title: Treatment of Clostridium difficile infection using SQ641, a capuramycin analogue, increases post-treatment survival and improves clinical measures of disease in a murine model.
abstract: OBJECTIVE
  Clostridium difficile infection (CDI) is a primary cause of antibiotic-associated diarrhoeal illness. Current therapies are insufficient as relapse rates following antibiotic treatment range from 25% for initial treatment to 60% for treatment of recurrence. In this study, we looked at the efficacy of SQ641 in a murine model of CDI. SQ641 is an analogue of capuramycin, a naturally occurring nucleoside-based compound produced by Streptomyces griseus.
  
  
  METHODS
  In a series of experiments, C57BL/6 mice were treated with a cocktail of antibiotics and inoculated with C. difficile strain VPI10463. Animals were treated orally with SQ641 for 5 days at a dose range of 0.1-300 mg/kg/day, 20 mg/kg/day vancomycin or drug vehicle. Animals were monitored for disease severity, clostridial shedding and faecal toxin levels for 14 days post-infection.
  
  
  RESULTS
  Five day treatment of CDI with SQ641 resulted in higher 14 day survival rates in mice compared with either vancomycin or vehicle alone. CDI survival rates were 100% (13 of 13) and 94% (32 of 34), respectively, in the 1 and 10 mg/kg/day SQ641 treatment groups, 37% (7 of 19) with vancomycin treatment at 20 mg/kg/day and 32% (14 of 44) in the vehicle-only control group. Secondary measures of efficacy, such as prevention of weight loss, decreased disease severity, decreased C. difficile shedding and decreased toxin in faeces, were observed with SQ641 and vancomycin treatment.
  
  
  CONCLUSIONS
  SQ641 is effective for CDI treatment with prevention of relapse in the murine model of CDI.
authors.affiliation: Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Moore
authors.affiliation: Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: van Opstal
authors.affiliation: Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Glynis L
authors.initials: GL
authors.lastname: Kolling
authors.affiliation: Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Jae Hyun
authors.initials: JH
authors.lastname: Shin
authors.affiliation: Sequella Inc., Rockville, MD 20850, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Bogatcheva
authors.affiliation: Sequella Inc., Rockville, MD 20850, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: Nikonenko
authors.affiliation: Sequella Inc., Rockville, MD 20850, USA.
authors.forename: Leo
authors.initials: L
authors.lastname: Einck
authors.affiliation: Sequella Inc., Rockville, MD 20850, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Phipps
authors.affiliation: Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Guerrant
authors.affiliation: Sequella Inc., Rockville, MD 20850, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Protopopova
authors.affiliation: Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA 22908, USA ca6t@virginia.edu.
authors.forename: Cirle Alcantara
authors.initials: CA
authors.lastname: Warren
mesh_terms: D000284:Administration, Oral; D000617:Aminoglycosides / Q000627:therapeutic use*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D057138:Bacterial Shedding; D001427:Bacterial Toxins / Q000032:analysis; D016360:Clostridioides difficile / Q000187:drug effects*; D004195:Disease Models, Animal; D004761:Enterocolitis, Pseudomembranous / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D005243:Feces / Q000737:chemistry / Q000382:microbiology; D008297:Male; D008810:Mice, Inbred C57BL; D012720:Severity of Illness Index; D016019:Survival Analysis; D016896:Treatment Outcome; D014529:Uridine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D001427:Bacterial Toxins; C000599107:SQ-641; C049983:capuramycin; D014529:Uridine
references.citation: J Antimicrob Chemother. 2011 Mar;66(3):578-87
references.pmid: 21186194
references.citation: Ther Clin Risk Manag. 2008 Oct;4(5):949-64
references.pmid: 19209277
references.citation: Nat Rev Gastroenterol Hepatol. 2011 Jun;8(6):330-9
references.pmid: 21502971
references.citation: Foodborne Pathog Dis. 2010 Jun;7(6):719-26
references.pmid: 20113206
references.citation: Clin Infect Dis. 2012 Aug;55 Suppl 2:S132-42
references.pmid: 22752862
references.citation: J Antimicrob Chemother. 2010 Dec;65(12):2590-7
references.pmid: 20952419
references.citation: Clin Microbiol Infect. 2014 Mar;20 Suppl 2:1-26
references.pmid: 24118601
references.citation: Antimicrob Agents Chemother. 2009 Jan;53(1):261-3
references.pmid: 18955523
references.citation: Am J Gastroenterol. 2002 Jul;97(7):1769-75
references.pmid: 12135033
references.citation: Gut Pathog. 2013 Aug 13;5(1):23
references.pmid: 23941657
references.citation: Antimicrob Agents Chemother. 2013 Feb;57(2):689-96
references.pmid: 23147742
references.citation: Clin Infect Dis. 2008 Jan 15;46 Suppl 1:S19-31
references.pmid: 18177218
references.citation: Microbiology. 2010 Nov;156(Pt 11):3354-9
references.pmid: 20724385
references.citation: Infect Disord Drug Targets. 2006 Jun;6(2):85-106
references.pmid: 16789873
references.citation: N Engl J Med. 2011 Feb 3;364(5):422-31
references.pmid: 21288078
references.citation: J Hepatol. 2014 Apr;60(4):824-31
references.pmid: 24316517
references.citation: Infect Control Hosp Epidemiol. 2010 May;31(5):431-55
references.pmid: 20307191
references.citation: Clin Infect Dis. 2012 Aug;55 Suppl 2:S65-70
references.pmid: 22752867
references.citation: J Infect Dis. 2010 Dec 1;202(11):1708-12
references.pmid: 20977342