1383. In vivo Pharmacokinetic/Pharmacodynamic (PK/PD) Evaluation of NOSO-502, a First-in-class Odilorhabdin Antibiotic, against E. coli (EC) and K. pneumoniae (KPN) in the Murine Neutropenic Thigh Model
Session: Poster Abstract Session: PK/PD Studies
Friday, October 5, 2018
Room: S Poster Hall
Posters
  • NOSO ID week poster final.pdf (124.1 kB)
  • Background: NOSO-502 is a novel, first-in-class Odilorhabdin antibiotic targeting bacterial protein translation, with potent in vitro activity against Enterobacteriaceae including strains with MDR or CRE-phenotype. The goal of this study was to determine the PK/PD characteristics of NOSO-502 using the murine thigh infection model against a diverse group of EC and KPN strains.

    Methods: 12 strains (6 EC, 6 KPN) were utilized, including those with tetracycline or beta-lactam resistance. MICs were determined by CLSI methods. Single dose murine plasma PK of NOSO-502 was determined after administration of 7.81, 31.25, 125 and 500 mg/kg by SC route. Dose fractionation (DF) study was used to determine which PK/PD index was associated with efficacy. The relationship between each PK/PD indice and CFU outcome data was analyzed using the sigmoid Emax (Hill) model with non-linear regression. Treatment studies were then performed with the remaining 11 strains. Four-fold increasing NOSO-502 doses (3.91-1000 mg/kg/6h SC route) were administered. Treatment data and AUC/MIC was analyzed to determine AUC/MIC targets associated with net stasis and 1-log kill (when achieved) for all strains.

    Results: MICs ranged from 1-4 mg/L. PK ranges for doses included: Cmax 1.5-85 mg/L, AUC0-∞ 1.9-352 mg*h/L, T1/2 0.4-1.1 h. DF regression analysis: AUC/MIC R2 0.86, Cmax/MIC R2 0.70, T>MIC R2 0.77. Against each of the 12 strains there was dose-dependent activity and net stasis was achieved against all strains, with maximal activity of 1-2 log killing in EC and almost 3 log killing in KPN. The 24h stasis total and free drug PD targets are shown (table). 1-log kill targets were determined for KPN and noted at a median 24h fAUC/MIC of 11.

    24h Static Dose (mg/kg)

    Stasis tAUC/MIC

    Stasis fAUC/MIC

    EC

    Mean

    374

    53

    10

    Median

    409

    59

    12

    SD

    182

    32

    6.3

    KPN

    Mean

    81

    21

    4.2

    Median

    56

    9.1

    1.8

    SD

    56

    24

    4.7

    Conclusion: NOSO-502 demonstrated in vivo potency against a diverse group of EC and KPN strains including those with resistance to tetracycline and beta-lactams. The PK/PD index predictive of efficacy is AUC/MIC. Stasis 24 h AUC/MIC targets were numerically low for KPN and EC. This data suggests NOSO-502 is a promising novel agent and these targets will provide a basis for developing human dosing regimens to optimize efficacy.

    Miao Zhao, MS, PhD, Alexander J. Lepak, M.D. and David R. Andes, M.D., FIDSA, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI

    Disclosures:

    M. Zhao, Nosopharm: Research Contractor , Research support .

    A. J. Lepak, Nosopharm: Research Contractor , Research support .

    D. R. Andes, Nosopharm: Research Contractor , Research support .

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