Activity of Simulated Human Dosage Regimens of Meropenem and Vaborbactam against Carbapenem-resistant Enterobacteriaceae in an In Vitro Hollow Fiber Model [PublishAheadOfPrint]

The objective of these studies was to evaluate the exposures of meropenem and vaborbactam that would produce antibacterial activity and prevent resistance development in carbapenem-resistant, Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae strains when tested at an inocula of 10⁸ CFU/mL. Thirteen K. pneumoniae isolates, three Enterobacter cloacae isolates, and one Escherichia coli isolate were examined in an in vitro hollow fiber model over 32 hours. Simulated dosage regimens of meropenem 1-2 g with vaborbactam 1-2 g, meropenem administered every 8 hours by 3 hour infusion based on Phase 1 or Phase 3 patient pharmacokinetic data were studied in the model. Meropenem 2 g in combination with vaborbactam 2 g was bactericidal against K. pneumoniae, E. cloacae, and E. coli strains with meropenem-vaborbactam MICs of up to 8 mg/L. When the vaborbactam exposure was adjusted to the levels observed in patients enrolled in Phase 3 trials (24 h free AUC ~ 550 vs 320 mg*h/L in the Phase 1 studies), meropenem 2 g with vaborbactam 2 g was also bactericidal against strains with meropenem-vaborbactam MICs of 16 mg/L. In addition, this level of vaborbactam, also suppressed the development of resistance observed using Phase 1 exposures. In this pharmacodynamic model, exposures similar to meropenem 2 g in combination with vaborbactam 2 g administered every 8 hours by 3 hour infusion in Phase 3 trials produced antibacterial activity and suppressed the development of resistance against carbapenem resistant, KPC producing strains of Enterobacteriaceae.

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