Intrapulmonary pharmacokinetics and safety of eravacycline in critically ill patients with HAP/VAP caused by carbapenem-resistant Acinetobacter baumannii and Enterobacterales: A prospective study.

OBJECTIVES

To characterize the pulmonary pharmacokinetics (PK), safety, and exploratory efficacy of eravacycline in critically ill patients with hospital-acquired or ventilator-associated pneumonia (HAP/VAP) caused by carbapenem-resistant pathogens.

METHODS

In this prospective, single-center, open-label study, 16 critically ill adults with HAP/VAP caused by carbapenem-resistant Acinetobacter baumannii (CRAB) or carbapenem-resistant Enterobacterales (CRE) received intravenous eravacycline (1 mg/kg every 12 h) for 7-14 days. Plasma and epithelial lining fluid (ELF) PK were assessed at steady state. Pulmonary penetration was evaluated using the ELF-to-plasma AUC0-12h ratio. Safety and exploratory efficacy were assessed at end of therapy (EOT).

RESULTS

Sixteen patients were included (13/16 VAP, 3/16 HAP), with a median APACHE II score of 23 (IQR 18-25). Mean plasma AUC0-12h and fAUC0-12h were 2.35 ± 0.84 and 1.48 ± 0.54 µg·h/mL, respectively. ELF exposure was higher than plasma, with ELF-to-free plasma AUC0-12h ratios of 4.0. Eravacycline was well tolerated; treatment-related adverse events (TRAEs) occurred in 7/16 (43.8%) patients and were all mild to moderate, including rash (2/16, 12.5%), prolonged activated partial thromboplastin time (APTT, 2/16, 12.5%), prolonged thrombin time (TT, 1/16, 6.3%), diarrhea (1/16, 6.3%), and vomiting (1/16, 6.3%). All patients received eravacycline-based combination therapy. Clinical response at EOT was observed in 13/16 (81.2%, 95% CI: 54.4-95.9%) patients, and microbiological eradication in 10/16 (62.5%, 95% CI: 35.4-84.8%).

CONCLUSIONS

Eravacycline achieved substantial pulmonary exposure in critically ill patients with HAP/VAP despite reduced plasma exposure, with acceptable safety and encouraging clinical responses. Notably, eravacycline's independent contribution to clinical outcomes cannot be determined due to concurrent antimicrobial use.