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Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD)

  1. Samantha C Herath1,*,
  2. Phillippa Poole2

Editorial Group: Cochrane Airways Group

Published Online: 28 NOV 2013

Assessed as up-to-date: 29 AUG 2013

DOI: 10.1002/14651858.CD009764.pub2


How to Cite

Herath SC, Poole P. Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD). Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD009764. DOI: 10.1002/14651858.CD009764.pub2.

Author Information

  1. 1

    431 Glebe Point Road, Woolcock Institute of Medical Research, Sydney, New South Wales, Australia

  2. 2

    University of Auckland, Department of Medicine, Auckland, New Zealand

*Samantha C Herath, Woolcock Institute of Medical Research, 431 Glebe Point Road, Sydney, New South Wales, 2037, Australia. scherath@yahoo.com.

Publication History

  1. Publication Status: New
  2. Published Online: 28 NOV 2013

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Characteristics of included studies [ordered by study ID]
Albert 2011

MethodsProspective, randomised, double-blind, placebo controlled clinical trial with 12 month treatment duration

Intention-to-treat analysis


ParticipantsN=1142. Aged 40 or over. Mean age 65 years (azithromycin) and 66 (placebo)

41% female

Severity of COPD moderate or worse as defined by GOLD criteria

Mean FEV1 1.10±0.50 (azithromycin) and 1.12±0.52 (placebo)

Presence of either a) using continuous supplemental oxygen or b) received systemic glucocorticoids within the previous year /had gone to an emergency room/hospitalisation for an acute exacerbation

No acute exacerbation of COPD for at least 4 weeks

Exclusions: asthma, resting heart rate>100/min, Prolonged QT interval > 450 ms, using medications that prolong QTc, hearing impairment documented by audiometry


InterventionsProphylaxis:

1. Azithromycin 250 mg daily

2. Placebo


OutcomesPrimary:

1. Time to the first acute exacerbation of COPD

Secondary:

1. Quality of life

2. Nasopharyngeal colonisation of selected respiratory pathogens

3. Compliance to the treatment

4. Adverse events


NotesFunding: Grants listed from National Institutes of Health


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe stratified random sequence generation was well described in the journal article under "protocol"

Allocation concealment (selection bias)Low riskWell explained. Central allocation was pharmacy controlled

Blinding of participants and personnel (performance bias)
All outcomes
Low riskActive drug and placebo will be identical in appearance. Both patients and treating medical staff were blinded

Blinding of outcome assessment (detection bias)
All outcomes
Low riskTrial staff were unaware of the randomisation

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAll outcome data accounted for in a consort diagram for the entire study

However data on the secondary outcome: HRQOL had reported loss to follow-up of 20% in the prophylactic antibiotic arm and 18% on the placebo arm. The reasons for the missing data pertaining to HRQOL were not given

Selective reporting (reporting bias)Low riskAll pre-specified outcomes have been reported

Other biasLow riskNo other bias identified

Banerjee 2004

MethodsProspective, randomised, double-blind, placebo controlled clinical trial. Treatment duration of 3 months. Intention-to-treat analysis


ParticipantsN=67

Mean age 65.1 (clarithromycin) versus 68.1 years (placebo)

Mean FEV1 1.12 (clarithromycin) versus 1.13 (placebo)

Severity of COPD moderate or worse according to BTS guidelines. All patients were taking inhaled corticosteroids

Patients enrolled from hospital clinics

No acute exacerbations of COPD over the last 6 weeks

Exclusions: Previous documented allergies to macrolides; a clinical history of lung cancer, asthma or bronchiectasis


InterventionsProphylaxis:

1. Clarithromycin (long acting Klaricid XL 500 mg/daily)

2. Placebo


OutcomesPrimary:

1. Health-related quality of life

Secondary:

1. Infective exacerbation rate

2. Shuttle walk test

3. Serum C-reactive protein level

4. Sputum bacterial quantities load


NotesFunding: Received grant support from Abbott Pharmaceuticals


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBlock randomisation was carried out

