Inhaled anti‐pseudomonal antibiotics for long‐term therapy in cystic fibrosis

Sherie Smith; Nicola J Rowbotham

doi:10.1002/14651858.CD001021.pub4

Cochrane Database of Systematic Reviews

Inhaled anti‐pseudomonal antibiotics for long‐term therapy in cystic fibrosis

Información

DOI:

https://doi.org/10.1002/14651858.CD001021.pub4 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

14 noviembre 2022see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Fibrosis quística y enfermedades genéticas

Copyright:

Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Contraer

Autores

Sherie Smith

Correspondencia a: Division of Child Health, Obstetrics & Gynaecology (COG), School of Medicine, University of Nottingham, Nottingham, UK

[email protected]
Nicola J Rowbotham

Division of Child Health, Obstetrics & Gynaecology (COG), School of Medicine, University of Nottingham, Nottingham, UK

Contributions of authors

Previous contributions

Somnath Mukhopadhyay developed the protocol.
Meenu Singh selected trials and assessed trial quality.
Gerard Ryan was involved in all aspects of the protocol and the original review.
Gerard Ryan completed the updates up to 2018 with Meenu Singh and Kerry Dwan and previously acted as guarantor of the review.

At the 2018 update, new references were screened by two authors (Sherie Smith and Nicola Rowbotham). Data from newly included trials were extracted by Sherie Smith, Nicola Rowbotham and Kate Regan and entered into Revman by Sherie Smith. SS (with advice from NJ) carried out analyses on the newly included trials.

All authors contributed to writing and reviewing the main text.

Current contributions

At this update all screening of new references and data extraction was carried out by SS and NR. The same authors updated the review to include extra data and contributed to writing and reviewing the text.

Sources of support

Internal sources

Clinical Staff Education Fund, Sir Charles Gairdner Hospital, Australia

Funding for original author to work on review.

External sources

National Institute for Health and Care Research (NIHR), UK

This systematic review was supported by the NIHR, via Cochrane Infrastructure funding to the Cochrane Cystic Fibrosis and Genetic Disorders Group.

Declarations of interest

Nicola Rowbotham: none known.
Sherie Smith: none known.

Acknowledgements

We would like to thank previous authors of this review for their input: Gerard Ryan (Sir Charles Gairdner Hospital, Perth, Australia), Meenu Singh, Kerry Dwan and Somnath Mukhopadhyay (University of Dundee) and Kate Regan (NHS Lothian, Edinburgh, UK).

This project was supported by the National Institute for Health and Care Research (NIHR), via Cochrane Infrastructure funding to the Cochrane Cystic Fibrosis and Genetic Disorders Group. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health and Social Care.

Version history

Published

Title

Stage

Authors

Version

2022 Nov 14

Inhaled anti‐pseudomonal antibiotics for long‐term therapy in cystic fibrosis

Review

Sherie Smith, Nicola J Rowbotham

https://doi.org/10.1002/14651858.CD001021.pub4

2018 Mar 30

Inhaled anti‐pseudomonal antibiotics for long‐term therapy in cystic fibrosis

Review

Sherie Smith, Nicola J Rowbotham, Kate H Regan

https://doi.org/10.1002/14651858.CD001021.pub3

Event

Description

2018 Mar 15

New citation required and conclusions have changed

The title of the review has changed to focus on treatment of chronic infection with Pseudomonas aeruginosa and a new author team is now in place.

Conclusions have changed due to the removal of shorter‐term trials. We have also included the need for harmonising of outcomes in trials to allow combining of results.

2018 Mar 15

New search has been performed

Changes to the scope of the review

We have now focused on inhaled anti‐pseudomonal antibiotics and as such have now excluded two previously included trials which looked at other antibiotic regimens (Ledson 2002; Nolan 1982).

We have also changed the inclusion criteria so as to only include trials with a duration of three months or longer (previously 28 days and over). A total of 20 trials have been excluded due to insufficient duration and their characteristics and summary results presented in an additional table for the readers' reference; 11 of these were previously included in the review (Dupont 2008; Geller 2011b; Gibson 2003; Goss 2009; Hodson 2002; Konstan 2010a; Lenoir 2007; McCoy 2008; Ramsey 1993; Retsch‐Bogart 2007; Wainwright 2011), one was previously listed as 'Awaiting assessment' (Davies 2004) and eight were newly identified at this update (see below) (Dorkin 2015; Galeva 2011; Geller 2011a; Mainz 2014; Mazurek 2014; Nasr 2004; Sands 2014; Trapnell 2012).

New search results

A search of the Cystic Fibrosis and Genetic Disorders Review Group's Cystic Fibrosis Trials Register identified 123 references to 32 trials.

Four new trials (25 references) were included (Assael 2013; Bilton 2014; Elborn 2015; Flume 2016b), 10 new trials (39 references) were excluded (Dorkin 2015; Flume 2016a; Galeva 2011; Geller 2011a; Mainz 2014; Mazurek 2014; Nasr 2004; Ruddy 2013; Sands 2014; Trapnell 2012) and 11 new references to four already excluded trials have been identified (Al‐Aloul 2004; McCoy 2008; Ramsey 2005; Stass 2014). Two new trials (two references) have been listed as 'Awaiting classification' (Herrmann 2017; Ramsey 2017).

Trials previously listed as 'Awaiting classification'

Two new references were identified to one trial previously listed as 'Awaiting assessment' which has now been excluded (Coates 2011). 10 new references were identified to a further trial which has also now been excluded (Wainwright 2008). Finally, one additional reference to a trial previously listed as 'Awaiting classification' has been identified and the trial has been excluded (Wainwright 2011).

The EVOLVE trial was previously listed in 'Awaiting classification' both under a clinical trials identifier and as the Konstan 2009 trial (two abstracts). An additional three references to this trial have been identified and all references are now listed under the trial which has been included (Konstan 2010b).

A further 28 new references were added to seven trials previously listed as 'Awaiting classification'; one trial (four new references) has been included (Schuster 2013) and six trials (25 new references) excluded (Dupont 2008; Geller 2011b; Goss 2009; Konstan 2010a; Retsch‐Bogart 2007; Rietschel 2009).

No new references were found to one trial listed as 'Awaiting classification', but it has been excluded on the grounds of insufficient duration after the change in inclusion criteria (Davies 2004). One trial remains in 'Awaiting classification' pending further information (Nikonova 2010).

Trial previously listed as 'Ongoing'

Two additional references were identified to one trial previously listed as ongoing under the study ID Bayer 2010; following publication of the new abstracts, this has now been excluded under a new trial ID (Dorkin 2015).

We have added a summary of findings table for each of the comparisons we present within this review.

2011 Mar 16

Inhaled antibiotics for long‐term therapy in cystic fibrosis

Review

Gerard Ryan, Meenu Singh, Kerry Dwan

https://doi.org/10.1002/14651858.CD001021.pub2

Event

Description

2011 Feb 01

New search has been performed

The search of the Group's Cystic Fibrosis Trials Register in April 2010 identified 62 new citations to 36 studies.

A total of 11 citations to four new studies have been included (Ledson 2002; McCoy 2008; Nikolaizik 2008; Nolan 1982). One citation was added to an already included study (Ramsey 1999). Two studies previously awaiting classification have now been included and one new citation added to each (Chuchalin 2007; Lenoir 2007). Two previously excluded trials have now been included; a consequence of not restricting the review to nebulised anti‐pseudomonas antibiotics (Ledson 2002; Nolan 1982).

Thirteen new studies (19 citations) have been excluded (Bruinenberg 2008; Dodd 1998; Geller 2007; Griffith 2008; Mullinger 2005; Noah 2007; Proesmans 2008; Rosenfeld 2006; Shatunov 2001; Stass 2008; Stass 2009; Steinkamp 2006; Tramper‐Stranders 2009). A total of eight citations were added to six already excluded studies (Al‐Aloul 2004; Poli 2005; Ratjen 2006; Ramsey 2005; Retsch‐Bogart 2008; Westerman 2007). One previously included study has now been excluded as it is not clear that the effects of the intervention were due to the inhaled antibiotic (Carswell 1987).

Eleven new studies with a total of 21 citations have been listed as awaiting classification (Davies 2004; Dupont 2008; Flume 2010; Goldman 2008; Goss 2009; Keller 2010; Konstan 2009; Nikonova 2010; Retsch‐Bogart 2007; Rietschel 2009; Wainwright 2010).

The Plain Language Summary has also been updated in line with the latest guidance from The Cochrane Collaboration.

2011 Feb 01

New citation required but conclusions have not changed

The title of the review has been changed from 'Nebulised anti‐pseudomonal antibiotics for cystic fibrosis' to 'Inhaled antibiotics for long‐term therapy cystic fibrosis' to better reflect:
1. that organisms other than Pseudomonas aeruginosa may be the target of inhaled antibiotic treatment; and
2. methods to generate aerosols of antibacterial agents other than nebulisers are being developed.

One co‐author, Somnath Mukhopadhyay, has stepped down from the review team. A new co‐author has joined the team, Kerry Dwan.

2003 Jul 21

Nebulised anti‐pseudomonal antibiotics for cystic fibrosis

Review

Gerard Ryan, Somnath Mukhopadhyay, Meenu Singh

https://doi.org/10.1002/14651858.CD001021

Revision date This is the date when the review was published	Event	Description
2008 Nov 11	Amended	The Plain Language Summary has also been updated in line with the latest guidance from The Cochrane Collaboration.
2008 Nov 11	Amended	Converted to new review format.
2007 Feb 21	New search has been performed	The search of the Group's Cystic Fibrosis Trials Register to September 2006 identified 18 new citations to 11 trials: ADDITIONAL CITATIONS TO ALREADY INCLUDED TRIALS Gibson 2003 (1 citation added) Ramsey 1999 (1 citation added) Results for weight, a secondary outcome, is now reported for the Gibson 2003 citation and is included. NEW TRIALS Two trials have been published as abstracts and have been added to the section 'Awating Assessment' until the full papers have been published. Chuchalin 2005 (2 citations) Lenoir 2005 (2 citations) EXCLUDED TRIALS The remaining 12 citations to 7 trials have been excluded.
2006 Jan 26	New search has been performed	The search of the Group's Cystic Fibrosis Trials Register to September 2005 identified 32 new citations of 16 trials: ADDITIONAL CITATIONS TO ALREADY EXCLUDED TRIALS Chua 1990 (1 additional citation added) Dodd 1997 (1 additional citation added) Frederiksen 1997 (1 additional citation added) Alothman 2002 (1 additional citation added) ADDITIONAL CITATIONS TO ALREADY INCLUDED TRIALS Ramsey 1999 (10 additional citations added) Hodson 2002 (2 additional citations added) These additional reports of results from these two included trials did not add new results to the review compared to the reports already included. These citations either reported results already included in this review, or included outcomes that were not in the protocol for this review; or reported sub‐group analyses, or results from open‐label extension. NEWLY EXCLUDED Adeboyeku 2001(1 citation) Geborek 2003 (1 citation) Geller 2004 (2 citations) Gullliver 2003 (1 citation) Ledson 1998 (2 citations) Pradal 2002 ( 1 citation) Wainwright 2002 (1 citation) Westerman 2003 (2 citations) NEWLY INCLUDED Gibson 2003 (2 citations) Murphy 2004 (3 citations) Wiesemann 1998 (2 citations) Methodological quality of included studies This section has been revised by using a new method to classify quality criteria, describing the criteria for individual studies in a table and summarising the results in the text. The results of this quality assessment has not been used for study selection or in analysis. Results The inclusion of three studies has not significantly changed the results. Gibson 2003 reported only adverse effects, the primary outcome of the study was density of Pseudomonas aeruginosa, which was not an outcome of this review. Murphy 2004 added some results to respiratory tract exacerbations (hospitalisation, antibiotic use), lung function, adverse events. Wiesemann 1998 studied people with CF and early acquisition of Pseudomonas. The primary outcome was time to eradication of Pseudomonas; lung function was measured and reported as not different without numbers.

