Comparison of tigecycline penetration into the epithelial lining fluid of infected and uninfected murine lungs

Objectives: When evaluating the pharmacodynamics of antimicrobials, assumptions are often made relative to their pharmacokinetics. One example of this is applying tissue penetration results of uninfected hosts to those displaying a targeted illness. As tigecycline evolves into a potential treatment option for pneumonia, we determined whether the presence of a lung infection affected the penetration of the drug into the epithelial lining fluid (ELF). Methods: Single doses of tigecycline 50 and 25 mg/kg were administered to neutropenic ICR mice with or without the presence of an Acinetobacter baumannii lung infection. Serum samples were gathered at 0.5-24 h after tigecycline administration; bronchoalveolar lavage was conducted at 1, 1.5, 4 and 8 h. Tigecycline concentrations were determined by HPLC. Comparisons of ELF penetration in infected and uninfected lungs were based on the ratios of the AUC(0-8) in ELF and the free AUC(0-8) in serum. AUCs were calculated by the trapezoidal rule. Results: The group without pulmonary infection displayed an ELF penetration ratio of 8.1 and 6.2 for the 50 and 25 mg/kg doses, respectively. The respective penetration ratios in the infected lungs were 23.3 and 12.9. Conclusions: While tigecycline exhibits excellent ELF penetration in healthy and infected murine lungs, the presence of infection greatly enhances penetration. Moreover, increased systemic exposures of tigecycline result in greater ELF penetration, regardless of infection status. When future tigecycline clinical trials for the treatment of pneumonia are considered, escalated doses may reap greater than expected benefits towards achieving adequate pharmacodynamic indexes within the lungs.