Therapies on the horizon for Clostridium difficile infections

Expert Opinion on Investigational Drugs

Volumn 25, Issue 5, 2016, Pages 541-555

  McFarland, Lynne V ^a  

^a UNIVERSITY OF WASHINGTON   (United States)

Author keywords

Antibiotics; clostridium difficile; fecal microbial transplant; monoclonal antibodies; novel therapeutics; prevention; probiotics; toxin binders; treatments; vaccines

Indexed keywords

ACTIVATED CARBON; ANTIBIOTIC AGENT; BACTERIAL VACCINE; BEZLOTOXUMAB; CADAZOLID; CLOSTRIDIUM DIFFICILE TOXIN A; CLOSTRIDIUM DIFFICILE TOXIN B; CLOSTRIDIUM DIFFICILE VACCINE; CNCM I 745; DAV 132; FIDAXOMICIN; FUSIDIC ACID; LFF 571; METRONIDAZOLE; NEW DRUG; NITAZOXANIDE; NVB 302; PF 06425090; PROBIOTIC AGENT; RAMOPLANIN; RIFAMPICIN; RIFAXIMIN; SUROTOMYCIN; SYN 004; TEICOPLANIN; TIGECYCLINE; TOLEVAMER; UNCLASSIFIED DRUG; UNINDEXED DRUG; VANCOMYCIN; [2,2' BIS (4 PYRIDYL) 3H,3'H 5,5' BIBENZIMIDAZOLE]; ANTIINFECTIVE AGENT;

ACTIVE IMMUNIZATION; ANTIBIOTIC THERAPY; BACTERIAL COLONIZATION; CLOSTRIDIUM BUTYRICUM; CLOSTRIDIUM DIFFICILE INFECTION; COLON FLORA; DISINFECTION; DRUG EFFICACY; DRUG EXPOSURE; DRUG USE; EXPERIMENTAL THERAPY; FECAL MICROBIOTA TRANSPLANTATION; GROUPS BY AGE; HAND WASHING; HOSPITALIZATION; HOST RESISTANCE; HUMAN; INFECTION CONTROL; INFECTION PREVENTION; MAXIMUM PLASMA CONCENTRATION; MINIMUM MICROBICIDAL CONCENTRATION; MONOTHERAPY; NONHUMAN; NUCLEIC ACID SYNTHESIS; NURSING HOME; PASSIVE IMMUNIZATION; PEPTOCLOSTRIDIUM DIFFICILE; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHASE 4 CLINICAL TRIAL (TOPIC); PRIMARY PREVENTION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SACCHAROMYCES BOULARDII; SPORE GERMINATION; ANIMAL; CLOSTRIDIUM INFECTION;

ANIMALS; ANTI-BACTERIAL AGENTS; CLOSTRIDIUM DIFFICILE; CLOSTRIDIUM INFECTIONS; DRUGS, INVESTIGATIONAL; HUMANS;

EID: 84961392817     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.2016.1161025     Document Type: Review

References (87)

1. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Eng J Med. 2015; 372: 825-834.
2. Magill SS, Edwards JR, Bamberg W, et al. Multistate point-prevalence survey of health care-associated infections. N Engl J Med. 2014; 370 (13): 1198-1208.
3. Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med. 2015; 372 (16): 1539-1548.
4. Evans CT, Safdar N. Current Trends in the epidemiology and outcomes of Clostridium difficile infection. Clin Infect Dis. 2015; 60 (S2): S66-1.
5. Sammons JS, Toltzis P. Recent trends in the epidemiology and treatment of C. difficile infection in children. Curr Opin Pediatr. 2013; 25: 116-121.
6. McFarland LV, Brandmarker SA, Guandalini S. Pediatric Clostridium difficile: a phantom menace or clinical reality? J Pediatr Gastroenterol Nutr. 2000; 31 (3): 220-231.
7. McFarland LV. Renewed interest in a difficult disease: Clostridium difficile infections-epidemiology and current treatment strategies. Curr Opin Gastroenterol. 2008; 25: 24-35.
8. Ramanathan S, Johnson S, Burns SP, et al. Recurrence of Clostridium difficile infection among veterans with spinal cord injury and disorder. Am J Infect Control. 2014; 42 (2): 168-173.
9. Jarrad AM, Karoli T, Blaskovich MA, et al. Clostridium difficile drug pipeline: challenges in discovery and development of new agents. J Med Chem. 2015; 58: 5164-5185.
10. Ünal CM, Steinert M. Novel therapeutic strategies for Clostridium difficile infections. Expert Opin Ther Targets. 2015; 13: 1-7.
11. Clinical trials website. [ Cited 2015 Nov 13[. Available from: http://clinicaltrials.gov.
12. McFarland LV, Beneda HW, Clarridge JE, et al. Implications of the changing face of Clostridium difficile disease for health care practitioners. Am J Infect Control. 2007; 35: 237-253.
13. Huang H, Wu S, Chen R, et al. Risk factors of Clostridium difficile infections among patients in a university hospital in Shanghai, China. Anaerobe. 2014; 30: 65-69.
14. McFarland LV, Mulligan ME, Kwok RYY, et al. Nosocomial acquisition of Clostridium difficile infection. N Engl J Med. 1989; 320: 204-210.
15. Brazier JS, Fitzgerald TC, Hosein I, et al. Screening for carriage and nosocomial acquisition of Clostridium difficile by culture: a study of 284 admissions of elderly patients to six general hospitals in Wales. J Hosp Infect. 1999; 43 (4): 317-319.
16. Dietrich CG, Kottmann T, Alavi M. Commercially available probiotic drinks containing Lactobacillus casei DN-114001 reduce antibiotic-associated diarrhea. World J Gastroenterol. 2014; 20 (42): 15837-15844.
17. McFarland LV, Surawicz CM, Rubin M, et al. Recurrent Clostridium difficile disease: epidemiology and clinical characteristics. Infect Control Hosp Epidemiol. 1999; 20: 43-50.
18. Fekety R, McFarland LV, Surawicz CM, et al. Recurrent Clostridium difficile diarrhea: characteristics of and risk factors for patients enrolled in a prospective, randomized, double-blinded trial. Clin Infect Dis. 1997; 24: 324-333.
19. Lofgren ET. Hospital-acquired Clostridium difficile infections: estimating all-cause mortality and length of stay. Epidemiology. 2014; 25 (4): 570-575.
20. Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013; 108 (4): 478-498.
21. Goldstein EJ, Johnson S, Maziade PJ, et al. Pathway to prevention of nosocomial Clostridium difficile infection. Clin Infect Dis. 2015; 60 (S2): S148-158.
22. Wenisch JM, Equiluz-Bruck S, Fudel M, et al. Decreasing Clostridium difficile infections by an antimicrobial stewardship program that reduces moxifloxacin use. Antimicrob Agents Chemother. 2014; 58 (9): 5079-5083.
23. Halsey J. Current and future treatment modalities for Clostridium difficile-associated disease. Am J Health Syst Pharm. 2008; 65 (8): 705-715.
24. Maziade PJ, Andriessen JA, Pereira P, et al. Impact of adding prophylactic probiotics to a bundle of standard preventative measures for Clostridium difficile infections: enhanced and sustained decrease in the incidence and severity of infection at a community hospital. Curr Med Res Opin. 2013; 29 (10): 1341-347.
25. Maziade PJ, Pereira P, Goldstein EJ. A decade of experience in primary prevention of Clostridium difficile infection at a Community Hospital using the probiotic combination Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R, and Lactobacillus rhamnosus CLR2 (Bio-K+). Clin Infect Dis. 2015; 60 (S2): S144-147.
26. Olson B, Floyd RA, Howard J, et al. A multipronged approach to decrease the risk of C. difficile infection at a community hospital and long-term care facility. J Clin Outcomes Manag. 2015; 22 (9): 398-06.
27. Sartelli M, Malangoni MA, Abu-Zidan FM, et al. WSES guidelines for management of Clostridium difficile infection in surgical patients. World J Emerg Surg. 2015; 10: 38.
28. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol. 2002; 97 (7): 1769-1775.
29. Cornely OA, Miller MA, Louie TJ, et al. Treatment of first recurrence of Clostridium difficile infection: fidaxomicin versus vancomycin. Clin Infect Dis. 2012; 55 (S2): S154-161.
30. 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.
31. Babakhani F, Bouillaut L, Gomez A, et al. Fidaxomicin inhibits spore production in Clostridium difficile. Clin Infect Dis. 2012; 55 (S2): S162-169.
32. 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.
33. Wagner M, Lavoie L, Goetghebeur M. Clinical and economic consequences of vancomycin and fidaxomicin for the treatment of Clostridium difficile infection in Canada. Can J Infect Dis Med Microbiol. 2014; 25 (2): 87-94.
34. Hu MY, Katchar K, Kyne L, et al. Prospective derivation and validation of a clinical prediction rule for recurrent Clostridium difficile infection. Gastroenterol. 2009; 136 (4): 1206-1214.
35. McFarland LV. Update on the changing epidemiology of Clostridium difficile-associated disease. Nature Clin Pract Gastroenterol Hepatol. 2008; 5 (1): 40-48.
36. 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 (10): 6266-6273.
37. Wullt M, Odenholt I. A double-blind randomized controlled trial of fusidic acid and metronidazole for treatment of an initial episode of Clostridium difficile-associated dharrhoea. J Antimicrob Chemother. 2004; 54: 211-216.
38. Bhansali SG, Mullane K, Ting LS, et al. Pharmacokinetics of LFF571 and vancomycin in patients with moderate Clostridium difficile infections. Antimicrob Agents Chemother. 2015; 59 (3): 1441-1445.
39. 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 (4): e41.
40. Novacta website. NVB302. [ Cited 2015 Nov 13[. Available from: http://www.novactabio.com.
41. Fulco P, Wenzel RP. Ramoplanin: a topical lipoglycodepsipeptide antibacterial agent. Expert Rev Anti Infect. 2006; 4: 939-945.
42. Lagrotteria D, Holmes S, Smiega 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.
43. 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 diarrhea in patients with Clostridium difficile infection. J Antimicrob Chemother. 2011; 66: 2850-2855.
44. Vickers R, Robinson N, Best E, et al. A randomized phase 1 study to investigate safety, pharmacokinetics and impact on gut microbiota following single and multiple oral doses in healthy male subjects of SMT19969, a novel agent for C. difficile infections. BMC Infect Dis. 2015; 15: 91-101.
45. Chesnel L, Sambol S, Gerding D, et al. Treatment of CDAD with oral CB-183 315: time to recurrence, relapse and re-infection rates compared with vancomycin. Clin Microbiol Infect. 2012; 18 (S3): 380. Meeting abstract #P1439. 22nd Euro Congress Clinic Micro & Infect Disease, London March 31-April 3, 2012.
46. Wenisch C, Parschalk B, Hasenhündl 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.
47. de Gunzburg J, Ducher A, Modess C, et al. Targeted adsorption of molecules in the colon with the novel adsorbent-based medicinal product, DAV132: A proof of concept study in healthy subjects. J Clin Pharmacol. 2015; 55 (1): 10-16.
48. 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.
49. Pochapin M. The effect of probiotics on Clostridium difficile diarrhea. Am J Gastroenterol. 2000; 95 (S1): S11-13.
50. Wullt M, Hagslatt MJ, 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.
51. Van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013; 368 (5): 407-415.
52. Fujii H, Maruyama K, Moriguti M, et al. Effect of C. butyricum when combined with vancomycin in treatment of Clostridium difficile-associated diarrhea. Jap J Pharmaceut Health Care Sci. 2006; 32: 1-6.
53. 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. J Amer Med Asso. 2015; 313 (17): 1719-1727.
54. Juang P, Skledar SJ, Zgheib NK, et al. Clinical outcomes of intravenous immune globulin in severe Clostridium difficile-associated diarrhea. Am J Infect Control. 2007; 35: 131-137.
55. Gerding D. Bezlotoxumab prevents C. difficile infection recurrence: results of the MODIFY II trial. 2015 Abstract 2028. Presented at the ICAAC/ICC Meeting; 2015 Sept 17-21; San Diego.
56. Demarest SJ, Hariharan M, Elia M, et al. Neutralization of Clostridium difficile toxin A using antibody combinations. MAbs. 2010; 2 (2): 190-198.
57. Marozsan AJ, Ma D, Nagashima KA, et al. Protection against Clostridium difficile infection with broadly neutralizing antitoxin monoclonal antibodies. J Infect Dis. 2012; 206 (5): 706-713.
58. Foglia G, Shah S, Luxemburger C, et al. Clostridium difficile: development of a novel candidate vaccine. Vaccine. 2012; 30 (29): 4307-4309.
