Extended-pulsed fidaxomicin regimen for treatment of Clostridioides (formerly Clostridium) difficile infection (CDI) maintained fidaxomicin stool concentrations above the C difficile minimum inhibitory concentration required to inhibit the growth of 90% of the bacteria (MIC90) until day 26±1 and there was no evidence of fidaxomicin accumulation in stool or plasma while systemic exposure to fidaxomicin and its major active metabolite, OP-1118, was low. This is according to data published in The Journal of Antimicrobial Chemotherapy investigating the pharmacokinetic profile of fidaxomicin in an extended-pulsed fidaxomicin regimen.
Investigators used data from the phase 3b/4 EXTEND trial in which patients aged ≥ 60 years with toxin-confirmed CDI were randomized to receive extended-pulsed fidaxomicin (oral fidaxomicin twice daily, days 1–5; once daily on alternate days, days 7–25). Plasma samples from 14 patients were included and stool from 12 of these was also provided. Fidaxomicin and OP-1118 concentrations were determined using post-dose plasma samples obtained on days 5±1, 12±1 and 25/26, and post-dose stool samples obtained on days 5±1, 12±1 and 26±1.
The median fidaxomicin plasma concentrations on day 5±1 and day 25/26 were 0.0252 mg/L (range, 0.0038–0.1220) and 0.0069 mg/L (range, 0–0.0887), respectively and those of OP-1118 were 0.0648 mg/L (range, 0.0142–0.3250) and 0.0206 mg/L (range, 0–0.3720), respectively. Median stool concentration of fidaxomicin on day 26 ± 1 were 272.5 mg/kg (range, 0–524) and were 280.5 mg/kg (range, 0–1120) for OP-1118. The investigators summated the findings by stating that using the extended-pulsed fidaxomicin regimen sustained median stool fidaxomicin concentrations well in excess of the fidaxomicin MIC90 until the end of treatment, despite the reduction in effective daily dose to one-quarter of that used in the standard 10 day regimen.
According to investigators, this work showed, “that the [extended-pulsed fidaxomicin] regimen led to minimal systemic exposure while providing high fidaxomicin and OP-1118 stool concentrations.” This supports the clinical efficacy findings that extended-pulsed fidaxomicin shows superior sustained clinical cure and reduced CDI recurrence compared with standard vancomycin therapy, in patients aged >60 years. They further report, “no evidence of fidaxomicin or OP-1118 accumulation in either plasma or stool, and fidaxomicin metabolism appeared unchanged by the extended dosing scheme.”
Guery B, Georgopali A, Karas A, et al. Pharmacokinetic analysis of an extended-pulsed fidaxomicin regimen for the treatment of Clostridioides (Clostridium) difficile infection in patients aged 60 years and older in the EXTEND randomized controlled trial. J Antimicrob Chemother. 2020;75:1014-1018.