In vitro and in vivo characterization of CB-183,315, a novel lipopeptide antibiotic for treatment of Clostridium difficile.
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.
Cubist Pharmaceuticals, Inc., Lexington, Massachusetts, USA. carmela.mascio@cubist.com
Carmela T M
CT
Mascio
Lawrence I
LI
Mortin
Karen T
KT
Howland
Andrew D G
AD
Van Praagh
Shuxin
S
Zhang
Anu
A
Arya
Cun Lan
CL
Chuong
Chunfeng
C
Kang
Tongchuan
T
Li
Jared A
JA
Silverman
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016360:Clostridioides difficile / Q000187:drug effects*; D006224:Cricetinae; D004761:Enterocolitis, Pseudomembranous / Q000188:drug therapy; D055666:Lipopeptides / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D008647:Mesocricetus; D008826:Microbial Sensitivity Tests; D010456:Peptides, Cyclic / Q000494:pharmacology* / Q000627:therapeutic use*; D014640:Vancomycin / Q000494:pharmacology
D000900:Anti-Bacterial Agents; C574454:CB-183,315; D055666:Lipopeptides; D010456:Peptides, Cyclic; D014640:Vancomycin