Susceptibility of Clostridium difficile isolates from a Phase 2 clinical trial of cadazolid and vancomycin in C. difficile infection.

OBJECTIVES: The 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. METHODS: Ribotyping 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. RESULTS: Seventy-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. CONCLUSIONS: For 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.

Activities of garenoxacin (BMS-284756) and other agents against anaerobic clinical isolates.

A total of 590 clinical isolates consisting of 33 species of both gram-positive and gram-negative anaerobes were collected from nine centers in the Chicago area in 1998-1999. The largest number of isolates (330 isolates, 56%) belonged to the Bacteroides group. Isolates were tested by agar dilution against garenoxacin (BMS-284756, T-3811 ME), trovafloxacin, moxifloxacin, clindamycin, imipenem, piperacillin-tazobactam, and cefoxitin. All but one species (2% of Bacteroides vulgatus isolates) were fully susceptible to piperacillin-tazobactam and imipenem. A number of species were resistant to clindamycin. Among the fluoroquinolones, garenoxacin and trovafloxacin had an MIC at which 90% of the isolates tested were inhibited of <4 micro g/ml for all but two species (Fusobacterium mortiferum/varium and Peptostreptococcus anaerobius).

Comparison of activities of trovafloxacin (CP-99,219) and five other agents against 585 anaerobes with use of three media.

Agar dilution testing was used to compare the in vitro activities of trovafloxacin and ofloxacin, ciprofloxacin, imipenem, metronidazole, and clindamycin against 585 anaerobes. The activity of trovafloxacin was superior to those of ofloxacin and ciprofloxacin, with 94%, 91%, 96%, 100%, 90%, and 100% inhibition of Bacteroides fragilis, non-fragilis Bacteroides species, Peptostreptococcus magnus/Peptostreptococcus micros, Clostridium perfringens, Prevotella bivia/Prevotella disiens, and Fusobacterium species, respectively, at a breakpoint of 2 micrograms/mL. Trovafloxacin was more active than clindamycin against most anaerobes and slightly less active than imipenem and metronidazole. Different testing media, which were compared side by side, did affect the in vitro activities of trovafloxacin, ofloxacin, and ciprofloxacin but did not affect those of the other antibiotics. Testing with supplemented brain-heart infusion agar demonstrated lower minimum inhibitory concentrations than did testing with Wilkins-Chalgren agar and supplemented brucella agar. The activity of trovafloxacin was twofold lower when the pH of the testing media was adjusted to 6.0 than when the pH of the testing media was adjusted to 7.0 or 7.5.

Susceptibility results for the Bacteroides fragilis group: comparison of the broth microdilution and agar dilution methods.

The antimicrobial susceptibilities of members of the Bacteroides fragilis group were compared using the agar dilution and broth microdilution methods. A total of 455 B. fragilis group isolates were tested against 10 antibiotics. Significant disparity in susceptibility results for most antibiotics was observed between the two methods. Broth microdilution susceptibility results were most similar to agar dilution results when a twofold lower breakpoint was used. In addition, broth microdilution failed to detect resistance to some antibiotics when the recommended agar dilution breakpoint was used. MIC50, MIC90, and geometric mean MIC values for broth microdilution were consistently twofold to fourfold less than those for agar dilution. Susceptibilities of Bacteroides that are determined with use of broth microdilution may more accurately correspond to those determined with use of agar dilution if lower breakpoints are used for interpretation.

Variation in the susceptibility of Bacteroides fragilis group isolates from six Chicago hospitals.

The antimicrobial susceptibility of isolates of the Bacteroides fragilis group from six hospitals in the Chicago area varied from one institution to another; this variation was similar to the geographic variation documented in a national survey. A total of 365 B. fragilis group isolates were tested against 10 antibiotics. Imipenem, piperacillin/tazobactam, ampicillin/sulbactam, ticarcillin/clavulanate, and cefoperazone/sulbactam had excellent activity against all members of the B. fragilis group, with little interhospital variation. Cefoxitin and ceftizoxime had very good activity, also with little variation among hospitals. Clindamycin, cefotetan, and cefmetazole had the lowest level of activity, with unusually high-level resistance confined to three of the six hospitals. These data indicate that variation in the antimicrobial susceptibility of these bacteria is likely based in the hospital rather than in the geographic region and that the in vitro activity of certain antibiotics against B. fragilis group isolates from individual hospitals cannot be predicted from the data obtained in larger-scale surveys.