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

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) (0.12/0.25 μg/mL) were used. A computerised pharmacodynamic bicompartmental model simulated three tigecycline twice-daily dosing regimens over 48 h: 50 mg (100 mg loading dose); 100 mg; and 150 mg. 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 × 106 colony-forming units (CFU)/mL], linear increases in area under the concentration–time curve (AUC)/MIC (25.6 for 50 mg, 53.76 for 100 mg and 79.52 for 150 mg) produced linear increases in activity against Gram-positive organisms (mean ABBCs of 120.60, 143.20 and 195.80 log CFU × h/mL for S. aureus and of 95.75, 172.55 and 216.90 log CFU × h/mL for E. faecium, respectively), with the activity of the 150 mg regimen being significantly higher (P < 0.01) than that of the other two regimens. ABBCs obtained with the 100 mg regimen using standard inocula were similar to those obtained with the 150 mg regimen when using high inocula (ca. 1 × 107 CFU/mL). Against E. coli, the highest dosing regimen was required to obtain significant antibacterial activity compared with control (mean ABBCs of 145.75 log CFU × h/mL with standard inocula and 63.33 log CFU × 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.