Patient-specific modeling of regional antibiotic concentration levels in airways of patients with cystic fibrosis: are we dosing high enough?
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.
Department of Pediatric Pulmonology, Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, the Netherlands; Department of Radiology, Erasmus Medical Centre, Rotterdam, the Netherlands.
Aukje C
AC
Bos
FluidDA nv, Kontich, Belgium.
Cedric
C
van Holsbeke
FluidDA nv, Kontich, Belgium.
Jan W
JW
de Backer
Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Centre, Rotterdam, the Netherlands.
Mireille
M
van Westreenen
Department of Pediatric Pulmonology, Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, the Netherlands.
Hettie M
HM
Janssens
FluidDA nv, Kontich, Belgium.
Wim G
WG
Vos
Department of Pediatric Pulmonology, Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, the Netherlands; Department of Radiology, Erasmus Medical Centre, Rotterdam, the Netherlands.
Harm A W M
HA
Tiddens
D000280:Administration, Inhalation; D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001398:Aztreonam / Q000493:pharmacokinetics* / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000382:microbiology / Q000473:pathology; D008297:Male; D008826:Microbial Sensitivity Tests; D066230:Patient-Specific Modeling; D011552:Pseudomonas Infections / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development; D056152:Respiratory Rate; D012189:Retrospective Studies; D013990:Tidal Volume; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
D000900:Anti-Bacterial Agents; D001398:Aztreonam