Pharmacodynamics of β-Lactamase Inhibition by NXL104 in Combination with Ceftaroline: Examining Organisms with Multiple Types of β-Lactamases

摘要: New broad-spectrum β-lactamases such as KPC enzymes and CTX-M-15 threaten to markedly reduce the utility of our armamentarium β-lactam agents, even most potent drugs, carbapenems. NXL104 is a non-β-lactam β-lactamase inhibitor. In this evaluation, we examined organisms carrying defined identified doses schedules in combination with new cephalosporin ceftaroline, which would maintain good bacterial cell kill suppress resistance emergence for clinically relevant period 10 days hollow-fiber infection model. We three strains Klebsiella pneumoniae one isolate Enterobacter cloacae. K. 27-908M carried KPC-2, SHV-27, TEM-1 β-lactamases. Its isogenic mutant, 4207J, was "cured" plasmid expressing KPC-2 enzyme. 24-1318A enzyme, E. cloacae 2-77C expressed stably derepressed AmpC chromosomal β-lactamase. Dose-ranging experiments administered continuous infusion ceftaroline at 600 mg every 8 h allowed identification 24-h area under concentration-time curve (AUC) that mediated bactericidal activity suppression. Dose fractionation "time > threshold" pharmacodynamic index linked Given these results, conclude combined on an 8-hourly administration schedule be optimal circumstances highly resistant pathogens are likely encountered. This dosing regimen should allow (highest likelihood successful clinical outcome) suppression emergence.