Exposure–response analysis of tigecycline in pharmacodynamic simulations using different size inocula of target bacteria

Abstract 

This study explored tigecycline exposure–bacterial responses in pharmacodynamic simulations (in vitro kinetic model) using different inocula. One meticillin-resistant vancomycin-heteroresistant Staphylococcus aureus, one Enterococcus faecium and one extended-spectrum β-lactamase-producing Escherichia coli with equal tigecycline minimum inhibitory concentrations/minimum bactericidal concentrations (MICs/MBCs) (0.12/0.25μg/mL) were used. A computerised pharmacodynamic bicompartmental model simulated three tigecycline twice-daily dosing regimens over 48h: 50mg (100mg loading dose); 100mg; and 150mg. Areas under bacterial growth curves were calculated, and differences between the growth curve used as control and the killing curve of bacteria exposed to tigecycline (ABBC) were determined. With standard inocula [ca. 1×10⁶colony-forming units (CFU)/mL], linear increases in area under the concentration–time curve (AUC)/MIC (25.6 for 50mg, 53.76 for 100mg and 79.52 for 150mg) produced linear increases in activity against Gram-positive organisms (mean ABBCs of 120.60, 143.20 and 195.80logCFU×h/mL for S. aureus and of 95.75, 172.55 and 216.90logCFU×h/mL for E. faecium, respectively), with the activity of the 150mg regimen being significantly higher (P<0.01) than that of the other two regimens. ABBCs obtained with the 100mg regimen using standard inocula were similar to those obtained with the 150mg regimen when using high inocula (ca. 1×10⁷CFU/mL). Against E. coli, the highest dosing regimen was required to obtain significant antibacterial activity compared with control (mean ABBCs of 145.75logCFU×h/mL with standard inocula and 63.33logCFU×h/mL with high inocula). An increase in tigecycline dosing appears to be an interesting therapeutic option to maximise antibacterial activity owing to its linear pharmacokinetics and pharmacodynamics, especially when severe infections with high bacterial load are suspected.

Keywords: Staphylococcus aureus, Enterococcus faecium, Glycylcyclines, Pharmacodynamics, Inoculum effect