Allocation concealment (selection bias)Low riskPatient randomisation was not known to the trial staff. Randomisation carried out by the Birmingham Hospital pharmacy department

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind study

Blinding of outcome assessment (detection bias)
All outcomes
Low riskTrial staff were unaware of the randomisation

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll outcome data described

Selective reporting (reporting bias)Low riskAll pre-specified outcomes were reported

Other biasLow riskNo other bias identified

He 2010

MethodsProspective, randomised, double-blind, placebo controlled clinical trial. Treatment duration was 6 months. Intention-to-treat analysis


ParticipantsN=36. Patients were 40 years or older. Mean age 68.8y (erythromycin) versus 69.3 (placebo)

Females 17% (erythromycin) versus 10% (placebo)

FEV1 between 30-70% predicted. Mean FEV1 1.12 (erythromycin) versus 1.02 (placebo)

At least 10 pack/year smoking history

No acute exacerbations during the previous 1 month

Exclusions: Patients with significant other respiratory disorders other than COPD; history of unstable cardiovascular disease; hypersensitivity to macrolides


InterventionsProphylaxis:

1. Erythromycin 250 mg 3 times a day

2. Placebo


OutcomesPrimary:

1. Number of acute COPD exacerbations

2. Neutrophil count in sputum

Secondary:

1. Quality of life

2. Spirometry


NotesFunding: Not stated


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation done but not clearly explained

Allocation concealment (selection bias)Unclear riskAllocation concealment not well explained

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind trial

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskUnknown

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll outcome data described using a CONSORT diagram

Selective reporting (reporting bias)Low riskAll pre-specified outcomes were reported

Other biasLow riskNo other bias identified

Mygind 2010

MethodsProspective, randomised, placebo controlled double-blind study. Treatment duration was 36 months. Intention-to-treat analysis


ParticipantsN=575. Aged >50 years.

Severity of COPD was moderate or severe with FEV1<60% predicted. Mean FEV1 was 0.9 (both treatment and placebo arms)

At least one admission to hospital with exacerbation of COPD

Ex or current smokers

Exclusions: End stage COPD patients (if not expected to survive over 3 years), or bedridden patients; patients with a history of asthma, bronchiectasis or other significant respiratory disease; history of azithromycin allergy; patients with heart, liver or renal insufficiency; already receiving prophylactic antibiotic


InterventionsIntermittent prophylaxis:

1. Azithromycin 500 mg/daily for 3 days every months, for 36 months

2. Placebo daily for 3 days every month, for 36 months


OutcomesPrimary:

1. Rate of decline in lung function (FEV1)

Secondary:

1. Frequency of exacerbation

2. Health-related quality of life (SGRQ)

3. Adverse events

4. Mortality

5. Duration of exacerbations

6. Number of days of hospitalisation

7. Frequency of hospitalisation


NotesFunding: Not stated


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomised but paucity of data on sequence generation

Allocation concealment (selection bias)Unclear riskNot explained well

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThis was a double-blind study

Blinding of outcome assessment (detection bias)
All outcomes
Low riskUnknown

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAll outcome data were presented. Only 55% completed 3 years

Selective reporting (reporting bias)Low riskAll pre-specified outcomes were reported

Other biasUnclear riskThis was a conference presentation and not a full publication. Attempts to contact the authors was not successful. Only limited data are available for evaluation of the risk of bias

Seemungal 2008

MethodsProspective, randomised, double-blind, placebo controlled clinical trial with 12 month follow-up


ParticipantsN=109. Patients recruited from outpatient chest clinic from a single centre

Mean age 66 ( treatment arm) versus 68 in placebo arm

Females 38% (treatment arm) versus 36% in placebo arm

Severity of COPD was moderate to severe. FEV1 between 30-70%). Mean FEV1 1.27 (treatment arm) versus1.36 (placebo arm)

Exclusions: History of asthma, bronchiectasis, neoplasia, unstable cardiac status (including prolonged QTc and arrhythmias), macrolide allergy or history of abnormal liver functions


