title: Fidaxomicin inhibits toxin production in Clostridium difficile.
abstract: OBJECTIVE
  Fidaxomicin, which was recently approved for the treatment of Clostridium difficile-associated diarrhoea, demonstrates narrow-spectrum bactericidal activity via inhibition of RNA polymerase. In this study we evaluated its inhibitory activity versus C. difficile toxin gene expression and toxin production by quantifying toxin mRNA and protein.
  
  
  METHODS
  The effects of fidaxomicin, its major metabolite (OP-1118), vancomycin and metronidazole on toxin A and toxin B production were determined by assaying culture supernatants of two C. difficile isolates (ATCC 43255, a high-level toxin-producing strain, and UK-14, a NAP1/027/BI epidemic strain) using a commercial ELISA. The effects of the drugs on toxin gene expression were assessed in stationary-phase cells of C. difficile strain UK-1 (NAP1/027/BI type epidemic strain) and in the closely related non-epidemic strain CD196 by quantitative RT-PCR.
  
  
  RESULTS
  Subinhibitory levels (1/4× MIC) of fidaxomicin or OP-1118 (but not vancomycin or metronidazole) strongly suppressed toxin production in C. difficile (≥ 60%) through at least 1 week of culture. Additionally, transcripts from the pathogenicity loci (tcdR, tcdA and tcdB) were nearly completely inhibited by both fidaxomicin (2× MIC) and OP-1118 (2.5× MIC), but not vancomycin (2.5× MIC).
  
  
  CONCLUSIONS
  Both fidaxomicin and OP-1118 are able to inhibit toxin production in vitro, which may explain prior post-treatment observations of less frequent detectable toxin in fidaxomicin-treated patients (27 subjects) than those treated with vancomycin (8 patients).
authors.affiliation: Optimer Pharmaceuticals, Inc., 4755 Nexus Center Drive, San Diego, CA 92121, USA. fbabakhani@optimerpharma.com
authors.forename: Farah
authors.initials: F
authors.lastname: Babakhani
authors.forename: Laurent
authors.initials: L
authors.lastname: Bouillaut
authors.forename: Pamela
authors.initials: P
authors.lastname: Sears
authors.forename: Carlee
authors.initials: C
authors.lastname: Sims
authors.forename: Abraham
authors.initials: A
authors.lastname: Gomez
authors.forename: Abraham L
authors.initials: AL
authors.lastname: Sonenshein
mesh_terms: D000617:Aminoglycosides / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016360:Clostridioides difficile / Q000187:drug effects*; D003470:Culture Media / Q000737:chemistry; D004768:Enterotoxins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D000077732:Fidaxomicin; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D008795:Metronidazole / Q000378:metabolism; D014640:Vancomycin / Q000378:metabolism
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D003470:Culture Media; D004768:Enterotoxins; C561044:OP-1118; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile; D008795:Metronidazole; D014640:Vancomycin; D000077732:Fidaxomicin