Differences between protocol and review

March 2018
The title of the review was revised again to 'Inhaled anti‐pseudomonal antibiotics for long‐term therapy in cystic fibrosis' and the duration of the intervention restricted to over three months and not over one month. This was to reflect the treatment for long‐term suppression rather than in acute exacerbations.

At this update, summary of findings tables were included for each comparison presented in the review.

February 2011
The title of the review has been changed from 'Nebulised anti‐pseudomonal antibiotics for cystic fibrosis' to 'Inhaled antibiotics for long‐term therapy in cystic fibrosis' to better reflect the interventions included in the review.

While updating the Methods section of the review the authors added a second planned sensitivity analysis (with and without cross‐over trials), as they felt this was relevant given that a combination of parallel and cross‐over trials are included in the review.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Adolescent; Adult; Child; Child, Preschool; Humans; Middle Aged; Young Adult;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

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Figure 4

Forest plot of comparison: 1 Inhaled anti‐pseudomonal antibiotic versus placebo, outcome: 1.6 Mean change in FVC (% predicted).

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Comparison 1: Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo, Outcome 1: Mean absolute FEV1 (% predicted)

Analysis 1.1

Comparison 1: Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo, Outcome 1: Mean absolute FEV₁ (% predicted)

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Comparison 1: Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo, Outcome 2: Mean change in FEV1 (% predicted)

Analysis 1.2

Comparison 1: Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo, Outcome 2: Mean change in FEV₁ (% predicted)

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Comparison 1: Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo, Outcome 3: Mean change in % predicted FEV1

Analysis 1.3

Comparison 1: Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo, Outcome 3: Mean change in % predicted FEV₁

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Comparison 1: Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo, Outcome 4: Rate of change of FEV1 (% predicted per year)

Analysis 1.4

Comparison 1: Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo, Outcome 4: Rate of change of FEV₁ (% predicted per year)

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Analysis 1.5

Comparison 1: Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo, Outcome 5: Mean absolute FVC (% predicted) at end of treatment

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Analysis 1.6

Comparison 1: Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo, Outcome 6: Mean change in FVC (% predicted)

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Analysis 1.7

Comparison 1: Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo, Outcome 7: Rate of change of FVC (% predicted per year)

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Analysis 1.8

Comparison 1: Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo, Outcome 8: Frequency of one or more hospital admissions

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Analysis 1.9

Comparison 1: Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo, Outcome 9: Hospital admissions, mean number of days in hospital

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Analysis 1.10

Comparison 1: Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo, Outcome 10: Frequency of one or more courses of intravenous antibiotics

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Analysis 1.11

Comparison 1: Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo, Outcome 11: Pulmonary exacerbations

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Analysis 1.12

Comparison 1: Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo, Outcome 12: Lost school or working days

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Analysis 1.13

Comparison 1: Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo, Outcome 13: Deaths

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Analysis 1.14

Comparison 1: Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo, Outcome 14: Frequency of tobramycin‐resistant P. aeruginosa at end of study

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Analysis 1.15

Comparison 1: Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo, Outcome 15: Frequency of new isolates of drug resistant organisms (at end of study)

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Analysis 1.16

Comparison 1: Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo, Outcome 16: Number experiencing adverse event (at end of study)

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Analysis 2.1

Comparison 2: Colistimethate sodium dry powder (CDPI) versus tobramycin for inhalation solution (TIS), Outcome 1: Number of pulmonary exacerbations

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Analysis 2.2

Comparison 2: Colistimethate sodium dry powder (CDPI) versus tobramycin for inhalation solution (TIS), Outcome 2: Time to first pulmonary exacerbation

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Analysis 2.3

Comparison 2: Colistimethate sodium dry powder (CDPI) versus tobramycin for inhalation solution (TIS), Outcome 3: Deaths

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Analysis 2.4

Comparison 2: Colistimethate sodium dry powder (CDPI) versus tobramycin for inhalation solution (TIS), Outcome 4: Adverse events (at end of study)

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Comparison 3: Inhaled TOBI® (IV preparation) versus tobramycin for inhalation solution (TIS), Outcome 1: FEV1 % predicted

Analysis 3.1

Comparison 3: Inhaled TOBI® (IV preparation) versus tobramycin for inhalation solution (TIS), Outcome 1: FEV₁ % predicted

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Analysis 3.2

Comparison 3: Inhaled TOBI® (IV preparation) versus tobramycin for inhalation solution (TIS), Outcome 2: FVC

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Comparison 4: Tobramycin inhalation powder (TIP) versus tobramycin for inhalation solution (TIS), Outcome 1: FEV1 (% predicted) relative change

Analysis 4.1

Comparison 4: Tobramycin inhalation powder (TIP) versus tobramycin for inhalation solution (TIS), Outcome 1: FEV₁ (% predicted) relative change

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Analysis 4.2

Comparison 4: Tobramycin inhalation powder (TIP) versus tobramycin for inhalation solution (TIS), Outcome 2: Hospitalisations

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Analysis 4.3

Comparison 4: Tobramycin inhalation powder (TIP) versus tobramycin for inhalation solution (TIS), Outcome 3: Pulmonary exacerbations

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Analysis 4.4

Comparison 4: Tobramycin inhalation powder (TIP) versus tobramycin for inhalation solution (TIS), Outcome 4: Deaths

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Analysis 4.5

Comparison 4: Tobramycin inhalation powder (TIP) versus tobramycin for inhalation solution (TIS), Outcome 5: Adverse events (at end of study)

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Comparison 5: Inhaled aztreonam lysine (AZLI) versus tobramycin for inhalation solution (TIS), Outcome 1: FEV1 % predicted ‐ mean relative change from baseline

Analysis 5.1

Comparison 5: Inhaled aztreonam lysine (AZLI) versus tobramycin for inhalation solution (TIS), Outcome 1: FEV₁ % predicted ‐ mean relative change from baseline

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Comparison 5: Inhaled aztreonam lysine (AZLI) versus tobramycin for inhalation solution (TIS), Outcome 2: FEV1 % predicted ‐ mean actual change from baseline

Analysis 5.2

Comparison 5: Inhaled aztreonam lysine (AZLI) versus tobramycin for inhalation solution (TIS), Outcome 2: FEV₁ % predicted ‐ mean actual change from baseline

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Analysis 5.3

Comparison 5: Inhaled aztreonam lysine (AZLI) versus tobramycin for inhalation solution (TIS), Outcome 3: Need for additional antibiotics

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Analysis 5.4

Comparison 5: Inhaled aztreonam lysine (AZLI) versus tobramycin for inhalation solution (TIS), Outcome 4: Number of days of additional antibiotics

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Analysis 5.5

Comparison 5: Inhaled aztreonam lysine (AZLI) versus tobramycin for inhalation solution (TIS), Outcome 5: Weight (relative change from baseline)

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Analysis 5.6

Comparison 5: Inhaled aztreonam lysine (AZLI) versus tobramycin for inhalation solution (TIS), Outcome 6: Quality of Life ‐ CFQR respiratory symptom scale

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Analysis 5.7

Comparison 5: Inhaled aztreonam lysine (AZLI) versus tobramycin for inhalation solution (TIS), Outcome 7: TSQM ‐ effectiveness

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Analysis 5.8

Comparison 5: Inhaled aztreonam lysine (AZLI) versus tobramycin for inhalation solution (TIS), Outcome 8: TSQM ‐ global satisfaction

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Analysis 5.9

Comparison 5: Inhaled aztreonam lysine (AZLI) versus tobramycin for inhalation solution (TIS), Outcome 9: TSQM ‐ side effects

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Analysis 5.10

Comparison 5: Inhaled aztreonam lysine (AZLI) versus tobramycin for inhalation solution (TIS), Outcome 10: TSQM ‐ convenience

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Comparison 5: Inhaled aztreonam lysine (AZLI) versus tobramycin for inhalation solution (TIS), Outcome 11: Log10Pseudomonas aeruginosa CFU/g sputum

Analysis 5.11

Comparison 5: Inhaled aztreonam lysine (AZLI) versus tobramycin for inhalation solution (TIS), Outcome 11: Log₁₀Pseudomonas aeruginosa CFU/g sputum

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Analysis 5.12

Comparison 5: Inhaled aztreonam lysine (AZLI) versus tobramycin for inhalation solution (TIS), Outcome 12: Adverse events (at end of study)

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Analysis 6.1

Comparison 6: Amikacin liposome inhalation suspension (ALIS) versus TOBI^®, Outcome 1: Hospitalisations ‐ number of participants hospitalised (all‐cause)

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Analysis 6.2

Comparison 6: Amikacin liposome inhalation suspension (ALIS) versus TOBI^®, Outcome 2: Change from baseline in CFQ‐R domain scores

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Analysis 6.3

Comparison 6: Amikacin liposome inhalation suspension (ALIS) versus TOBI^®, Outcome 3: Treatment‐emergent adverse events (TEAEs)

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Comparison 7: Levofloxacin for inhalation solution (LIS) versus tobramycin for inhalation solution (TIS), Outcome 1: Absolute change in FEV1 % predicted

Analysis 7.1

Comparison 7: Levofloxacin for inhalation solution (LIS) versus tobramycin for inhalation solution (TIS), Outcome 1: Absolute change in FEV₁ % predicted

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Comparison 7: Levofloxacin for inhalation solution (LIS) versus tobramycin for inhalation solution (TIS), Outcome 2: Relative change in FEV1 % predicted

Analysis 7.2

Comparison 7: Levofloxacin for inhalation solution (LIS) versus tobramycin for inhalation solution (TIS), Outcome 2: Relative change in FEV₁ % predicted

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Analysis 7.3

Comparison 7: Levofloxacin for inhalation solution (LIS) versus tobramycin for inhalation solution (TIS), Outcome 3: Absolute change in FVC % predicted

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Analysis 7.4

Comparison 7: Levofloxacin for inhalation solution (LIS) versus tobramycin for inhalation solution (TIS), Outcome 4: Relative change in FVC % predicted

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Analysis 7.5

Comparison 7: Levofloxacin for inhalation solution (LIS) versus tobramycin for inhalation solution (TIS), Outcome 5: Hospitalisations due to respiratory exacerbations

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Analysis 7.6

Comparison 7: Levofloxacin for inhalation solution (LIS) versus tobramycin for inhalation solution (TIS), Outcome 6: Weight decrease

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Analysis 7.7

Comparison 7: Levofloxacin for inhalation solution (LIS) versus tobramycin for inhalation solution (TIS), Outcome 7: Change in P aeruginosa sputum density (log₁₀ CFU/g)

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Analysis 7.8

Comparison 7: Levofloxacin for inhalation solution (LIS) versus tobramycin for inhalation solution (TIS), Outcome 8: Adverse events (at end of study)

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Comparison 8: Continuous aztreonam (AZLI)/tobramycin (TIS) versus intermittent tobramycin (TIS), Outcome 1: Mean change from baseline ‐ FEV1 % predicted

Analysis 8.1

Comparison 8: Continuous aztreonam (AZLI)/tobramycin (TIS) versus intermittent tobramycin (TIS), Outcome 1: Mean change from baseline ‐ FEV₁ % predicted

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Analysis 8.2

Comparison 8: Continuous aztreonam (AZLI)/tobramycin (TIS) versus intermittent tobramycin (TIS), Outcome 2: Rate of hospitalisation per participant year

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Analysis 8.3

Comparison 8: Continuous aztreonam (AZLI)/tobramycin (TIS) versus intermittent tobramycin (TIS), Outcome 3: Need for additional antibiotics for an exacerbation

