Critical Care Medicine  |   August 2019
Lung Pharmacokinetics of Tobramycin by Intravenous and Nebulized Dosing in a Mechanically Ventilated Healthy Ovine Model
Author Notes
  • From the University of Queensland Centre for Clinical Research, Faculty of Medicine (J.A.D., J. Cohen, S.L.P., S.C.W., C.B., J.A.R.), Critical Care Research Group (J.A.D., S.D., J. Chaudhary, J.F.F.), and Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy (J.A.R.), The University of Queensland, Brisbane, Australia; Department of Intensive Care Medicine (J.A.D., J. Cohen, J.A.R.), and Department of Pharmacy (J.A.R.), Royal Brisbane & Women’s Hospital, Brisbane, Australia; Institute of Health and Biomedical Innovation & School of Public Health and Social Work, Queensland University of Technology, Kelvin Grove, Brisbane, Australia (A.B.); Department of Anaesthesiology and Intensive Care, and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden (M.C.); the Pierre Garraud Hospital, Civil Hospitals of Lyon, Lyon, France (C.B.); and the National Center for Scientific Research 5558, Biometrics Laboratory and Evolutionary Biology, Claude Bernard University Lyon 1, Lyon, France (C.B.).
  • This article is featured in “This Month in Anesthesiology,” page 1A.
    This article is featured in “This Month in Anesthesiology,” page 1A.×
  • This article is accompanied by an editorial on p. 229.
    This article is accompanied by an editorial on p. 229.×
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Submitted for publication April 13, 2018. Accepted for publication March 18, 2019.
    Submitted for publication April 13, 2018. Accepted for publication March 18, 2019.×
  • Address correspondence to Dr. Dhanani: UQ Centre for Clinical Research, Level 7, The University of Queensland, Herston, QLD, Australia 4029. jadhanani@hotmail.com. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Basic Science / Critical Care / Pharmacology / Respiratory System
Critical Care Medicine   |   August 2019
Lung Pharmacokinetics of Tobramycin by Intravenous and Nebulized Dosing in a Mechanically Ventilated Healthy Ovine Model
Anesthesiology 8 2019, Vol.131, 344-355. doi:10.1097/ALN.0000000000002752
Anesthesiology 8 2019, Vol.131, 344-355. doi:10.1097/ALN.0000000000002752
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • For most bacterial pneumonia, the lung interstitium is considered to be the site of infection, and adequate antibiotic concentrations are important for drug effect

  • Despite systemic antibiotic therapy, therapeutic failure is common, perhaps due to poor lung penetration, and resulting low interstitial space fluid antibiotic concentrations

  • Increasing systemic antibiotic doses in order to increase interstitial space fluid antibiotic concentrations could lead to toxicities such as nephrotoxicity

What This Article Tells Us That Is New:

  • In a mechanically ventilated healthy large animal model, nebulized tobramycin produced higher peak lung interstitial space fluid concentrations, as well as higher initial epithelial lining fluid concentrations, with lower plasma concentrations than were observed after intravenous administration due to more extensive lung penetration

Background: Nebulized antibiotics may be used to treat ventilator-associated pneumonia. In previous pharmacokinetic studies, lung interstitial space fluid concentrations have never been reported. The aim of the study was to compare intravenous and nebulized tobramycin concentrations in the lung interstitial space fluid, epithelial lining fluid, and plasma in mechanically ventilated sheep with healthy lungs.

Methods: Ten anesthetized and mechanically ventilated healthy ewes underwent surgical insertion of microdialysis catheters in upper and lower lobes of both lungs and the jugular vein. Five ewes were given intravenous tobramycin 400 mg, and five were given nebulized tobramycin 400 mg. Microdialysis samples were collected every 20 min for 8 h. Bronchoalveolar lavage was performed at 1 and 6 h.

Results: The peak lung interstitial space fluid concentrations were lower with intravenous tobramycin 20.2 mg/l (interquartile range, 12 mg/l, 26.2 mg/l) versus the nebulized route 48.3 mg/l (interquartile range, 8.7 mg/l, 513 mg/l), P = 0.002. For nebulized tobramycin, the median epithelial lining fluid concentrations were higher than the interstitial space fluid concentrations at 1 h (1,637; interquartile range, 650, 1,781, vs. 16 mg/l, interquartile range, 7, 86, P < 0.001) and 6 h (48, interquartile range, 17, 93, vs. 4 mg/l, interquartile range, 2, 9, P < 0.001). For intravenous tobramycin, the median epithelial lining fluid concentrations were lower than the interstitial space fluid concentrations at 1 h (0.19, interquartile range, 0.11, 0.31, vs. 18.5 mg/l, interquartile range, 9.8, 23.4, P < 0.001) and 6 h (0.34, interquartile range, 0.2, 0.48, vs. 3.2 mg/l, interquartile range, 0.9, 4.4, P < 0.001).

Conclusions: Compared with intravenous tobramycin, nebulized tobramycin achieved higher lung interstitial fluid and epithelial lining fluid concentrations without increasing systemic concentrations.