012).
  • Kopterides P, Papageorgiou C, Antoniadou A et al. Failure of tigecycline to treat severe Clostridium difficile infection. Anaesth. Intensive Care 38(4), 755–758 (2010).
  • Johnson S, Schriever C, Galang M, Kelly CP, Gerding DN. Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin. Infect. Dis. 44, 846–848 (2007).
  • Pelaez T, Alcala L, Alonso R et al. In vitro activity of ramoplanin against Clostridium difficile, including strains with reduced susceptibility to vancomycin or with resistance to metronidazole. Antimicrob. Agents Chemother. 49, 1157–1159 (2005).
  • Freeman J, Baines SD, Jabes D, Wilcox MH. Comparison of the efficacy of ramoplanin and vancomycin in both in vitro and in vivo models of clindamycin-induced Clostridium difficile infection. J. Antimicrob. Chemother. 56, 717–725 (2005).
  • Chen YX, Cabana B, Kivel N, Michaelis A. Effect of food on the pharmacokinetics of rifalazil, a novel antibacterial, in healthy male volunteers. J. Clin. Pharmacol. 47, 841–849 (2007).
  • Anton PM, O’Brien M, Kokkotou E et al. Rifalazil treats and prevents relapse of Clostridium difficile-associated diarrhea in hamsters. Antimicrob. Agents Chemother. 48, 3975–3979 (2004).
  • Zoetendal EG, Vaughan EE, De Vos WM. A microbial world within us. Mol. Microbiol. 59(6), 1639–1650 (2006).
  • Mercenier A, Muller-Alouf H, Grangette C. Lactic acid bacteria as live vaccines. Curr. Issues Mol. Biol. 2(1), 17–25 (2000).
  • Goldenberg JZ, Ma SS, Saxton JD et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst. Rev. 5, CD006095 (2013).
  • Jena PK, Trivedi D, Chaudhary H, Sahoo TK, Seshadri S. Bacteriocin PJ4 active against enteric pathogen produced by Lactobacillus helveticus PJ4 isolated from gut microflora of wistar rat (Rattus norvegicus): partial purification and characterization of bacteriocin. Appl. Biochem. Biotechnol. 169(7), 2088–2100 (2013).
  • Mcfarland LV, Surawicz CM, Greenberg RN et al. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA 271, 1913–1918 (1994).
  • 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. 31, 1012–1017 (2000).
  • Eiseman B, Silen W, Bascom GS, Kauvar AJ. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 44(5), 854–859 (1958).
  • Van NE, Vrieze A, Nieuwdorp M et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368, 407–415 (2013).
  • Rohlke F, Stollman N. Fecal microbiota transplantation in relapsing Clostridium difficile infection. Therap. Adv. Gastroenterol. 5, 403–420 (2012).
  • Chang JY, Antonopoulos DA, Kalra A et al. Decreased diversity of the fecal Microbiome in recurrent Clostridium difficile-associated diarrhea. J. Infect. Dis. 197, 435–438 (2008).
  • Kelly CP. Fecal microbiota transplantation - an old therapy comes of age. N. Engl. J. Med. 368(5), 474–475 (2013).
  • Vyas D, L’esperance H E, Vyas A. Stool therapy may become a preferred treatment of recurrent Clostridium difficile? World J. Gastroenterol. 19(29), 4635–4637 (2013).
  • Allen-Vercoe E, Petrof EO. Artificial stool transplantation: progress towards a safer, more effective and acceptable alternative. Expert Rev. Gastroenterol. Hepatol. 7, 291–293 (2013).
  • Shone C, Landon J. Antibodies to Clostridium difficile toxins. ( WO2010094970 A1), 53pp. (2010).
  • Warny M, Vaerman JP, Avesani V, Delmee M. Human antibody response to Clostridium difficile toxin A in relation to clinical course of infection. Infect. Immun. 62(2), 384–389 (1994).
  • Kyne L, Warny M, Qamar A, Kelly CP. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet 357(9251), 189–193 (2001).
  • Phillips C. Serum antibody responses to Clostridium difficile toxin A: predictive and protective? Gut 49(2), 167–168 (2001).
  • Giannasca PJ, Warny M. Active and passive immunization against Clostridium difficile diarrhea and colitis. Vaccine 22(7), 848–856 (2004).
  • Kyne L. Clostridium difficile - Beyond antibiotics. N. Engl. J. Med. 362(3), 264–265 (2010).
  • Yoshida M, Kobayashi K, Kuo TT et al. Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria. J. Clin. Invest. 116(8), 2142–2151 (2006).
  • Leung DYM, Kelly CP, Boguniewicz M, Pothoulakis C, Lamont JT, Flores A. Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin. J. Pediatrics 118(4 I), 633–637 (1991).
