In Vivo Pharmacodynamic Characterization of a Novel Antibiotic Odilorhabdins, NOSO-502 against Escherichia coli and Klebsiella pneumoniae in a Murine Thigh Infection Model [PublishAheadOfPrint]

NOSO-502 is a novel odilorhabdin antibiotic with potent activity against Enterobacteriaceae. The goal of these studies was to determine which pharmacokinetic/pharmacodynamic (PK/PD) indice and magnitude best correlated with efficacy in the murine thigh infection model. Six E. coli and 6 K. pneumoniae were utilized. MICs were determined using CLSI methods and ranged from 1 to 4 mg/L. A neutropenic murine thigh infection model was utilized for all treatment studies. Single-dose plasma pharmacokinetics were determined in mice after subcutaneous administration of 7.81, 31.25, 125 and 500 mg/kg. Pharmacokinetic studies exhibited peak concentration (C_max) values of 1.49 to 84.6 mg/L, area under the concentration-time curve (AUC_0-) values of 1.94 to 352 mg*h/L, and beta-elimination half-lives of 0.41 to 1.1 h. Dose fractionation studies were performed using total drug doses 7.81 mg/kg to 2000 mg/kg fractionated into q3-, q6-, q12-, or q24-hourly regimens. Nonlinear regression analysis demonstrated AUC/MIC was the PK/PD parameter that best correlated with efficacy (R² 0.86). In subsequent studies, we used the neutropenic murine thigh infection model to determine the magnitude of NOSO-502 AUC/MIC needed for the efficacy against a diverse group of Enterobacteriaceae. Mice were treated with four-fold increasing doses (range 3.91 to 1000 mg/kg) of NOSO-502 every 6 hours. The mean fAUC/MIC magnitudes associated with net stasis and 1-log kill endpoint for K. pneumoniae were 4.22 and 17.7, respectively. The mean fAUC/MIC magnitude associated with net stasis endpoint for E. coli was 10.4. NOSO-502 represents a promising novel, first-in-class odilorhabdin antibiotic with in vivo potency against Enterobacteriaceae.

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