Head‐to‐head trials of antibiotics for bronchiectasis

Axel Kaehne; Stephen J Milan; Lambert M Felix; Emer Sheridan; Paul A Marsden; Sally Spencer

doi:10.1002/14651858.CD012590.pub2

Cochrane Database of Systematic Reviews

Head‐to‐head trials of antibiotics for bronchiectasis

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DOI:

https://doi.org/10.1002/14651858.CD012590.pub2 Copy DOI

Database:

Cochrane Database of Systematic Reviews

Version published:

05 September 2018see what's new

Type:

Intervention

Stage:

Review

Cochrane Editorial Group:

Cochrane Airways Group

Copyright:

Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Authors

Axel Kaehne

EPRC, Faculty of Health and Social Care, Edge Hill University, Ormskirk, UK
Stephen J Milan

Medical School, Lancaster University, Lancaster, UK
Lambert M Felix

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Oxford, UK
Emer Sheridan

Pharmacy, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK
Paul A Marsden

Department of Respiratory Medicine, Lancashire Teaching Hospitals Trust, Preston, UK

Faculty of Health and Medicine, Lancaster University, Lancaster, UK
Sally Spencer

Correspondence to: Postgraduate Medical Institute, Edge Hill University, Ormskirk, UK

[email protected]

Contributions of authors

All protocol authors contributed to the Background section. SJM, SS, LF, and PM contributed to the Methods section.

ES and LF screened the searches; AK and LF extracted data and completed the risk of bias assessment; LF transferred data to Review Manager; LF and SS undertook data analysis; AK, LF, and SS completed the results section; and all review authors contributed to the Discussion and Authors' conclusions.

Sources of support

Internal sources

Edge Hill University, Other.

Funded SS to provide support for a series of reviews on bronchiectasis

External sources

The authors declare that no external funding was received for this systematic review, Other.

Declarations of interest

SS: lead applicant on a grant from Edge Hill University that provided support to LF for several bronchiectasis reviews. She is also an editor with the Cochrane Airways Group.

AK: none known.

SJM: none known.

LF: none known.

ES: none known.

PM: received lecture fees and conference accommodations/fees from industry unrelated to the current review.

Acknowledgements

We thank Edge Hill University and the Cochrane Airways Group for their support.

We also thank Haley Harrison (HH) for searching trial registries. HH was an NIHR intern based at the Postgraduate Medical Institute, Edge Hill University.

Rebecca Normansell was the Editor for this protocol and commented critically on the document.

The Background and Methods section of this protocol are based on a standard template used by Cochrane Airways.

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

Version history

Published

Title

Stage

Authors

Version

2018 Sep 05

Head‐to‐head trials of antibiotics for bronchiectasis

Review

Axel Kaehne, Stephen J Milan, Lambert M Felix, Emer Sheridan, Paul A Marsden, Sally Spencer

https://doi.org/10.1002/14651858.CD012590.pub2

2017 Mar 13

Head‐to‐head trials of antibiotics for non‐cystic fibrosis bronchiectasis

Protocol

Axel Kaehne, Stephen J Milan, Lambert M Felix, Sally Spencer, Emer Sheridan, Paul A Marsden

https://doi.org/10.1002/14651858.CD012590

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Adult; Child; Humans;

PICOs

Population

Intervention

Comparison

Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

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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Analysis 1.1

Comparison 1 Fluoroquinolones versus β‐lactam (amoxicillin), Outcome 1 Response rate ‐ treatment failure.

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Analysis 1.2

Comparison 1 Fluoroquinolones versus β‐lactam (amoxicillin), Outcome 2 Response rate ‐ microbiological response: patients with organisms eliminated.

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Analysis 1.3

Comparison 1 Fluoroquinolones versus β‐lactam (amoxicillin), Outcome 3 Response rate ‐ improvement in sputum purulence (excellent).

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Analysis 1.4

Comparison 1 Fluoroquinolones versus β‐lactam (amoxicillin), Outcome 4 Response rate ‐ improvement in sputum purulence (fair).

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Analysis 1.5

Comparison 1 Fluoroquinolones versus β‐lactam (amoxicillin), Outcome 5 Response rate ‐ relapse of sputum purulence at 3‐month follow‐up.

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Analysis 1.6

Comparison 1 Fluoroquinolones versus β‐lactam (amoxicillin), Outcome 6 Sputum volume (change mL).

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Analysis 1.7

Comparison 1 Fluoroquinolones versus β‐lactam (amoxicillin), Outcome 7 FEV1 % predicted (change).

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Analysis 2.1

Comparison 2 Polymyxins versus aminoglycosides, Outcome 1 Response rate ‐ improvement in sputum purulence.

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Analysis 2.2

Comparison 2 Polymyxins versus aminoglycosides, Outcome 2 Response rate ‐ P aeruginosa eradication.

