Fidaxomicin Inhibits Spore Production in Clostridium difficile

Abstract

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 recurrences 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 sporulation kinetics was compared with that of vancomycin, metronidazole, and rifaximin. Drugs at subminimum 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, metronidazole, and rifaximin (at similar sub-MICs) 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 also was inhibited by FDX and OP-1118 but not significantly by vancomycin. Both FDX and OP-1118 (unlike vancomycin, rifaximin, and metronidazole) effectively inhibited sporulation by C. difficile . The inhibitory effect of FDX 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.

In VitroandIn VivoAntibacterial Evaluation of Cadazolid, a New Antibiotic for Treatment of Clostridium difficile Infections

“…Our data indicate that cadazolid does not promote the formation of spores; on the contrary, it strongly inhibited or delayed spore formation at sub-growth-inhibitory concentrations, while this was not observed for vancomycin. Inhibition of spore formation in vitro has been shown also for fidaxomicin (24) as well as for REP3123 (21) and may be linked to a mode of action leading to inhibition of de novo protein synthesis.…”

“…Spores surviving in the gut of patients or in the environment may play a major role in reinfection and relapse of CDAD (2, 9) after antibiotic treatment, and it has been speculated that inhibition of spore formation may be beneficial for the treatment of CDAD by potentially reducing the persistence and the spread of the organism (21,24). In vitro promotion of spore formation at sub-growth-inhibitory concentrations has been reported for the antibiotics metronidazole and vancomycin (21).…”

“…In order to investigate the effects of cadazolid and vancomycin on spore formation, antibiotics were added to growing cultures of C. difficile at late exponential growth phase, and ethanol-resistant spore and total viable cell counts were determined for up to 5 days (21,24). The antibiotic concentrations chosen were the highest concentrations (MIC fold change) that had no significant impact on C. difficile growth under the test conditions (sub-growth-inhibitory concentrations) and represented 0.5ϫ and 1ϫ the agar dilution MICs.…”

Esporas de Clostridium difficile y su relevancia en la persistencia y transmisión de la infección

“…La única molécula conocida a la fecha que inhibe la esporulación de C. difficile es el antibacteriano inhibidor de la ARN polimerasa, fidaxomicina, el que, a pesar que tiene el potencial de fracasar por resistencia durante el tratamiento y, por esta razón, se recomienda su uso sólo en casos específicos, ha demostrado disminuir la tasa de recurrencia comparado con otros antimicrobianos 41 . El mecanismo preciso de cómo afecta la esporulación no está del todo claro 42 . En suma, la inhibición del proceso de esporulación podría constituir un nuevo blanco terapéutico para combatir las IACD.…”

“…Estudios in vitro han demostrado que, tanto metronidazol como vancomicina, no inhiben la formación de esporas de C. difficile 84,85 , lo que es consistente con las elevadas tasas de recurrencia de IACD observadas en estudios clínicos 89 . En contraste, fidaxomicina, a concentraciones sub-inhibitorias, inhibe la formación de esporas de C. difficile in vitro 42 , y los estudios clínicos han demostrado que reduce a la mitad los episodios de recurrencia de IACD, comparado con vancomicina 41,90 , debido posiblemente a la inhibición de la formación de esporas durante el tratamiento. Ninguno de estos tres antibacterianos afecta la viabilidad de las esporas latentes de C. difficile.…”