Abstract
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
Twelve strains (6 EC, 6 KPN) were utilized, including those with tetracycline or β-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 indices and CFU outcome data were analyzed using the sigmoid Emax (Hill) model with nonlinear regression. Treatment studies were then performed with the remaining 11 strains. Four-fold increasing NOSO-502 doses (3.91–1,000 mg/kg/6 hours 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 to 4 mg/L. PK ranges for doses included: Cmax 1.5–85 mg/L, AUC0-∞ 1.9–352 mg hour/L, T1/2 0.4–1.1 hour. 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 24 hours stasis total and free drug PD targets are shown (table). 1-log kill targets were determined for KPN and noted at a median 24 hours fAUC/MIC of 11.
| 24 hours 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 β-lactams. The PK/PD index predictive of efficacy is AUC/MIC. Stasis 24 hours AUC/MIC targets were numerically low for KPN and EC. This data suggest that NOSO-502 is a promising novel agent and these targets will provide a basis for developing human dosing regimens to optimize efficacy.
Disclosures
M. Zhao, Nosopharm: Research Contractor, Research support. A. J. Lepak, Nosopharm: Research Contractor, Research support. D. R. Andes, Nosopharm: Research Contractor, Research support.
Session: 145. PK/PD Studies
Friday, October 5, 2018: 12:30 PM