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Analysis 8.4

Comparison 8: Continuous aztreonam (AZLI)/tobramycin (TIS) versus intermittent tobramycin (TIS), Outcome 4: Rate of protocol defined pulmonary exacerbations per participant year

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Analysis 8.5

Comparison 8: Continuous aztreonam (AZLI)/tobramycin (TIS) versus intermittent tobramycin (TIS), Outcome 5: Quality of life ‐ CFQ‐R respiratory symptom score

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Analysis 8.6

Comparison 8: Continuous aztreonam (AZLI)/tobramycin (TIS) versus intermittent tobramycin (TIS), Outcome 6: Incidence of other respiratory pathogens (at end of study)

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Analysis 8.7

Comparison 8: Continuous aztreonam (AZLI)/tobramycin (TIS) versus intermittent tobramycin (TIS), Outcome 7: Adverse events (at end of study)

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Analysis 8.8

Comparison 8: Continuous aztreonam (AZLI)/tobramycin (TIS) versus intermittent tobramycin (TIS), Outcome 8: Treatment‐emergent adverse events (at end of study)

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Summary of findings 1. Summary of findings: anti‐pseudomonal antibiotics versus placebo

Anti‐pseudomonal antibiotics compared with placebo for long‐term therapy in CF
Patient population: adults and children with CF and P aeruginosa Settings: outpatients Intervention: inhaled anti‐pseudomonal antibiotics Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Certainty of evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Inhaled anti‐pseudomonal antibiotics
FEV₁ (% predicted) Follow‐up: at 3 months and up to 36 months	4 trials found a significant improvement in FEV₁ with inhaled antibiotics compared to placebo, although no data were available for 3 of these. 1 trial reported that the rate of decline in FEV₁ favoured antibiotics. The remaining 6 trials showed no significant difference between inhaled antibiotics and placebo.		NA	1130 (11)	⊕⊕⊝⊝ low^a	The included trials all measured FEV₁ but in different ways and for different lengths of time. It was not possible to combine the trials in a meta‐analysis.
FVC (% predicted) Follow‐up: at 3 months and up to 36 months	5 of the 10 trials found significant changes in FVC at the end of the trial period, favouring inhaled antibiotics when compared to placebo. 1 trial found no significant difference in absolute values of FVC % predicted between inhaled antibiotics and control but found that mean change in FVC % predicted was significantly different (favouring antibiotics). 1 trial found a combination of gentamycin and carbenicillin versus placebo to be significantly different and favouring antibiotics yet ceftazidime versus placebo was not significantly different. 3 trials found no significant difference between antibiotics and placebo with regard to FVC % predicted.		NA	1097 (10)	⊕⊕⊝⊝ low^a	FVC was measured differently across the trials.
Pulmonary exacerbations: frequency of one or more hospital admissions Follow‐up: over 3 months and up to 12 months	397 per 1000	262 per 1000 (187 to 369 per 1000)	RR 0.66 (0.47 to 0.93)	946 (3)	⊕⊕⊝⊝ low^a
Quality of life: lost school or working days Follow‐up: over 3 months and up to 12 months	The mean number of lost school or working days in the control group was 10 days.	The mean number of lost school or working days in the inhaled antibiotic group was 5.3 days lower (8.59 lower to 2.01 lower).	NA	245 (1)	⊕⊕⊝⊝ low^b,c
Survival: number of deaths Follow‐up: over 3 months and up to 12 months	17 per 1000	3 per 1000 (1 to 19 per 1000)	RR 0.17 (0.03 to 1.09)	767 (2)	⊕⊕⊝⊝ low^b,c
Antibiotic resistance: frequency of tobramycin‐resistant P aeruginosa Follow‐up: at end of trial (12 months)	105 per 1000	205 per 1000 (90 to 464 per 1000)	RR 1.95 (0.86 to 4.42)	672 (2)	⊕⊕⊕⊝ moderate^b
Adverse events Follow‐up: at the end of the trial (84 days to 33 months)	There were no significant differences between inhaled antibiotics and placebo for auditory impairment, pneumothorax, haemoptysis. Tinnitus and voice alteration were significantly more common in the inhaled antibiotics groups.		NA	1014 (6)	⊕⊝⊝⊝ very low^a,c	Rate of auditory impairment reported in 5 trials for 996 participants. Rate of pneumothorax reported in 3 trials for 558 participants. Rate of haemoptysis reported in 1 trial for 520 participants. Rate of tinnitus reported in 1 trial for 520 participants. Rate of voice alteration reported in 2 trials for 701 participants.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CF: cystic fibrosis; CI: confidence interval; FEV₁ : forced expiratory volume at 1 second; FVC: forced vital capacity; *P aeruginosa* : Pseudomonas aeruginosa; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded twice due to most trials included in the comparison being at unclear or high risk of bias. 3 trials were at high or unclear risk of bias across all domains. All the 11 trials were at high or unclear risk of bias for randomisation or allocation concealment (or both) and also blinding of participants or outcome assessors (or both). ^bDowngraded once because of unclear risk of bias across some domains (randomisation or allocation concealment (or both) and blinding of participants or outcome assessment (or both)) of the included trials. ^cDowngraded once due to imprecision due to low event rates.

Summary of findings 1. Summary of findings: anti‐pseudomonal antibiotics versus placebo

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Summary of findings 2. Summary of findings: colistimethate dry powder for inhalation (Colobreathe®) versus tobramycin for inhalation solution

Colistimethate dry powder (Colobreathe®) compared with TISfor long‐term therapy in CF
Patient population: children and adults with CF and P aeruginosa infection Settings: outpatients Intervention: colistimethate dry powder for inhalation (1 1.6625 MU capsule twice daily for 24 weeks) Comparison: TIS (3 cycles of 28 days of TIS (300 mg/5 mL) twice daily followed by a 28‐day off period)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Certainty of evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	TIS	Colistimethate dry powder for inhalation (Colobreathe®)
FEV₁ (% predicted): mean change from baseline Follow‐up: 24 weeks	Adjusted mean difference between the groups (ITT population LOCF) for the change in FEV₁ % predicted, MD ‐0.98% (95% CI‐2.74% to 0.86%). There was no significant difference between the 2 groups for this outcome.		NA	374 (1)	⊕⊕⊝⊝ low^a,b	The data were not normally distributed and were analysed using log‐transformation analysis. We have reported the results directly from the paper.
FVC (% predicted): mean change from baseline Follow‐up: 24 weeks	There was no significant difference between groups for FVC % predicted in the ITT population (LOCF), MD 0.01 L (95% CI ‐0.09 to 0.10).		NA	374 (1)	⊕⊕⊝⊝ low^a,b	The data were not normally distributed and were analysed using log‐transformation analysis. We have reported the results directly from the paper.
Pulmonary exacerbations: number of pulmonary exacerbations Follow‐up: 24 weeks	262 per 1000	312 per 1000 (225 to 430 per 1000)	RR 1.19 (0.86 to 1.64)	374 (1)	⊕⊕⊕⊝ moderate^a
Quality of life: adjusted mean change in CFQ‐R score at the end of treatment Follow‐up: 24 weeks	The adjusted mean changes at the end of the trial favoured the Colobreathe® group in terms of treatment burden (P = 0.091). This difference was significant at Week 4 (P < 0.001).		NA	374 (1)	⊕⊕⊝⊝ low^a,c	The trial was not powered to detect differences in overall quality of life. Results reported directly from paper.
Survival: number of deaths Follow‐up: over 3 months and up to 12 months	10 per 1000	2 per 1000 (0 to 43 per 1000)	RR 0.21 (0.01 to 4.32)	374 (1)	⊕⊕⊝⊝ low^a,d
Antibiotic resistance: change in mean MIC₅₀ and MIC₉₀ at the end of the trial Follow‐up: 24 weeks	The mean MIC₅₀ (breakpoint of ≥ 8 mg/L) changed in the TIS group by 0.5 compared to 0.0 in the Colobreathe® group. The mean MIC₉₀ (breakpoint of ≥ 8 mg/L) changed in the both groups by 4.0.		NA	374 (1)	⊕⊕⊝⊝ low^a,c
Adverse events: number of treatment related adverse events Follow‐up: 24 weeks	466 per 1000	820 per 1000 (699 to 969 per 1000)	RR 1.76 (1.50 to 2.08)	379 (1)	⊕⊕⊝⊝ low^a,d	Treatment‐related adverse events were significantly lower in the TIS group than the Colobreathe® group P < 0.0001.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CF: cystic fibrosis; CI: confidence interval; FEV₁ : forced expiratory volume at 1 second; FVC: forced vital capacity; ITT: intention‐to‐treat; LOCF: last observation carried forward; MIC: minimum inhibitory concentration; *P aeruginosa* : Pseudomonas aeruginosa; RR: risk ratio; TIS: tobramycin for inhalation solution.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded once due to an unclear or high risk of bias across 4 out of the 7 domains, particularly randomisation, allocation concealment and participant blinding. ^bDowngraded once due to LOCF analysis increasing risk of bias. ^cDowngraded once for imprecision; the trial was underpowered to detect differences in overall quality of life. ^dDowngraded once for imprecision due to low event rates.

Summary of findings 2. Summary of findings: colistimethate dry powder for inhalation (Colobreathe®) versus tobramycin for inhalation solution

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Summary of findings 3. Summary of findings: inhaled TOBI® (IV preparation) versus tobramycin for inhalation solution

Inhaled TOBI® (IV preparation) compared with TIS for long‐term therapy in CF
Patient population: adults and children with CF and P aeruginosa Settings: outpatients Intervention: inhaled tobramycin (TOBI®) (IV preparation) continuous twice‐daily 80 mg Comparison: TIS intermittent (4‐weekly on‐off cycles) twice‐daily 300 mg/5 mL
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Certainty of evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	TIS intermittent	Inhaled tobramycin (IV preparation) continuous
FEV₁ (% predicted): change from baseline Follow‐up: the end of the first treatment phase (12 weeks)	The change from baseline in FEV₁ % predicted was on average 1.07% less in the TIS group than in the inhaled tobramycin (IV preparation) group, values ranged from 11.20% less to 9.06% higher.		NA	32 (1)	⊕⊝⊝⊝ very low^a,b	Trial investigators provided individual participant data for lung function and we have analysed the first‐period data ourselves using the generic inverse variance method in RevMan.
FVC (% predicted): change from baseline Follow‐up: the end of the first treatment phase (12 weeks)	The change from baseline in FVC % predicted was on average 0.01% more in the TIS group than in the inhaled tobramycin (IV preparation) group, values ranged from 9.48% less to 9.50% higher.		NA	32 (1)	⊕⊝⊝⊝ very low^a,b	Trial investigators provided individual participant data for lung function and we have analysed the first‐period data ourselves using the generic inverse variance method in RevMan.
Pulmonary exacerbations Follow‐up: NA	Outcome not reported.				NA
Quality of life Follow‐up: NA	Outcome not reported.				NA
Survival Follow‐up: NA	Outcome not reported.				NA
Antibiotic resistance Follow‐up: NA	Outcome not reported.				NA
Adverse events Follow‐up: NA	Outcome not reported.				NA
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CF: cystic fibrosis; CI: confidence interval; FEV₁: forced expiratory volume at 1 second; FVC: forced vital capacity; IV: intravenous; NA: not applicable; *P aeruginosa* : Pseudomonas aeruginosa;TIS: tobramycin for inhalation solution.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded twice due to risk of bias being unclear or high across all the domains. The trial was at risk due to lack of blinding of participants or outcome measurement. This was because of the interventions being significantly different making it impossible to blind. Some outcomes (sputum bacteriology and oxygen saturation) were listed in the methods but not reported in the results. ^bDowngraded once due to imprecision. The sample size was small as only the first arm of a cross‐over trial was used.

