Giuseppe
Emeritus
[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]
Cadazolid, a New Antibiotic for the Treatment of Clostridium difficile Infections: In Vitro and in Vivo Antibacterial Evaluation
Hans H. Locher 1#, Peter Seiler 1, Xinhua Chen 2, Susanne Schroeder 1, Philippe Pfaff 1, Michel Enderlin 1, Axel Klenk 1, Elvire Fournier 1, Christian Hubschwerlen 1, Daniel Ritz 1, Ciaran P. Kelly 2 and Wolfgang Keck 1
Author Affiliations: <SUP>1</SUP>Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. <SUP>2</SUP>Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Published ahead of print 25 November 2013, doi: 10.1128/AAC.01830-13 <CITE>AAC.01830-13 </CITE>
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<CITE></CITE>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 0.125-0.5 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 sub-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 vancomycin. These findings support further investigations of cadazolid for the treatment of CDAD.
FOOTNOTES
# Correspondence: Hans H. Locher, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland, FAX : +41 61 565 80 90, E-mail : hans.locher@actelion.com
Copyright ? 2013, American Society for Microbiology. All Rights Reserved.
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Cadazolid, a New Antibiotic for the Treatment of Clostridium difficile Infections: In Vitro and in Vivo Antibacterial Evaluation
Hans H. Locher 1#, Peter Seiler 1, Xinhua Chen 2, Susanne Schroeder 1, Philippe Pfaff 1, Michel Enderlin 1, Axel Klenk 1, Elvire Fournier 1, Christian Hubschwerlen 1, Daniel Ritz 1, Ciaran P. Kelly 2 and Wolfgang Keck 1
Author Affiliations: <SUP>1</SUP>Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. <SUP>2</SUP>Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Published ahead of print 25 November 2013, doi: 10.1128/AAC.01830-13 <CITE>AAC.01830-13 </CITE>
<CITE></CITE>
<CITE></CITE>
<CITE></CITE>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 0.125-0.5 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 sub-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 vancomycin. These findings support further investigations of cadazolid for the treatment of CDAD.
FOOTNOTES
# Correspondence: Hans H. Locher, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland, FAX : +41 61 565 80 90, E-mail : hans.locher@actelion.com
Copyright ? 2013, American Society for Microbiology. All Rights Reserved.
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