Susceptibility ofClostridium difficileisolates from a Phase 2 clinical trial of cadazolid and vancomycin inC. difficileinfection

Abstract

ObjectivesThe aim of this study was to evaluate the susceptibilities of Clostridium difficile isolates to cadazolid, a novel antibiotic for the treatment of C. difficile infection.MethodsRibotyping and susceptibilities were determined for C. difficile isolates from a multicentre, double-blind, Phase 2 study of oral cadazolid in patients with C. difficile infection (NCT01222702, ClinicalTrials.gov; EudraCT 2010-020941-29, European Clinical Trials Database). Patients were randomized to receive 250, 500 or 1000 mg of cadazolid twice daily or 125 mg of vancomycin four times daily, for 10 days. MICs of cadazolid, vancomycin, fidaxomicin, linezolid and moxifloxacin were determined at baseline for all patients and post-baseline for patients with clinical failure or recurrence, using the agar dilution method.ResultsSeventy-eight of 84 patients had an evaluable toxigenic C. difficile isolate at baseline. The most frequent PCR ribotype was 027 (15.4%). Cadazolid MICs for baseline isolates (including epidemic strain 027) ranged from 0.06 to 0.25 mg/L. Baseline cadazolid MICs were similar to those of fidaxomicin and lower than those of vancomycin, linezolid and moxifloxacin. For each clinical outcome group (clinical cure, clinical failure, sustained clinical response and clinical failure or recurrence), the baseline cadazolid MIC range was 0.06–0.25 mg/L. Mean (min–max) cadazolid faecal concentration (μg/g) on day 5 was 884 (101–2710), 1706 (204–4230) and 3226 (1481–12 600) for the doses 250, 500 and 1000 mg, respectively.ConclusionsFor all cadazolid doses, the faecal concentration was in excess of several thousand-fold the MIC90 for C. difficile. The MIC of cadazolid for all C. difficile isolates, including epidemic strains, was low and in the same narrow range regardless of treatment outcome.

Different Resistance Mechanisms for Cadazolid and Linezolid in Clostridium difficile Found by Whole-Genome Sequencing Analysis

“…Correlation of MIC values with IVTT IC 50 values strongly indicates a connection of ribosomal mutations with altered ribosome function. The observation that CDZ shows a lower MIC increase than LZD during passage experiments correlates with the finding that emergence of CDZ-resistant mutants during CDI treatment has not been detected in phase 2 clinical studies (27). Determination of the MIC.…”

“…The MIC was defined as the lowest concentration that completely inhibited visible growth compared to the drug-free control. C. difficile strain ATCC 700057 was used as the quality control strain, and MICs of cadazolid and other antibiotics were shown to be within the quality control limits specified by the CLSI, if available (27).…”

Multicenter, Double-Blind, Randomized, Phase 2 Study Evaluating the Novel Antibiotic Cadazolid in Patients with Clostridium difficile Infection

“…In the present study, the most frequent PCR ribotype and restriction endonuclease analysis (REA) group were 027 and BI, respectively. Fecal cadazolid concentrations for all dosages of cadazolid were several thousandfold higher than the C. difficile MIC (21), and the baseline and postbaseline cadazolid MICs were low (Յ0.5 mg/liter), including those for the epidemic strains. In addition, minimal impacts on the intestinal microflora were observed at all dosages of cadazolid (M. Wilcox and T. Louie, unpublished data).…”

Modifications of quinolones and fluoroquinolones: hybrid compounds and dual-action molecules

“…The MIC values of epidemic strains isolated from patients from phase 2 clinical trial were low an in the narrow range. Even for the lowest dosage of cadazolid, the faecal concentration of the drug was in higher than MIC for C. difficile [136]. To our best knowledge, results from phase 3 trials have not been published yet and are still analyzed.

Fig.

…”