Intrapulmonary pharmacokinetics of high doses of tigecycline in patients with ventilator-associated pneumonia

Tigecycline is commonly used for infections by multidrug-resistant bacteria. However, it is not approved for ventilator-associated pneumonia (VAP) as increased mortality has been reported in VAP patients treated with conventional doses. The purpose of this study was to prospectively evaluate the intrapulmonary pharmacokinetics of off-label high-dose tigecycline in patients with VAP. Nine mechanically ventilated patients received tigecycline intravenously (loading dose 200 mg followed by 100 mg every 12 h). After ≥5 doses, two bronchoscopies were performed in each patient on consecutive days and eight blood samples were collected. Tigecycline concentrations in plasma and bronchoalveolar lavage fluid were determined by liquid chromatography. The urea dilution method was used to calculate epithelial lining fluid (ELF) concentrations. A two-compartmental pharmacokinetic (PK) model with linear elimination was used to estimate PK parameters. Mean patient age was 69 ± 11.86 years and mean APACHE II score was 21. The estimated population mean PK parameters (relative standard error) were: clearance, 11.64 L/h (54%); volume of distribution in central compartment, 79.01 L (37%); volume of distribution in peripheral compartment, 92.95 L (17%); intercompartmental clearance, 62.81 L/h (34%); and ELF penetration ratio, 2.41 (40%). Cmax, Cmin, plasma AUC0–12, plasma fAUC0–12 and ELF AUC0–12 were 1.99 ± 1.82 μg/mL, 0.81 ± 1.27 μg/mL, 12.89 ± 17.25 μg•h/mL, 3.24 ± 3.09 μg•h/mL and 7.13 ± 2.61 μg•h/mL, respectively. The increased plasma and ELF AUC0–12 achieved with a 200 mg daily tigecycline dose, combined with high ELF penetration, support the effectiveness of off-label high-dose tigecycline in VAP.