Antibiotic exposure and interpersonal variance mask the effect of ivacaftor on respiratory microbiota composition

Anton Y. Peleg, Jocelyn M. Choo, Katherine M. Langan, Deirdre Edgeworth, Dominic Keating, John Wilson, Geraint B. Rogers, Tom Kotsimbos

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background G551D is a class III mutation of the cystic fibrosis transmembrane regulator (CFTR) that results in impaired chloride channel function in cystic fibrosis (CF). Ivacaftor, a CFTR-potentiating agent improves sweat chloride, weight, lung function, and pulmonary exacerbation rate in CF patients with G551D mutations, but its effect on the airway microbiome remains poorly characterised. Methods Twenty CF patients with at least one G551D mutation from a single centre were recruited to a 4 month double-blind, placebo-controlled, crossover study of ivacaftor with 28 days of active treatment. Sputum microbiota composition was assessed by 16S rRNA gene amplicon sequencing and quantitative PCR at five key time points, along with regular clinical review, respiratory function assessment, and peripheral blood testing. Results No significant difference in microbiota composition was observed in subjects following ivacaftor treatment or placebo (PERMANOVA P = 0.95, square root ECV = − 4.94, 9479 permutations). Microbiota composition variance was significantly greater between subjects, than within subjects over time (P < 0.0001, Mann Whitney U test), and an additional within-patient paired assessment of microbiota similarity was therefore performed. Again, change in microbiota composition was not significantly greater during treatment with ivacaftor compared to placebo (Wilcoxon test, P = 0.51). A significant change in microbiota composition was however associated with any change in antibiotic exposure, regardless of whether ivacaftor or placebo was administered (P = 0.006). In a small, subgroup analysis of subjects whose antibiotic exposure did not change within the study period, a significant reduction in total bacterial load was observed during treatment with ivacaftor (P = 0.004, two-tailed paired Student's t-test). Conclusions The short-term impact of ivacaftor therapy on sputum microbiota composition in patients with G551D mutations are modest compared to those resulting from antibiotic exposure, and may be masked by changes in antibiotic treatment regimen.

Original languageEnglish
Pages (from-to)50-56
Number of pages7
JournalJournal of Cystic Fibrosis
Volume17
Issue number1
DOIs
Publication statusPublished - 1 Jan 2018

Keywords

  • Antibiotics
  • Ivacaftor
  • Respiratory microbiome

Cite this

@article{5ed0699a52474258a7def8dc5b92a304,
title = "Antibiotic exposure and interpersonal variance mask the effect of ivacaftor on respiratory microbiota composition",
abstract = "Background G551D is a class III mutation of the cystic fibrosis transmembrane regulator (CFTR) that results in impaired chloride channel function in cystic fibrosis (CF). Ivacaftor, a CFTR-potentiating agent improves sweat chloride, weight, lung function, and pulmonary exacerbation rate in CF patients with G551D mutations, but its effect on the airway microbiome remains poorly characterised. Methods Twenty CF patients with at least one G551D mutation from a single centre were recruited to a 4 month double-blind, placebo-controlled, crossover study of ivacaftor with 28 days of active treatment. Sputum microbiota composition was assessed by 16S rRNA gene amplicon sequencing and quantitative PCR at five key time points, along with regular clinical review, respiratory function assessment, and peripheral blood testing. Results No significant difference in microbiota composition was observed in subjects following ivacaftor treatment or placebo (PERMANOVA P = 0.95, square root ECV = − 4.94, 9479 permutations). Microbiota composition variance was significantly greater between subjects, than within subjects over time (P < 0.0001, Mann Whitney U test), and an additional within-patient paired assessment of microbiota similarity was therefore performed. Again, change in microbiota composition was not significantly greater during treatment with ivacaftor compared to placebo (Wilcoxon test, P = 0.51). A significant change in microbiota composition was however associated with any change in antibiotic exposure, regardless of whether ivacaftor or placebo was administered (P = 0.006). In a small, subgroup analysis of subjects whose antibiotic exposure did not change within the study period, a significant reduction in total bacterial load was observed during treatment with ivacaftor (P = 0.004, two-tailed paired Student's t-test). Conclusions The short-term impact of ivacaftor therapy on sputum microbiota composition in patients with G551D mutations are modest compared to those resulting from antibiotic exposure, and may be masked by changes in antibiotic treatment regimen.",
keywords = "Antibiotics, Ivacaftor, Respiratory microbiome",
author = "Peleg, {Anton Y.} and Choo, {Jocelyn M.} and Langan, {Katherine M.} and Deirdre Edgeworth and Dominic Keating and John Wilson and Rogers, {Geraint B.} and Tom Kotsimbos",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.jcf.2017.08.002",
language = "English",
volume = "17",
pages = "50--56",
journal = "Journal of Cystic Fibrosis",
issn = "1569-1993",
publisher = "Elsevier",
number = "1",

}

Antibiotic exposure and interpersonal variance mask the effect of ivacaftor on respiratory microbiota composition. / Peleg, Anton Y.; Choo, Jocelyn M.; Langan, Katherine M.; Edgeworth, Deirdre; Keating, Dominic; Wilson, John; Rogers, Geraint B.; Kotsimbos, Tom.

