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Randomized Controlled Trial
. 2025 Aug 8;66(2):2402443.
doi: 10.1183/13993003.02443-2024. Print 2025 Aug.

Cystic Fibrosis Microbiome-directed Antibiotic Therapy Trial in Exacerbations Results Stratified (CFMATTERS): results of a multicentre randomised controlled trial

Barry J Plant  1   2   3 , Gisli G Einarsson  4 , Kevin F Deasy  5   2   3 , Darren Dahly  2 , Pradeep K Singh  6 , Peter J Barry  7   8 , Christopher H Goss  9 , Isabelle Fajac  10   11   12 , Tamara Vagg  5   2   3 , Isabelle Durieu  12   13   14 , Evelyn Flanagan  2 , Grace O'Callaghan  2 , Clémence Martin  11   12   15 , Pierre-Régis Burgel  11   12   15 , Charles S Haworth  16 , R Andres Floto  17   18 , Damian G Downey  19 , Lieven J Dupont  20   21 , Andrew M Jones  7   8 , J Stuart Elborn  22 , Joseph A Eustace  5   2 , Marcus A Mall  23   24   25 , Michael M Tunney  4
Affiliations
Randomized Controlled Trial

Cystic Fibrosis Microbiome-directed Antibiotic Therapy Trial in Exacerbations Results Stratified (CFMATTERS): results of a multicentre randomised controlled trial

Barry J Plant et al. Eur Respir J. .

Abstract

Background: This study explores the effectiveness and safety of microbiome-directed antimicrobial therapy versus usual antimicrobial therapy in adult cystic fibrosis pulmonary exacerbations.

Methods: A multicentre two-arm parallel randomised control trial conducted across Europe/North-America enrolled 223 participants (January 2015 to August 2017). All participants were chronically colonised with Pseudomonas aeruginosa and were randomised 1:1 into two study arms. The "usual therapy" group received 2 weeks of intravenous ceftazidime 3 g thrice daily (for allergies: aztreonam 2 g thrice daily) and tobramycin 5-10 mg·kg-1 once daily. The "microbiome-directed" group received the same usual therapy plus an additional antibiotic with greatest presumed activity against the second, third and fourth most abundant genera present in the sputum microbiome, selected by a consensus expert treatment panel. The primary outcome was change in percentage of predicted forced expiratory volume in 1 s (ppFEV1) at 14 days post initiation of antibiotics. Secondary outcomes examined ppFEV1 at 7 days, 28 days and 3 months; time to next exacerbation; symptom burden at 7 days; health-related quality of life (HRQoL) at 28 days; and number of exacerbations and i.v. antibiotic days at 12 months.

Results: 149 participants had an eligible exacerbation (usual therapy n=83, microbiome-directed therapy n=66). There was no difference between the groups for ppFEV1 at day 14 (-1.1%, 95% CI -3.9-1.7%; p=0.46), or ppFEV1 measured at other time points, or for time to next exacerbation (microbiome-directed versus usual therapy hazard ratio 0.91, 95% CI 0.60-1.38; p=0.66). The microbiome-directed group trended to have more i.v. days (median 42 days versus 28 days; p=0.08) and more subsequent exacerbations (median three versus two; p=0.044) the following year. There were no appreciable differences in symptom burden; however, HRQoL subscores were consistently worse in the microbiome-directed group (-4.3 points versus usual therapy, 95% CI -8.3--0.3 points; p=0.033).

Conclusion: The addition of a third antibiotic based on sputum microbiome sequencing analysis did not result in improved clinical outcomes.

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Conflict of interest statement

