Pharmacokinetics/Pharmacodynamics of Vaborbactam, a Novel Beta-lactamase Inhibitor, in Combination with Meropenem [Experimental Therapeutics]

Vaborbactam is a novel beta-lactamase inhibitor with activity against important beta-lactamases, in particular, serine carbapenemases, and is currently approved in combination with meropenem as Vabomere™ for the treatment of complicated urinary tract infections, including pyelonephritis. This combination is highly active against Gram-negative pathogens, especially KPC-producing, carbapenem-resistant, Enterobacteriaceae. The objective of these studies was to evaluate vaborbactam pharmacokinetics (PK) and pharmacodynamics (PD) relationships for efficacy in a neutropenic mouse thigh infection model and as well in an in vitro hollow fiber infection model, in combination with a fixed exposure of meropenem using KPC-containing strains of Enterobacteriaceae. For both models, the meropenem dosage regimen was designed to simulate a 2 g dose administered every eight hours (q8h) by three hour infusion. Vaborbactam dosage regimens were designed to produce a wide range of 24 hour AUCs in the thigh infection model. However, for the hollow fiber model, the AUCs were limited to values of 192, 320 or 550 mg*h/L. In both the animal and in vitro models, the PK-PD parameter that best described the antibacterial activity of vaborbactam, when administered in combination with meropenem at exposures equivalent to 2 g dosed q8h by three hour infusion in humans, was the 24 hour free vaborbactam AUC/meropenem-vaborbactam (with vaborbactam at 8 mg/L) MIC ratio. The magnitude of this ratio for bacteriostasis was 9 -12 and the magnitude to observe a 1-log kill was 18 – 38. In addition, a magnitude greater than 24 suppressed the development of resistance in the in vitro hollow fiber model.

https://ift.tt/2qv3D4A