Summary of findings 3. Summary of findings: inhaled TOBI® (IV preparation) versus tobramycin for inhalation solution

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Summary of findings 4. Summary of findings: tobramycin for inhalation powder versus tobramycin for inhalation solution

TIP compared with TIS for long‐term therapy in CF
Patient population: children and adults with CF and P aeruginosa Settings: outpatients Intervention: TIP twice‐daily 4 capsules (total of 112 mg) (3 cycles (28 days on‐drug, 28 days off‐drug)) Comparison: TIS twice‐daily 300 mg/5 mL
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Certainty of evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	TIS	TIP
FEV₁ (% predicted): relative change from baseline Follow‐up: 24 weeks	The MD between the 2 groups was 1.10 (95% CI ‐2.33 to 4.53) favouring TIS, but not significantly.		NA	517 (1)	⊕⊕⊕⊝ moderate^a	TIP was found to be non‐inferior to TIS.
FVC Follow‐up: NA	Outcome not reported.				NA
Pulmonary exacerbations: number of participants experiencing pulmonary exacerbation Follow‐up: 24 weeks	301 per 1000	337 per 1000 (259 to 436 per 1000)	RR 1.12 (0.86 to 1.45)	517 (1)	⊕⊕⊕⊝ moderate^a
Quality of life Follow‐up: NA	Outcome not reported.				NA
Survival: number of deaths Follow‐up: 24 weeks	Not calculable as there were no deaths in the TIS group. There were 3 deaths in the TIP group.		RR4.76 (0.25 to 91.62)	517 (1)	⊕⊕⊝⊝ low^a,b
Antibiotic resistance: mean change from baseline in P aeruginosa sputum density Follow‐up: 24 weeks	Mucoid and non‐mucoid P aeruginosa sputum densities showed a decrease from baseline in both groups at all time points. Mean change was ‐1.6 versus ‐0.92 log₁₀ CFU/g for mucoid phenotype and ‐1.77 versus ‐0.73 log₁₀ CFU/g for non‐mucoid phenotype.		NA	517 (1)	⊕⊕⊕⊝ moderate^a
Adverse events: number of any adverse event reported Follow‐up: 24 weeks	842 per 1000	901 per 1000 (842 to 968 per 1000)	RR 1.07 (1.00 to 1.15)	517 (1)	⊕⊕⊕⊝ moderate^a	A range of adverse events were reported but the only adverse events which were significantly different between the 2 groups were favouring TIS cough: RR 1.56 (95% CI 1.23 to 1.96) hoarseness: 3.56 (95% CI 1.71 to 7.43).
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CF: cystic fibrosis; CFU: colony forming units; CI: confidence interval; FEV₁ : forced expiratory volume at 1 second; FVC: forced vital capacity; MD: mean difference; NA: not applicable; *P aeruginosa* : Pseudomonas aeruginosa; RR: risk ratio; TIP: tobramycin inhalation powder TIS: tobramycin for inhalation solution.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded once due to risk of bias within the trial. This was an open‐label trial and so was at high risk of bias for blinding and had an unclear risk for randomisation and allocation concealment. ^bDowngraded once for imprecision due to low event rates.

Summary of findings 4. Summary of findings: tobramycin for inhalation powder versus tobramycin for inhalation solution

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Summary of findings 5. Summary of findings: aztreonam lysine for inhalation versus tobramycin for inhalation solution

AZLI compared with TIS for long‐term therapy in CF
Patient population: children and adults with CF and P aeruginosa Settings: outpatients Intervention: AZLI 75 mg 3 times daily Comparison: TIS 300 mg twice‐daily
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Certainty of evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	TIS	AZLI
FEV₁ (% predicted): mean relative change from baseline averaged across 3 cycles Follow‐up: 24 weeks	The MD between groups was ‐3.40 (95% CI ‐6.63 to ‐0.17), favouring AZLI.		NA	268 (1)	⊕⊕⊕⊝ moderate^a
FVC Follow‐up: NA	Outcome not reported.				NA
Pulmonary exacerbations: need for additional antibiotics Follow‐up: 24 weeks	576 per 1000	380 per 1000 (294 to 495 per 1000)	RR 0.66 (0.51 to 0.86)	268 (1)	⊕⊕⊕⊝ moderate^a
Quality of life: mean change from baseline in CFQ‐R respiratory symptom scale averaged across 3 cycles Follow‐up: 24 weeks	The mean (SD) change in CFQ‐R score was 2.2 (17.7) in the TIS group.	The mean change in CFQ‐R score in the AZLI group was 4.10 points higher (0.06 points lower to 8.26 points higher).	NA	268 (1)	⊕⊕⊕⊝ moderate^a
Survival Follow‐up: 24 weeks	See comments.			268 (1)	⊕⊕⊝⊝ low^a,b	2 participants died during the trial, but neither were related to treatment and the treatment group was not specified.
Antibiotic resistance: change from baseline in P aeruginosa CFU/g of sputum at week 24 Follow‐up: 24 weeks	The mean (SD) change in log₁₀ CFU/g was ‐0.32 (1.87) in the TIS group.	The mean change in log₁₀ CFU/g in the AZLI group was 0.23 lower (0.76 lower to 0.3 log₁₀ CFU/g higher).	NA	268 (1)	⊕⊕⊕⊝ moderate^a
Adverse events: number of treatment‐related adverse events Follow‐up: 24 weeks	129 per 1000	228 per 1000 (133 to 392 per 1000)	RR 1.77 (1.03 to 3.04)	268 (1)	⊕⊕⊕⊝ moderate^a	Whilst treatment‐related events were significantly more likely in the AZLI‐treated group P < 0.04), the difference in serious adverse events (also more likely in the AZLI group) did not quite reach significance. No significant difference was reported for any other reported adverse event.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AZLI: aztreonam lysine for inhalation; CFQ‐R: cystic fibrosis questionnaire ‐ revised; CF: cystic fibrosis; CFU: colony forming units; CI: confidence interval; FEV₁ : forced expiratory volume at 1 second; FVC: forced vital capacity; MD: mean difference; NA: not applicable; *P aeruginosa* : Pseudomonas aeruginosa;RR: risk ratio; SD: standard deviation; TIS: tobramycin for inhalation solution.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded once due to risk of bias within the trial. The trial was open‐label with the treatments given at a different frequency and so obvious to participants. There was also an unclear risk attributed to blinding of outcome assessment. ^bDowngraded once due to imprecision from low event rates.

Summary of findings 5. Summary of findings: aztreonam lysine for inhalation versus tobramycin for inhalation solution

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Summary of findings 6. Summary of findings: amikacin liposome inhalation suspension (ALIS) versus tobramycin for inhalation solution

ALIS compared with TIS for long‐term therapy in CF
Patient or population: children and adults with CF and P aeruginosa Settings: outpatients Intervention: ALIS 590 mg once daily with eFlow® nebuliser Comparison: TIS 300 mg twice daily via PARI LC® PLUS nebuliser
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Certainty of evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	TIS	ALIS
FEV₁ : LS mean FEV₁ (L) Follow‐up: 168 days	The difference in LS mean FEV₁ (L) adjusted for treatment and randomisation strata, at the end of treatment was MD –1.31% (95% CI, –4.95 to 2.34; P = 0.48).		NA	262 (1)	⊕⊕⊕⊝ moderate^a	This analysis was carried out on the per‐protocol data. The lower CI was above ‐5% indicating non‐inferiority of ALIS to TIS.
FVC Follow‐up: NA	Outcome not reported.				NA
Pulmonary exacerbations: frequency of pulmonary exacerbations Follow‐up: 168 days	There were more participants in the ALIS group experiencing an exacerbation than in the TIS group (63.5% in the ALIS group compared to 51.4% in the TIS group, P = 0.02).		NA	294 (1)	⊕⊕⊕⊝ moderate^a	The study also reported on hospitalisations and found that there was no difference, RR 0.82 (95% CI 0.50 to 1.33). Time to first exacerbation was also shorter in the ALIS group, HR 1.51 (95% CI 1.07 to 2.13) P = 0.03.
Quality of life: change in CFQ‐R domain scores (mean CFQ‐R score) Follow‐up: 168 days	There was no difference in change in CFQ‐R scores between groups at the end of the study across any domain.		NA	294 (1)	⊕⊕⊕⊝ moderate^a
Survival Follow‐up: NA	Outcome not reported.				NA	No deaths were reported in either group for the duration of the study (Bilton 2020).
Antibiotic resistance: change from baseline in P aeruginosa CFU/g of sputum density Follow‐up: 168 days	LS mean difference was no different between groups at the end of the study P = 0.13		NA	259 (1)	⊕⊕⊕⊝ moderate^a	The authors also report that mean P aeruginosa sputum densities were below baseline level at day 168 in both the ALIS group and the TIS group (Bilton 2020).
Adverse events: number of participants experiencing any TEAE Follow‐up: 168 days	788 per 1000	1000 per 1000 (638 to 1000 per 1000)	RR 1.47 (0.81 to 2.66)	294 (1)	⊕⊕⊕⊝ moderate^a	There were no differences between groups by severity of TEAE.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ALIS: amikacin liposome inhalation solution; CFU colony forming units; CF: cystic fibrosis; CFQ‐R: cystic fibrosis questionnaire ‐ revised; CI: confidence interval; FEV₁ : forced expiratory volume at 1 second; HR: hazard ratio; LS: least squares; MD: mean difference; NA: not applicable; *P aeruginosa* : Pseudomonas aeruginosa;RR: risk ratio; TEAE: treatment‐related adverse event; TIS: tobramycin for inhalation solution.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded once due to risk of bias within the trial being unclear or high across all domains, largely due to the trial being open label with unclear process for generation of sequence and allocation concealment.

Summary of findings 6. Summary of findings: amikacin liposome inhalation suspension (ALIS) versus tobramycin for inhalation solution

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Summary of findings 7. Summary of findings: levofloxacin for inhalation solution versus tobramycin for inhalation solution

LIS compared with TIS for long‐term therapy in CF
Patient population: adults and children aged over 12 with CF and P aeruginosa Settings: outpatients Intervention: LIS (Aeroquin™, MP376, APT‐1026) 240 mg (2.4 mL of 100 mg per mL solution) twice daily Comparison: TIS 300 mg/5 mL twice daily
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Certainty of evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	TIS	LIS
FEV₁ (% predicted): relative mean change from baseline Follow‐up: 6 months	The mean (SD) change in % predicted FEV₁ was ‐1.5 (14.8) in the TIS group.	The mean change in % predicted FEV₁ in the LIS group was 0.30 higher (3.02 lower to 3.62 higher).	NA	282 (1)	⊕⊕⊕⊕ high
FVC(% predicted): relative mean change from baseline Follow‐up: 6 months	The mean (SD) change in FVC % predicted was ‐1.3 (12.8) in the TIS group.	The mean change in FVC % predicted in the LIS group was 0.60 higher (2.23 lower to 3.43 higher).	NA	282 (1)	⊕⊕⊕⊕ high
Pulmonary exacerbations: number of hospitalisations due to respiratory exacerbations Follow‐up: 6 months	280 per 1000	173 per 1000 (112 to 274 per 1000)	RR 0.62 (0.40 to 0.98)	282 (1)	⊕⊕⊕⊕ high
Quality of life: change from baseline in CFQ‐R Follow‐up: 6 months	The trial reported that scores in the respiratory domain of the CFQ‐R were similar in the 2 groups at baseline, increased in the LIS group and decreased in the TIS group at day 28 and were similar again by the end of the trial.		NA	282 (1)	⊕⊕⊝⊝ low^a,b	No data could be entered into analysis.
Survival Follow‐up: NA	Outcome not reported.				NA
Antibiotic resistance: mean change in P aeruginosa sputum density (log₁₀ CFU/g) Follow‐up: 6 months	The mean (SD) sputum density in the TIS group was ‐0.25 (1.76) log₁₀ CFU/g.	The mean sputum density in the LIS group was 0.12 higher (0.31 log₁₀ CFU/g lower to 0.55 log₁₀ CFU/g higher).	NA	282 (1)	⊕⊕⊕⊕ high
Adverse events: number of treatment‐related adverse events Follow‐up: 6 months	Significantly fewer participants in the LIS group reported epistaxis, RR 0.2 (95% CI 0.04 to 1.00), general malaise, RR 0.1 (95% CI 0.01 to 0.83) and increased blood glucose, RR 0.28 (95% CI 0.08 to 0.94). Significantly more participants in the LIS group reported dysgeusia, RR 46.25 (95% CI 2.88 to 742). No other differences were noted.		NA	282 (1)	⊕⊕⊕⊕ high
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CF: cystic fibrosis; CFU: colony forming units; CI: confidence interval; FEV₁ : forced expiratory volume at 1 second; FVC: forced vital capacity; LIS: levofloxacin for inhalation solution; NA: not applicable; *P aeruginosa* : Pseudomonas aeruginosa;RR: risk ratio; TIS: tobramycin for inhalation solution.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded once due to indirectness. Quality of life was measured by the CFQ‐R score but no data were provided, just a summary. It is unclear which participants were included in this outcome. ^bDowngraded once due to publication bias as the results were not presented in full for this outcome.

