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

Eur Respir J. 2025 Aug 8;66(2):2402443. doi: 10.1183/13993003.02443-2024. Print 2025 Aug.

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.

Publication types

  • Randomized Controlled Trial
  • Multicenter Study

MeSH terms

  • Adult
  • Anti-Bacterial Agents* / administration & dosage
  • Anti-Bacterial Agents* / therapeutic use
  • Aztreonam / administration & dosage
  • Aztreonam / therapeutic use
  • Ceftazidime / administration & dosage
  • Ceftazidime / therapeutic use
  • Cystic Fibrosis* / complications
  • Cystic Fibrosis* / drug therapy
  • Cystic Fibrosis* / microbiology
  • Cystic Fibrosis* / physiopathology
  • Disease Progression
  • Europe
  • Female
  • Forced Expiratory Volume
  • Humans
  • Male
  • Microbiota* / drug effects
  • Middle Aged
  • Pseudomonas Infections* / complications
  • Pseudomonas Infections* / drug therapy
  • Pseudomonas Infections* / microbiology
  • Pseudomonas aeruginosa
  • Quality of Life
  • Sputum / microbiology
  • Tobramycin / administration & dosage
  • Tobramycin / therapeutic use
  • Treatment Outcome
  • Young Adult

Substances

  • Anti-Bacterial Agents
  • Tobramycin
  • Aztreonam
  • Ceftazidime