Antimicrobial resistance is a significant challenge facing global healthcare. The unnecessary use of antibiotics is a key driver in the development of antibiotic resistance. Cystic Fibrosis (CF) represents a unique disease model to study bacterial resistance and to explore therapeutic strategies for same, as chronic lung infection overlaps with acute lung exacerbation's caused by a multitude of organisms. With time, chronic polymicrobial infection develops, with the most dominant infecting organism being Pseudomonas aeruginosa. In acute CF infections, empiric intravenous antibiotics are usually given for two weeks. Recurrent infections and treatments result in increasing antimicrobial resistance, and alterations in pathogen host interactions in the lung and gut flora. Next-generation DNA sequencing technology now offers DNA-based personalised diagnostics and treatment strategies. Enhancing our knowledge of the microbiome allows the use of stratified targeted antibacterial therapy that can be compared with standard empirical antibacterial therapy currently used. Cystic Fibrosis Microbiome-determined Antimicrobial Therapy Trial in Exacerbations: Results Stratified (CFMATTERS) will provide a randomized multi-centre controlled trial of microbiome-derived antimicrobial treatments versus current empirical therapy.

Inclusion Criteria:

• Written and informed consent, and assent where required.
• Age 16 years or older at enrolment
• Diagnosis of CF by standard sweat test and/or genetic analysis
• Persistent pulmonary Pseudomonas aeruginosa colonization confirmed on at least 2 occasions in the preceding 12 months
• Screening FEV1 predicted of >25%
• Able to perform spirometry reproducibly prior to enrolment
• Able to expectorate and provide a sputum sample at least once daily
• ≥1 non-elective course of intravenous antibiotics in the preceding year
• Able to understand and comply with protocol requirements, restrictions and instructions and likely to complete the study as planned, as judged by the investigator

Exclusion Criteria:

• Life expectancy less than 6 months
• They are a solid organ transplant recipient
• Have a requirement for immunosuppression ≥10mg corticosteroids per day
• Previous positive culture of non-tuberculosis mycobacteria species M.avium, M.abscessus or M.intracellulare within the last 12 months or undergoing active therapy
• Positive culture of any Burkholderia cepacia species within the last 12 months or undergoing active therapy
• Allergic bronchopulmonary aspergillosis on treatment
• Known allergies to more than 3 different classes of antibiotics, and intolerance or allergy to tobramycin.
• Liver portal hypertension, determined by identification of oesophageal varices
• Advanced kidney disease requiring a dose reduction of ceftazidime or contraindicating aminoglycosides
• History of any illness that in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject
• If patient undergoes a pulmonary exacerbation before the Microbiome analysis is reviewed by the Consensus Treatment Panel and i.v. antibiotics are administered. In this case, a repeat sputum will be sent for analysis 4 weeks after end of antibiotic treatment.
• Pregnant or breast-feeding at time of eligible pulmonary exacerbation