Head‐to‐head oral prophylactic antibiotic therapy for chronic obstructive pulmonary disease

Christopher JD Threapleton; Sadia Janjua; Rebecca Fortescue; Emma H Baker

doi:10.1002/14651858.CD013024.pub2

Comparación directa de antibióticos profilácticos orales para la enfermedad pulmonar obstructiva crónica

Appendices

Appendix 1. Sources and search methods for the Cochrane Airways Group's Specialised Register (CAGR)

Electronic searches: core databases

Database	Dates searched	Frequency of search
CENTRAL (via the Cochrane Register of Studies (CRS))	From inception	Monthly
MEDLINE (Ovid)	1946 onwards	Weekly
EMBASE (Ovid)	1974 onwards	Weekly
PsycINFO (Ovid)	1967 onwards	Monthly
CINAHL (EBSCO)	1937 onwards	Monthly
AMED (EBSCO)	From inception	Monthly

Handsearches: core respiratory conference abstracts

Conference	Years searched
American Academy of Allergy, Asthma and Immunology (AAAAI)	2001 onwards
American Thoracic Society (ATS)	2001 onwards
Asia Pacific Society of Respirology (APSR)	2004 onwards
British Thoracic Society Winter Meeting (BTS)	2000 onwards
Chest Meeting	2003 onwards
European Respiratory Society (ERS)	1992, 1994, 2000 onwards
International Primary Care Respiratory Group Congress (IPCRG)	2002 onwards
Thoracic Society of Australia and New Zealand (TSANZ)	1999 onwards

MEDLINE search strategy used to identify studies for the Cochrane Airways Trials Register

COPD search

1. Lung Diseases, Obstructive/

2. exp Pulmonary Disease, Chronic Obstructive/

3. emphysema$.mp.

4. (chronic$ adj3 bronchiti$).mp.

5. (obstruct$ adj3 (pulmonary or lung$ or airway$ or airflow$ or bronch$ or respirat$)).mp.

6. COPD.mp.

7. COAD.mp.

8. COBD.mp.

9. AECB.mp.

10. or/1‐9

Filter to identify RCTs

1. exp "clinical trial [publication type]"/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1‐7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

The MEDLINE strategy and RCT filter are adapted to identify studies in other electronic databases.

Appendix 2. Search strategy to identify relevant studies from the Cochrane Airways Trials Register

#1 MeSH DESCRIPTOR Pulmonary Disease, Chronic Obstructive Explode All
#2 MeSH DESCRIPTOR Bronchitis, Chronic
#3 (obstruct*) near3 (pulmonary or lung* or airway* or airflow* or bronch* or respirat*)
#4 COPD:MISC1
#5 (COPD OR COAD OR COBD OR AECOPD):TI,AB,KW
#6 #1 OR #2 OR #3 OR #4 OR #5
#7 MESH DESCRIPTOR Anti‐Bacterial Agents EXPLODE ALL
#8 antibiotic* NEAR prophyla*
#9 continuous NEAR antibiotic*
#10 antibiotic*
#11 penicillin
#12 phenoxymethylpenicillin
#13 phenethicillin
#14 amoxicillin
#15 amoxycillin
#16 clavulanic acid
#17 tetracycline
#18 oxytetracycline
#19 doxycycline
#20 quinolone
#21 ciprofloxacin
#22 moxifloxacin
#23 macrolide*
#24 erythromycin
#25 roxithromycin
#26 azithromycin
#27 sulphonamide
#28 co‐trimoxazole
#29 sulphaphenazole
#30 trimethoprim
#31 sigmamycin
#32 tetracycline AND oleandomycin
#33 sulfamethoxazole
#34 sulfaphenazole
#35 sulfonamide
#36 anti‐bacteri* or antibacteri*
#37 ceph*
#38 sulpha*
#39 {OR #7‐#38}
#40 #39 AND #6

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 Macrolide+tetracycline versus macrolide, Outcome 1 Mean time to first exacerbation (days).

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Analysis 1.2

Comparison 1 Macrolide+tetracycline versus macrolide, Outcome 2 CRQ quality of life; change; endpoint 12 weeks.