Conflicts of interest: B.J. Plant reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Vertex, Viatris and Chiesi Pharmaceuticals, and consultancy fees from Vertex, Viatris and Chiesi Pharmaceuticals. P.K. Singh reports support for the present study from Cystic Fibrosis Foundation and NIH. P.J. Barry reports consultancy fees from INSMED, payment or honoraria for lectures, presentations, manuscript writing or educational events from Chiesi and Vertex Pharmaceuticals, and participation on a data safety monitoring board or advisory board with Vertex and INSMED. C.H. Goss reports support for the present study from NIH NIDDK, grants from Cystic Fibrosis Foundation, FDA Orphan Prod. Div., and NIH NCRR, consultancy fees from Enterprise Therapeutics, payment or honoraria for lectures, presentations, manuscript writing or educational events from Gilead Sciences and Vertex Pharmaceuticals, support for attending meetings from Vertex Pharmaceuticals and Enterprise Therapeutics, participation on a data safety monitoring board or advisory board with Novartis, leadership role with ATS, and stock (or stock options) with Air Therapeutics. I. Fajac reports support for the present study from FP7, grants from AbbVie, Bayer, Boehringer Ingelheim, Insmed, GSK, Vertex Pharmaceuticals and Zambon, payment or honoraria for lectures, presentations, manuscript writing or educational events from Vertex Pharmaceuticals, participation on a data safety monitoring board or advisory board with AbbVie, Boehringer Ingelheim, Genvade, Kither Biotech and Vertex Pharmaceuticals, and the following financial (or non-financial) interests: European Cystic Fibrosis Society. T. Vagg reports grants from Vertex Pharmaceuticals. C. Martin reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Chiesi, AstraZeneca, Boehringer Ingelheim and GSK, and support for attending meetings from Chiesi and Boehringer Ingelheim. P-R. Burgel reports support for the present study from Association Vaincre la Mucoviscidose, Société Française de la Mucoviscidose, and Filière Maladie Rare Muco CFTR, grants from Vertex Pharmaceuticals and GSK, consultancy fees from AstraZeneca, Chiesi, GSK, Insmed, Vertex, Viatris and Zambon, and support for attending meetings from AstraZeneca and Chiesi. C.S. Haworth reports consultancy fees and payment or honoraria for lectures, presentations, manuscript writing or educational events from 30 Technology, CSL Behring, Chiesi, Janssen, LifeArc, Meiji, Mylan, Pneumagen, Shionogi, Vertex and Zambon. R.A. Floto reports grants from Wellcome Trust, MRC and LifeArc, payment or honoraria for lectures, presentations, manuscript writing or educational events from Insmed, and a leadership role with British Thoracic Society. D.G. Downey reports grants from Chiesi Farmaceutici, CF Foundation, and CF Trust, consultancy fees from Vertex and Insmed, payment or honoraria for lectures, presentations, manuscript writing or educational events from Chiesi and Gilead, support for attending meetings from European CF Society and CF Foundation, participation on a data safety monitoring board or advisory board with Nomab trial and CSL Behring, and a leadership role as Director of the European CF Society Clinical Trials Network, 2021–2023. L.J. Dupont reports consultancy fees from INSMED, payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, GSK and MSD, and participation on a data safety monitoring board or advisory board with Vertex pharmaceuticals and AstraZeneca. A.M. Jones reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Vertex Pharmaceuticals. M.A. Mall reports support for the present study from European Commission, grants from German Research Foundation (DFG), German Ministry for Education and Research (BMBF), German Innovation Fund, and Vertex Pharmaceuticals, consultancy fees from Abbvie, Antabio, Arrowhead Pharmaceuticals, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Prieris, Recode, Santhera, Splisense and Vertex Pharmaceuticals, payment or honoraria for lectures, presentations, manuscript writing or educational events from Vertex Pharmaceuticals, support for attending meetings from Boehringer Ingelheim and Vertex Pharmaceuticals, participation on a data safety monitoring board or advisory board with Abbvie, Antabio, Arrowhead Pharmaceuticals, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Pari, Santhera and Vertex Pharmaceuticals, and a leadership role as Fellow of ERS (FERS). M.M. Tunney reports grants from the Northern Ireland Health and Social Care Research and Development Office, the EU Innovative Medicines Initiative, Novartis, Basilea Pharmaceutica, Alaxia SAS, Spexsis, Shionogi and Antabio. The remaining authors have no potential conflicts of interest to disclose.

Figures

None
CFMATTERS: Cystic Fibrosis Microbiome-directed Antibiotic Therapy Trial in Exacerbations Results Stratified. ppFEV1: percentage predicted forced expiratory volume in 1 s; P. aeruginosa: Pseudomonas aeruginosa; CFRSD: Cystic Fibrosis Respiratory Symptom Diary; CFQR : Cystic Fibrosis Questionnaire Revised; i.v.: intravenous; UT: usual therapy; MD: microbiome-directed group.
FIGURE 1
FIGURE 1
Consolidated Standards of Reporting Trials flow diagram. ppFEV1: percentage predicted forced expiratory volume in 1 s; CFRSD: Cystic Fibrosis Respiratory Symptom Diary; CFQR: Cystic Fibrosis Questionnaire Revised.
FIGURE 2
FIGURE 2
Distribution of percent predicted forced expiratory volume in 1 s (ppFEV1), by group and time point. UT: usual therapy; MD: microbiome-directed.
FIGURE 3
FIGURE 3
Survival plot for time to second exacerbation by study group (n=142).
See this image and copyright information in PMC

Comment in

References

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