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

G Dimopoulos; M P Almyroudi; I Kapralos; O Apostolopoulou; A Flevari; D P Nicolau; A Dokoumetzidis

doi:10.1016/j.ijantimicag.2021.106487

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

Int J Antimicrob Agents. 2022 Jan;59(1):106487. doi: 10.1016/j.ijantimicag.2021.106487. Epub 2021 Nov 26.

Authors

G Dimopoulos¹, M P Almyroudi², I Kapralos³, O Apostolopoulou¹, A Flevari¹, D P Nicolau⁴, A Dokoumetzidis³

Affiliations

¹ Department of Critical Care, University Hospital ATTIKON at Haidari-Athens, Medical School, National and Kapodistrian University of Athens, 1 Rimini str, 12462 Haidari, Greece.
² Department of Critical Care, University Hospital ATTIKON at Haidari-Athens, Medical School, National and Kapodistrian University of Athens, 1 Rimini str, 12462 Haidari, Greece. Electronic address: mariotaalm@yahoo.gr.
³ Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece.
⁴ Center for Anti-Infective Research & Development at Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.

PMID: 34843925
DOI: 10.1016/j.ijantimicag.2021.106487

Abstract

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%). C_max, C_min, plasma AUC_0-12, plasma fAUC_0-12 and ELF AUC_0-12 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 AUC_0-12 achieved with a 200 mg daily tigecycline dose, combined with high ELF penetration, support the effectiveness of off-label high-dose tigecycline in VAP.

Keywords: Intrapulmonary pharmacokinetics; Tigecycline; VAP; Ventilator-associated pneumonia.

MeSH terms

Aged
Aged, 80 and over
Anti-Bacterial Agents / pharmacokinetics*
Anti-Bacterial Agents / therapeutic use*
Chemical and Drug Induced Liver Injury, Chronic / etiology*
Chemical and Drug Induced Liver Injury, Chronic / physiopathology*
Female
Humans
Male
Middle Aged
Pneumonia, Ventilator-Associated / drug therapy*
Tigecycline / pharmacokinetics*
Tigecycline / therapeutic use*

Substances

Anti-Bacterial Agents
Tigecycline