title: Killing kinetics of fidaxomicin and its major metabolite, OP-1118, against Clostridium difficile.
abstract: The kinetics of bacterial killing for fidaxomicin and its major metabolite, OP-1118, were investigated against Clostridium difficile strains, including two clinical strains belonging to the restriction endonuclease analysis group BI (ORG 1687 and 1698), the ATCC 43255 strain and two laboratory-derived mutant strains with decreased susceptibility to fidaxomicin (ORG 919 and 1620). Both fidaxomicin and OP-1118 demonstrated time-dependent killing of C. difficile strains. Fidaxomicin (at 4× MIC) reduced bacterial counts of the ATCC 43255 strain, clinical strain ORG 1687 and the two laboratory-generated mutant strains by ≥3 logs within 48 h of exposure. The other BI strain, ORG 1698, was tested at 2× MIC fidaxomicin with bacterial counts decreasing 1 log in 48 h. Exposure to OP-1118 (at 4× MIC) also resulted in a ≥3 log drop in c.f.u. counts for the ATCC 43255 strain, the clinical BI strain ORG 1687 and the mutant strain ORG 919. Higher concentrations of OP-1118 (32× MIC) were required for a 3 log reduction in c.f.u. counts for the other BI strain, ORG 1698. In summary, the results indicate that both fidaxomicin and its major metabolite, OP-1118, are bactericidal against C. difficile strains, including the hypervirulent restriction endonuclease analysis group BI strains, at concentrations that are many fold below the detected faecal concentrations of these compounds after oral administration of fidaxomicin.
authors.affiliation: Optimer Pharmaceuticals, San Diego, CA, USA.
authors.forename: Farah
authors.initials: F
authors.lastname: Babakhani
authors.affiliation: Optimer Pharmaceuticals, San Diego, CA, USA.
authors.forename: Abraham
authors.initials: A
authors.lastname: Gomez
authors.affiliation: Optimer Pharmaceuticals, San Diego, CA, USA.
authors.forename: Nikki
authors.initials: N
authors.lastname: Robert
authors.affiliation: Optimer Pharmaceuticals, San Diego, CA, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Sears
mesh_terms: D000617:Aminoglycosides / Q000378:metabolism / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D016360:Clostridioides difficile / Q000187:drug effects* / Q000235:genetics; D024881:Drug Resistance, Bacterial; D000077732:Fidaxomicin; D008826:Microbial Sensitivity Tests; D013997:Time Factors; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; C561044:OP-1118; D014640:Vancomycin; D000077732:Fidaxomicin