InterventionsProphylaxis:

1. Erythromycin 250 mg twice daily

2. Placebo


OutcomesPrimary:

1. Exacerbation frequency

2. Airway inflammation


NotesCalculated sample size was 115 for 90% power and P value 0.05. However only 109 patients were recruited

Funding: British Lung Foundation


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer generated permuted block random sequence generation carried out

Allocation concealment (selection bias)Low riskRandomisation numbers were stored in sealed envelopes

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo and erythromycin were concealed in identical capsules

Blinding of outcome assessment (detection bias)
All outcomes
Low riskUnblinding occurred only after data entry

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll outcomes/dropouts explained in a CONSORT diagram

Selective reporting (reporting bias)Low riskAll pre-specified outcomes were reported

Other biasLow riskNo other bias identified

Sethi 2010

MethodsProspective double-blind randomised controlled clinical trial. Total treatment period was 48 weeks

1. Analysis was done using intention-to-treat and per protocol. For this review only the results of the intention-to-treat analysis were taken

2. Exacerbation of COPD was defined by two definitions. A primary definition (any confirmed acute exacerbation of COPD, unconfirmed pneumonia or any other lower respiratory tract infections) and a secondary definition (only confirmed exacerbations of COPD, excluding confirmed/unconfirmed pneumonia and any other lower respiratory tract infection)

For this review only the primary definition was used as it was an extended definition and hence was the more conservative definition


ParticipantsN= 1157. Aged 45 or over. Severity of COPD was GOLD stage 2 or worse. Had at least 2 exacerbations requiring treatment with antibiotics and/or oral steroids in the 12 months prior to enrolment

Total follow-up period was 72 weeks. Total treatment period was 48 weeks


InterventionsPulsed prophylaxis:

1. Moxifloxacin 400 mg/daily for 5 days. Treatment repeated every 8 weeks for a total of 6 courses

2. Placebo daily for 5 days. Treatment repeated every 8 weeks for a total of 6 courses


OutcomesPrimary:

1. Frequency of exacerbations

Secondary:

1. Health-related quality of life (assessed using SGRQ)

2. Hospitalisations

3. Mortality

4. Changes in lung function

5. Adverse events


NotesFunding: Received grant support from Bayer HealthCare AG


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandomisation was done but sequence generation not well explained

Allocation concealment (selection bias)Unclear riskNot explained

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind study

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNot explained

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAll outcome data were described using a CONSORT diagram for the entire study

However data on the secondary outcome: HRQOL had reported loss to follow-up of 12% in the prophylactic antibiotic arm and 10% in the placebo arm. The reasons for the missing data pertaining to HRQOL outcome were not given

Selective reporting (reporting bias)Low riskAll pre-specified outcomes were well described

Other biasLow riskData was analysed as intention-to-treat as well as per protocol analysis.Both analysis were published

Suzuki 2001

MethodsProspective, randomised, placebo controlled clinical trial. Non-blinded


Participantsn=109

Mean age 69y in erythromycin group and 72 in placebo group

Mean FEV1 1.47 in erythromycin group versus1.30 in placebo group

Females 13% in erythromycin group versus 18% in placebo group

All study participants were treated with sustained release theophylline and inhaled anticholinergic agents

Exclusions: Patients diagnosed with bronchiectasis or diffuse pan bronchiolitis


InterventionsProphylaxis:

1. Erythromycin 200 mg to 400 mg/daily

2. Placebo


Outcomes1. Acute exacerbations of COPD

2. Adverse events


NotesFunding: not stated


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation performed by random-number table

Allocation concealment (selection bias)Low riskThe randomisation list was held independently from the investigators

Blinding of participants and personnel (performance bias)
All outcomes
High riskThis study was not blinded

Blinding of outcome assessment (detection bias)
All outcomes
High riskAs the study was not blinded the assessment of outcome would be biased

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patient outcomes were presented in a graph

Selective reporting (reporting bias)Low riskAll pre-specified outcomes were reported

