Aaron 2005.

Methods	Randomised, double‐blind controlled trial. Parallel design. Duration: 14 days treatment, follow up every 3 months for up to 4.5 years. Location: multicentre, 10 sites in Canada and 2 in Australia.
Participants	Participants at least 12 years of age with CF chronically infected with multiresistant Burkholderia cepacia complex, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, or Achromobacter xylosoxidans bacteria (at least 2 sputum cultures within the past 12 months that had grown these organisms). 132 participants with acute pulmonary exacerbations of CF (defined according to criteria published by the 1994 Cystic Fibrosis Foundation Microbiology and Infectious Disease Consensus Conference) infected with multiresistant bacteria randomised on admittance for treatment. MCBT group n = 64, 43 (67.2%) infected with Pseudomonas aeruginosa. Age (mean (SD)): 29.5 (8.2) years. Gender: 29 males, 35 females. FEV₁ % predicted (mean (SD)): 44·0 (16.4)%. Diabetes: 15 (23.4%). Pancreatic insufficiency: 63 (98.4%). Liver disease: 6 (9.4%). Conventional treatment group n = 68, 39 (57.4%) infected with Pseudomonas aeruginosa. Age (mean (SD)): 25.8 (6.5) years. Gender: 31 males, 37 females. FEV₁ % predicted (mean (SD)): 39.1 (16.7)%. Diabetes: 13 (19.1%). Pancreatic insufficiency: 65 (95.6%). Liver disease: 8 (11.8%).
Interventions	14‐day course of any two IV antibiotics chosen on the basis of MCBT or control (separate testing). IV aminoglycosides were given once daily at 2 study sites, 2x daily at 1 site, and thrice daily at the 9 other sites. In each case MCBT orders, and control orders, conformed to the local centre’s treatment practice.
Outcomes	Lung function (FEV₁ and FVC), time to next pulmonary exacerbation, length of hospital stay, sputum bacterial density, adverse events, mortality, dyspnoea, treatment failures, white blood cell counts, C‐reactive protein concentrations in serum, and erythrocyte sedimentation rates, compliance.
Notes	Study sample size was calculated based on expected median survival times to next exacerbation; 132 participants were randomised, resulting in 83% power to show a difference between the two treatment groups. The study sponsors had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was done centrally through the research pharmacy using a computer‐generated random listing of the two treatment assignments blocked in groups of four and stratified by site.
Allocation concealment (selection bias)	Low risk	The research staff, participants and caregivers were unaware of the allocation. The principal investigator in Ottawa (SDA) was the only physician with access to the MCBT test results and he ordered the MCBT‐directed therapy for all participants. The research pharmacist at each hospital was the only member of the investigative team aware of the randomisation assignment,
Blinding (performance bias and detection bias) All outcomes	Low risk	Each hospital pharmacist prepared the two blinded IV antibiotics for administration (labelled “antibiotic #1” and “antibiotic #2”) and also prepared nebulised tobramycin, or nebulised identical placebo tobramycin, for each randomised patient. Blinded study drugs were administered on the hospital wards, or in some cases, in the participants' homes under supervision by home‐care nursing staff.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All 132 participants receiving an intervention were included in the final analysis (intention‐to‐treat analysis). There were no withdrawals from the study.
Selective reporting (reporting bias)	Low risk	Although the study itself reported all the data for all participants enrolled (n = 132), we were only able to retrieve 1 study outcome (time to subsequent exacerbation) for participants infected with P aeruginosa. However, this was the study's primary outcome and is a clinically relevant outcome to this review.
Other bias	Unclear risk	A potential limitation of this study is that antibiotics were prescribed for participants randomised to the MCBT arm by one investigator, whereas antibiotics were prescribed for participants randomised to the control arm by the participants' own doctors. This approach was necessary, since the local physicians had to remain blinded to the MCBT results, but it could have affected the study outcomes. A second limitation is that this study was powered to show a 79% increase in the time to next exacerbation and did not have the statistical power to exclude a smaller effect of MCBT‐directed therapy. Conventional clinical microbiological testing, and MCBT testing, involves the culture of planktonically growing bacteria (i.e. free floating bacteria growing in broth). Bacteria growing in biofilms, e.g. Pseudomonas aeruginosa, have been shown to be significantly more resistant to antimicrobials than those growing planktonically.

CF: cystic fibrosis
 FEV₁: forced expiratory volume in one second
 FVC: forced vital capacity
 IV: intravenous
 MCBT: multiple combination bactericidal antibiotic testing 
 SD: standard deviation