Fidaxomicin was recently approved for the treatment of Clostridium difficile associated diarrhea. This is a novel narrow spectrum antibacterial agent that demonstrates potent bactericidal activity against C. difficile. In recent clinical trials with over 1100 CDI subjects, FDX was shown to be superior to vancomycin in providing sustained clinical response (response without recurrence of disease) at 25 days following therapy. A possible mechanism for reduced recurrences is that FDX may exert an inhibitory effect on sporulation.
FDX and its major metabolite, OP–1118, were evaluated with comparator drugs vancomycin, metronidazole, and rifaximin for their effects on kinetics of C. difficile (UK–14, an epidemic NAP1/BI/027 strain and ATCC 43255, a high toxin producer strain) growth and sporulation. Drugs were added to cells at early stationary phase of growth followed by collection of cells, at various time intervals, for quantitation of total viable cell count and spore counts (by heating to kill the vegetative cells) on media containing taurocholate. The effect of drugs on sporulation gene expression in the C. difficile NAP1/BI/027 type epidemic strain UK1 was also compared via qRT–PCR using Roche LightCycler 480 and SYBR Green fluorescence. Transcript levels for test genes were normalized to levels of 16s rRNA and rpoC mRNA.
Both FDX and OP–1118 at sub–MIC concentrations (1/4xMIC) inhibited sporulation when added to early stationary phase cells in C. difficile strains UK–14 and ATCC 432455. In contrast, vancomycin, metronidazole and rifaximin (at similar sub–MIC levels) did not inhibit sporulation. The number of spores following treatment with comparator drugs increased to the same level as the no–drug control treatment. Expression of mother cell–specific (spoIIID) and forespore–specific (spoIIR) sporulation genes was also inhibited by fidaxomicin and OP–1118, but not by vancomycin.
Both FDX and OP–1118, unlike vancomycin, rifaximin, or metronidazole, effectively inhibited sporulation by C. difficile. Fidaxomicin’s inhibitory effect on C. difficile sporulation may contribute to its superior performance in sustaining clinical response and reducing recurrences and may also be beneficial in decreasing shedding and transmission of this pathogen.