767. S-649266, a Novel Siderophore Cephalosporin: In Vitro Activities against Multidrug-Resistant and Carbapenem Resistant Gram-Negative Pathogens in an in vitro Pharmacodynamic Model
Session: Poster Abstract Session: Antimicrobial Agents: Novel Agents
Friday, October 9, 2015
Room: Poster Hall
  • 767_IDWeek2015_final.pdf (4.2 MB)
  • Background: S-649266 ('266) is a novel parenteral catechol-substituted siderophore cephalosporin for injection discovered by Shionogi & Co., Ltd. In this study, in vitro activities of ‘266 against multidrug-resistant P. aeruginosa (MDRP), A. baumannii (MDRA), and carbapenem-resistant Enterobacteriaceae (CRE) isolates were evaluated by using an in vitro pharmacodynamic model.

    Methods: MICs were measured by broth microdilution method according to the Clinical and Laboratory Standard Institute except that iron deficient broth, which was prepared by treatment with Chelex resin, was used for evaluation of ‘266. A total of 2 MDRP, 2 MDRA, and 4 CRE clinical isolates including 2 KPC producing and 2 NDM producing isolates were used in this study. The test strains were included to show MIC corresponding MIC90 values of ‘266 which were 4, 2, and 8 µg/mL against MDRP, MDRA, and CRE, respectively. In vitro activities of ‘266 were evaluated by using an in vitro pharmacodynamic model recreating plasma concentration-time profiles in human plasma. The recreated human PK profiles of ‘266, colistin, amikacin, and meropenem were based on the clinical data as follows: 2 g as a 1-hour infusion for ‘266, 2.5 mg/kg colistin methanesulfonate sodium as a 0.5-hours infusion for colistin, 5 mg/kg as a 0.5-hours infusion for amikacin, and 1 g as a 1-hour infusion for meropenem.

    Results: The treatment of ‘266 q8h showed the bactericidal activities against MDR and CRE isolates whose MICs were up to 16 µg/mL, and caused >3-log10 reduction of the viable cells in 24-hours, where %Tf>MIC was ≥40%. The treatment by the combination of colistin q12h and amikacin q8h caused only 1.6-log10 reduction of the viable cells of MDRP, and 2-log10 reduction of MDRA in 24 hours. Meropenem was not effective against MDR strains whose MICs were ≥16 µg/mL.

    Conclusion: IV infusion of 2 g ‘266 q8h showed potent in vitro activities against MDRP, MDRA, and CRE isolates in an in vitro pharmacodynamic model. Two g ‘266 q8h regimen should be effective for the treatment of infections caused by multidrug-resistant Gram-negative pathogens.

    Masakatsu Tsuji, Ph.D, Rio Nakamura, bachelor's degree, Sachi Kanazawa, Ph.D, Shuhei Matsumoto, master's degree, Takafumi Sato, Ph.D and Yoshinori Yamano, Ph.D, Infectious Diseases, SHIONOGI & CO., LTD., Osaka, Japan


    M. Tsuji, Shionogi & CO. LTD.: Employee , Salary

    R. Nakamura, Shionogi LTD.: Employee , Salary

    S. Kanazawa, Shionogi &CO., LTD: Employee , Salary

    S. Matsumoto, Shionogi & CO.,LTD.: Employee , Salary

    T. Sato, Shionogi & CO., LTD.: Employee , Salary

    Y. Yamano, Shionogi & CO., LTD.: Employee , Salary

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