Other biasLow riskNo other bias identified

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Banerjee 2004aDuplicate of the study by Banerjee et al 2004 published in Respiratory Medicine 2005;99:208-15

Bier 1971Comparison: Doxycyclin versus placebo

Problem: Spirometric criteria were not used in diagnosing COPD

Blasi 2010Comparison: Azithromycin 500 mg three day a week for 6 months versus placebo

Problem: Pilot study, uncontrolled

Study done on tracheostomy patients

Bruninx 1973Comparison: Bactrim versus Ledermycin over 1070 months

Problem: 1) Heterogenic patient population including bronchiectasis, anthracosilicosis and bronchitis; 2) No placebo arm

Buchanan 1958Comparison: tetracycline 250 mg BD versus placebo for 12 months duration

Problems: Single blinded (only patients were blinded); Spirometric criteria were not used to diagnosed COPD

Bussi 1980Comparison: Intermittent tetracycline 200 mg /weekly for 3 years versus placebo

Problem: Spirometry criteria not used for diagnosis of COPD. Heterogenic group of patients

Calder 1968Duplicate of Fletcher et al 1966

Davies 1961Comparison: Tetracycline for 2 days each week versus placebo

Problem: Spirometric criteria were not used in diagnosing COPD; blinding not known

Douglas 1957Not a randomised controlled trial

Heterogenic group of patients including large proportion with bronchiectasis

Intial treatment with intramuscular penicillin

Patients who failed penicillin were allocated to either chloramphenicol 0.5g Q6h or oxytetracycline 0.5g Q6h.

Edwards 1958Comparison: Oxytetracycline or sulphonamide versus placebo

Problems: H. influenzae vaccination co-administered; no suitable outcome measures

Elmes 1957Comparison: Oxytetracycline versus placebo

Problem: Not truly prophylactic, antibiotic versus placebo at the onset of symptoms

Fletcher 1966Comparison: Treatment for 7 months/year over 5 year period. 1) Oxytetracycline 0.5g daily for 7 months over years 1 to 3; 2) Oxytetracycline 0.5g BD over 7 months in year 4; 3) Oxytetacyline 1g BD over 7 months in year 5; versus placebo

Problem: Spirometric criteria not used to diagnose COPD

Frances 1964Problem: Spirometric criteria were not used to diagnose COPD

Francis 1960Comparison: 3 groups: 1) Tetracycline 250 mg BD for 3 months; 2) Penicillin V 312 mg BD for 3 months; 3) Placebo for 3 months

Problems: Spirometric criteria were not used in diagnosing COPD

Goslings 1967Comparison: 1) Sulfaphenazole 500 mg BD; 2) Tetracycline 500 mg BD; 3) saccharum 500 mg BD (placebo)

over 5 month period

Problem: Spirometric criteria were not used to diagnose COPD

Grossman 1998Comparison: Ciprofloxacin 500 mg BD versus placebo for acute exacerbations of chronic bronchitis, treatment given during acute exacerbations during 12 month period versus usual care during an acute exacerbation

Problem: Ciprofloxacin was given during an exacerbation of chronic bronchitis. Not truly prophylaxis

Hahn 1972Comparison: Tetracycline or ampicillin versus placebo

Problems: Not a true long term prophylaxis. Prophylaxis is defined as antibiotics instituted by the patients at the first sign of a cold and were continued only for 5 days

Hallett 1959Comparison: Erythromycin 250 mg 4 times a day versus placebo for 12 week duration

Problem: Not a randomised controlled trial; Patients were matched in pairs (treatment and placebo groups) on the basis of similar clinical characteristics

Helm 1956Not a randomised controlled trial

Johnston 1961Comparison:

Four treatment arms

1.Tetracycline 500 mg BD for 6 months treatment per year for 5 years

2. Placebo for 6 months treatment per year for 5 years

3. Tetracycline for the first 2 winters and placebo for the next three

4. Placebo for 2 winters and tetracycline for the next three

Problem:

Partial crossover due to re: randomisation after two years

Spirometric criteria were not used to diagnose COPD

Johnston 1961Comparison: Phenethicillin versus placebo

Problems: Spirometric criteria were not used to diagnose COPD

Kilpatrick 1954Comparison: Sulphadimidine 0.5 g TDS versus placebo for 3 to 6 months

Problem: Spirometric criteria were not used when diagnosing COPD

Legler 1977Problem: Not randomised

Spirometric criteria were not used for diagnosing COPD

Liippo 1987Comparison: Trimethoprim 300 mg day versus placebo. Treatment for 6 months duration

Problem: Heterogenic group of patients. Patients with bronchiectasis and asthma included. Spirometry criteria for COPD not used

Maraffi 2010Review article on 13 previous randomised controlled trials from 1957 to 2010

May RJ 1956Comparison: Oxytetracycline or tetracycline versus "controlled group" who were observed and antibiotic prophylaxis was not given

Problem: Not a true randomised controlled trial. The "controlled group" consisted of 14 patients who were observed without any prophylactic therapy. They were not randomly selected

Miravitlles 2009Comparison: Moxifloxacin 400 mg daily versus placebo

Problem: Short duration of study with only 5 days of treatment

Moyes 1959Comparison: Four groups: 1) Erythromycin 1g daily for 7 days ,then a course of 1g daily for five days taken at the sign of first infection; 2) Erythromycin 1g daily for 7 days, then a regular course of 1g daily for five days every 4 weeks; 3) Tetracycline 1g daily for 7 days , then a course of 1g daily for five days taken at the sign of first infection

4) Tetracycline 1g daily for 7 days , then 750 mg/daily for 4 months

Problems: No placebo group

Murdoch 1959Comparison: Sigamycin (167 mg of tetracycline and 83 mg of oleandomycin ) versus placebo for 3 months

Problem: Spirometric criteria not used in diagnosing COPD

Murray 1964Comparison: Ampicillin 250 mg 4 times daily versus placebo over 17 months

Problem: Spirometric criteria were not used to diagnose COPD. Unclear whether randomisation took place

Norman 1962Comparison: Tetracycline 1 g daily or placebo for 3 months and crossover the groups with continuation of treatment for further 3 months

Problem: Randomised crossover trial. Spirometry criteria not used when diagnosing COPD

Pines 1967Comparison: Sulphormethoxine 2 g weekly for 10 weeks versus placebo

Problems: Spirometric criteria were not used in diagnosing COPD patients

Pridie 1960Comparison: Penicillin-sulphonamide, oxytetracycline versus placebo

Problem: Spirometric criteria were not taken into account when diagnosing COPD

Ras 1984Comparison: 1) Erythromycin 1500 mg/day for 2 weeks followed by 100 mg/day for 12 weeks; 2) Amoxycillin 1500 mg/day for 2 weeks followed by 100 mg/day for 12 weeks; 3) Placebo

Problem: Randomisation not well explained. Spirometric criteria not used when diagnosing COPD

Takizawa 1994Comparison: Three oral prophylactic antibiotic regimens: 1) Ciprofloxacin 200 mg daily for 6 months (Regimen A); 2) Erythromycin 200 mg daily for 6 months (Regimen B); 3) Ciprofloxacin 200 mg/d and Erythromycin 200 mg/d for 6 months (Regimen C)

Problems: No placebo arm. Heterogenic group of patients including large number with bronchiectasis

Torrence 1999Duplicate of Grossman 1998

Vandenbergh 1970Comparison: sulphonamide 2 g once a week versus placebo for 6 months

Problem: None of the primary outcomes were measured (frequency of exacerbations or quality of life)

Spirometric criteria were not used in diagnosing COPD

Watanabe 1991Comparison; 1) Ofloxacin 200 mg daily for 6 months; 2) Ofloxacin 200 mg TDS for 2 weeks followed by 2 weeks without treatment for 6 months

Problem: Prophylaxis was given to patients with ANY chronic respiratory tract infection, including bronchiectasis and pulmonary tuberculosis. No placebo arm