Summary of findings 7. Summary of findings: levofloxacin for inhalation solution versus tobramycin for inhalation solution

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Summary of findings 8. Summary of findings: continuous cycles alternating aztreonam lysine for inhalation with tobramycin for inhalation solution versus continuous cycles alternating placebo with tobramycin for inhalation solution

Continuous AZLI/TIScompared with continuous placebo/TIS (i.e. intermittent TIS) for long‐term therapy in CF
Patient population: children and adults with CF and P aeruginosa Settings: outpatients Intervention: continuous alternating cycles of AZLI (75 mg (diluted in 0.17% NaCL) 3 times‐daily) and TIS (300 mg/5 mL twice‐daily) Comparison: alternating cycles of placebo (lactose monohydrate and sodium chloride reconstituted with the same diluent used for AZLI 3 times daily) and TIS (300 mg/5 mL twice‐daily)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Certainty of evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	TIS/placebo	AZLI/TIS
FEV₁ (% predicted): mean change from baseline (average values across the end of the 3 treatment cycles) Follow‐up: 6 months (24 weeks)	The change from baseline in FEV₁ % predicted was on average 1.33% more in the AZLI/TIS group than in the in the TIS/placebo group, values ranged from 0.51% lower to 3.17% higher.		NA	90 (1)	⊕⊕⊝⊝ low^a,b
FVC Follow‐up: NA	Outcome not reported.				NA
Pulmonary exacerbations: rate of PDEs per participant year Follow‐up: 24 weeks	489 per 1000	347 per 1000 (210 to 577 per 1000)	RR 0.71 (0.43 to 1.18)	90 (1)	⊕⊕⊝⊝ low^a,b	The rate of PDEs was lower in the AZLI/TIS group (1.31 PDEs per participant year) than in the placebo/TIS group (1.76 PDEs per participant year). The difference between the groups was not reported to be significant (P = 0.25, RR 0.74 (95% CI 0.45 to 1.24)).
Quality of life: CFQ‐R respiratory symptom scores averaged from weeks 4, 12 and 20 Follow‐up: 24 weeks	Scores improved by a mean (SE) 1.00 (1.74) in the AZLI/tobramycin group, they worsened by a mean (SE) ‐2.06 (1.63) in the placebo/TIS group. The difference between the groups was not found to be significant, MD 3.06 (95% CI ‐1.61 to 7.73).		NA	90 (1)	⊕⊕⊝⊝ low^a,b
Survival Follow‐up: NA	Outcome not reported.				NA
Antibiotic resistance: mean change from baseline in Paeruginosa sputum density (CFU/g) Follow‐up: 24 weeks	Adjusted mean changes from baseline sputum Paeruginosa density after each course of AZLI/placebo or TIS during the comparative phase were small (0.36 to ‐0.55 log₁₀ CFU/g) and differences between treatment groups were not statistically significant.		NA	87 (1)	⊕⊕⊝⊝ low^a,b	Results reported narratively from the paper.
Adverse events: any adverse event in the comparative phase Follow‐up: 24 weeks	978 per 1000	949 per 1000 (880 to 1000)	RR 0.97 (0.90 to 1.05)	88 (1)	⊕⊕⊝⊝ low^a,b	A range of adverse events were reported but the only adverse events which were significantly different between the 2 groups were: favouring continuous treatment dyspnoea: RR 0.59 (95% CI 0.35 to 1.01); decrease in exercise tolerance: RR 0.27 (95% CI 0.08 to 0.90); decreased appetite: RR 0.34 (95% CI 0.14 to 0.85) favouring intermittent treatment nasal congestion: RR 3.01 (95% CI 1.04 to 8.74).
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AZLI: inhaled aztreonam lysine; CF: cystic fibrosis;CFQ‐R: cystic fibrosis questionnaire ‐ revised; CFU: colony forming units; CI: confidence interval; FEV₁: forced expiratory volume at 1 second; FVC: forced vital capacity; MD: mean difference; NA: not applicable; PDE: protocol‐defined exacerbation; *P aeruginosa* : Pseudomonas aeruginosa;RR: risk ratio; SE: standard error; TIS: tobramycin for inhalation solution.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded once due to risk of bias being unclear across 5 of the domains around randomisation, allocation concealment, blinding of participants and incomplete outcome data. ^bDowngraded once due to imprecision as trial enrolment was limited and the trial was underpowered.

Summary of findings 8. Summary of findings: continuous cycles alternating aztreonam lysine for inhalation with tobramycin for inhalation solution versus continuous cycles alternating placebo with tobramycin for inhalation solution

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Table 1. Summary of excluded short‐term studies (28 days or longer)

Trial

Trial characteristics

Participants

Interventions

Summary of results

Dorkin 2015

Duration: 28 days.

Design: double‐blind, placebo‐controlled parallel RCT.

Location: multicentre ‐ 73 sites in 9 countries (USA, Australia and Europe).

Clinical trials identifier: NCT00645788

Number: estimated enrolment 245, 288 randomised but only 286 received 1 of the 4 treatments.

Age: 12 years and older (split children 12 ‐ 17 years and adults 18 years and over).

Gender: males or females.

Disease status: chronic colonisation with P aeruginosa, clinically stable.

Intervention 1: 32.5 mg ciprofloxacin betaine corresponding to 50 mg ciprofloxacin Pulmonsphere inhalation powder 2x daily.

Intervention 2: placebo (50 mg matching placebo powder formulation) 2x daily.

Intervention 3: 48.75 mg ciprofloxacin betaine corresponding to 75 mg ciprofloxacin Pulmonsphere inhalation powder 2x daily.

Intervention 4: placebo (75 mg matching placebo powder formulation) 2x daily.

Interventions 3 and 4 were introduced after amendment 2.

No significant difference in change in FEV₁ between ciprofloxacin dry powder inhalation at either dose (P = 0.154).

In pooled analyses, FEV₁ decline from baseline to treatment end was significantly lower with ciprofloxacin
DPI than with placebo (pooled data; P = 0.02).

There were positive effects on sputum bacterial load and quality of life which weren't maintained in the 4‐week follow‐up.

There were no significant
differences in type/incidence of treatment‐emergent
adverse events by treatment group (P = 0.115).

Dupont 2008

Duration: 28 days.

Design: placebo‐controlled phase IIa parallel RCT (stratified by baseline FEV₁ (% predicted) and randomised 2:1 to Arikace™ or placebo).

Location: multicentre ‐ 13 centres in Europe.

Number: 66 participants enrolled.

Age: 23 adults, 25 adolescents (13 ‐ 18 years) and 18 children (6 ‐ 12 years).

Gender: no details.

Disease status: chronic P aeruginosa infection; baseline FEV₁ (% predicted) 40 ‐ 75% in 43 participants; >75% in 23 participants.

Cohort 1: (n = 32) 280 mg Arikace™ or placebo (hypertonic saline solution (1.5% NaCl)) once daily.
Cohort 2: (n = 34) 560 mg Arikace™ or placebo (hypertonic saline solution (1.5% NaCl)) once daily.

Inhaled with PARI eFlow® nebuliser.

Relative change in FEV₁ was higher in the 560 mg group at day 28 (P = 0.033) compared to placebo.

The adverse event profile was similar among Arikace™ and placebo groups.

Galeva 2013

Duration: 28 days.

Design: placebo‐controlled parallel RCT.

Location: multicentre ‐ 17 centres in 8 countries.

Number: 62 randomised (target was 100).

Age: 6 to 21 years.

Gender: no details.

Disease status: diagnosed with CF by at least 1 clinical feature plus sweat test, FEV₁ of 25 ‐ 80% predicted.

Intervention 1: TIP (n = 32) 112 mg 2x daily.

Intervention 2: placebo (n = 30) 2x daily.

Mean treatment difference in absolute change in FEV₁ between TIP ‐ placebo was 4.4 % (P < 0.05).

Mean treatment difference in relative change in FEV₁ between TIP ‐ placebo was 5.9 % (P < 0.0.184).

TIP significantly reduced sputum density.

Geller 2011b

Duration: 28 days.

Design: double‐blind, placebo‐controlled parallel RCT (3 arms).

Location: multicentre ‐ 51 centres across USA and Europe.

Number: 151 randomised.

Age: mean age 29 years.

Gender: 85 males, 66 females.

Disease status: diagnosed CF, chronic P aeruginosa airways infection, FEV₁ between 25 ‐ 85% predicted, and 3 courses of inhaled antibiotics over the past 12 months.

Intervention 1: (n = 38) MP‐376 120 mg daily.

Intervention 2: (n = 37) MP‐376 240 mg daily.

Intervention 3: (n = 39) MP‐376 240 mg 2x daily.

Intervention 4: (n = 37) placebo.

Delivered by a customized investigational PARI eFlow nebulizer.

All doses of MP‐376 resulted in reduced sputum density at day 28 (240 mg twice a day showed a 0.96 log difference compared with placebo P = 0.001)

There was a dose‐dependent increase in FEV₁ for MP‐376. There was a difference of 8.7 % in FEV₁ between MP‐376 240 mg twice a day and placebo (P = 0.003).

There was a significant reduction in the need for other anti‐pseudomonal antibiotics compared to placebo.

Gibson 2003

Duration: 28 days.

Design: double‐blind, placebo‐controlled parallel RCT.

Early termination due to poor recruitment.

Number: 21 randomised (planned 98).

Age: 6 months ‐ 6 years.

Gender: 11 males, 10 females.

Disease status: positive P aeruginosa culture.

Intervention 1: (n = 8) tobramycin 300 mg 2x daily.

Intervention 2: (n = 13) placebo 2x daily.

There was a significant difference between treatment groups and placebo in the reduction in P aeruginosa density (no P aeruginosa was detected at day 28 in 8 out of 8 active group patients compared to 1 out of 13 placebo patients).

There were no significant differences between treatment groups for clinical indices or adverse events.

Goss 2013

Duration: 28 days (with 28‐day follow‐up).

Design: placebo‐controlled parallel phase 2 RCT (stratified by baseline FEV₁ (% predicted) and randomised 2:1 to Arikace™ or placebo).

