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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.

Authors+Show Affiliations

Cubist Pharmaceuticals, Inc., Lexington, Massachusetts, USA. carmela.mascio@cubist.comNo affiliation info availableNo affiliation info availableNo 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

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 -