  • Salcedo J, Keates S, Pothoulakis C et al. Intravenous immunoglobulin therapy for severe Clostridium difficile colitis. Gut 41(3), 366–370 (1997).
  • Wilcox MH. Descriptive study of intravenous immunoglobulin for the treatment of recurrent Clostridium difficile diarrhoea. J. Antimicrob. Chemother. 53(5), 882–884 (2004).
  • 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. 342(6), 390–397 (2000).
  • Kelly CP. Immune response to Clostridium difficile infection. Eur. J. Gastroenterol. Hepatol. 8(11), 1048–1053 (1996).
  • Kyne L, Kelly CP. Prospects for a vaccine for Clostridium difficile. BioDrugs 10, 173–181 (1998).
  • Lyerly DM, Phelps CJ, Toth J, Wilkins TD. Characterization of toxins A and B of Clostridium difficile with monoclonal antibodies. Infect. Immun. 54(1), 70–76 (1986).
  • Jori G, Fabris C, Soncin M et al. Photodynamic therapy in the treatment of microbial infections: basic principles and perspective applications. Lasers Surg. Med. 38, 468–481 (2006).
  • Babcock GJ, Broering TJ, Hernandez HJ et al. Human monoclonal antibodies directed against toxins A and B prevent Clostridium difficile-induced mortality in hamsters. Infect. Immun. 74(11), 6339–6347 (2006).
  • Johnson S, Gerding DN, Janoff EN. Systemic and mucosal antibody responses to toxin A in patients infected with Clostridium difficile. J. Infect. Dis 166(6), 1287–1294 (1992).
  • Fekety R. Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis. Am. J. Gastroenterol. 92(5), 739–750 (1997).
  • Kelly CP, Pothoulakis C, Vavva F et al. Anti-Clostridium difficile bovine immunoglobulin concentrate inhibits cytotoxicity and enterotoxicity of C. difficile toxins. Antimicrob. Agents Chemother. 40(2), 373–379 (1996).
  • Giannasca PJ, Zhang ZX, Lei WD et al. Serum antitoxin antibodies mediate systemic and mucosal protection from Clostridium difficile disease in hamsters. Infect. Immun. 67(2), 527–538 (1999).
  • Powers DB, Amersdorfer P, Poul MA et al. Expression of single-chain Fv-Fc fusions in Pichia pastoris. J. Immunol. Methods 251(1–2), 123–135 (2001).
  • Zhang J, Mackenzie R, Durocher Y. Production of chimeric heavy-chain antibodies. Methods Mol. Biol. 525, 323–336 (2009).
  • Harmsen MM, De Haard HJ. Properties, production, and applications of camelid single-domain antibody fragments. Appl. Microbiol. Biotechnol. 77(1), 13–22 (2007).
  • Harmsen MM, Van Solt CB, Van Zijderveld-Van Bemmel AM, Niewold TA, Van Zijderveld FG. Selection and optimization of proteolytically stable llama single-domain antibody fragments for oral immunotherapy. Appl. Microbiol. Biotechnol. 72(3), 544–551 (2006).
  • Famm K, Hansen L, Christ D, Winter G. Thermodynamically stable aggregation-resistant antibody domains throughdirected evolution. J. Mol. Biol. 376(4), 926–931 (2008).
  • Jespers L, Schon O, Famm K, Winter G. Aggregation-resistant domain antibodies selected on phage by heat denaturation. Nature Biotechnol. 22(9), 1161–1165 (2004).
  • Stijlemans B, Conrath K, Cortez-Retamozo V et al. Efficient targeting of conserved cryptic epitopes of infectious agents by single domain antibodies: African trypanosomes as paradigm. J. Biol. Chem. 279(2), 1256–1261 (2004).
  • De Genst E, Silence K, Decanniere K et al. Molecular basis for the preferential cleft recognition by dromedary heavy-chain antibodies. Proc. Natl Acad. Sci. USA 103(12), 4586–4591 (2006).
  • Stanfield RL, Dooley H, Flajnik MF, Wilson IA. Crystal structure of a shark single-domain antibody V region in complex with lysozyme. Science 305(5691), 1770–1773 (2004).
  • Desmyter A, Transue TR, Ghahroudi MA et al. Crystal structure of a camel single-domain V(H) antibody fragment in complex with lysozyme. Nat. Structural. Biol. 3(9), 803–811 (1996).
  • Hussack G, Tanha J. Toxin-specific antibodies for the treatment of Clostridium difficile: current status and future perspectives. Toxins 2, 998–1018 (2010).
  • Jori G, Brown SB. Photosensitized inactivation of microorganisms. Photochem. Photobiol. Sci. 3, 403–405 (2004).
  • Bonnett R. Chemical Aspects of Photodynamic Therapy. Gordon & Breach, UK, 451, (2000).
