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In vitro activity of cadazolid against clinically relevant Clostridium difficile isolates and in an in vitro gut model of C. difficile infection.
J Antimicrob Chemother. 2014 Mar; 69(3):697-705.JA

Abstract

OBJECTIVES

We investigated the in vitro activity of cadazolid against 100 Clostridium difficile isolates and its efficacy in a simulated human gut model of C. difficile infection (CDI).

METHODS

MICs of cadazolid, metronidazole, vancomycin, moxifloxacin and linezolid were determined using agar incorporation for 100 C. difficile isolates, including 30 epidemic strains (ribotypes 027, 106 and 001) with reduced metronidazole susceptibility, 2 linezolid-resistant isolates and 2 moxifloxacin-resistant isolates. We evaluated the efficacy of two cadazolid dosing regimens (250 versus 750 mg/L twice daily for 7 days) to treat simulated CDI. Microflora populations, C. difficile total viable counts and spores, cytotoxin titres, possible emergence of cadazolid, linezolid or quinolone resistance, and antimicrobial concentrations were monitored throughout.

RESULTS

Cadazolid was active against all (including linezolid- and moxifloxacin-resistant) C. difficile strains (MIC90 0.125, range 0.03-0.25 mg/L). The cadazolid geometric mean MIC was 152-fold, 16-fold, 9-fold and 7-fold lower than those of moxifloxacin, linezolid, metronidazole and vancomycin, respectively. Both cadazolid dosing regimens rapidly reduced C. difficile viable counts and cytotoxin with no evidence of recurrence. Cadazolid levels persisted at 50-100-fold supra-MIC for 14 days post-dosing. Cadazolid inhibition of enumerated gut microflora was limited, with the exception of bifidobacteria; Bacteroides fragilis group and Lactobacillus spp. counts were unaffected. There was no evidence for selection of strains resistant to cadazolid, quinolones or linezolid.

CONCLUSIONS

Cadazolid activity was greater than other tested antimicrobials against 100 C. difficile strains. Cadazolid effectively treated simulated CDI in a gut model, with limited impact on the enumerated gut microflora and no signs of recurrence or emergence of resistance within the experimental timeframe.

Authors+Show Affiliations

Leeds Institute for Molecular Medicine, University of Leeds, Leeds, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24128668

Citation

Chilton, C H., et al. "In Vitro Activity of Cadazolid Against Clinically Relevant Clostridium Difficile Isolates and in an in Vitro Gut Model of C. Difficile Infection." The Journal of Antimicrobial Chemotherapy, vol. 69, no. 3, 2014, pp. 697-705.
Chilton CH, Crowther GS, Baines SD, et al. In vitro activity of cadazolid against clinically relevant Clostridium difficile isolates and in an in vitro gut model of C. difficile infection. J Antimicrob Chemother. 2014;69(3):697-705.
Chilton, C. H., Crowther, G. S., Baines, S. D., Todhunter, S. L., Freeman, J., Locher, H. H., Athanasiou, A., & Wilcox, M. H. (2014). In vitro activity of cadazolid against clinically relevant Clostridium difficile isolates and in an in vitro gut model of C. difficile infection. The Journal of Antimicrobial Chemotherapy, 69(3), 697-705. https://doi.org/10.1093/jac/dkt411
Chilton CH, et al. In Vitro Activity of Cadazolid Against Clinically Relevant Clostridium Difficile Isolates and in an in Vitro Gut Model of C. Difficile Infection. J Antimicrob Chemother. 2014;69(3):697-705. PubMed PMID: 24128668.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro activity of cadazolid against clinically relevant Clostridium difficile isolates and in an in vitro gut model of C. difficile infection. AU - Chilton,C H, AU - Crowther,G S, AU - Baines,S D, AU - Todhunter,S L, AU - Freeman,J, AU - Locher,H H, AU - Athanasiou,A, AU - Wilcox,M H, Y1 - 2013/10/14/ PY - 2013/10/17/entrez PY - 2013/10/17/pubmed PY - 2015/7/16/medline KW - MICs KW - antimicrobial persistence KW - chemostat SP - 697 EP - 705 JF - The Journal of antimicrobial chemotherapy JO - J Antimicrob Chemother VL - 69 IS - 3 N2 - OBJECTIVES: We investigated the in vitro activity of cadazolid against 100 Clostridium difficile isolates and its efficacy in a simulated human gut model of C. difficile infection (CDI). METHODS: MICs of cadazolid, metronidazole, vancomycin, moxifloxacin and linezolid were determined using agar incorporation for 100 C. difficile isolates, including 30 epidemic strains (ribotypes 027, 106 and 001) with reduced metronidazole susceptibility, 2 linezolid-resistant isolates and 2 moxifloxacin-resistant isolates. We evaluated the efficacy of two cadazolid dosing regimens (250 versus 750 mg/L twice daily for 7 days) to treat simulated CDI. Microflora populations, C. difficile total viable counts and spores, cytotoxin titres, possible emergence of cadazolid, linezolid or quinolone resistance, and antimicrobial concentrations were monitored throughout. RESULTS: Cadazolid was active against all (including linezolid- and moxifloxacin-resistant) C. difficile strains (MIC90 0.125, range 0.03-0.25 mg/L). The cadazolid geometric mean MIC was 152-fold, 16-fold, 9-fold and 7-fold lower than those of moxifloxacin, linezolid, metronidazole and vancomycin, respectively. Both cadazolid dosing regimens rapidly reduced C. difficile viable counts and cytotoxin with no evidence of recurrence. Cadazolid levels persisted at 50-100-fold supra-MIC for 14 days post-dosing. Cadazolid inhibition of enumerated gut microflora was limited, with the exception of bifidobacteria; Bacteroides fragilis group and Lactobacillus spp. counts were unaffected. There was no evidence for selection of strains resistant to cadazolid, quinolones or linezolid. CONCLUSIONS: Cadazolid activity was greater than other tested antimicrobials against 100 C. difficile strains. Cadazolid effectively treated simulated CDI in a gut model, with limited impact on the enumerated gut microflora and no signs of recurrence or emergence of resistance within the experimental timeframe. SN - 1460-2091 UR - https://www.unboundmedicine.com/medline/citation/24128668/In_vitro_activity_of_cadazolid_against_clinically_relevant_Clostridium_difficile_isolates_and_in_an_in_vitro_gut_model_of_C__difficile_infection_ L2 - https://academic.oup.com/jac/article-lookup/doi/10.1093/jac/dkt411 DB - PRIME DP - Unbound Medicine ER -