Effect Of Fidaxomicin Research Articles

Mo1844 Effect of Fidaxomicin on Susceptibility to Intestinal Colonization With Vancomycin-Resistant Enterococci and Klebsiella pneumoniae in Mice

Mo1844 Effect of Fidaxomicin on Susceptibility to Intestinal Colonization With Vancomycin-Resistant Enterococci and Klebsiella pneumoniae in Mice

Fidaxomicin inhibits toxin production in Clostridium difficile

Fidaxomicin, which was recently approved for the treatment of Clostridium difficile-associated diarrhoea, demonstrates narrow-spectrum bactericidal activity via inhibition of RNA polymerase. In this study we evaluated its inhibitory activity versus C. difficile toxin gene expression and toxin production by quantifying toxin mRNA and protein. The effects of fidaxomicin, its major metabolite (OP-1118), vancomycin and metronidazole on toxin A and toxin B production were determined by assaying culture supernatants of two C. difficile isolates (ATCC 43255, a high-level toxin-producing strain, and UK-14, a NAP1/027/BI epidemic strain) using a commercial ELISA. The effects of the drugs on toxin gene expression were assessed in stationary-phase cells of C. difficile strain UK-1 (NAP1/027/BI type epidemic strain) and in the closely related non-epidemic strain CD196 by quantitative RT-PCR. Subinhibitory levels (1/4× MIC) of fidaxomicin or OP-1118 (but not vancomycin or metronidazole) strongly suppressed toxin production in C. difficile (≥ 60%) through at least 1 week of culture. Additionally, transcripts from the pathogenicity loci (tcdR, tcdA and tcdB) were nearly completely inhibited by both fidaxomicin (2× MIC) and OP-1118 (2.5× MIC), but not vancomycin (2.5× MIC). Both fidaxomicin and OP-1118 are able to inhibit toxin production in vitro, which may explain prior post-treatment observations of less frequent detectable toxin in fidaxomicin-treated patients (27 subjects) than those treated with vancomycin (8 patients).

Risk of Recurrence and Time to Recurrence Following Treatment of Clostridium difficile Infection: Patient Characteristics and the Differential Effect of Fidaxomicin vs. Vancomycin

Risk of Recurrence and Time to Recurrence Following Treatment of Clostridium difficile Infection: Patient Characteristics and the Differential Effect of Fidaxomicin vs. Vancomycin

Antimicrobial Peptides Are Differentially Expressed in Clostridium difficile Infection

rence. Methods: Adults with CDI symptoms and a positive toxin test received oral fidaxomicin or vancomycin for ten days as part of a phase 3 clinical trial. Recurrence was defined as the reappearance of diarrhea and a positive stool toxin test within 4 weeks following completion of therapy. Multivariate analysis was used to identify patient characteristics at either the beginning or completion of therapy that correlated with recurrence or time to recurrence. Results: Of 518 patients (253 treatedwith fidaxomicin and 265with vancomycin), 106 had a recurrence of CDI (20.5%). The distribution of recurrences over timewas consistent with two distinct periods: early (within the first 2 weeks after stopping initial therapy; 10.5 reoccurrences/1000 patient days) and late (2 to 4 weeks after stopping initial therapy; 5.0 reoccurrences/1000 patient days). The table summarizes patient characteristics associated with increased incidence of early or late recurrence. Treatment with fidaxomicin was associated with a lower rate of early recurrence (5.9 recurrences/1000 patient days) compared with vancomycin (15.1 recurrences/1000 patient days, p<0.001). There was no difference between treatments in the rate of recurrence during weeks 3 and 4 of follow-up. Conclusions: CDI treatment with fidaxomicin resulted in a lower rate of early recurrence (within 14 days of completing therapy) than vancomycin. This differential effect is likely due to a less deleterious effect of fidaxomicin on normal fecal microflora. Late recurrence is likely related to a new infection and is affected by patient-related factors, not initial treatment choices. Such factors may define a group at high risk of a new infection and could guide prevention measures and treatment choices.