Location: multicentre ‐ 18 centres across USA.

Number: 46 randomised.

Age: mean (SD)

Arikace™ 70 mg: 33.1 (9.7) years.

Arikace™ 140 mg: 35.4 (6.0) years.

Placebo 70 mg and 140 mg: 24.4 (6.3) years

Arikace™ 560 mg: 31.5 (14.5) years.

Placebo 560 mg: 26.3 (6.7) years.

Gender: 27 males, 19 females.

Disease status: Cohorts 1 and 2: baseline FEV₁ % predicted 40 ‐ 75% n = 16 and > 75% n = 5.

Cohort 3: baseline FEV₁ % predicted 40 ‐ 75% n = 19 and > 75% n = 6.

More details on lung function and BMI in supplementary papers

Arikace™ or placebo (hypertonic saline (1.5% NaCl).

Cohort 1: (n = 14) 70 mg Arikace™ or placebo 1x daily.

Cohort 2: (n = 12) 40 mg Arikace™ or placebo 1x daily.

Cohort 3: (n = 22) 560 mg Arikace™ or placebo 1x daily.

Inhaled using eFlow nebulizer system (PARI Pharma GmbH).

Follow‐up for 28 days after trial finish. Review of interim data in combination with data from similar European trial led to addition of Cohort 3 for a further 28 days with follow‐up of 56 days after trial finish.

Arikace™ was well tolerated at doses of 70 mg, 140 mg and 560 mg.

Hodson 2002

Duration: 28 days.

Design: open‐label parallel RCT (stratified by age and centre).
Location: multcentre.

Number: 126 randomised, 11 withdrew before treatment, 115 treated.

Age: range 7 ‐ 50 years.

Gender: males 45% of total.

Disease status: criteria for diagnosis abnormal sweat electrolytes, gene mutation.

Intervention 1: tobramycin 300 mg in 5 mL 2x daily, delivered by Pari LC plus nebuliser with CR50 compressor.

Intervention 2: colistin 1MU in 3 mL in saline 2x daily, delivered by Ventstream nebuliser with CR50 compressor.

Tobramycin significantly improved lung function (mean improvement in FEV₁ % predicted from baseline to week 4 was 6.7 % P = 0.006). The mean change in FEV₁ % predicted was not significant in the colistin group (0.37 %).

Both antibiotic regimes produced a significant decrease in sputum density, there was no development of highly resistant strains and the safety profile for both antibiotics was good.

Konstan 2010a

Duration: total of 24 weeks, 3 cycles each of 28 days on treatment followed by 28 days off treatment (only cycle 1 was double‐blind and randomised, cycles 2 and 3 were open‐label extension phases in which all participants received the same treatment).

Design: double‐blind, placebo‐controlled parallel RCT.

Location; multicentre ‐ 38 centres in Europe, Latin America and USA.

Clinical trials identifier: NCT00125346.

Known as the EVOLVE Trial.

Trial terminated after showing a statistically significant benefit of TIP.

Number: 102 randomised, 95 received intended treatment, unclear in which group 7 withdrawals were from.

Age: mean (SD): TIP 13.4 (4.42) years; placebo 13.2 (3.91) years.

Gender: 42 males, 53 females.

Disease status: baseline lung function (FEV₁ % predicted) (mean (SD)): TIP 54.7 (18.89)%; placebo 58.5 (20.03)%.

Intervention1: (n = 46) TIP 112 mg 2x daily.

Intervention 2: (n = 49) placebo 2x daily.

Cycle 1 (28 days on and 28 days off treatment or placebo).

Cycles 2 and 3: open‐label cycles of TIP for all participants.

TIP significantly improved FEV₁ % predicted from baseline to day 28 (difference 13.3, 95% CI 5.31 to 21.28 P = 0.0016).

TIP reduced sputum P aeruginosa density, respiratory related hospitalisation and anti‐pseudomonal antibiotic use.

The most common adverse event was cough but the frequency was higher in the placebo group (26.5 %) versus TIP (13.0%).

No evidence of ototoxicity or nephrotoxicity.

Lenoir 2007

Duration: 4 weeks followed by a 4‐week run‐out phase.

Design: double‐blind, placebo‐controlled parallel RCT.

Location: multicentre ‐ 13 sites in 4 countries.

Number: 59 participants.

Age: range 6 ‐ 30 years.

Gender: 32 males, 27 females.

Disease status: participants diagnosed with CF and P aeruginosa.

Intervention 1: tobramycin 300 mg (Bramitob®) 2x daily.

Intervention 2: placebo 2x daily.

Active drug and placebo both delivered by Pari LC Plus nebuliser and Pari TurboBoy compressor.

There was a significant increase in FEV₁ from baseline in the tobramycin group but not in the placebo group (absolute difference 13.3% P = 0.003). Similar improvements were also seen for FVC in the tobramycin group.

Adverse events were lower in the in the tobramycin group.

Microbiological outcomes were significantly improved.

Mainz 2014

Duration: 28 days.

Design: double‐blind placebo‐controlled parallel RCT.

Location: multicentre ‐ 2 centres in Germany (Jena and Tuebingen).

Number: 9 participants.

Age: mean (SD): 22.4 (7.6) years; range 10.6 to 38.7 years.

Gender: 6 males, 3 females.

Disease status: diagnosed with CF by 2 positive sweat tests or genetic analysis (or both) and with chronic P aeruginosa colonisation.

Intervention 1: 80 mg tobramycin daily.

Intervention 2: placebo (isotonic saline).

Sinonasal inhalation using PARI Sinus™ compressor with a PARI LC SPRINT STAR™ nebuliser. Drug administered to each nostril for 4 minutes with the other nostril occluded, maximum volume of 1 mL per nostril.

P aeruginosa quantity decreased in 4 out of 6 (67%) participants receiving tobramycin and in none of the placebo group.

Sinonasal inhalation was well tolerated.

Mazurek 2014

Duration: single cycle of 28 days on and 28 days off (8 weeks total duration).

Design: parallel RCT (non‐inferiority trial).

Location: multicentre ‐ 38 centres in Europe.

Clinical trials identifier: NCT00885365.

Follow‐on 48 week extension of TNS4 only: ClinicalTrials ID: NCT01111383.

Number: 406 individuals screened, 324 participants randomised.

Age: mean (SD): TNS4 15.89 (6.25) years; TNS5 15.58 (7.31) years.

Gender: no details.

Disease status: diagnosed with CF. Chronic P aeruginosa infection and FEV₁ ≥ 40% and ≤ 80% predicted.

Intervention 1: (n = 156) TNS4 (Bramitob®) 300 mg/4 mL 2x daily.

Intervention 2: (n = 168) TNS5 (TOBI®) 300 mg/5 mL 2x daily.

Both interventions delivered via PARI Boy N® compressor and the PARI LC Plus® nebuliser.

Other standard therapies allowed.

TNS4 showed similar short‐term clinical benefits to TNS5.

Adverse event reporting was similar between the 2 treatment groups.

McCoy 2008

Duration: 4 weeks.

Design: double‐blind, placebo‐controlled parallel RCT.

Location: multicentre ‐ 56 centres in USA.

Number: 246 participants randomised; 173 completed 28‐day treatment phase; and 90 completed open‐label follow‐up for 56 days.

Age: 7 to 65 years.

Gender: 121 males.

Disease status: documented diagnosis of CF and P aeruginosa, 3 or more courses of tobramycin in previous year, FEV₁ between 25 and 75% predicted.

Intervention 1: aztreonam 75 mg for 4 weeks, 2x or 3xdaily.

Intervention 2: placebo (5 mg lactose in 1mL 0.17% NaCl) for 4 weeks, 2x or 3x daily.

AZLI treatment increased the median time to need for additional anti‐pseudomonal antibiotics by 21 days compared to placebo (AZLI 92 days; placebo 71 days P = 0.007).

AZLI improved mean CFQ‐R respiratory scores (P = 0.02) and sputum density (P = 0.006.

Adverse events were reported in both groups but were consistent with CF lung disease.

Nasr 2006

Duration: 28 days.

Design: double‐blind, placebo‐controlled parallel RCT.

Location: single centre in USA.

Number: 32 people with CF (31 completed).

Age: mean (SD) and range ‐ TSI group 11.81 (7.46) years, 6.0 to 34.7 years; placebo group 15.86 (7.25) years, 7.4 to 28.8 years.

Gender: 12 males, 20 females ‐ TSI group 6 males and 10 females, placebo group 6 males and 10 females.

Disease status: CF diagnosis by sweat test or genotype testing. Colonised with P aeruginosa. Lung function FEV₁ % predicted mean (SD) and range: TSI group 95.73 (17.21)%, 55.0% to 134.1%; placebo group 83.71 (21.07)%, 45.0% to 108.73%.

Intervention 1: (n = 16) TSI 5 mL (solution of 300 mg tobramycin and 11.25 mg sodium chloride in sterile water) 2x daily.

Intervention 2: (n = 16) placebo (solution of 1.25 quinine sulphate in normal saline) 2x daily.

Interventions both administered using PARI LC Plus™ jet nebuliser and PulmoAide compressor.

% predicted FEV₁ increased slightly for both groups by mean (SD) 1.29 (3.33) for TSI and 1.17 (1.4) for placebo.

Ramsey 1993

Duration: 3x 28‐day periods (only results of first 28‐day parallel group comparison suitable for analysis).

Design: double‐blind placebo‐controlled 3‐period cross‐over RCT.

Number: 71 participants.

Age: mean (SD): 17.7 (1.25) years and 16.6 (1.24) years in 2 groups.

Gender: 37 males, 34 females.

Disease status: CF diagnosed by sweat test. Sputum culture of P aeruginosa susceptible to tobramycin. Mean baseline FEV₁ 55% (SE 3.7) and 60% (SE 3.2) predicted in 2 treatment arms.

Intervention 1: tobramycin 600 mg 3x daily for 28 days, then cross‐over for 2 further 28‐day periods.

Intervention 2: placebo (0.5 normal saline) 3x daily for 28 days, then cross‐over for 2 further 28‐day periods.

Delivered by Ultrasonic (Ultraneb 100/99) nebuliser with 30 mL solution and 200 inhalations.

In the first 28‐day period there was an increase in % predicted FEV₁ compared to placebo (P < 0.001) and FVC (P = 0.014).

There was a decrease in the density of P aeruginosa in sputum (P < 0.001).

Retsch‐Bogart 2007

Duration: 28 days.

Design: double‐blind, placebo‐controlled parallel Phase III RCT.

Location: multicentre: 53 centres in USA, Canada, Australia and New Zealand.

Clinical trials identifier:

NCT00112359.

Known as AIR‐CF1 Trial.

Number: 164 participants.

Age: mean (range)): AZLI 27.4 (7 – 54) years; placebo 31.7 (11 – 74) years.

Gender: 93 males, 71 females.

Disease status: stable condition. P aeruginosa in sputum or throat swab. No use of anti‐pseudomonal antibiotics in previous 14 days. Baseline lung function (FEV₁ % predicted) (mean (SD)): AZLI 54.4 (13.4)%; placebo 54.8 (14.0)%.

Intervention 1: AZLI 75 mg 3x daily.

Intervention 2: placebo 3x daily.

Doses administered at least 4 hours apart using PARI eFlow™ Electronic Nebuliser after pre‐treatment with bronchodilator.

Concommitant standard CF therapies allowed except anti‐pseudomonal antibiotics, azithromycin or hypertonic saline.

AZLI improved FEV₁ % predicted (P < 0.001), CFQ‐R respiratory score (P < 0.001) and sputum P aeruginosa density (P < 0.001) compared to placebo.

Adverse events were comparable between groups with the exception of productive cough. This outcome was reduced by half in AZLI‐treated participants.