Watanabe 1994Comparison: ciprofloxacin 200 mg/daily versus erythromycin 200 mg/daily versus combined ciprofloxacin 200 mg/d + erythromycin 200 mg/d

Problem: No placebo. Patients with bronchiectasis included

Watanabe 1995Duplicate study of Watanabe 1991 with addition of 7 patients

Webster 1971Comparison: Trimethoprim-sulphamethoxazole versus sulphamethoxazole

Problem: No placebo group. Treatment duration was only 10 days

 
Characteristics of ongoing studies [ordered by study ID]
Uzun 2012

Trial name or titleInfluence of macrolide maintenance therapy and bacterial colonisation on exacerbation frequency and progression of COPD

MethodsRandomised controlled trial

ParticipantsInclusion criteria:

Age 18 years and older

Diagnosis of COPD according to GOLD criteria and classified according to GOLD 1-1V

Three or more exacerbations of COPD in one year for which a course of prednisone and/or antibiotic therapy was started

Clinically stable for 1 months prior to recruitment in to the trial

Exclusion criteria:

Use of antibiotics or high dose systemic steroids within a month prior to involvement in the study

Addition of inhalation steroids to the patient's therapy shortly before entering the study

Pregnant or lactating women

Allergy to macrolides

Use of drugs that could adversely interact with macrolides for which therapeutic monitoring could not be undertaken

A diagnosis of malignancy, heart failure,bronchiectasis or asthma

InterventionsAzithromycin 500 mg, 3 times a week versus placebo 3 times a week for 12 months

OutcomesPrimary:

1. Reduction in number of exacerbations

Secondary outcomes:

1. Lung function parameters

2. Health related quality of life measured by SGRQ

3. Indication of anxiety and depression by Hospital anxiety and depression scale.

4. Microbiology in sputum

5. Measurement of inflammatory markers in sputum

6. Adverse events on treatment

7. Length of hospital stay

8. Time till next exacerbation

9. Effect of maintenance macrolides on intestinal bacterial resistance patterns

10. Serology and PCR for atypical microorganisms in serum

11. intestinal bacterial resistance patterns

Starting dateMay 2010. Estimated primary completion date June 2013

Contact informationDr Djamin R.S, Amphia Hospital, Netherlands

NotesInformation from www.ClinicalTrials.gov NCT00985244

 
Comparison 1. Antibiotics versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number of people with one or more exacerbations42411Odds Ratio (M-H, Random, 95% CI)0.64 [0.45, 0.90]

    1.1 Continuous antibiotics
31262Odds Ratio (M-H, Random, 95% CI)0.55 [0.39, 0.77]

    1.2 Pulsed antibiotics
11149Odds Ratio (M-H, Random, 95% CI)0.87 [0.69, 1.09]

 2 Number of patients with one or more exacerbations on continuous antibiotics (regardless of blinding)41371Odds Ratio (M-H, Random, 95% CI)0.31 [0.13, 0.72]

