Fidaxomicin Inhibits Spore Production in Clostridium difficile

Fidaxomicin (FDX) is a novel antimicrobial agent with narrow-spectrum and potent bactericidal activity against Clostridium difficile. In recent clinical trials, FDX was superior to vancomycin in preventing recur-rences of C. difficile infection. A possible mechanism of reducing recurrence may be through an inhibitory effect on sporulation. The effect of FDX and its major metabolite, OP-1118, on C. difficile growth and spor-ulation kinetics was compared with that of vancomycin, metronidazole, and rifaximin. Drugs at submini-mum inhibitory concentrations (sub-MICs) were added to cells at an early stationary phase of growth; this was followed by collection of cells at various intervals for quantitation of total viable cell and heat-resistant spore counts on taurocholate-containing media. The effect of the drugs at 2–2.5 × MIC on the expression of sporulation genes in C. difficile was also compared using quantitative reverse-transcriptase polymerase chain reaction. Both FDX and OP-1118 (1/4 × MIC) inhibited sporulation when added to early-stationary-phase cells in C. difficile strains, including the epidemic NAP1/BI/027 strain. In contrast, vancomycin, metronida-zole, and rifaximin (at similar sub-MICs) did not inhibit sporulation. The number of spores following treat-ment 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 also was inhibited by FDX and OP-1118 but not significantly by vancomycin. Both FDX and OP-1118 (unlike vancomycin, rifaximin