PKPD study of IV-administered Tobramycin in children with cystic fibrosis
Background: Chronic pulmonary infection with pathogens such as Pseudomonas aeruginosa (P. aeruginosa) is associated with decline in lung function and increased mortality and morbidity in people with cystic fibrosis (CF). It is unclear whether increased bacterial density in the lung triggers pulmonary exacerbations directly and so whether interventions that enhance bacterial killing will correlate with clinical improvement. This study aimed to explore the relationship between sputum bacterial load and clinical response to antibiotic treatment of pulmonary exacerbations in children with CF.   Methods: A multicentre prospective cohort study of children aged between 1-18 years between December 2020 and December 2022. Children were eligible for inclusion if they had a known Gram-negative bacteria isolated from their sputum within the prior 6 months, were able to expectorate sputum, and received intravenous tobramycin at time of pulmonary exacerbation. Changes in pulmonary function (assessed by forced expiratory volume in 1 second, FEV1) as well as sputum P. aeruginosa and total bacterial load (TBL) were assessed before and after antibiotic treatment.  Results: Thirteen children who experienced 15 admissions for pulmonary exacerbations were enrolled and provided =2 sputum samples, of which 11 children (13 admissions) also had =2 lung function test results available. In 10 admissions where FEV1 improved, only 5 showed a reduction in live TBL in whom median reduction was 8.65?106/g (range 1.24×105 - 1.18×108). Live P. aeruginosa was isolated from 8 of these admissions where 7 experienced a median reduction of 2.99×107/g (range 2.39×104 - 3.97×108). There was no correlation between concomitant CFTR modulator use with increased TBL and reduced P. aeruginosa, nor improved lung function. Furthermore, those who achieved target AUC24,ss/MIC of =80 did not show greater reduction in live P. aeruginosa bacterial load. Discussion: Overall, no relationship between live and live/dead sputum TBL and P. aeruginosa bacterial load with improved clinical outcomes following antibiotic treatment was identified in children with CF. Furthermore, concomitant CFTR modulator use, AUC24,ss/MIC, and type of P. aeruginosa phenotype cultured, did not impact change in sputum bacterial load or clinical response.