Rietschel 2009

Duration: 20 weeks in total (8 weeks intervention 1, followed by 4 week washout, followed by 8 weeks intervention 2).

Design: cross‐over.

Location: multicentre in Germany.

Number: 35 stated as randomised in first abstract, but 29 randomised and 24/29 as having completed in second abstract.

Age: 6 years and over, mean (SD) age 19.8 (6.3) years, range 8 ‐ 35 years.

Disease status: chronically infected with P aeruginosa.

Intervention 1: continuous TIS 300 mg/d 1x daily.

Intervention 2: continuous TIS 300 mg/d 2x daily.

Mean FEV₁ was not markedly different between treatment periods or from baseline.

No audiological or nephrotoxic side effects were noted.

Once or twice daily dose was shown to be safe and tolerable.

Sands 2014

Duration: 3 months in total, but only 4 weeks taking each intervention (4 weeks intervention 1, 4 weeks washout period, 4 weeks intervention 2).

Design: Cross‐over.

Location: multicentre in Poland.

Number: 58 randomised, 54 in ITT population

Age: 4 years and older. Mean (SD) age 15.4 (6.81) years, range 7 to 36 years.

Gender: 25 males, 33 females.

Disease status: mean (SD) FEV₁ % predicted: VANTOBRA group 63.8 (17.1)%, range 30.0% to 82.8%; TIS group 64.2 (17.7)%, range 28.0% to 83.9%.

Intervention 1 (n = 28): T100 also known as VANTOBRA (170 mg tobramycin in 1.7 mL solution) via drug‐specific eFlow nebuliser Tolero with an eBase controller 2x daily.

Intervention 2 (n = 30): TOBI (300 mg tobramycin in 5 mL solution) via PARI LC Plus nebuliser with PARI BOY SX compressor 2x daily.

Treatment with both products were comparable in terms of clinical efficacy (reduction of P aeruginosa density and improvement in lung function.

Safety profiles were also comparable.

Trapnell 2012

Duration: 28 days.

Design: placebo‐controlled parallel RCT.

Location: multicentre ‐ 33 sites in the USA.

Number: 119 participants randomised.

Age: mean (SD)): FTI 80/20mg 35 (10.9) years; FTI 160/40mg 31 (10.2) years; placebo 31 (8.8) years.

Gender: 68 males, 51 females.

Disease status: lung function (FEV₁ % predicted) (mean (SD)): FTI 80/20mg 50 (13.4)%; FTI 160/40mg 21 (51)%; placebo 48 (13.6)%.

Intervention 1: (n = 38) FTI 80/20 mg 2x daily.

Intervention 2: (n = 41) FTI 160/40 mg 2x daily.

Intervention 3: (n = 40) placebo 2x daily.

Improvements in mean FEV₁ % predicted achieved in the AZLI run‐in period were maintained in the FTI group compared with placebo (P = 0.002).

The treatment effect on P aeruginosa sputum density significantly favoured FTI compared to placebo.

Respiratory symptoms were less common in the FTI group.

Wainwright 2011

Duration: 28 days.

Design: placebo‐controlled parallel RCT.

Location: multicentre ‐ 40 centres in USA, Canada and Australia.

Number: 160 people randomised, 157 received treatment.

Age: mean (SD): AZLI 19.5 (9.1) years; placebo 18.9 (9.1) years.

Gender: 90 males, 70 females.

Disease status: FEV₁ % predicted: AZLI 95.5 (12.7)%; placebo 94.7 (12.9)%.

Intervention 1: (n = 76; 75 analysed, 1 discontinued trial) AZLI (75 mg aztreonam, 52.5 mg lysine monohydrate diluted in 0.17% saline (1 mL)) 3x daily.

Intervention 2: (n = 81) placebo (5 mg lactose, 7.3 mg NaCl diluted in 0.17% saline (1 mL)) 3x daily.

Both interventions self‐administered with the investigational eFlow® electronic nebulizer (PARI GmbH, Starnberg, Germany).

Treatment effect at 28 days for relative FEV₁ % predicted was 2.7 % (P = 0.021 favouring AZLI).

Treatment effect for CFQ‐R respiratory symptom score at day 28 was modest at 1.8 points (95% CI ‐2.8 to 6.4 P = 0.443).

Sputum density was improved in the AZLI group (P = 0.016).

AZLI: aztreonam lysine for inhalation.
CF: cystic fibrosis.
FEV₁: forced expiratory volume in one second.
FTI: fosfomycin/tobramycin for inhalation.
ITT: intention to treat.
P aeruginosa: Pseudomonas aeruginosa.
RCT: randomised controlled trial.
SD: standard deviation.
SE: standard error.
TIP: tobramycin inhalation powder.

Table 1. Summary of excluded short‐term studies (28 days or longer)

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Comparison 1. Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Mean absolute FEV₁ (% predicted) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.1.1 At 3 months	1	29	Mean Difference (IV, Fixed, 95% CI)	‐2.00 [‐22.41, 18.41]
1.1.2 Over 3 months and up to 12 months	1	245	Mean Difference (IV, Fixed, 95% CI)	3.10 [‐2.35, 8.55]
1.2 Mean change in FEV₁ (% predicted) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.2.1 At 3 months	1	29	Mean Difference (IV, Fixed, 95% CI)	6.00 [‐1.07, 13.07]
1.3 Mean change in % predicted FEV₁ Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.3.1 Over 3 months and up to 12 months	1		Mean Difference (IV, Fixed, 95% CI)	6.38 [2.94, 9.82]
1.4 Rate of change of FEV₁ (% predicted per year) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.4.1 Over 24 months and up to 36 months	1	27	Mean Difference (IV, Fixed, 95% CI)	7.80 [3.29, 12.31]
1.5 Mean absolute FVC (% predicted) at end of treatment Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.5.1 At 1 to 3 months	1	29	Mean Difference (IV, Fixed, 95% CI)	8.00 [‐12.18, 28.18]
1.6 Mean change in FVC (% predicted) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.6.1 At 1 to 3 months	1	29	Mean Difference (IV, Fixed, 95% CI)	11.00 [1.94, 20.06]
1.6.2 Over 3 months and up to 12 months	1	245	Mean Difference (IV, Fixed, 95% CI)	4.60 [1.01, 8.19]
1.7 Rate of change of FVC (% predicted per year) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.7.1 Over 24 months and up to 36 months	1	27	Mean Difference (IV, Fixed, 95% CI)	5.40 [0.86, 9.94]
1.8 Frequency of one or more hospital admissions Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.8.1 Over 3 months and up to 12 months	3	946	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.47, 0.93]
1.8.2 Over 12 months and up to 24 months	1	181	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.34, 1.05]
1.8.3 Over 24 months and up to 36 months	1	27	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.39, 1.65]
1.9 Hospital admissions, mean number of days in hospital Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.9.1 Over 24 months and up to 36 months	1	27	Mean Difference (IV, Fixed, 95% CI)	‐3.20 [‐9.04, 2.64]
1.10 Frequency of one or more courses of intravenous antibiotics Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.10.1 Over 3 months and up to 12 months	2	765	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.67, 0.88]
1.10.2 Over 12 months and up to 24 months	1	175	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.35, 1.08]
1.11 Pulmonary exacerbations Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.11.1 Over 3 months and up to 12 months	1	245	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.59, 1.03]
1.12 Lost school or working days Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.12.1 Over 3 months and up to 12 months	1	245	Mean Difference (IV, Fixed, 95% CI)	‐5.30 [‐8.59, ‐2.01]
1.13 Deaths Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.13.1 Over 3 months and up to 12 months	2	767	Risk Ratio (M‐H, Fixed, 95% CI)	0.17 [0.03, 1.09]
1.13.2 Over 24 months and up to 36 months	1	27	Risk Ratio (M‐H, Fixed, 95% CI)	0.27 [0.01, 6.11]
1.14 Frequency of tobramycin‐resistant P. aeruginosa at end of study Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.14.1 Over 3 months and up to 12 months	2	672	Risk Ratio (M‐H, Random, 95% CI)	1.95 [0.86, 4.42]
1.14.2 Over 24 months and up to 36 months	1	26	Risk Ratio (M‐H, Random, 95% CI)	7.80 [0.46, 131.62]
1.15 Frequency of new isolates of drug resistant organisms (at end of study) Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.15.1 Burkholderia cepacia	2	536	Risk Ratio (M‐H, Fixed, 95% CI)	0.26 [0.03, 1.99]
1.15.2 Stenotrophomonas maltophilia	1	520	Risk Ratio (M‐H, Fixed, 95% CI)	3.05 [0.32, 29.10]
1.15.3 Alcaligenes xylosoxidans	1	520	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.06, 16.15]
1.15.4 Aspergillus species	1	389	Risk Ratio (M‐H, Fixed, 95% CI)	2.12 [1.29, 3.46]
1.16 Number experiencing adverse event (at end of study) Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.16.1 Auditory impairment	4	540	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
1.16.2 Tinnitus	1	520	Risk Ratio (M‐H, Random, 95% CI)	17.26 [1.00, 297.54]
1.16.3 Voice alteration	2	701	Risk Ratio (M‐H, Random, 95% CI)	2.66 [1.14, 6.25]
1.16.4 Pneumothorax	1	520	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.03, 2.26]
1.16.5 Hemoptysis	1	520	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.66, 1.13]

Comparison 1. Inhaled anti‐pseudomonal antibiotic (IAPA) versus placebo

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Comparison 2. Colistimethate sodium dry powder (CDPI) versus tobramycin for inhalation solution (TIS)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Number of pulmonary exacerbations Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.1.1 Over 3 months and up to 12 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.2 Time to first pulmonary exacerbation Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.2.1 Over 3 months and up to 12 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.3 Deaths Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.3.1 Over 3 months and up to 12 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.4 Adverse events (at end of study) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.4.1 Total adverse events	1	379	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.99, 1.12]
2.4.2 Treatment‐related adverse events	1	379	Risk Ratio (M‐H, Fixed, 95% CI)	1.76 [1.50, 2.08]
2.4.3 Mild adverse events	1	379	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.92, 1.09]
2.4.4 Moderate adverse events	1	379	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [1.11, 1.57]
2.4.5 Severe adverse events	1	379	Risk Ratio (M‐H, Fixed, 95% CI)	3.83 [2.15, 6.83]

Comparison 2. Colistimethate sodium dry powder (CDPI) versus tobramycin for inhalation solution (TIS)

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Comparison 3. Inhaled TOBI® (IV preparation) versus tobramycin for inhalation solution (TIS)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 FEV₁ % predicted Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

3.1.1 At 1 to 3 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.2 FVC Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

3.2.1 At 1 to 3 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 3. Inhaled TOBI® (IV preparation) versus tobramycin for inhalation solution (TIS)

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Comparison 4. Tobramycin inhalation powder (TIP) versus tobramycin for inhalation solution (TIS)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 FEV₁ (% predicted) relative change Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

4.1.1 Over 3 months and up to 12 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.2 Hospitalisations Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4.2.1 Over 3 months and up to 12 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.3 Pulmonary exacerbations Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4.3.1 Over 3 months and up to 12 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.4 Deaths Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4.5 Adverse events (at end of study) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4.5.1 Any adverse event	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.2 Bronchospasm	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.3 Cough	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.4 Productive cough	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.5 Dyspnoea	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.6 Pyrexia	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.7 Oropharyngeal pain	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.8 Dysphonia (hoarseness)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.9 Haemoptysis	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.10 Headache	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.11 Nasal congestion	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.12 Nausea	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.13 Rales	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.14 Rhinorrhea	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.15 Pulmonary function test decreased	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.16 Upper respiratory tract infection	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.17 Wheezing	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.18 Chest discomfort	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.19 Fatigue	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.20 Vomiting	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.21 Sinusitis	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.5.22 Pulmonary congestion	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 4. Tobramycin inhalation powder (TIP) versus tobramycin for inhalation solution (TIS)