    2.1 Continuous antibiotics
41371Odds Ratio (M-H, Random, 95% CI)0.31 [0.13, 0.72]

 3 Rate of exacerbation per patient per year3Rate Ratio (Random, 95% CI)0.73 [0.58, 0.91]

    3.1 Continuous antibiotics
3Rate Ratio (Random, 95% CI)0.73 [0.58, 0.91]

 4 Time to the first exacerbationOther dataNo numeric data

    4.1 Continous antibiotic
Other dataNo numeric data

    4.2 Pulsed antibiotics
Other dataNo numeric data

 5 COPD exacerbations according to severity of COPD (Gold staging system)Other dataNo numeric data

    5.1 Continuous antibiotics
Other dataNo numeric data

    5.2 Pulsed antibiotics
Other dataNo numeric data

 6 HRQOL, SGRQ (total score)31962Mean Difference (IV, Fixed, 95% CI)-1.78 [-2.95, -0.61]

 7 HRQOL, SGRQ (symptoms)21926Mean Difference (IV, Fixed, 95% CI)-3.75 [-5.48, -2.01]

 8 HRQOL, SGRQ (impact)21926Mean Difference (IV, Fixed, 95% CI)-1.71 [-3.10, -0.32]

 9 HRQOL, SGRQ (activity)21926Mean Difference (IV, Fixed, 95% CI)-0.81 [-2.26, 0.63]

 10 Duration of exacerbationOther dataNo numeric data

    10.1 Continuous antibiotics
Other dataNo numeric data

    10.2 Pulsed antibiotics
Other dataNo numeric data

 11 Frequency of hospital admissionsOther dataNo numeric data

    11.1 Continuous antibiotics
Other dataNo numeric data

    11.2 Pulsed antibiotics
Other dataNo numeric data

 12 All cause mortality32841Odds Ratio (M-H, Fixed, 95% CI)0.89 [0.67, 1.19]

 13 Respiratory related mortality22266Odds Ratio (M-H, Fixed, 95% CI)1.18 [0.63, 2.18]

 14 Serious adverse events42411Odds Ratio (M-H, Fixed, 95% CI)0.88 [0.73, 1.07]

 15 Adverse events: respiratory disorders22266Odds Ratio (M-H, Fixed, 95% CI)0.83 [0.52, 1.31]

 16 Adverse events: gastrointestinal disorders42408Odds Ratio (M-H, Fixed, 95% CI)1.58 [1.01, 2.47]

 17 Adverse events: QTc prolongation1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 18 Adverse events: hearing impairment1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 19 Adverse events: musculoskeletal disorders1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 20 Adverse events: hypersensitivity/skin rash21258Odds Ratio (M-H, Fixed, 95% CI)1.63 [0.63, 4.26]

 21 Adverse events: nervous system disorders1Odds Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Analysis 1.4 Comparison 1 Antibiotics versus placebo, Outcome 4 Time to the first exacerbation.
Time to the first exacerbation

StudyMEDIAN Time to 1st exacerbation (days) treatmentMEDIAN Time to 1st exacerbation (days) placeboP valueTest usedHazard ratio

Continous antibiotic

Albert 2011266 (227-313)174 (143-215) P<0.001log -rank test0.73 (0.63 ,0.84)

He 201015586P=0.032Kaplan -Meier survival analysisnot given

Seemungal 200827189P=0.02log -rank testnot given

Pulsed antibiotics

Sethi 2010364336P=0.062Kaplan-Meier survival analysisnot given

 
Analysis 1.5 Comparison 1 Antibiotics versus placebo, Outcome 5 COPD exacerbations according to severity of COPD (Gold staging system).
COPD exacerbations according to severity of COPD (Gold staging system)

StudyGold stageRate of Exacerbations per patient year on azithromycin (Mean +/-SD)Rate on placebo (Mean +/-SD)

Continuous antibiotics

Albert 20112 : FEV1 (80%-50%)1.02 (+/- 0.15)1.68 (+/- 0.16)

Albert 20113 : FEV1 (50-30%)1.53 (+/- 0.13)1.75 (+/- 0.13)

Albert 20114 : FEV1 <30%1.75 (+/- 0.12)2.05 (+/- 0.28)

Pulsed antibiotics

Sethi 20102 : FEV1 (80%-50%)0.65 (0.39-1.06)0.091

Sethi 20103 : FEV1 (50-30%)0.81 (0.58 - 1.10)0.192

Sethi 20104 : FEV1 <30%0.83 (0.54 - 1.28)0.459

 
Analysis 1.10 Comparison 1 Antibiotics versus placebo, Outcome 10 Duration of exacerbation.
Duration of exacerbation

StudyMedian days of exacerbation treatment armMedian days of exacerbation placebo armP value

Continuous antibiotics

Seemungal 20089 (6-14)13 (6-24)0.036 Mann-Whitney test

Pulsed antibiotics

Mygind 2010931110.04

 
Analysis 1.11 Comparison 1 Antibiotics versus placebo, Outcome 11 Frequency of hospital admissions.
Frequency of hospital admissions

