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In vitro and in vivo characterization of CB-183,315, a novel lipopeptide antibiotic for treatment of Clostridium difficile.
Antimicrob Agents Chemother. 2012 Oct; 56(10):5023-30.AA

Abstract

CB-183,315 is a novel lipopeptide antibiotic structurally related to daptomycin currently in phase 3 clinical development for Clostridium difficile-associated diarrhea (CDAD). We report here the in vitro mechanism of action, spontaneous resistance incidence, resistance by serial passage, time-kill kinetics, postantibiotic effect, and efficacy of CB-183,315 in a hamster model of lethal infection. In vitro data showed that CB-183,315 dissipated the membrane potential of Staphylococcus aureus without inducing changes in membrane permeability to small molecules. The rate of spontaneous resistance to CB-183,315 at 8× the MIC was below the limit of detection in C. difficile. Under selective pressure by serial passage with CB-183,315 against C. difficile, the susceptibility of the bacteria changed no more than 2-fold during 15 days of serial passages. At 16× the MIC, CB-183,315 produced a ≥3-log reduction of C. difficile in the time-kill assay. The postantibiotic effect of CB-183,315 at 8× the MIC was 0.9 h. At 80× the MIC the postantibiotic effect was more than 6 h. In the hamster model of CDAD, CB-183,315 and vancomycin both demonstrated potent efficacy in resolving initial disease onset, even at very low doses. After the conclusion of dosing, CB-183,315 and vancomycin showed a similar dose- and time-dependent pattern with respect to rates of CDAD recurrence.

Links

Publisher Full Text
ncbi.nlm.nih.gov
aac.asm.org
aac.asm.org
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Authors+Show Affiliations

Mascio CT
Cubist Pharmaceuticals, Inc., Lexington, Massachusetts, USA. carmela.mascio@cubist.com
Mortin LI
No affiliation info available
Howland KT
No affiliation info available
Van Praagh AD
No affiliation info available
Zhang S
No affiliation info available
Arya A
No affiliation info available
Chuong CL
No affiliation info available
Kang C
No affiliation info available
Li T
No affiliation info available
Silverman JA
No affiliation info available

MeSH

AnimalsAnti-Bacterial AgentsClostridioides difficileCricetinaeEnterocolitis, PseudomembranousLipopeptidesMaleMesocricetusMicrobial Sensitivity TestsPeptides, CyclicVancomycin

Pub Type(s)

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

Language

eng

PubMed ID

22802252

Citation

Mascio, Carmela T M., et al. "In Vitro and in Vivo Characterization of CB-183,315, a Novel Lipopeptide Antibiotic for Treatment of Clostridium Difficile." Antimicrobial Agents and Chemotherapy, vol. 56, no. 10, 2012, pp. 5023-30.
Mascio CT, Mortin LI, Howland KT, et al. In vitro and in vivo characterization of CB-183,315, a novel lipopeptide antibiotic for treatment of Clostridium difficile. Antimicrob Agents Chemother. 2012;56(10):5023-30.
Mascio, C. T., Mortin, L. I., Howland, K. T., Van Praagh, A. D., Zhang, S., Arya, A., Chuong, C. L., Kang, C., Li, T., & Silverman, J. A. (2012). In vitro and in vivo characterization of CB-183,315, a novel lipopeptide antibiotic for treatment of Clostridium difficile. Antimicrobial Agents and Chemotherapy, 56(10), 5023-30. https://doi.org/10.1128/AAC.00057-12
Mascio CT, et al. In Vitro and in Vivo Characterization of CB-183,315, a Novel Lipopeptide Antibiotic for Treatment of Clostridium Difficile. Antimicrob Agents Chemother. 2012;56(10):5023-30. PubMed PMID: 22802252.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro and in vivo characterization of CB-183,315, a novel lipopeptide antibiotic for treatment of Clostridium difficile. AU - Mascio,Carmela T M, AU - Mortin,Lawrence I, AU - Howland,Karen T, AU - Van Praagh,Andrew D G, AU - Zhang,Shuxin, AU - Arya,Anu, AU - Chuong,Cun Lan, AU - Kang,Chunfeng, AU - Li,Tongchuan, AU - Silverman,Jared A, Y1 - 2012/07/16/ PY - 2012/7/18/entrez PY - 2012/7/18/pubmed PY - 2013/2/5/medline SP - 5023 EP - 30 JF - Antimicrobial agents and chemotherapy JO - Antimicrob Agents Chemother VL - 56 IS - 10 N2 - CB-183,315 is a novel lipopeptide antibiotic structurally related to daptomycin currently in phase 3 clinical development for Clostridium difficile-associated diarrhea (CDAD). We report here the in vitro mechanism of action, spontaneous resistance incidence, resistance by serial passage, time-kill kinetics, postantibiotic effect, and efficacy of CB-183,315 in a hamster model of lethal infection. In vitro data showed that CB-183,315 dissipated the membrane potential of Staphylococcus aureus without inducing changes in membrane permeability to small molecules. The rate of spontaneous resistance to CB-183,315 at 8× the MIC was below the limit of detection in C. difficile. Under selective pressure by serial passage with CB-183,315 against C. difficile, the susceptibility of the bacteria changed no more than 2-fold during 15 days of serial passages. At 16× the MIC, CB-183,315 produced a ≥3-log reduction of C. difficile in the time-kill assay. The postantibiotic effect of CB-183,315 at 8× the MIC was 0.9 h. At 80× the MIC the postantibiotic effect was more than 6 h. In the hamster model of CDAD, CB-183,315 and vancomycin both demonstrated potent efficacy in resolving initial disease onset, even at very low doses. After the conclusion of dosing, CB-183,315 and vancomycin showed a similar dose- and time-dependent pattern with respect to rates of CDAD recurrence. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/22802252/In_vitro_and_in_vivo_characterization_of_CB_183315_a_novel_lipopeptide_antibiotic_for_treatment_of_Clostridium_difficile_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=22802252 DB - PRIME DP - Unbound Medicine ER -