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Analysis 1.3

Comparison 1 Macrolide+tetracycline versus macrolide, Outcome 3 CRQ quality of life; change; endpoint 60 weeks.

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Analysis 1.4

Comparison 1 Macrolide+tetracycline versus macrolide, Outcome 4 All‐cause serious adverse events; endpoint 60 weeks.

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Analysis 1.5

Comparison 1 Macrolide+tetracycline versus macrolide, Outcome 5 Treatment‐related serious adverse events; endpoint 60 weeks.

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Comparison 1 Macrolide+tetracycline versus macrolide, Outcome 6 Lung function (FEV1 trough); change; endpoint 12 weeks.

Analysis 1.6

Comparison 1 Macrolide+tetracycline versus macrolide, Outcome 6 Lung function (FEV₁ trough); change; endpoint 12 weeks.

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Analysis 1.7

Comparison 1 Macrolide+tetracycline versus macrolide, Outcome 7 Lung function (FVC); change; endpoint 12 weeks.

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Analysis 1.8

Comparison 1 Macrolide+tetracycline versus macrolide, Outcome 8 All‐cause mortality; endpoint 60 weeks.

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Analysis 1.9

Comparison 1 Macrolide+tetracycline versus macrolide, Outcome 9 All‐cause adverse events; endpoint 60 weeks.

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Analysis 1.10

Comparison 1 Macrolide+tetracycline versus macrolide, Outcome 10 Treatment‐related adverse events; endpoint 60 weeks.

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Comparison 1 Macrolide+tetracycline versus macrolide, Outcome 11 Lung function (FEV1 % predicted); change; endpoint 60 weeks.

Analysis 1.11

Comparison 1 Macrolide+tetracycline versus macrolide, Outcome 11 Lung function (FEV₁ % predicted); change; endpoint 60 weeks.

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Comparison 1 Macrolide+tetracycline versus macrolide, Outcome 12 Lung function (FEV1 trough); change; endpoint 60 weeks.

Analysis 1.12

Comparison 1 Macrolide+tetracycline versus macrolide, Outcome 12 Lung function (FEV₁ trough); change; endpoint 60 weeks.

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Comparison 1 Macrolide+tetracycline versus macrolide, Outcome 13 Lung function (FEV1 % predicted); change; endpoint 12 weeks.

Analysis 1.13

Comparison 1 Macrolide+tetracycline versus macrolide, Outcome 13 Lung function (FEV₁ % predicted); change; endpoint 12 weeks.

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Analysis 1.14

Comparison 1 Macrolide+tetracycline versus macrolide, Outcome 14 Lung function (FVC); change; endpoint 60 weeks.

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Analysis 2.1

Comparison 2 Quinolone versus tetracycline, Outcome 1 Number of people with one or more exacerbations.

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Analysis 3.1

Comparison 3 Quinolone versus macrolide, Outcome 1 Number of people with one or more exacerbations.

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Analysis 4.1

Comparison 4 Macrolide versus tetracycline, Outcome 1 Number of people with one or more exacerbations.

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Summary of findings for the main comparison. Macrolide+tetracycline versus macrolide

