Emergence and Spread of Clostridioides difficile Isolates With Reduced Fidaxomicin Susceptibility in an Acute Care...

There have been several recent reports of Clostridioides difficile infection (CDI) due to isolates with reduced fidaxomicin susceptibility (minimum inhibitory concentration [MIC] ≥ 2 µg/mL). However, the clinical implications are uncertain because fidaxomicin achieves high concentrations in the intestinal tract.

In an acute care hospital, we conducted a 3-year cohort study of patients with CDI to determine the frequency of infection with isolates with reduced fidaxomicin susceptibility and the impact on response to fidaxomicin treatment. Stool specimens were cultured for C. difficile, and susceptibility testing was performed using agar dilution. Whole-genome sequencing was used to identify mutations associated with reduced fidaxomicin susceptibility and to determine relatedness of isolates. For genomically related susceptible and reduced susceptibility isolates from the same patient, we compared rates of growth, sporulation, and toxin production.

Of 108 fidaxomicin-treated patients, 6 (5.6%) were infected with isolates that possessed reduced fidaxomicin susceptibility (MICs 8-32 µg/mL), including 3 with initially susceptible isolates followed by clinical failure with subsequent recovery of genomically related isolates with reduced susceptibility. Isolates with reduced fidaxomicin susceptibility harbored mutations in RNA polymerase associated with reduced susceptibility and exhibited reduced toxin production, and 20% to 40% of isolates tested had reduced growth and/or sporulation in comparison with susceptible isolates. Three patients were infected with genomically indistinguishable ribotype 097 isolates with reduced fidaxomicin susceptibility.

Our findings highlight the potential for the emergence on therapy of clinically relevant reduced fidaxomicin susceptibility in C. difficile and its spread via transmission to other patients.