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Comparison 5. Inhaled aztreonam lysine (AZLI) versus tobramycin for inhalation solution (TIS)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 FEV₁ % predicted ‐ mean relative change from baseline Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5.1.1 At Week 24 (average across 3 cycles)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.2 FEV₁ % predicted ‐ mean actual change from baseline Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5.2.1 At Week 24 (averaged across 3 cycles)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.3 Need for additional antibiotics Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5.3.1 At Week 24	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5.4 Number of days of additional antibiotics Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5.4.1 At Week 24	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.5 Weight (relative change from baseline) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5.5.1 At Week 24	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.6 Quality of Life ‐ CFQR respiratory symptom scale Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5.6.1 At Week 24 (average across 3 cycles)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.7 TSQM ‐ effectiveness Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5.7.1 At week 24 (average across 3 cycles)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.8 TSQM ‐ global satisfaction Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5.8.1 At Week 24	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.9 TSQM ‐ side effects Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5.9.1 At Week 24	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.10 TSQM ‐ convenience Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5.10.1 At Week 24	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.11 Log₁₀Pseudomonas aeruginosa CFU/g sputum Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5.11.1 At Week 24 (average across 3 cycles)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5.12 Adverse events (at end of study) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.12.1 Treatment‐related adverse events	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	1.77 [1.03, 3.04]
5.12.2 Serious adverse events	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	1.94 [0.98, 3.84]
5.12.3 Cough	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.78, 1.03]
5.12.4 Productive cough	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.69, 1.07]
5.12.5 Pyrexia	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.73, 1.49]
5.12.6 Oropharyngeal pain	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.64, 1.40]
5.12.7 Dyspnoea	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.57, 1.30]
5.12.8 Haemoptysis	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.87, 2.36]
5.12.9 Rales	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.54, 1.27]
5.12.10 Headache	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.65, 1.66]
5.12.11 Nasal congestion	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.68, 1.74]
5.12.12 Rhinorrhea	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.46, 1.17]
5.12.13 Exercise tolerance decreased	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.55, 1.46]
5.12.14 Fatigue	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.56, 1.55]
5.12.15 Decreased appetite	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.54, 1.75]
5.12.16 Abdominal pain	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	2.18 [0.98, 4.85]
5.12.17 Respiratory tract congestion	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.44, 1.52]
5.12.18 Wheezing	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.42, 1.43]
5.12.19 Chest discomfort	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.51, 2.14]
5.12.20 Nausea	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	1.36 [0.63, 2.95]
5.12.21 Vomiting	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.48, 1.96]
5.12.22 Pulmonary function decreased	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.31, 1.29]
5.12.23 Breath sounds abnormal	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.23, 1.18]

Comparison 5. Inhaled aztreonam lysine (AZLI) versus tobramycin for inhalation solution (TIS)

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Comparison 6. Amikacin liposome inhalation suspension (ALIS) versus TOBI®

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Hospitalisations ‐ number of participants hospitalised (all‐cause) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.2 Change from baseline in CFQ‐R domain scores Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6.2.1 Respiratory domain	1	294	Mean Difference (IV, Fixed, 95% CI)	‐0.06 [‐4.55, 4.43]
6.2.2 Body image domain	1	294	Mean Difference (IV, Fixed, 95% CI)	1.16 [‐4.54, 6.86]
6.2.3 Digestive domain	1	294	Mean Difference (IV, Fixed, 95% CI)	1.15 [‐3.51, 5.81]
6.2.4 Eating disturbances domain	1	294	Mean Difference (IV, Fixed, 95% CI)	‐2.41 [‐6.50, 1.68]
6.2.5 Emotions domain	1	294	Mean Difference (IV, Fixed, 95% CI)	0.22 [‐2.95, 3.39]
6.2.6 Energy and wellbeing	1	294	Mean Difference (IV, Fixed, 95% CI)	1.15 [‐3.91, 6.21]
6.2.7 Health perception domain	1	294	Mean Difference (IV, Fixed, 95% CI)	2.05 [‐2.91, 7.01]
6.2.8 Physical domain	1	294	Mean Difference (IV, Fixed, 95% CI)	‐1.44 [‐6.66, 3.78]
6.2.9 Role limitations domain	1	294	Mean Difference (IV, Fixed, 95% CI)	0.55 [‐4.86, 5.96]
6.2.10 Social limitations domain	1	294	Mean Difference (IV, Fixed, 95% CI)	‐1.12 [‐4.79, 2.55]
6.2.11 Treatment burden domain	1	294	Mean Difference (IV, Fixed, 95% CI)	0.35 [‐4.10, 4.80]
6.3 Treatment‐emergent adverse events (TEAEs) Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.3.1 Number of participants with any TEAE	1	294	Odds Ratio (M‐H, Fixed, 95% CI)	1.47 [0.81, 2.66]
6.3.2 Participants experiencing a mild TEAE	1	294	Odds Ratio (M‐H, Fixed, 95% CI)	1.04 [0.64, 1.68]
6.3.3 Participants experienciing a moderate TEAE	1	294	Odds Ratio (M‐H, Fixed, 95% CI)	1.06 [0.67, 1.69]
6.3.4 Participants experiencing a severe TEAE	1	294	Odds Ratio (M‐H, Fixed, 95% CI)	2.26 [0.77, 6.69]
6.3.5 Participants experiencing treatment‐emergent SAEs	1	294	Odds Ratio (M‐H, Fixed, 95% CI)	0.86 [0.48, 1.55]

Comparison 6. Amikacin liposome inhalation suspension (ALIS) versus TOBI®

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Comparison 7. Levofloxacin for inhalation solution (LIS) versus tobramycin for inhalation solution (TIS)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Absolute change in FEV₁ % predicted Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

7.1.1 At three months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.1.2 Over 3 months and up to 12 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.2 Relative change in FEV₁ % predicted Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

7.2.1 At three months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.2.2 Over 3 months and up to 12 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.3 Absolute change in FVC % predicted Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

7.3.1 At three months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.3.2 Over 3 months and up to 12 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.4 Relative change in FVC % predicted Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

7.4.1 At three months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.4.2 Over 3 months and up to 12 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.5 Hospitalisations due to respiratory exacerbations Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

7.5.1 Over 3 months and up to 12 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.6 Weight decrease Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

7.6.1 Over 3 months and up to 12 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.7 Change in P aeruginosa sputum density (log₁₀ CFU/g) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

7.7.1 Over 3 months and up to 12 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7.8 Adverse events (at end of study) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

7.8.1 Cough	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.2 Increased sputum	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.3 Respiratory tract congestion	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.4 Increased viscosity of bronchial secretions	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.5 Paranasal sinus hypersecretion	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.6 Haemoptysis	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.7 Discoloured sputum	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.8 Exertional dyspnoea	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.9 Rales	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.10 Dyspnoea	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.11 Oropharyngeal pain	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.12 Epistaxis	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.13 Disease progression	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.14 Fatigue	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.15 Decreased exercise tolerance	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.16 Pyrexia	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.17 Malaise	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.18 Increase in blood glucose	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.19 Dysgeusia	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.20 Sinus headache	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.21 Headache	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.22 Nasopharyngitis	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.23 Sinusitis	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.24 Upper respiratory tract infection	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.25 Abdominal pain	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.26 Nausea	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.27 Arthralgia	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.28 Decreased appetite	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.8.29 Rash	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 7. Levofloxacin for inhalation solution (LIS) versus tobramycin for inhalation solution (TIS)

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Comparison 8. Continuous aztreonam (AZLI)/tobramycin (TIS) versus intermittent tobramycin (TIS)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Mean change from baseline ‐ FEV₁ % predicted Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

8.1.1 Over 3 months and up to 12 months (values from end of 3 cycles averaged)	1		Mean Difference (IV, Fixed, 95% CI)	1.33 [‐0.51, 3.17]
8.2 Rate of hospitalisation per participant year Show forest plot	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.35, 1.11]

8.2.1 Over 3 months and up to 12 months	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.35, 1.11]
8.3 Need for additional antibiotics for an exacerbation Show forest plot	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.59, 1.32]

8.3.1 Over 3 months and up to 12 months	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.59, 1.32]
8.4 Rate of protocol defined pulmonary exacerbations per participant year Show forest plot	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.43, 1.18]

8.4.1 Over 3 months and up to 12 months	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.43, 1.18]
8.5 Quality of life ‐ CFQ‐R respiratory symptom score Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	3.06 [‐1.61, 7.73]

8.5.1 Over 3 months and up to 12 months	1		Mean Difference (IV, Fixed, 95% CI)	3.06 [‐1.61, 7.73]
8.6 Incidence of other respiratory pathogens (at end of study) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

8.6.1 P aeruginosa	1	87	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.94, 1.06]
8.6.2 Achromobacter species	1	87	Risk Ratio (M‐H, Fixed, 95% CI)	1.29 [0.42, 3.90]
8.6.3 Stenotrophomonas maltophilia	1	87	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.40, 1.90]
8.6.4 Aspergillus spp.	1	87	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.35, 1.22]
8.6.5 MRSA	1	87	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.35, 1.22]
8.6.6 Burkholderia spp.	1	87	Risk Ratio (M‐H, Fixed, 95% CI)	3.21 [0.13, 76.67]
8.6.7 MSSA	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.35, 1.33]
8.7 Adverse events (at end of study) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

8.7.1 Any comparative phase adverse event	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.90, 1.05]
8.7.2 Adverse events grade 1‐2 severity	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.23, 5.13]
8.7.3 Adverse events grade 3‐4 severity	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.54, 1.91]
8.7.4 Serious adverse events	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.64, 1.44]
8.8 Treatment‐emergent adverse events (at end of study) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

8.8.1 Cough	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.83, 1.36]
8.8.2 Sputum increased	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.49, 1.03]
8.8.3 Dyspnoea	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.35, 1.01]
8.8.4 Fatigue	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.38, 1.33]
8.8.5 Haemoptysis	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.53, 2.26]
8.8.6 Nasal congestion	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	3.01 [1.04, 8.74]
8.8.7 Pulmonary function test decreased	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.57, 2.54]
8.8.8 Respiratory tract congestion	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.53, 2.26]
8.8.9 Infective pulmonary exacerbation of CF	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	2.19 [0.82, 5.89]
8.8.10 Lung disorder	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.36, 1.59]
8.8.11 Wheezing	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.48, 2.50]
8.8.12 Chest discomfort	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.31, 1.46]
8.8.13 Pyrexia	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.31, 1.46]
8.8.14 Headache	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.38, 2.41]
8.8.15 Diarrhoea	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [0.43, 3.99]
8.8.16 Nausea	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.26, 1.65]
8.8.17 Oropharyngeal pain	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [0.43, 3.99]
8.8.18 Decreased Appetite	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.14, 0.85]
8.8.19 Dyspnoea exertional	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	2.74 [0.56, 13.37]
8.8.20 Rhinorrhoea	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.24, 1.93]
8.8.21 Sputum discoloured	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	1.83 [0.46, 7.18]
8.8.22 Vomiting	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.22, 1.67]
8.8.23 Chest pain	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.20, 1.99]
8.8.24 Weight decreased	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.25, 3.05]
8.8.25 Chills	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.17, 2.58]
8.8.26 Exercise tolerance decreased	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	0.27 [0.08, 0.90]
8.8.27 Sinus congestion	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.13, 1.70]

Comparison 8. Continuous aztreonam (AZLI)/tobramycin (TIS) versus intermittent tobramycin (TIS)

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Inhaled anti‐pseudomonal antibiotics for long‐term therapy in cystic fibrosis

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