Study characteristics

Methods

Randomized, double‐blind controlled clinical trial.

Multicenter: 7 centers in USA.

Participants randomized on the basis of results from either conventional or biofilm antimicrobial susceptibility testing of their P aeruginosa isolate cultured from the sputum obtained at the screening visit.

Participants

39 participants with CF: biofilm‐treated group (n = 20) and conventionally‐treated (control) group (n = 19).

Mean (SD) age: biofilm group 32 (9.3) years; control group 28.2 (8.6) years.

Gender: biofilm group, 16 males and 4 females; control group, 9 males and 10 females.

Genotype delta F508 homozygous: biofilm group n = 11; control group n = 9.

Pancreatic insufficiency: biofilm group n = 18; control group n = 16.

Mean (SD) baseline FEV₁ % predicted: biofilm group 62.2% (23.2); control group 64% (28.2).

Inclusion criteria: confirmed diagnosis of CF; 14 years of age or older; could spontaneously produce sputum; able to perform pulmonary function tests; chronically infected with P aeruginosa; clinically stable at the time of enrolment; provided written consent.

Exclusion criteria: sputum P aeruginosa density was < 10⁵ CFU/g at screening; infected with BCC at screening or in the previous 24 months; allergic to more than 2 classes of antibiotics; received a lung transplantation; pregnant.

Interventions

A 14‐day course of any 2 antibiotics (IV or oral) chosen on the basis of results from either conventional or biofilm antimicrobial susceptibility testing of their P aeruginosa isolate cultured from the sputum obtained at the screening visit.

Outcomes

Primary outcome: microbiological response to antibiotic therapy, measured by the change in P aeruginosa sputum density, calculated as logarithm₁₀ (log₁₀) of end‐of‐treatment density minus log₁₀ of screening density in CFU/g.

Secondary outcomes: pulmonary response, measured as change in FEV₁ L, calculated as end‐of‐treatment FEV₁ L minus the baseline FEV₁ L.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants assigned to treatment groups using a block randomization procedure, stratified by trial site, using computer‐generated random numbers.

Allocation concealment (selection bias)

Low risk

Randomization assignments placed in numbered sealed envelopes which were opened sequentially at the time of randomization by the statistician or their designated representative. The remaining research staff, the participants and their caregivers were unaware of the allocation.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

The person responsible for participant care and the participant were aware of the antibiotic choices but were blinded to the testing method (biofilm or conventional) upon which this choice was based.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

The outcome assessor was aware of the antibiotic choices but was blinded to the testing method (biofilm or conventional) upon which this choice was based.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

39 participants randomized (20 to the biofilm‐treated group, 19 to the conventionally‐treated (control) group).

1 participant randomized, but withdrawn prior to treatment and subsequently re‐randomized and treated.

Biofilm group: 2 withdrew prior to treatment; 1 discontinued treatment due to adverse events.

Control group: 3 withdrew prior to treatment. 1 discontinued treatment due to adverse events.

In the modified intent‐to‐treat analysis, 18 of the 20 participants in the biofilm group and 16 of the 19 participants in the control group were analyzed. Therefore, < 15% of the participants randomized in the trial were excluded from the final analysis.

Selective reporting (reporting bias)

Unclear risk

Trial outcomes published in the original trial protocol on www.clinicaltrials.gov (NCT00153634) were almost the same as the ones reported in the final manuscript. Hospitalization data would likely be collected for safety issues and so the lack of reporting for this outcome is not a risk of bias. However, for lung function, the trial only reports results for FEV₁, although we would expect FVC and FEF_25-75% to have been undertaken as part of the standard set of lung function tests at clinic visits, hence unclear risk.

Other bias

Low risk

No other potential sources of bias identified.

Study characteristics

Methods

Randomized, double‐blind controlled clinical trial.

Multicenter: 5 CF centers in Canada.
Participants randomized at the time of a pulmonary exacerbation on the basis of results from either conventional or biofilm antimicrobial susceptibility testing of their P aeruginosa isolate cultured from the sputum obtained at the screening visit.

Participants

Inclusion criteria: diagnosis of CF, chronic infection with P aeruginosa (> 50% of respiratory specimens positive in the 24 months prior to screening) and the ability to produce sputum and to reproducibly perform pulmonary function testing; provided written consent.

Exclusion criteria: sputum culture either negative for P aeruginosa or with a density of less than 10⁵ CFU/mL at screening, history of B cepacia positive respiratory culture within 24 months prior to or at screening, physician’s decision to use antibiotics other than those prescribed by the principal investigator (VW), history of allergy to more than 2 classes of antibiotics or anaphylaxis to any antibiotic, status post lung transplantation or listed for lung transplantation, pregnant or clinically unstable.

39 participants with CF: biofilm‐treated group (n = 24, 48 exacerbations) and the conventionally‐treated (control) group (n = 15, 26 exacerbations).

Age: mean (range)

At first exacerbation: biofilm group 29.4 (11.3 to 49.2) years; control group 22.6 (10.1 to 53.2) years.

All exacerbations: biofilm group 27.2 (10.2 to 49.9) years; control group 20.3 (10.1 to 53.2) years.

Gender

At first exacerbation: biofilm group, 11 males and 13 females; control group, 3 males and 12 females.

All exacerbations: biofilm group, 22 males and 26 females; control group, 6 males and 20 females.

Genotype delta F508 homozygous

At first exacerbation: biofilm group n = 11 (48%); control group n = 9 (60%).

All exacerbations: biofilm group n = 26 (54%); control group n = 16 (61%).

CFRD

At first exacerbation: biofilm group n = 8 (33%); control group n = 3 (20%).