In: Journal of Cystic Fibrosis, Vol. 17, No. 1, 01.01.2018, p. 50-56.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Antibiotic exposure and interpersonal variance mask the effect of ivacaftor on respiratory microbiota composition

AU - Peleg, Anton Y.

AU - Choo, Jocelyn M.

AU - Langan, Katherine M.

AU - Edgeworth, Deirdre

AU - Keating, Dominic

AU - Wilson, John

AU - Rogers, Geraint B.

AU - Kotsimbos, Tom

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background G551D is a class III mutation of the cystic fibrosis transmembrane regulator (CFTR) that results in impaired chloride channel function in cystic fibrosis (CF). Ivacaftor, a CFTR-potentiating agent improves sweat chloride, weight, lung function, and pulmonary exacerbation rate in CF patients with G551D mutations, but its effect on the airway microbiome remains poorly characterised. Methods Twenty CF patients with at least one G551D mutation from a single centre were recruited to a 4 month double-blind, placebo-controlled, crossover study of ivacaftor with 28 days of active treatment. Sputum microbiota composition was assessed by 16S rRNA gene amplicon sequencing and quantitative PCR at five key time points, along with regular clinical review, respiratory function assessment, and peripheral blood testing. Results No significant difference in microbiota composition was observed in subjects following ivacaftor treatment or placebo (PERMANOVA P = 0.95, square root ECV = − 4.94, 9479 permutations). Microbiota composition variance was significantly greater between subjects, than within subjects over time (P < 0.0001, Mann Whitney U test), and an additional within-patient paired assessment of microbiota similarity was therefore performed. Again, change in microbiota composition was not significantly greater during treatment with ivacaftor compared to placebo (Wilcoxon test, P = 0.51). A significant change in microbiota composition was however associated with any change in antibiotic exposure, regardless of whether ivacaftor or placebo was administered (P = 0.006). In a small, subgroup analysis of subjects whose antibiotic exposure did not change within the study period, a significant reduction in total bacterial load was observed during treatment with ivacaftor (P = 0.004, two-tailed paired Student's t-test). Conclusions The short-term impact of ivacaftor therapy on sputum microbiota composition in patients with G551D mutations are modest compared to those resulting from antibiotic exposure, and may be masked by changes in antibiotic treatment regimen.

AB - Background G551D is a class III mutation of the cystic fibrosis transmembrane regulator (CFTR) that results in impaired chloride channel function in cystic fibrosis (CF). Ivacaftor, a CFTR-potentiating agent improves sweat chloride, weight, lung function, and pulmonary exacerbation rate in CF patients with G551D mutations, but its effect on the airway microbiome remains poorly characterised. Methods Twenty CF patients with at least one G551D mutation from a single centre were recruited to a 4 month double-blind, placebo-controlled, crossover study of ivacaftor with 28 days of active treatment. Sputum microbiota composition was assessed by 16S rRNA gene amplicon sequencing and quantitative PCR at five key time points, along with regular clinical review, respiratory function assessment, and peripheral blood testing. Results No significant difference in microbiota composition was observed in subjects following ivacaftor treatment or placebo (PERMANOVA P = 0.95, square root ECV = − 4.94, 9479 permutations). Microbiota composition variance was significantly greater between subjects, than within subjects over time (P < 0.0001, Mann Whitney U test), and an additional within-patient paired assessment of microbiota similarity was therefore performed. Again, change in microbiota composition was not significantly greater during treatment with ivacaftor compared to placebo (Wilcoxon test, P = 0.51). A significant change in microbiota composition was however associated with any change in antibiotic exposure, regardless of whether ivacaftor or placebo was administered (P = 0.006). In a small, subgroup analysis of subjects whose antibiotic exposure did not change within the study period, a significant reduction in total bacterial load was observed during treatment with ivacaftor (P = 0.004, two-tailed paired Student's t-test). Conclusions The short-term impact of ivacaftor therapy on sputum microbiota composition in patients with G551D mutations are modest compared to those resulting from antibiotic exposure, and may be masked by changes in antibiotic treatment regimen.

KW - Antibiotics

KW - Ivacaftor

KW - Respiratory microbiome

UR - http://www.scopus.com/inward/record.url?scp=85031416314&partnerID=8YFLogxK

U2 - 10.1016/j.jcf.2017.08.002

DO - 10.1016/j.jcf.2017.08.002

M3 - Article

VL - 17

SP - 50

EP - 56

JO - Journal of Cystic Fibrosis

JF - Journal of Cystic Fibrosis

SN - 1569-1993

IS - 1

ER -