Fidaxomicin preserves the intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin reexpression and recurrence of CDI

Abstract

The microflora-sparing properties of fidaxomicin were examined during the conduct of a randomized clinical trial comparing vancomycin 125 mg 4 times per day versus fidaxomicin 200 mg twice per day for 10 days as treatment of Clostridium difficile infection (CDI). Fecal samples were obtained from 89 patients (45 received fidaxomicin, and 44 received vancomycin) at study entry and on days 4, 10, 14, 21, 28, and 38 for quantitative cultures for C. difficile and cytotoxin B fecal filtrate concentrations. Additionally, samples from 10 patients, each receiving vancomycin or fidaxomicin, and 10 samples from healthy controls were analyzed by quantitative real-time polymerase chain reaction with multiple group-specific primers to evaluate the impact of antibiotic treatment on the microbiome. Compared with controls, patients with CDI at study entry had counts of major microbiome components that were 2-3-log(10) colony-forming units (CFU)/g lower. In patients with CDI, fidaxomicin allowed the major components to persist, whereas vancomycin was associated with a further 2-4-log(10) CFU reduction of Bacteroides/Prevotella group organisms, which persisted to day 28 of the study, and shorter term and temporary suppression of both Clostridium coccoides and Clostridium leptum group organisms. In the posttreatment period, C. difficile counts similarly persisted in both study populations, but reappearance of toxin in fecal filtrates was observed in 28% of vancomycin-treated patient samples (29 of 94), compared with 14% of fidaxomicin-treated patient samples (13 of 91; P = .03). Similarly, 23% of vancomycin-treated patients (10 of 44) and 11% of fidaxomicin-treated patients (5 of 44) had recurrence of CDI. Whereas vancomycin and fidaxomicin are equally effective in resolving CDI symptoms, preservation of the microflora by fidaxomicin is associated with a lower likelihood of CDI recurrence.

Trial registration: ClinicalTrials.gov NCT00314951.

Figure 1.

Bacteroides microflora levels over time in 10 patients receiving vancomycin (A), 10 patients receiving fidaxomicin (B), and 10 healthy controls (boxes). Abbreviation: CFU, colony-forming units.

Figure 2.

Clostridium coccoides microflora levels over time in 10 patients receiving vancomycin (A), 10 patients receiving fidaxomicin (B), and 10 healthy controls (boxes). Abbreviation: CFU, colony-forming units.

Figure 3.

Clostridium leptum microflora levels over time in 10 patients receiving vancomycin (A), 10 patients receiving fidaxomicin (B), and 10 healthy controls (boxes). Abbreviation: CFU, colony-forming units.

Figure 4.

Prevotella microflora levels over time in 10 patients receiving vancomycin (A), 10 patients receiving fidaxomicin (B), and 10 healthy controls (boxes). Abbreviation: CFU, colony-forming units.

Figure 5.

Veillonella microflora levels over time in 10 patients receiving vancomycin (A), 10 patients receiving fidaxomicin (B), and 10 healthy controls (boxes). Abbreviation: CFU, colony-forming units.

Figure 6.

Bifidobacterium microflora levels over time in 10 patients receiving vancomycin (A), 10 patients receiving fidaxomicin (B), and 10 healthy controls (boxes). Abbreviation: CFU, colony-forming units.

Figure 7.

Lactobacillus microflora levels over time in 10 patients receiving vancomycin (A), 10 patients receiving fidaxomicin (B), and 10 healthy controls (boxes). Abbreviation: CFU, colony-forming units.

Figure 8.

Desulfovibrio microflora levels over time in 10 patients receiving vancomycin (A), 10 patients receiving fidaxomicin (B), and 10 healthy controls (boxes). Abbreviation: CFU, colony-forming units.

Figure 9.

Enterobacteriaceae microflora levels over time in 10 patients receiving vancomycin (A), 10 patients receiving fidaxomicin (B), and 10 healthy controls (boxes). Abbreviation: CFU, colony-forming units.

Figure 10.

Enterococcaceae microflora levels over time in 10 patients receiving vancomycin (A), 10 patients receiving fidaxomicin (B), and 10 healthy controls (boxes). Abbreviation: CFU, colony-forming units.

Figure 11.

Levels of major cultivable and noncultivable genera of the normal fecal microbiota in 20 patients with Clostridium difficile infection who were randomly assigned to receive treatment with fidaxomicin or vancomycin (10 patients/treatment arm). All patients responded to treatment without recurrence. Abbreviations: FDX, fidaxomicin; VAN, vancomycin.