Journal review: Emergence and Spread of C difficile Isolates With reduced Fidaxomicin Susceptibilti in an Acute Care Hospital.

Sarah N Redmond et al, Emergence and Spread of Clostridioides difficile Isolates With Reduced Fidaxomicin Susceptibility in an Acute Care Hospital, Clinical Infectious Diseases, 2025;, ciaf028, https://doi.org/10.1093/cid/ciaf028

Introduction & Background:

• The study addresses the growing concern about Clostridioides difficile infection (CDI) isolates exhibiting reduced susceptibility to fidaxomicin, a primary antibiotic used for CDI treatment. While reduced susceptibility to fidaxomicin has been reported, the clinical implications remain uncertain. The research aims to determine the frequency of such infections and their impact on treatment outcomes within an acute care hospital. The study notes that while fidaxomicin and vancomycin have remained largely effective, "recent reports have raised concern that isolates with reduced susceptibility to fidaxomicin and vancomycin may be emerging."
• Fidaxomicin targets bacterial RNA polymerase. Reduced susceptibility is associated with mutations in the rpoB and rpoC genes, which encode subunits of the RNA polymerase complex.
• Previous research suggests that such mutations may compromise the efficacy of fidaxomicin due to defects in growth, sporulation, and toxin production. However, the impact on clinical cure remains unclear.

Methods:

• A 3-year cohort study was conducted at the Cleveland VA Medical Center on patients with CDI (positive NAAT test).
• Stool specimens were cultured for C. difficile, and isolates were tested for fidaxomicin susceptibility using agar dilution. Reduced susceptibility was defined as MIC ≥2 µg/mL. Resistance as MIC ≥16 µg/ mL [15].
• Whole-genome sequencing (WGS) was performed on isolates with reduced susceptibility and related susceptible isolates to identify mutations and determine relatedness.
• Growth rates, sporulation, and toxin production were compared between susceptible and reduced susceptibility isolates.
• Medical records were reviewed for demographic, laboratory, and treatment response data.
• Additional screening was performed for patients with initial fidaxomicin-susceptible isolates followed by recovery of isolates with reduced susceptibility using C. difficile brucella agar and broth that contained 2 µg/mL of fidaxomicin.

Key Findings:

• Frequency of Reduced Susceptibility: 5.6% (6 out of 108) of fidaxomicin-treated patients were infected with isolates demonstrating reduced fidaxomicin susceptibility (MICs 8–32 µg/mL).
• Treatment Failure & Emergence on Therapy: 3 of the 6 patients experienced clinical failure or refractory CDI with subsequent recovery of isolates with reduced susceptibility that were genomically related to initially susceptible isolates.
• Mutations: Isolates with reduced fidaxomicin susceptibility harboured mutations in RNA polymerase (rpoB and rpoC genes), confirming known resistance mechanisms. Specific mutations included A265G in rpoC (R89G substitution) and T3428G/A in rpoB (V1143G/D substitution). None of the isolates had mutations in the marR homolog CD22120.
• Reduced Toxin Production: Isolates with reduced susceptibility exhibited significantly reduced toxin production compared to susceptible isolates.
• Variable Growth & Sporulation: Growth and sporulation were not consistently altered in isolates with reduced susceptibility, although some isolates showed reduced growth. "In comparison with susceptible isolates, growth rates were significantly decreased at time points ≥10 hours in isolates with reduced fidaxomicin susceptibility for patients 2 and 6 (P < .001) but not patient 1 (P = .07)."
• Transmission: Evidence suggests potential transmission of isolates with reduced fidaxomicin susceptibility within the facility. Three patients were infected with genomically indistinguishable ribotype 097 isolates. "Our findings suggest that isolates with reduced fidaxomicin susceptibility may have spread from patient to patient in our fa-cility."
• "For the 4 patients with initial recovery of susceptible isolates followed by recovery of isolates with reduced susceptibility (pa-tients 1, 2, 4, and 6), additional screening of the initial stool specimens did not identify subpopulations of C. difficile with reduced fidaxomicin susceptibility (ie, no colonies recovered from media containing 2 µg/mL of fidaxomicin)."

Discussion & Implications:

• The study suggests that reduced fidaxomicin susceptibility can emerge during therapy and potentially contribute to treatment failure. The authors explicitly state, "Our findings highlight the potential for the emergence on therapy of clinically relevant reduced fidaxomicin susceptibility in C. difficile."
• The spread of isolates with reduced susceptibility raises concerns about infection control within healthcare settings.
• Clinicians should consider reduced susceptibility as a potential factor in fidaxomicin treatment failure.
• While reduced toxin production was observed in resistant isolates, its impact on disease severity is unclear, as one patient with severe CDI had a toxin-negative stool sample.

Some points to consider

• The study includes 296 patients, with only 108 receiving fidaxomicin and 6 exhibiting reduced susceptibility. This small subset limits statistical power, particularly for drawing firm conclusions about treatment failure. A power calculation is not mentioned, which is a notable omission.
• The single-center design, small sample of resistant isolates, and lack of a control group (e.g., non-fidaxomicin-treated resistant cases) are not adequately addressed as limitations. We must be careful about generalising it.
• Selection Bias - Fidaxomicin use was restricted to specific groups (e.g., ≥65 years, immunocompromised), potentially skewing the population toward higher-risk patients.
• Stool specimens were only collected from treatment failures to assess resistance emergence, which may miss subclinical resistance development in successfully treated patients. This selective sampling could bias the results.
• Only three patients had paired susceptible and resistant isolates for growth/sporulation/toxin analysis, limiting the robustness of these comparisons. The statistical significance (e.g., P < .001 for toxin production) must be interpreted cautiously given the small sample.
• The manuscript does not report susceptibility testing results for all 328 CDI episodes, focusing only on the six patients with reduced fidaxomicin susceptibility. A broader susceptibility profile could contextualize the prevalence of resistance.