Evaluation of a potent LpxC inhibitor for post-exposure prophylaxis treatment of antibiotic-resistant Burkholderia pseudomallei in a murine infection model.

Abstract

LPC-233 (a.k.a. VB-233) is a potent antibiotic targeting the essential enzyme LpxC in Gram-negative bacteria. We present herein the pharmacokinetics and pharmacodynamics data of LPC-233 for treating murine infections caused by Burkholderia pseudomallei, a potential biodefense pathogen. A range of doses was evaluated in a post-aerosol exposure model of B. pseudomallei-infected mice. After the aerosol challenge with the B. pseudomallei strain K96243, treatment was initiated with 10, 30, or 90 mg/kg of LPC-233 orally every 12 h (q12h) or 90 mg/kg intraperitoneally q12h for 14 days. A vehicle-control arm and a positive-control arm consisting of one of the recommended standards of care, ceftazidime (150 mg/kg, q6h) injected subcutaneously, were included. LPC-233 significantly and dose-dependently rescued mice from B. pseudomallei infection in comparison with the vehicle (P < 0.0001). At dose levels of 30 mg/kg or higher, the survival rate with LPC-233 was significantly higher than that from the ceftazidime arm (P range: 0.001-0.05). LPC-233 reversed the murine body weight loss caused by the B. pseudomallei infection more rapidly than ceftazidime did, suggesting that it is a faster-acting antibiotic in this dosing regimen. Despite the outstanding survival advantage of LPC-233 over ceftazidime, no significant differences in tissue burdens (liver, lung, spleen, and blood) were observed among any of the treatment groups surviving to the termination of the experiment, suggesting that similar to commercial antibiotics, LPC-233 treatment for lethal B. pseudomallei infection may likely require both an acute phase of intensive treatment and an eradication phase of prolonged treatment.