Newly Published
Critical Care Medicine  |   February 2020
Nebulization of Vancomycin Provides Higher Lung Tissue Concentrations than Intravenous Administration in Ventilated Female Piglets with Healthy Lungs
Author Notes
  • From the Laboratory of Anesthesiology, School of Medicine, São Paulo University, São Paulo, Brazil (C.L.d.M.M., M.J.C.C., D.R.R.M., J.O.C.A., D.A.O.); Laboratory of Clinical and Experimental Pharmacology, Department of Pharmacology, Institute of Biological Sciences, Federal University of Juiz de Fora, Juiz de Fora, Brazil (J.W.L.N., A.C.R.); Anesthesiology Division, School of Medicine, Pontifical Catholic University of Chile, Santiago de Chile, Chile (L.I.C.); and Sorbonne University, Multidisciplinary Intensive Care Unit, Pitié-Salpêtrière Hospital, Public Assistance Hospitals of Paris, Paris, France (A.M., J.-J.R.).
  • 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 January 14, 2019. Accepted for publication January 6, 2020.
    Submitted for publication January 14, 2019. Accepted for publication January 6, 2020.×
  • Correspondence: Address correspondence to Dr. Auler: Laboratório de Anestesiologia LIM 08 Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 455 (Sala 2120, 2nd Floor), São Paulo 01246-903, Brazil. auler.junior@hc.fm.usp.br. 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 / Critical Care / Infectious Disease / Respiratory System
Critical Care Medicine   |   February 2020
Nebulization of Vancomycin Provides Higher Lung Tissue Concentrations than Intravenous Administration in Ventilated Female Piglets with Healthy Lungs
Anesthesiology Newly Published on February 10, 2020. doi:https://doi.org/10.1097/ALN.0000000000003171
Anesthesiology Newly Published on February 10, 2020. doi:https://doi.org/10.1097/ALN.0000000000003171
Abstract

Background: Intravenous vancomycin is used to treat ventilator-associated pneumonia caused by methicillin-resistant Staphylococcus aureus, but achieves high rates of failure. Vancomycin nebulization may be efficient to provide high vancomycin lung tissue concentrations. The aim of this study was to compare lung tissue and serum concentrations of vancomycin administered intravenously and by aerosol in mechanically ventilated and anesthetized healthy piglets.

Methods: Twelve female piglets received a single intravenous dose of vancomycin (15 mg/kg) and were killed 1 (n = 6) or 12 h (n = 6) after the end of administration. Twelve piglets received a single nebulized dose of vancomycin (37.5 mg/kg) and were killed 1 (n = 6) or 12 h (n = 6) after the end of the aerosol administration. In each group, vancomycin lung tissue concentrations were assessed on postmortem lung specimens using high-performance liquid chromatography. Blood samples were collected for serum vancomycin concentration measurement 30 min and 1, 2, 4, 6, 8, and 12 h after the end of vancomycin administration. Pharmacokinetics was analyzed by nonlinear mixed effect modeling.

Results: One hour after vancomycin administration, lung tissue concentrations in the aerosol group were 13 times the concentrations in the intravenous group (median and interquartile range: 161 [71, 301] μg/g versus 12 [4, 42] μg/g; P < 0.0001). Twelve hours after vancomycin administration, lung tissue concentrations in the aerosol group were 63 (23, 119) μg/g and 0 (0, 19) μg/g in the intravenous group (P < 0.0001). A two-compartment weight-scaled allometric model with first-order absorption and elimination best fit serum pharmacokinetics after both routes of administration. Area under the time-concentration curve from 0 to 12 h was lower in the aerosol group in comparison to the intravenous group (56 [8, 70] mg · h · l−1 vs. 121 [103, 149] mg · h · l−1, P = 0.002). Using a population model, vancomycin bioavailability was 13% (95% CI, 6 to 69; coefficient of variation = 85%) and absorption rate was slow (absorption half life = 0.3 h).

Conclusions: Administration of vancomycin by nebulization resulted in higher lung tissue concentrations than the intravenous route.

Editor’s Perspective:

What We Already Know about This Topic:

  • Intravenously administered vancomycin is the recommended treatment for methicillin-resistant Staphylococcus aureus ventilator-associated pneumonia

  • High rates of vancomycin treatment failure may be due to poor lung tissue drug penetration

  • Administration of nebulized antibiotics can produce high lung tissue concentrations, resulting in more efficient bacterial killing with reduced systemic toxicity

What This Article Tells Us That Is New:

  • The hypothesis that lung tissue vancomycin concentrations will be higher after administration as an inhaled aerosol than after intravenous administration was tested in healthy, anesthetized, mechanically ventilated female piglets

  • One hour after administration of a 37.5 mg/kg aerosol dose, the median lung tissue vancomycin concentration (161 µg/g) was 13 times that after intravenous administration of 15 mg/kg (12 µg/g)

  • Twelve hours after aerosol administration, the median lung tissue vancomycin concentration was 63 µg/g, while 12 h after intravenous administration, vancomycin was undetectable in 60% of lung specimens