StudyRate of Hospitalisations per patient year on moxifloxacin (Mean +/-SD)Rate on placebo (Mean +/-SD)P value

Continuous antibiotics

Albert 20112 : FEV1 (80%-50%)0.50 +/-0.120.65 +/-0.11

Albert 20113 : FEV1 (50-30%)0.85 +/- 0.120.96+/-0.12

Albert 20114 : FEV1 <30%0.74 +/- 0.121.03 +/- 0.27

Pulsed antibiotics

Sethi 20101311360.46

Sethi 201023.02%23.45%

Sethi 2010

 
Summary of findings for the main comparison. Antibiotics versus placebo for COPD

Antibiotics versus placebo for COPD (data from pulsed and continuous courses of antibiotics presented in the same table)

Patient or population: Adults (aged 40 or over) with COPD presenting with 1 or more exacerbations in the previous year. The 2 larger studies (Albert 2011; Sethi 2010) recruited patients who required systemic steroids or antibiotics for exacerbations or patients on supplemental oxygen

Settings: Outpatients presenting to hospital clinics

Intervention: Administration of an oral prophylactic antibiotic continuously or intermittently

Comparison: Administration of a placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlAntibiotics versus placebo

Number of people with one or more exacerbations60 per 10049 per 100
(41 to 58)
OR 0.64
(0.45 to 0.9)
2411
(4 studies)
⊕⊕⊕⊝
moderate1
The four studies looked at a different antibiotics (azithromycin and moxifloxacin) and the trial by Albert 2011 is on continuous antibiotics while Sethi 2010 trial is on pulsed antibiotics. Therefore there is clinical heterogeneity in the combined results and we downgraded by one point for inconsistency

Number of people with one or more exacerbations - Continuous antibiotics
Follow-up: 6 to 12 months
69 per 10055 per 100
(46 to 63)
OR 0.55
(0.39 to 0.77)
1262
(3 studies)
⊕⊕⊕⊕
high

Number of people with one or more exacerbations - Pulsed antibiotics
Follow-up: 18 months
51 per 10047 per 100
(42 to 53)
OR 0.87
(0.69 to 1.09)
1149
(1 study)
⊕⊕⊕⊝
moderate2

Rate of exacerbation per patient/year

(Continuous antibiotic use)

6 to 12 months
Rate Ratio 0.73 (0.58 to 0.91)1262

(3 studies)
⊕⊕⊕⊝

moderate1
I2=47%

HRQOL, SGRQ (change in total score)
Scale from: 0 to 100. SGRQ comprises of responses to 50 items, 0 being the best possible score and 100 the worst.
Follow-up: 6 to 18 months
The mean change in SGRQ ranged across control groups from
-0.6 to -2.8 units
The mean SGRQ (total score) in the intervention groups was
1.78 better
(2.95 to 0.61 better)
1962
(3 studies)
⊕⊕⊕⊝
moderate3
The minimally clinically important response to treatment is described as 4 points

All cause mortality
Follow-up: 6 to 36 months
83 per 100074 per 1000
(57 to 97)
OR 0.89
(0.67 to 1.19)
2841
(3 studies)
⊕⊕⊕⊝
moderate2

Serious adverse events
Follow-up: 6 to 18 months
267 per 1000243 per 1000
(210 to 281)
OR 0.88
(0.73 to 1.07)
2411
(4 studies)
⊕⊕⊕⊝
moderate2
See Effects of interventions for specific adverse events related to the individual antibiotics

*The basis for the assumed risk was the mean control group risk across studies. The corresponding risk (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

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Clinical and statistical heterogeneity between trials
2 Confidence intervals include the possibility that continuous antibiotics may increase or decrease the rate of exacerbations, mortality or serious adverse events
3 Risk of attrition bias. Both studies have unclear attrition bias associated with this outcome as there is loss to follow up reported between 10-20% and reasons for the incomplete data were not given therefore we downgraded one for limitations