In vitro effect of physiological concentrations of human albumin on the antibacterial activity of tigecycline

Abstract

Objectives: To determine Cmax tigecycline activity in the presence/absence of physiological concentrations of human albumin with free fraction concentrations as controls. Methods: Killing curves (final inoculum: 1.0-5.0 × 107 cfu/mL) were performed with 0.88 mg/L final concentrations (serum Cmax after a 100 mg 1 h infusion) in Mueller-Hinton broth supplemented with Ca2+ and Mg2+ (MH) and in MH with 4 g/dL human albumin. Controls were curves in MH with concentrations similar to the free fraction (fCmax = 0.17 mg/L) calculated using protein binding. Activity was measured as log10 initial inoculum reduction (log10 initial inoculum-log10 at 12 h/24 h). Target strains (tigecycline MIC/MBC; mg/L) were: methicillin-resistant Staphylococcus aureus heteroresistant to vancomycin (0.12/0.25); Enterococcus faecium (0.12/0.25); Escherichia coli producing extended-spectrum β-lactamase (0.12/0.25); and Acinetobacter baumannii (0.25/1). Results: At 24 h the fCmax produced mean decreases of ≤0.1 cfu/mL for all strains, in contrast to the bactericidal activity (mean >3 log10 reduction) provided by Cmax concentrations in the presence or absence of albumin for E. coli and E. faecium, and an activity nearly bactericidal for S. aureus (mean ∼2.8 log10 reduction). In the case of the A. baumannii isolate the Cmax in the presence or absence of albumin produced a mean reduction of 2.56 log10 cfu/mL at 12 h (time of one dosing interval), with a bacteriostatic profile when considering 24 h colony counts (similar counts at 0 and 24 h). Conclusions: Correcting the total concentration for the reported literature binding values is unreliable since tigecycline antibacterial activity was greater than that suggested by the free fraction of the drug. © The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.