2109. In vitro and in vivo Killing Kinetics of Zosurabalpin (RG6006) Against Acinetobacter baumannii

BACKGROUND: Zosurabalpin (RG6006) is a novel antibiotic active against Acinetobacter spp., including carbapenem-resistant Acinetobacter calcoaceticus-baumannii complex organisms. Here we describe and compare the kinetics of killing in static in vitro and in vivo neutropenic murine thigh and lung infection models. METHODS: The killing activity of Zosurabalpin was evaluated against 8 carbapenem resistant A. baumannii (CRAB) isolates (MIC range of 0.12 to 8 mg/L). In vitro Time-Kill studies were performed over 24 hours at sub-MIC and multiples of the MIC (from 0.25x to 128x MIC) with regular time point samplings (from 0, 2, 4, 8, 12, 16, 20 and 24 hours), plating, and CFU counting. The in vivo killing efficacy of RG6006 at 2 or 3 dose levels was assessed in 5 thigh and 5 lung infection models induced by 6 A. baumannii (MIC range 0.125 - 8 mg/L). Bacterial burden in matrices of interest was determined at different timepoints up to 48 hours. RESULTS: In vitro, the bactericidal activity (defined as a 99.9% [or ≥ 3 log10] reduction in CFUs) of Zosurabalpin was reached in all tested isolates (lowest bactericidal concentration: 4x-32x MIC) and with a relatively slow killing kinetic (≥ 12 hours). No regrowth was observed at or above 8x/16x MIC depending on the isolate. In vivo, generally, no regrowth was observed. In all 5 lung and 3 thigh infection studies, all dosing regimen achieving a net bacterial reduction after 24 hours, showed continued suppression of growth over the 48 hours period. In 2 thigh infection studies induced by isolates with MIC 4 and 8 mg/L full bactericidal efficacy was observed without any signs of regrowth at the highest dose tested. CONCLUSION: Zosurabalpin overall exhibited a bacterial killing effect, both in vitro and in vivo, against CRAB. The comparison of in vitro and in vivo time-kill data demonstrates that in vitro observed regrowth generally does not translate into, and potentially overestimates, in vivo regrowth. This project has been funded by BARDA (HHSO100201600038C) DISCLOSURES: Isabelle Erbetti, n/a, F. Hoffmann-La Roche Ltd.: Grant/Research Support Livia Ferrari, n/a, F. Hoffmann-La Roche Ltd.: Grant/Research Support Alessia Ortombina, n/a, F. Hoffmann-La Roche Ltd.: Grant/Research Support Paola Savoia, n/a, F. Hoffmann-La Roche Ltd.: Grant/Research Support Antonio Felici, n/a, F. Hoffmann-La Roche Ltd.: Grant/Research Support Caterina Bissantz, n/a, F. Hoffmann-La Roche Ltd.: Full time employee of Roche Claudia Zampaloni, n/a, F. Hoffmann-La Roche Ltd.: Full time employee of Roche