Macrolide+tetracycline compared to macrolide for chronic obstructive pulmonary disease
Patient or population: chronic obstructive pulmonary disease Setting: 16 centres across Australia and New Zealand Intervention: roxithromycin (continuous; 300 mg daily) + doxycycline (continuous; 100 mg daily) Comparison: roxithromycin (continuous; 300 mg daily)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with macrolide	Risk with Macrolide+tetracycline	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Quality of life, measured by CRQ (dyspnoea, fatigue, emotional function, and mastery subscales) Follow‐up 12 weeks (end of treatment) Scale from 0 to 10. Higher scores on the scale indicates better quality of life	The mean change in CRQ HRQoL (dyspnoea) was 2.21	MD 0.58 higher (0.84 lower to 2.00 higher)	‐	187 (1 RCT)	⊕⊝⊝⊝ Very low^a,b,d	An increase of three points in this domain refers to a clinically significant reduction in dyspnoea (Jaeschke 1989; Jones 2002)
	The mean change in CRQ HRQoL (fatigue) was 0.68	MD 0.02 higher (1.08 lower to 1.12 higher)	‐	187 (1 RCT)	⊕⊝⊝⊝ Very low^a,b,d,e	An increase of four points in this domain refers to a clinically significant reduction in fatigue (Jaeschke 1989; Jones 2002)
	The mean change in CRQ HRQoL (emotional function) was 0.45	MD 0.37 lower (1.74 lower to 1.00 higher)	‐	187 (1 RCT)	⊕⊝⊝⊝ Very low^a,b,d,f	An increase of two points in this domain refers to a clinically significant improvement in emotional function (Jaeschke 1989; Jones 2002)
	The mean change in CRQ HRQoL (mastery) was 0.53	MD 0.79 lower (1.86 lower to 0.28 higher)	‐	187 (1 RCT)	⊕⊝⊝⊝ Very low^a,b,d,f	No reported minimally important difference (MID)
All‐cause serious adverse events 60 weeks (end of study)	237 per 1000	237 per 1000 (139 to 375)	OR 1.00 (0.52 to 1.93)	198 (1 RCT)	⊕⊝⊝⊝ Very low^a,d,e,g
Lung function (trough FEV₁) Change from baseline to 12 weeks (end of active treatment)	The mean change in trough FEV₁ was 0.047 L	MD 0.01 L lower (0.09 lower to 0.07 higher)		182 (1 RCT)	⊕⊝⊝⊝ Very low^a,b,d,f	An improvement of 100 mL (0.1 L) for FEV₁ trough is considered clinically significant (Donohue 2005)
All‐cause mortality 60 weeks (end of study)	31 per 1000	49 per 1000 (12 to 183)	OR 1.63 (0.38 to 7.02)	198 (1 RCT)	⊕⊝⊝⊝ Very low^a,b,d
Number of people experiencing one or more exacerbations, Drug resistance/microbial sensitivity (as reported by trialists), including emergence of atypical bacteria, Number of participants colonised with Pseudomonas aeruginosa	Information for these outcomes was not presented as data for head‐to‐head comparisons were not available
*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; CRQ: Chronic Respiratory Questionnaire; FEV₁: forced expiratory volume in one second; HRQoL: health‐related quality of life; MD: mean difference; OR: odds ratio; RCT: randomised controlled trial.
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.
^aThe evidence was downgraded by 1 due to attrition bias in the combined treatment arm. ^bThe evidence was downgraded by 2 due to indirectness of population and intervention. The aim was to assess eradication of C pneumoniae and not antibiotic prophylaxis. The comparison of interventions was not an inclusion criterion of this systematic review. ^cThe evidence was downgraded by 1 due to imprecision. The confidence interval crossed the line of no effect, and failed to exclude worsening of the outcome. ^dThe evidence was downgraded by 1 due to imprecision. The sample size was small, however, the confidence intervals fell within the minimally important difference for the outcome. ^eThe evidence was downgraded by 1 due to imprecision. The confidence intervals failed to exclude an important improvement or worsening of the outcome. ^fThe evidence was downgraded by 1 due to imprecision. The confidence interval crossed the line of no effect, and failed to exclude an important improvement of the outcome. ^gThe evidence was downgraded by 1 due to indirectness. The time frame when the outcome was measured (at 48 weeks follow‐up after the 12‐week active treatment period) was not included in the inclusion criteria of this review.

Summary of findings for the main comparison. Macrolide+tetracycline versus macrolide

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Summary of findings 2. Quinolone versus tetracycline

Quinolone compared with tetracycline for chronic obstructive pulmonary disease
Patient or population: chronic obstructive pulmonary disease Setting: hospital outpatients, UK Intervention: moxifloxacin (pulsed; 400 mg per day for 5 days every 4 weeks) Comparison: doxycycline (continuous; 100 mg daily)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	№ of Participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Quinlone	Tetracycline
Number of participants experiencing one or more exacerbations Quinolone versus tetracycline Follow‐up 13 weeks (end of treatment)	600 per 1000	398 per 1000 (174 to 674)	OR 0.44 (0.14 to 1.38)	50 (1 RCT)	⊕⊝⊝⊝ Low^a
All‐cause mortality Follow‐up 13 weeks (end of treatment)	‐	‐	‐	50 (1 RCT)	‐	No deaths reported in either treatment arm
Quality of life Drug resistance/microbial sensitivity Serious adverse events Lung function Hospitalisations Adverse events/side effects Number of participants colonised with P aeruginosa	Information for these outcomes was not presented as data for head‐to‐head comparisons were not available
*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 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.
^aThe evidence was downgraded by 2 due to imprecision. The sample size was small, and the confidence interval crossed the line of no effect, and failed to exclude important harm.

