Comparative Fidaxomicin Susceptibilities of Isolates Collected at Baseline, Failure, and Recurrence From Subjects in a Phase 3 Trial of Clostridium difficile Infection (CDI)

BACKGROUND A 10-day course of oral fidaxomicin (FDX; formerly OPT-80; 200 mg bid), a potent new macrocyclic antibiotic, was compared with vancomycin (VAN; 125 mg qid) in 629 adults (548 evaluable) with CDI in a phase 3 randomized, double-blind trial at sites across North America. METHODS Fecal specimens were collected from subjects at study entry and at failure or recurrence and cultured for C difficile . Antimicrobial susceptibilities of FDX, VAN, metronidazole (MTZ), and rifaximin (RFX) were determined using the CLSI reference method. Isolates were genotyped via restriction endonuclease analysis (REA) methods. RESULTS Susceptibility (MIC90) of baseline isolates did not predict clinical cure, failure, or recurrence for either FDX (MIC90, 0.25 µg/mL) or VAN (MIC90, 2 µg/mL). Of 10 failures in the mITT group (8 VAN and 2 FDX) with strains isolated at baseline and end of therapy, both FDX isolates were the same but 2 VAN were different REA types. Of 47 subjects with baseline and recurrence samples, 2/14 (14%) FDX and 6/33 (19%) VAN subjects had new strains at recurrence. There were no geographic differences in susceptibilities, except for RFX, where US MIC90 was > 256 µg/mL compared with Canada MIC90, 0.03 µg/mL. All RFX resistant isolates were from the US. No differences were present between the MIC50/90 of subjects admitted as MTZ failures and those who were not. CONCLUSIONS There was no relationship between the MIC of baseline clinical isolates and clinical outcome. No resistance to either FDX or VAN developed during the study. MIC90s were generally low (0.25 µg/mL for FDX and 2 µg/mL for VAN) and were not different in different REA groups, except that 24/166 (14%) of BI and 3/17 (18%) of K group strains were RFX resistant, and MTZ susceptibilities were also lower in these groups.