1389. Pharmacokinetic/Pharmacodynamic (PK/PD) Evaluation of a Novel Aminomethylcycline Antibiotic, KBP-7072, in the Neutropenic Murine Pneumonia Model Against S. aureus (SA) and S. pneumoniae (SPN)

Abstract

BackgroundKBP-7072 is a novel aminomethylcycline antibiotic with broad-spectrum activity that includes organisms with drug-resistance to β-lactams and tetracyclines. We examined the PK/PD relationship between KBP-7072 drug exposures and treatment effect using a neutropenic murine pneumonia model against a diverse group of SA and SPN.MethodsFive SAs (three MRSAs) and six SPNs (three PCNs NS, two TetR) strains were used. MICs were determined by CLSI Methods. Plasma and ELF PK was determined after SC dosing (range 1–256 mg/kg). Lung burden was assessed by CFU counts at the beginning and end of therapy (24 hours). Infected mice were treated with KBP-7072 by SC route: SA dose range 0.25–64 mg/kg/6 hours, SPN dose range 0.06–16 mg/kg/6 hours. The Emax Hill equation was used to model the dose–response data to the PK/PD index AUC/MIC. The magnitude of the PK/PD index (plasma free and ELF total concentrations) associated with net stasis, 1- and 2-log kill were determined in the pneumonia model for all strains.ResultsSA MICs were 0.25 mg/L for all isolates and SPN MICs were 0.008–0.016 mg/L. Plasma PK of KBP-7072 included: Cmax 0.12–25.2 mg/L, AUC0-∞ 1.1–234 mg hour/L, T1/2 3.2–4.6 h. ELF PK by urea correction methods included: Cmax 0.06–13.3 mg/L, AUC0-∞ 0.4–95 mg hour/L, T1/2 3.1–4 hours. ELF penetration based on free plasma drug concentrations (77.5% bound) ranged from 82 to 238%. AUC was linear over the dose range (R2 = 0.99). Potent dose-dependent cidal activity (3–5 log kill) was observed against all strains. AUC/MIC was a robust predictor of efficacy (SA R2 = 0.89, SPN R2 0.80). Median static, 1- and 2-log kill AUC/MIC values are shown in the table.GroupStasis Plasma fAUC/MICStasis ELF AUC/MIC1-Log Kill Plasma fAUC/MIC1-Log Kill ELF AUC/MIC2-Log Kill Plasma fAUC/MIC2-Log Kill ELF AUC/MICSA0.971.722.484.415.817.51SPN1.121.993.686.5413.0623.22ConclusionKBP-7072 demonstrated potent in vivo efficacy against SA and SPN, including strains with elevated minocycline MIC and β-lactam resistance, in the neutropenic murine pneumonia model. A 3–5 log kill was observed and AUC/MIC was strongly associated with efficacy. The AUC/MIC target for net stasis was comparable between SA and SPN at a plasma fAUC/MIC target of ~1 and ELF AUC/MIC target ~2. Cidal targets were similarly very low. All targets were numerically lower than comparative tetracyclines. These results should prove useful for clinical dosing regimen optimization.Disclosures A. J. Lepak, KBP Biosciences: Research Contractor, Research support. Q. Liu, KBP Biosciences: Employee, Salary. P. Wang, KBP Biosciences: Employee, Salary. Y. Wang, KBP Biosciences: Employee, Salary. J. C. Bader, KBP Biosciences: Research Contractor, Research support. P. G. Ambrose, KBP Biosciences: Research Contractor, Research support. D. R. Andes, KBP Biosciences: Research Contractor, Research support.