59. Sougioultzis S, Kyne L, Drudy D, et al. Clostridium difficile toxoid vaccine in recurrent C. difficile-associated diarrhea. Gastroenterol. 2005; 128: 764-767.
60. Pfizer website. PF-06425090 vaccine product. [ Cited 2015 Nov 13[. Available from: http://pfizer.com.
61. Mogg GA, George RH, Youngs D, et al. Randomized controlled trial of colestipol in antibiotic-associated colitis. Br J Surg. 1982; 69: 137-139.
62. Synsorb Biotech Inc. website. [ Cited 2011 Jun 3[. Available from: http://synsorb.com.
63. 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 (3): 345-354.
64. Locher HH, Caspers P, Bruyère T, et al. Investigations of the mode of action and resistance development of cadazolid, a new antibiotic for treatment of Clostridium difficile infections. Antimicrob Agents Chemother. 2014; 58 (2): 901-908.
65. Di Bella S, Nissi C, Petrosillo N. Is tigecycline a suitable option for Clostridium difficile infection? Internl J Antimicrob Agents. 2015; 46: 8-12.
66. Norén T, Wullt M, Akerlund T, et al. Frequent emergence of resistance in Clostridium difficile during treatment of C. difficile-associated diarrhea with fusidic acid. Antimicrob Agents Chemother. 2006; 50 (9): 3028-3032.
67. Cammarota G, Masucci L, Ianiro G, et al. A. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Therap. 2015; 41: 835-843.
68. Musher DM, Logan N, Mehendiratta V, et al. Clostridium difficile colitis that fails conventional metronidazole therapy: response to nitazoxanide. J Antimicrob Chemother. 2007; 59: 705-710.
69. Musher D, Logan N, Hamill RJ, et al. Nitazoxanide for the treatment of Clostridium difficile colitis. Clin Infect Dis. 2006; 43: 421-431.
70. Crowther GS, Baines SD, Todhunter SL, et al. Evaluation of NVB302 versus vancomycin activity in an in vitro human gut model of Clostridium difficile infection. J Antimicrob Chemother. 2013; 68 (1): 168-176.
71. Huang JS, Jiang ZD, Garey KW, et al. Use of rifamycin drugs and development of infection by rifamycin-resistant strains of Clostridium difficile. Antimicrob Agents Chemother. 2013; 57 (6): 2690-2693.
72. Cubist website 2010. [ Cited 2011 Jan 7[. Available from: www.cubist.com/downloads/CBST-Investor-Event2010-CDAD.pdf.
73. Nagy E, Dowzicky MJ. In vitro activity of tigecycline and comparators against a European compilation of anaerobes collected as part of the Tigecycline Evaluation and Surveillance Trial (TEST). Scand J Infect Dis. 2010; 42 (1): 33-38.
74. Hill C, Guarner F, Reid G, et al. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014; 11 (8): 506-514.
75. McFarland LV. From yaks to yogurt: the history, development and current use of probiotics. Clin Infect Dis. 2015; 60 (S2): S85-S90.
76. Surawicz CM, McFarland LV, Elmer GW, et al. Treatment of recurrent Clostridium difficile colitis with vancomycin and Saccharomyces boulardii. Am J Gastroenterol. 1989; 84 (10): 1285-1287.
77. 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. J Amer Med Asso. 1994; 271: 1913-1918.
78. Drekonja D, Reich J, Gezahegn S, et al. Fecal microbiota transplantation for C. difficile infection. A systematic review. Ann Intern Med. 2015; 162 (9): 630-639.
79. Hamilton MJ, Weingarden AR, Sadowsky MJ, et al. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012; 107: 761-767.
80. Youngster I, Sauk J, Pindar C, et al. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis. 2014; 58: 1515-1522.
81. Youngster I, Russell GH, Pindar C, et al. Oral capsulized, frozen fecal transplantation for relapsing Clostridium difficile infection. J Amer Med Asso. 2014; 12 (17): 1772-1778.
82. Orenstein R, Dubberke E, Hardi R, et al. PUNCH CD Investigators. Safety and durability of RBX2660 (microbiota suspension) for recurrent Clostridium difficile infection: results of the PUNCH CD Study. Clin Infect Dis. 2016; 62 (5): 596-602.
83. 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 (10): 5224-5229.
84. Brouwer MS, Roberts AP, Hussain H, et al. Horizontal gene transfer converts non-toxigenic Clostridium difficile strains into toxin producers. Nat Commun. 2013; 4: 2601.
85. Leav BA, Blair B, Leney M, et al. Serum anti-toxin B antibody correlates with protection from recurrent Clostridium difficile infection (CDI). Vaccine. 2010; 28 (4): 965-969.
86. Lowy I, Molrine DC, Leav BA, et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med. 2010; 362 (3): 197-205.
87. Louie TJ, Peppe J, Watt CK, et al. Tolevamer, a novel nonantibiotic polymer, compared with vancomycin in the treatment of mild to moderately severe Clostridium difficile associated diarrhea. Clin Infect Dis. 2006; 43: 411-420.