All exacerbations: biofilm group n = 12 (25%); control group n = 6 (23%).

Liver disease

At first exacerbation: biofilm group n = 3 (12%); control group n = 0 (0%).

All exacerbations: biofilm group n = 4 (8%); control group n = 0 (0%).

Pancreatic insufficiency:

At first exacerbation: biofilm group n = 22 (92%); control group n = 13 (87%).

All exacerbations: biofilm group n = 45 (97%); control group n = 24 (92%).

ABPA

At first exacerbation: biofilm group n = 3 (12%); control group n = 2 (13%).

All exacerbations: biofilm group n = 7 (14%); control group n = 5 (19%).

Baseline FEV₁% predicted: mean (range)
At first exacerbation: in the biofilm group was 53.3% (26.8 to 83.9) and was 60.6% (25.2 to 98.3) in the control group.

All exacerbations: in the biofilm group was 55.7% (25.6 to 111.3) and was 62.4% (25.2 to 98.3) in the control group.

Baseline FEV₁L: mean (range)
At first exacerbation: in the biofilm group was 1.9 (0.8 to 3.7) and was 1.9 (0.7 to 3.7) in the control group.

All exacerbations: in the biofilm group was 1.9 (0.8 to 4.2) and was 1.9 (0.7 to 3.7) in the control group.

At exacerbation FEV₁% predicted: mean (range)
At first exacerbation: in the biofilm group was 41.8% (23.9 to 71.1) and was 52.9% (21.2 to 91.0) in the control group.

All exacerbations: in the biofilm group was 45.0% (15.4 to 90.4) and was 53.1% (21.2 to 93.8) in the control group.

At exacerbation FEV₁L: mean (range)
At first exacerbation: in the biofilm group was 1.4 (0.6 to 3.1) and was 1.7 (0.6 to 3.2) in the control group.

All exacerbations: in the biofilm group was 1.5 (0.6 to 3.4) and was 1.7 (0.5 to 3.5) in the control group.

BMI (kg/m²) at baseline: mean (range)

At first exacerbation: in the biofilm group was 21.1 (14.6 to 30.1) and was 19.7 (14.2 to 26.8) in the control group.

All exacerbations: in the biofilm group was 20.6 (14.5 to 30.1) and was 19.2 (14.2 to 26.8) in the control group.

BMI (kg/m²) at exacerbation: mean (range)

At first exacerbation: in the biofilm group was 20.6 (13.5 to 27.9) and was 18.8 (13.9 to 23.0) in the control group.

All exacerbations: in the biofilm group was 20.2 (13.5 to 27.9) and was 18.5 (13.9 to 23.7) in the control group.

Maintenance treatment: dornase alfa
At first exacerbation: biofilm group n = 11 (46%); control group n = 7 (47%).

All exacerbations: biofilm group n = 28 (58%); control group n = 16 (61%).

Maintenance treatment: azithromycin
At first exacerbation: biofilm group n = 14 (58%); control group n = 4 (27%).

All exacerbations: biofilm group n = 11 (42%); control group n = 30 (62%).

Maintenance treatment: inhaled tobramycin
At first exacerbation: biofilm group n = 18 (75%); control group n = 12 (80%).

All exacerbations: biofilm group n = 36 (75%); control group n = 20 (77%).

Maintenance treatment: hypertonic saline
At first exacerbation: biofilm group n = 4 (17%); control group n = 2 (13%).

All exacerbations: biofilm group n = 11 (23%); control group n = 3 (11%).

Maintenance treatment: other inhaled antibiotics
At first exacerbation: biofilm group n = 2 (8%); control group n = 2 (13%).

All exacerbations: biofilm group n = 8 (17%); control group n = 5 (19%).

Interventions

Two IV antibiotics chosen on the basis of results from either conventional or biofilm antimicrobial susceptibility testing of their P aeruginosa isolate cultured from their most recent sputum.

Outcomes

Primary outcome: proportion of exacerbations in the biofilm versus conventional group in which a > 3 log₁₀ drop in sputum density of P aeruginosa in CFU/mL from Day 0 to Day 14 of antibiotic treatment, was achieved.

Secondary outcomes: pulmonary function tests (FEV₁, FVC), CFQ‐R, serum WBC, CRP, ESR and sputum IL‐8 and neutrophil elastase measured at Day 0, Day 14 of antibiotic therapy and at the 1‐month follow‐up visit.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Co‐PI randomized participants according to a random numbers table generated for each site based on the expected number of PEx during the study period. If a participant developed a second PEx during the study period they were re‐randomized to 1 of the 2 study arms (information provided in supplementary material).

Allocation concealment (selection bias)

Low risk

The method of selection (based on conventional or biofilm testing) was blinded to all participants, the treating team and all study personnel with the exception of co‐PI (YY) who was not directly involved in any patient care.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"Although the actual antibiotics themselves were not blinded, the method of selection (based on conventional or biofilm testing) was blinded to all subjects, the treating team and all study personnel with the exception of co‐PI YY (who was not directly involved in any patient care)."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"Although the actual antibiotics themselves were not blinded, the method of selection (based on conventional or biofilm testing) was blinded to all subjects, the treating team and all study personnel with the exception of co‐PI YY (who was not directly involved in any patient care)."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

41 participants randomised, 39 analysed, 2 (5%) excluded (one from each group) with no data available for either of these. Reasons for exclusion given ‐ 1 from conventional group lost to follow up and 1 from biofilm group did not grow P. aeruginosa on day 1.

Selective reporting (reporting bias)

Low risk

Protocol accessed from clinicaltrials.gov, all outcomes listed in the protocol are reported in the full paper.

Other bias

Low risk

No other potential sources of bias identified.