  • Wainwright M. Photodynamic antimicrobial chemotherapy (PACT). J. Antimicrob. Chemother. 42, 13–28 (1998).
  • Calin MA, Parasca SV. Light sources for photodynamic inactivation of bacteria. Lasers Med. Sci. 24, 453–460 (2009).
  • Hamblin MR, Hasan T. Photodynamic therapy: a new antimicrobial approach to infectious disease? Photochem. Photobiol. Sci. 3, 436–450 (2004).
  • Harris F, Chatfield LK, Phoenix DA. Phenothiazinium based photosensitisers - photodynamic agents with a multiplicity of cellular targets and clinical applications. Curr. Drug Targets 6, 615–627 (2005).
  • Ergaieg K, Chevanne M, Cillard J, Seux R. Involvement of both Type I and Type II mechanisms in Gram-positive and Gram-negative bacteria photosensitization by a meso-substituted cationic porphyrin. Sol. Energy 82, 1107–1117 (2008).
  • Van DBH, Mizeret J, Theumann JF et al. Light distributors for photodynamic therapy. Proc. SPIE Int. Soc. Opt. Eng. 2631, 173–198 (1995).
  • Tegos GP, Demidova TN, Arcila-Lopez D et al. Cationic fullerenes are effective and selective antimicrobial photosensitizers. Chem. Biol. 12, 1127–1135 (2005).
  • Huang L, Huang Y-Y, Mroz P et al. Stable synthetic cationic bacteriochlorins as selective antimicrobial photosensitizers. Antimicrob. Agents Chemother. 54, 3834–3841 (2010).
  • Castano AP, Demidova TN, Hamblin MR. Mechanisms in photodynamic therapy: part one-photosensitizers, photochemistry and cellular localization. Photodiagn. Photodyn. Ther. 1, 279–293 (2005).
  • Wainwright M, Phoenix DA, Laycock SL, Wareing DRA, Wright PA. Photobactericidal activity of phenothiazinium dyes against methicillin-resistant strains of Staphylococcus aureus. FEMS Microbiol. Lett. 160, 177–181 (1998).
  • Wainwright M, Phoenix DA, Gaskell M, Marshall B. Photobactericidal activity of methylene blue derivatives against vancomycin-resistant Enterococcus spp. J. Antimicrob. Chemother. 44, 823–825 (1999).
  • Demidova TN, Gad F, Zahra T, Francis KP, Hamblin MR. Monitoring photodynamic therapy of localized infections by bioluminescence imaging of genetically engineered bacteria. J. Photochem. Photobiol. B. 81, 15–25 (2005).
  • Caminos DA, Spesia MB, Durantini EN. Photodynamic inactivation of Escherichia coli by novel meso-substituted porphyrins by 4-(3-N,N,N-trimethylammoniumpropoxy)phenyl and 4-(trifluoromethyl)phenyl groups. Photochem. Photobiol. Sci. 5(1), 56–65 (2006).
  • Wainwright M, Dai T, Hamblin MR. Antimicrobial photodynamic therapy in the colon: delivering a light punch to the guts? Photochem. Photobiol. 87, 754–756 (2011).
  • Cassidy CM, Tunney MM, Caldwell DL, Andrews GP, Donnelly RF. Development of novel oral formulations prepared via hot melt extrusion for targeted delivery of photosensitizer to the colon. Photochem. Photobiol. 87, 867–876 (2011).
  • Foley JW, Song X, Demidova TN, Jilal F, Hamblin MR. Synthesis and properties of benzo[α]phenoxazinium chalcogen analogues as novel broad-spectrum antimicrobial photosensitizers. J. Med. Chem. 49, 5291–5299 (2006).
  • Evans CL, Abu-Yousif AO, Park YJ et al. Killing hypoxic cell populations in a 3D tumor model with EtNBS-PDT. PLoS ONE 6(8), e23434 (2011).
  • Zhang P, Ng K, Ling CC. Total synthesis of LeA-LacNAc pentasaccharide as a ligand for Clostridium difficile toxin A. Org. Biomol. Chem. 8(1), 128–136 (2010).
  • Bartlett JG, Perl TM. The new Clostridium difficile - What does it mean? N. Engl. J. Med. 353(23), 2503–2505 (2005).
  • Reinert DJ, Jank T, Aktories K, Schulz GE. Structural basis for the function of Clostridium difficile toxin B. J. Mol. Biol. 351(5), 973–981 (2005).
  • Pear SM, Williamson TH, Bettin KM, Gerding DN, Galgiani JN. Decrease in nosocomial Clostridium difficile-associated diarrhea by restricting clindamycin use. Ann. Intern. Med. 120(4), 272–277 (1994).

Patents

  • Fang L, Marquardt RR, Sellen RT: US20110020356 (2008).
  • Songer JG, Cama VA, Sterling CR: WO1999002188 (1999).

Website

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Order Reprints Request Corporate Permissions

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

Request Academic Permissions

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.