Summary of findings 2. Quinolone versus tetracycline

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Summary of findings 3. Quinolone versus macrolide

Quinlone compared with macrolide for chronic obstructive pulmonary disease
Patient or population: chronic obstructive pulmonary disease Setting: hospital outpatients, UK Intervention: moxifloxacin (pulsed; 400 mg per day for 5 days every 4 weeks) Comparison: azithromycin (intermittent; 250 mg 3 times per week)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	№ of Participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Quinlone	Macrolide
Number of participants experiencing one or more exacerbations Quinolone versus macrolide Follow‐up 13 weeks (end of treatment)	400 per 1000	400 per 1000 (176 to 674)	OR 1.00 (0.32 to 3.10)	50 (1 RCT)	⊕⊝⊝⊝ Low^a
All‐cause mortality Follow‐up 13 weeks (end of treatment)	‐	‐	‐	50 (1 RCT)	‐	No deaths reported in either treatment arm
Quality of life Drug resistance/microbial sensitivity Serious adverse events Lung function Hospitalisations Adverse events/side effects Number of participants colonised with P aeruginosa	Information for these outcomes was not presented as data for head‐to‐head comparisons were not available
*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 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.
^aThe evidence was downgraded by 2 due to imprecision. The sample size was small, and the confidence interval failed to exclude an important benefit or harm.

Summary of findings 3. Quinolone versus macrolide

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Summary of findings 4. Macrolide versus tetracycline

Macrolide compared with tetracycline for chronic obstructive pulmonary disease
Patient or population: chronic obstructive pulmonary disease Setting: hospital outpatients, UK Intervention: azithromycin (intermittent; 250 mg 3 times per week) Comparison: doxycycline (continuous; 100 mg daily)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	№ of Participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Quinlone	Macrolide
Number of participants experiencing one or more exacerbations Macrolide versus tetracycline Follow‐up 13 weeks (end of treatment)	600 per 1000	398 per 1000 (174 to 674)	OR 0.44 (0.14 to 1.38)	50 (1 RCT)	⊕⊝⊝⊝ Low^a
All‐cause mortality Follow‐up 13 weeks (end of treatment)	‐	‐	‐	50 (1 RCT)	‐	No deaths reported in either treatment arm
Quality of life Drug resistance/microbial sensitivity Serious adverse events Lung function Hospitalisations Adverse events/side effects Number of participants colonised with P aeruginosa	Information for these outcomes was not presented as data for head‐to‐head comparisons were not available
*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 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.
^aThe evidence was downgraded by 2 due to imprecision. The sample size was small, and the confidence interval crossed the line of no effect, and failed to exclude important harm.

Summary of findings 4. Macrolide versus tetracycline

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Table 1. Number of participants experiencing exacerbations

Study ID	Antibiotic class	Antibiotic	Antibiotic frequency and amount	Number of participants experiencing exacerbations (N)	Total number of participants (N)	Duration of treatment
Brill 2015	Quinolone	Moxifloxacin	Pulsed (400 mg daily for 5 days every 4 weeks)	10	25	13 weeks
Brill 2015	Tetracycline	Doxycycline	Continuous (100 mg daily)	15	25	13 weeks
Brill 2015	Macrolide	Azithromycin	Intermittent (250 mg 3 times per week)	10	25	13 weeks

