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In vitro and in vivo antibacterial evaluation of cadazolid, a new antibiotic for treatment of Clostridium difficile infections.
Antimicrob Agents Chemother. 2014; 58(2):892-900.AA

Abstract

Clostridium difficile is a leading cause of health care-associated diarrhea with significant morbidity and mortality, and new options for the treatment of C. difficile-associated diarrhea (CDAD) are needed. Cadazolid is a new oxazolidinone-type antibiotic that is currently in clinical development for treatment of CDAD. Here, we report the in vitro and in vivo antibacterial evaluation of cadazolid against C. difficile. Cadazolid showed potent in vitro activity against C. difficile with a MIC range of 0.125 to 0.5 μg/ml, including strains resistant to linezolid and fluoroquinolones. In time-kill kinetics experiments, cadazolid showed a bactericidal effect against C. difficile isolates, with >99.9% killing in 24 h, and was more bactericidal than vancomycin. In contrast to metronidazole and vancomycin, cadazolid strongly inhibited de novo toxin A and B formation in stationary-phase cultures of toxigenic C. difficile. Cadazolid also inhibited C. difficile spore formation substantially at growth-inhibitory concentrations. In the hamster and mouse models for CDAD, cadazolid was active, conferring full protection from diarrhea and death with a potency similar to that of vancomycin. These findings support further investigations of cadazolid for the treatment of CDAD.

Links

Publisher Full Text
ncbi.nlm.nih.gov
aac.asm.org
PMC Free PDF

Authors+Show Affiliations

Locher HH
Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Seiler P
No affiliation info available
Chen X
No affiliation info available
Schroeder S
No affiliation info available
Pfaff P
No affiliation info available
Enderlin M
No affiliation info available
Klenk A
No affiliation info available
Fournier E
No affiliation info available
Hubschwerlen C
No affiliation info available
Ritz D
No affiliation info available
Kelly CP
No affiliation info available
Keck W
No affiliation info available

MeSH

AcetamidesAnimalsAnti-Bacterial AgentsBacterial ProteinsBacterial ToxinsClostridium InfectionsClostridium difficileCricetinaeEnterocolitis, PseudomembranousEnterotoxinsFemaleFluoroquinolonesHumansLinezolidMaleMetronidazoleMiceMice, Inbred C57BLMicrobial Sensitivity TestsOxazolidinonesSpores, BacterialSurvival AnalysisVancomycin

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24277020

Citation

Locher, Hans H., et al. "In Vitro and in Vivo Antibacterial Evaluation of Cadazolid, a New Antibiotic for Treatment of Clostridium Difficile Infections." Antimicrobial Agents and Chemotherapy, vol. 58, no. 2, 2014, pp. 892-900.
Locher HH, Seiler P, Chen X, et al. In vitro and in vivo antibacterial evaluation of cadazolid, a new antibiotic for treatment of Clostridium difficile infections. Antimicrob Agents Chemother. 2014;58(2):892-900.
Locher, H. H., Seiler, P., Chen, X., Schroeder, S., Pfaff, P., Enderlin, M., Klenk, A., Fournier, E., Hubschwerlen, C., Ritz, D., Kelly, C. P., & Keck, W. (2014). In vitro and in vivo antibacterial evaluation of cadazolid, a new antibiotic for treatment of Clostridium difficile infections. Antimicrobial Agents and Chemotherapy, 58(2), 892-900. https://doi.org/10.1128/AAC.01830-13
Locher HH, et al. In Vitro and in Vivo Antibacterial Evaluation of Cadazolid, a New Antibiotic for Treatment of Clostridium Difficile Infections. Antimicrob Agents Chemother. 2014;58(2):892-900. PubMed PMID: 24277020.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro and in vivo antibacterial evaluation of cadazolid, a new antibiotic for treatment of Clostridium difficile infections. AU - Locher,Hans H, AU - Seiler,Peter, AU - Chen,Xinhua, AU - Schroeder,Susanne, AU - Pfaff,Philippe, AU - Enderlin,Michel, AU - Klenk,Axel, AU - Fournier,Elvire, AU - Hubschwerlen,Christian, AU - Ritz,Daniel, AU - Kelly,Ciaran P, AU - Keck,Wolfgang, Y1 - 2013/11/25/ PY - 2013/11/27/entrez PY - 2013/11/28/pubmed PY - 2014/9/23/medline SP - 892 EP - 900 JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 58 IS - 2 N2 - Clostridium difficile is a leading cause of health care-associated diarrhea with significant morbidity and mortality, and new options for the treatment of C. difficile-associated diarrhea (CDAD) are needed. Cadazolid is a new oxazolidinone-type antibiotic that is currently in clinical development for treatment of CDAD. Here, we report the in vitro and in vivo antibacterial evaluation of cadazolid against C. difficile. Cadazolid showed potent in vitro activity against C. difficile with a MIC range of 0.125 to 0.5 μg/ml, including strains resistant to linezolid and fluoroquinolones. In time-kill kinetics experiments, cadazolid showed a bactericidal effect against C. difficile isolates, with >99.9% killing in 24 h, and was more bactericidal than vancomycin. In contrast to metronidazole and vancomycin, cadazolid strongly inhibited de novo toxin A and B formation in stationary-phase cultures of toxigenic C. difficile. Cadazolid also inhibited C. difficile spore formation substantially at growth-inhibitory concentrations. In the hamster and mouse models for CDAD, cadazolid was active, conferring full protection from diarrhea and death with a potency similar to that of vancomycin. These findings support further investigations of cadazolid for the treatment of CDAD. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/24277020/In_vitro_and_in_vivo_antibacterial_evaluation_of_cadazolid_a_new_antibiotic_for_treatment_of_Clostridium_difficile_infections_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=24277020 DB - PRIME DP - Unbound Medicine ER -