S-649266, a Novel Siderophore Cephalosporin: Pharmacodynamic assessment by using MIC in Iron-depleted Cation-adjusted Mueller Hinton Broth (ID-CAMHB)

Background:S-649266, a novel siderophore cephalosporin, is active against carbapenem-resistant (CR) Gram-negative bacteria. Accurate in vitro testing of S-649266 by broth microdilution requires the use of iron-depleted conditions to mimic the condition in mammalian hosts. Iron‑depleted cation‑adjusted Mueller Hinton Broth (ID-CAMHB) was shown to be the best standard method for the determination of MIC values to S-649266. In this study, the correlation between MIC and in vivo efficacy was investigated, and pharmacodynamic assessment of S-649266 was evaluated using ID-CAMHB against murine thigh and lung infection models caused by CR Gram-negative isolates.

Methods: MIC was determined by BMD method according to CLSI except that ID-CAMHB. ICR mice (male, five weeks old, neutropenic, n=5) were used. The correlation between MIC and in vivo efficacy was investigated in a murine thigh infection model with 3 Enterobacteriaceae isolates. In murine thigh and lung infection models, PK/PD parameters required for efficacy were evaluated with each 6 strains of Pseudomonas aeruginosa and Acinetobacter baumannii including multidrug-resistant isolates and 16 Enterobacteriaceae including CR isolates. Administration was initiated 2 hours post-infection and repeated every 3 hours. Viable cells in tissues at 24 hours after the initiation of the treatment were evaluated. T_>MIC of S-649266 was calculated with MIC in ID-CAMHB.

Results:In vivo efficacy of S-649266 was correlated well with MIC determined using ID-CAMHB compared with that in CAMHB. S-649266 was highly efficacious in neutropenic murine thigh and lung infection model caused by Gram-negative bacilli. The mean of T_>MIC of S-649266 required for 1-log₁₀ reduction were approximately 78% against Enterobacteriaceae including CR strains. For all isolates tested, the mean value of T_>MIC required for 1-log₁₀ reduction was approximately 75%. T_>MIC required for efficacy were similar across animal models or bacterial species.

Conclusion:S-649266 MIC in ID-CAMHB showed a good correlation with in vivo efficacy in the animal models. T_>MIC is an appropriate PK/PD parameter for evaluating the efficacy of S-649266. S-649266 showed potent efficacy against Gram-negative bacteria including CR strains in murine infection models reflecting the potent in vitro activity determined under iron-depleted conditions.