Table 1. Number of participants experiencing exacerbations

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Table 2. Quality of life

Study ID	Antibiotic class	Antibiotic	Antibiotic frequency and amount	Quality of life scale	Mean CRQ (SD)	Total number of participants (N)	Duration of treatment
Shafuddin 2015	Macrolide+ tetracycline	Roxithromycin + doxycycline	Continuous (300 mg daily + 100 mg daily)	CRQ (dyspnoea)	2.21 (5.35)	93	12 weeks
Shafuddin 2015	Macrolide	Roxithromycin	Continuous (300 mg daily)	CRQ (dyspnoea)	1.63 (4.53)	94	12 weeks
Shafuddin 2015	Macrolide+ tetracycline	Roxithromycin + doxycycline	Continuous (300 mg daily + 100 mg daily)	CRQ (fatigue)	0.68 (3.79)	93	12 weeks
Shafuddin 2015	Macrolide	Roxithromycin	Continuous (300 mg daily)	CRQ (fatigue)	0.66 (3.87)	94	12 weeks
Shafuddin 2015	Macrolide+ tetracycline	Roxithromycin + doxycycline	Continuous (300 mg daily + 100 mg daily)	CRQ (emotional function)	0.45 (5.04)	93	12 weeks
Shafuddin 2015	Macrolide	Roxithromycin	Continuous (300 mg daily)	CRQ (emotional function)	0.82 (4.48)	94	12 weeks
Shafuddin 2015	Macrolide+ tetracycline	Roxithromycin + doxycycline	Continuous (300 mg daily + 100 mg daily)	CRQ (mastery)	0.53 (3.42)	93	12 weeks
Shafuddin 2015	Macrolide	Roxithromycin	Continuous (300 mg daily)	CRQ (mastery)	1.32 (4)	94	12 weeks
CRQ: Chronic Respiratory Questionnaire SD: standard deviation

Table 2. Quality of life

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Table 3. Number of participants experiencing serious adverse events (all‐cause)

Study ID	Antibiotic class	Antibiotic	Antibiotic frequency and amount	Number of participants experiencing SAEs (n)	Total number of participants (N)	Duration of treatment
Brill 2015	Quinolone	Moxifloxacin	Pulsed (400 mg daily for 5 days every 4 weeks)	0	25	13 weeks
Brill 2015	Tetracycline	Doxycycline	Continuous (100 mg daily)	0	25	13 weeks
Brill 2015	Macrolide	Azithromycin	Intermittent (250 mg 3 times per week)	0	25	13 weeks
Shafuddin 2015	Macrolide+ tetracycline	Roxithromycin+ doxycycline	Continuous (300 mg + 100 mg daily)	24	101	48 weeks follow‐up after 12 weeks active treatment (60 weeks)
Shafuddin 2015	Macrolide	Roxithromycin	Continuous (300 mg daily)	23	97	48 weeks follow‐up after 12 weeks active treatment (60 weeks)
SAE: serious adverse event

Table 3. Number of participants experiencing serious adverse events (all‐cause)

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Table 4. Lung function (FEV1, FEV1% predicted, and FVC)

Study ID	Antibiotic class	Antibiotic	Antibiotic frequency and amount	Mean FEV₁ (SD) (trough)	Mean FEV₁ % predicted (SD) (trough)	Mean FVC (SD)	Total number of participants (N)	Duration of treatment
Shafuddin 2015	Macrolide + tetracycline	Roxithromycin + doxycycline	Continuous (300 mg + 100 mg daily)	0.047 (026)	1.7 (9)	0.06 (0.46)	88	12 weeks
Shafuddin 2015	Macrolide	Roxithromycin	Continuous (300 mg daily)	0.057 (0.31)	1.87 (11)	0.09 (0.55)	94	12 weeks
FEV₁: forced expiratory volume in 1 second FVC: forced vital capacity SD: standard deviation

Table 4. Lung function (FEV1, FEV1% predicted, and FVC)

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Table 5. Mortality

Study ID

Antibiotic class

Antibiotic

Antibotic frequency and amount

All‐cause mortality (n)

Total number of participants (N)

Duration of treatment

Shafuddin 2015

Macrolide + tetracycline

Roxithromycin + doxycycline

Continuous (300 mg

+ 100 mg daily)

5

101

48 weeks follow‐up

after 12 weeks

active treatment

(60 weeks)

Shafuddin 2015

Macrolide

Roxithromycin

Continuous (100 mg daily)

