Patient-specific modeling of regional antibiotic concentration levels in airways of patients with cystic fibrosis: are we dosing high enough?

PLoS One. 2015 Mar 3;10(3):e0118454. doi: 10.1371/journal.pone.0118454. eCollection 2015.


Background: Pseudomonas aeruginosa (Pa) infection is an important contributor to the progression of cystic fibrosis (CF) lung disease. The cornerstone treatment for Pa infection is the use of inhaled antibiotics. However, there is substantial lung disease heterogeneity within and between patients that likely impacts deposition patterns of inhaled antibiotics. Therefore, this may result in airways below the minimal inhibitory concentration of the inhaled agent. Very little is known about antibiotic concentrations in small airways, in particular the effect of structural lung abnormalities. We therefore aimed to develop a patient-specific airway model to predict concentrations of inhaled antibiotics and to study the impact of structural lung changes and breathing profile on local concentrations in airways of patients with CF.

Methods: In- and expiratory CT-scans of children with CF (5-17 years) were scored (CF-CT score), segmented and reconstructed into 3D airway models. Computational fluid dynamic (CFD) simulations were performed on 40 airway models to predict local Aztreonam lysine for inhalation (AZLI) concentrations. Patient-specific lobar flow distribution and nebulization of 75 mg AZLI through a digital Pari eFlow model with mass median aerodynamic diameter range were used at the inlet of the airway model. AZLI concentrations for central and small airways were computed for different breathing patterns and airway surface liquid thicknesses.

Results: In most simulated conditions, concentrations in both central and small airways were well above the minimal inhibitory concentration. However, small airways in more diseased lobes were likely to receive suboptimal AZLI. Structural lung disease and increased tidal volumes, respiratory rates and larger particle sizes greatly reduced small airway concentrations.

Conclusions: CFD modeling showed that concentrations of inhaled antibiotic delivered to the small airways are highly patient specific and vary throughout the bronchial tree. These results suggest that anti-Pa treatment of especially the small airways can be improved.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Adolescent
  • Anti-Bacterial Agents / pharmacokinetics*
  • Anti-Bacterial Agents / pharmacology
  • Aztreonam / pharmacokinetics*
  • Aztreonam / pharmacology
  • Child
  • Child, Preschool
  • Cystic Fibrosis / complications
  • Cystic Fibrosis / drug therapy*
  • Cystic Fibrosis / microbiology
  • Cystic Fibrosis / pathology
  • Drug Dosage Calculations
  • Drug Monitoring
  • Female
  • Humans
  • Lung / drug effects*
  • Lung / microbiology
  • Lung / pathology
  • Male
  • Microbial Sensitivity Tests
  • Patient-Specific Modeling
  • Pseudomonas Infections / complications
  • Pseudomonas Infections / drug therapy*
  • Pseudomonas Infections / microbiology
  • Pseudomonas Infections / pathology
  • Pseudomonas aeruginosa / drug effects*
  • Pseudomonas aeruginosa / growth & development
  • Respiratory Rate
  • Retrospective Studies
  • Tidal Volume
  • Tomography, X-Ray Computed
  • Treatment Outcome


  • Anti-Bacterial Agents
  • Aztreonam

Grant support

This was an investigator initiated study. FluidDA nv received an unconditional grant from Gilead Sciences Inc. This grant was used for the Fluid dynamic modeling (JdB, CvH, WV). FluidDA NV covered the salary costs of the PhD student (AB) for the length of this study. Author Cedric van Holsbeke and Wim G. Vos are employed by FluidDA nv. J. de Backer and Wim G. Vos are shareholders of FluidDA NV, a company that commercializes some of the techniques used in this manuscript. FluidDA and investigators AB, HT and HJ have jointly developed the study design. AB, HT, MvW and HJ have acted as an independent party for this study. Study CT selection and assessment of lung disease severity was done by AB independently of FluidDA. FluidDA employees CvH and WV and investigators AB, HT and HJ have jointly analyzed the data and have jointly written the manuscript. The specific roles of the author are articulated in the ‘author contributions’ section. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.