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Analysis 2.3

Comparison 2 Polymyxins versus aminoglycosides, Outcome 3 Sputum purulence ‐ improvement in score at 3 months.

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Analysis 2.4

Comparison 2 Polymyxins versus aminoglycosides, Outcome 4 Adverse events.

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Summary of findings for the main comparison. Fluoroquinolones compared to amoxicillin for bronchiectasis

Fluoroquinolones compared to amoxicillin for bronchiectasis: short‐term studies (< 4 weeks)
Patient or population: adults aged 18 years and above with diagnosis of non‐cystic fibrosis bronchiectasis Setting: hospital, Hong Kong Intervention: fluoroquinolones (Chan 1996: ciprofloxacin, 500 mg, oral, twice daily, 7 days; Lam 1989: ofloxacin, 200 mg, oral, thrice daily, 10 days) Comparison: amoxicillin (Chan 1996: 1000 mg, oral, 3 times per day, 7 days; Lam 1989: 1000 mg, oral, 3 times per day, 10 days)
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with amoxicillin	Risk with fluoroquinolones	Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Exacerbations	‐	‐	Not estimable	‐	‐	Outcome not reported in included studies
Serious adverse events	0 per 1000	0 per 1000 (0 to 0)	Not estimable	83 (2 RCTs)	⊕⊕⊝⊝ LOW^a,b	Evidence graded on the overall quality of the study
Response rate ‐ treatment failure	429 per 1000	50 per 1000 (7 to 194)	OR 0.07 (0.01 to 0.32)	83 (2 RCTs)	⊕⊕⊝⊝ LOW^a,b
Response rate ‐ microbiological response	2 out of 8 participants responded.	8 out of 8 participants responded.	Peto OR 20.09 (2.83 to 142.59)	16 (1 RCT)	⊕⊕⊝⊝ LOW^a,b	Small single study. Peto OR used owing to 100% response in intervention arm
Response rate ‐ improvement in sputum purulence (excellent)	357 per 1000	566 per 1000 (348 to 761)	OR 2.35 (0.96 to 5.72)	83 (2 RCTs)	⊕⊝⊝⊝ VERY LOW^a,b,c
Deaths	0 per 1000	0 per 1000 (0 to 0)	Not estimable	83 (2 RCTs)	⊕⊕⊝⊝ LOW^a,b	No deaths reported. Evidence graded on the overall quality of the study
Quality of life	‐	‐	Not estimable	‐	‐	Outcome not reported in included studies
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial.
GRADE Working Group grades of evidence. High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: 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 quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aOne point deducted in relation to design and implementation of available studies suggesting likelihood of bias (unclear generation of randomisation sequence, potential selective reporting bias, and risk of other bias in Lam 1989). ^bOne point deducted for imprecision (small sample size and few events). ^cOne point deducted for imprecision (wide confidence interval).

Summary of findings for the main comparison. Fluoroquinolones compared to amoxicillin for bronchiectasis

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Summary of findings 2. Polymyxins compared to aminoglycosides for bronchiectasis

Polymyxins compared to aminoglycosides for bronchiectasis: long‐term studies (≥ 4 weeks)
Patient or population: adults aged 18 years and above with diagnosis of bronchiectasis Setting: not reported Intervention: polymyxins (Dimakou 2014: 300 mg, inhalation using Pari LC Plus jet nebulizer, twice daily, 4 weeks; Kaponi 2017: 300 mg, inhalation using Pari LC Plus jet nebulizer, twice daily, 3 months) Comparison: aminoglycosides (Dimakou 2014: 1 MU, inhalation using Pari LC Plus jet nebulizer, twice daily, 4 weeks; Kaponi 2017: 1 MU, inhalation using Pari LC Plus jet nebulizer, twice daily, 3 months)
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with aminoglycosides	Risk with polymyxins	Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Exacerbation	‐	‐	Not estimable	‐	‐	Outcome not reported in included studies
Serious adverse events	0 per 1000	0 per 1000 (0 to 0)	Not estimable	20 (1 RCT)	⊕⊝⊝⊝ VERY LOW^a,b,c	Evidence graded on the overall quality of the study
Response rate ‐ improvement in sputum purulence	800 per 1000	390 per 1000 (38 to 939)	OR 0.16 (0.01 to 3.85)	20 (1 RCT)	⊕⊝⊝⊝ VERY LOW^a,b,d	Definition of improvement not reported
Response rate ‐ P aeruginosa eradication	471 per 1000	554 per 1000 (242 to 826)	OR 1.40 (0.36 to 5.35)	35 (1 RCT)	⊕⊝⊝⊝ VERY LOW^a,b,d	Head‐to‐head comparison not reported directly
Deaths	0 per 1000	0 per 1000 (0 to 0)	Not estimable	20 (1 RCT)	⊕⊝⊝⊝ VERY LOW^a,b,c	No deaths reported. Evidence graded on the overall quality of the study
Quality of life	‐	‐	Not estimable	‐	‐	Outcome not reported in included studies
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio; P aeruginosa: Pseudomonas aeruginosa; RCT: randomised controlled trial.
GRADE Working Group grades of evidence. High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: 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 quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aOne point deducted in relation to design and implementation of available studies suggesting likelihood of bias (all study methods unclear). ^bOne point deducted for indirectness (no direct head‐to‐head comparisons). ^cOne point deducted for imprecision (small sample size and few events). ^dOne point deducted for imprecision (wide confidence intervals).