3

97

48 weeks follow‐up

after 12 weeks

active treatment

(60 weeks)

Table 5. Mortality

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Table 6. Number of people experiencing adverse events/side effects

Study ID	Antibiotic class	Antibiotic	Antibiotic frequency and amount	Adverse event type	Number of participants with adverse events/side effects (n)	Total number of participants (N)	Duration of treatment
Shafuddin 2015	Macrolide + tetracycline	Roxithromycin + doxycycline	Continuous (300 mg + 100 mg daily)	All‐cause	73	101	48 weeks follow‐up after 12 weeks active treatment (60 weeks)
Shafuddin 2015	Macrolide	Roxithromycin	Continuous (100 mg daily)	All‐cause	74	97	48 weeks follow‐up after 12 weeks active treatment (60 weeks)
Shafuddin 2015	Macrolide + tetracycline	Roxithromycin + doxycycline	Continuous (300 mg + 100 mg daily)	Treatment‐ related	31	101	48 weeks follow‐up after 12 weeks active treatment (60 weeks)
Shafuddin 2015	Macrolide	Roxithromycin	Continuous (100 mg daily)	Treatment‐ related	33	97	48 weeks follow‐up after 12 weeks active treatment (60 weeks)

Table 6. Number of people experiencing adverse events/side effects

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Comparison 1. Macrolide+tetracycline versus macrolide

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean time to first exacerbation (days) Show forest plot	1	179	Mean Difference (IV, Fixed, 95% CI)	‐19.0 [‐52.70, 14.70]

2 CRQ quality of life; change; endpoint 12 weeks Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.1 Dyspnoea	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Fatigue	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.3 Emotional function	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.4 Mastery	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 CRQ quality of life; change; endpoint 60 weeks Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

3.1 Dyspnoea	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Fatigue	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 Emotional function	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.4 Mastery	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 All‐cause serious adverse events; endpoint 60 weeks Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5 Treatment‐related serious adverse events; endpoint 60 weeks Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6 Lung function (FEV₁ trough); change; endpoint 12 weeks Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

7 Lung function (FVC); change; endpoint 12 weeks Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

8 All‐cause mortality; endpoint 60 weeks Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

9 All‐cause adverse events; endpoint 60 weeks Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

10 Treatment‐related adverse events; endpoint 60 weeks Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

11 Lung function (FEV₁ % predicted); change; endpoint 60 weeks Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

12 Lung function (FEV₁ trough); change; endpoint 60 weeks Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

13 Lung function (FEV₁ % predicted); change; endpoint 12 weeks Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

14 Lung function (FVC); change; endpoint 60 weeks Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

Comparison 1. Macrolide+tetracycline versus macrolide

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Comparison 2. Quinolone versus tetracycline

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of people with one or more exacerbations Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Comparison 2. Quinolone versus tetracycline

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Comparison 3. Quinolone versus macrolide

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of people with one or more exacerbations Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Comparison 3. Quinolone versus macrolide

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Comparison 4. Macrolide versus tetracycline

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of people with one or more exacerbations Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Comparison 4. Macrolide versus tetracycline

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Comparación directa de antibióticos profilácticos orales para la enfermedad pulmonar obstructiva crónica

Appendices

Appendix 1. Sources and search methods for the Cochrane Airways Group's Specialised Register (CAGR)

Electronic searches: core databases

Handsearches: core respiratory conference abstracts

MEDLINE search strategy used to identify studies for the Cochrane Airways Trials Register

COPD search

Filter to identify RCTs

Appendix 2. Search strategy to identify relevant studies from the Cochrane Airways Trials Register

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Instituciones a las que se accedió previamente

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Appendices

Appendix 1. Sources and search methods for the Cochrane Airways Group's Specialised Register (CAGR)

Electronic searches: core databases

Handsearches: core respiratory conference abstracts

MEDLINE search strategy used to identify studies for the Cochrane Airways Trials Register

COPD search

Filter to identify RCTs

Appendix 2. Search strategy to identify relevant studies from the Cochrane Airways Trials Register

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Instituciones a las que se accedió previamente

Usuarios institucionales

Instituciones a las que se accedió previamente

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