Summary of findings 2. Polymyxins compared to aminoglycosides for bronchiectasis

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Table 1. Study intervention characteristics

Study	Adults/ Children (N)	Arm 1			Arm 2			Arm 3			Duration
Study	Adults/ Children (N)	Antibiotic (N)	Dose/ Frequency	Mode of delivery	Antibiotic (N)	Dose/ Frequency	Mode of delivery	Comparison (N)	Dose/ Frequency	Mode of delivery	Duration
Fluoroquinolones vs β‐lactams (amoxicillin)
Chan 1996	Adults (42)	Ciprofloxacin (plus amoxicillin placebo) (21)	500 mg 3 times daily	Oral	Amoxicillin (plus ciprofloxacin placebo) (21)	1000 mg 3 times daily	Oral	‐	‐	‐	7 days
Lam 1989	Adults (41)	Ofloxacin (plus amoxicillin placebo) (20)	200 mg 3 times daily	Oral	Amoxicillin (plus ofloxacin placebo) (21)	1000 mg 3 times daily	Oral	‐	‐	‐	10 days
Aminoglycosides vs polymyxins
Dimakou 2014	Adults (29)	Tobramycin (10)	300 mg twice daily	Inhalation by nebuliser	1 MU colistimethate sodium (10)	300 mg twice daily	Inhalation by nebuliser	Saline solution (9)	4 mL of 0.9% solution	Inhalation by nebuliser	4 weeks
Kaponi 2017	Adults (52)	Tobramycin (17)	300 mg twice daily	Inhalation by nebuliser	1 MU colistimethate sodium (18)	300 mg twice daily	Inhalation by nebuliser	Saline solution (17)	4 mL of 0.9% solution	Inhalation by nebuliser	3 months
N: number of participants.

Table 1. Study intervention characteristics

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Comparison 1. Fluoroquinolones versus β‐lactam (amoxicillin)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Response rate ‐ treatment failure Show forest plot	2	83	Odds Ratio (M‐H, Fixed, 95% CI)	0.07 [0.01, 0.32]

1.1 Ciprofloxacin	1	42	Odds Ratio (M‐H, Fixed, 95% CI)	0.06 [0.01, 0.49]
1.2 Ofloxacin	1	41	Odds Ratio (M‐H, Fixed, 95% CI)	0.09 [0.01, 0.77]
2 Response rate ‐ microbiological response: patients with organisms eliminated Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

3 Response rate ‐ improvement in sputum purulence (excellent) Show forest plot	2	83	Odds Ratio (M‐H, Fixed, 95% CI)	2.35 [0.96, 5.72]

3.1 Ciprofloxacin vs amoxicillin	1	42	Odds Ratio (M‐H, Fixed, 95% CI)	1.5 [0.43, 5.25]
3.2 Ofloxacin vs amoxicillin	1	41	Odds Ratio (M‐H, Fixed, 95% CI)	3.79 [1.03, 13.91]
4 Response rate ‐ improvement in sputum purulence (fair) Show forest plot	2	83	Odds Ratio (M‐H, Fixed, 95% CI)	2.30 [0.88, 6.00]

4.1 Ciprofloxacin vs amoxicillin	1	42	Odds Ratio (M‐H, Fixed, 95% CI)	4.68 [1.17, 18.69]
4.2 Ofloxacin vs amoxicillin	1	41	Odds Ratio (M‐H, Fixed, 95% CI)	1.07 [0.26, 4.44]
5 Response rate ‐ relapse of sputum purulence at 3‐month follow‐up Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

6 Sputum volume (change mL) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

7 FEV1 % predicted (change) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 1. Fluoroquinolones versus β‐lactam (amoxicillin)

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Comparison 2. Polymyxins versus aminoglycosides

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Response rate ‐ improvement in sputum purulence Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Response rate ‐ P aeruginosa eradication Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3 Sputum purulence ‐ improvement in score at 3 months Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

4 Adverse events Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 2. Polymyxins versus aminoglycosides

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Head‐to‐head trials of antibiotics for bronchiectasis

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