Single versus combination intravenous anti‐pseudomonal antibiotic therapy for people with cystic fibrosis

Poppy Holland; Nikki Jahnke

doi:10.1002/14651858.CD002007.pub5

Tratamiento intravenoso con antibióticos antipseudomonas solos versus combinados para personas con fibrosis quística

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estudios excluidos
otras versiones publicadas

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Castellani C, Duff A, Bell SC, Heijerman HG, Munck A, Ratjen F, et al. ECFS best practice guidelines: the 2018 revision. Journal of Cystic Fibrosis 2018;17(2):153-78.

Cheng K, Smyth RL, Govan JR, Doherty C, Winstanley C, Denning N, et al. Spread of beta-lactam-resistant Pseudomonas aeruginosa in a cystic fibrosis clinic. Lancet 1996;348(9028):639-42.

Elbourne DR, Altman DG, Higgins JPT, Curtin F, Worthington HV, Vail A. Meta-analyses involving cross-over trials: methodological issues. International Journal of Epidemiology 2002;31(1):140-9.

Farrell P, Férec C, Macek M, Frischer T, Renner S, Riss K, et al. Estimating the age of p.(Phe508del) with family studies of geographically distinct European populations and the early spread of cystic fibrosis. European Journal of Human Genetics 2018;26(12):1832-9. [DOI: 10.1038/s41431-018-0234-z]

Flume, P A et al and the Clinical Practice Guidelines for Pulmonary Therapies Committee. Cystic Fibrosis Pulmonary Guidelines: Treatment of Pulmonary Exacerbations. American Journal of Respiratory and Critical Care Medicine 2008;180(9):802–808.

Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. American Journal of Respiratory and Critical Care Medicine 2003;168(8):918-51.

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327(7414):557-60.

Higgins JP, Altman DG, Sterne JA on behalf of the CSMG and the CBMG , editor(s). Chapter 8: Assessing risk of bias in included studies. In: Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.2 (updated June 2017). Cochrane, 2017. Available from training.cochrane.org/handbook/archive/v5.2.

Hoiby N. Antibiotic therapy for chronic infection of pseudomonas in the lung. Annual Review of Medicine 1993;44:1-10.

Katbamna B, Homnick DN, Marks JH. Contralateral suppression of distortion product otoacoustic emissions in children with cystic fibrosis: effects of tobramycin. Journal of the American Academy of Audiology 1998;9(3):172-8.

Kucers A, Crowe S, Grayson M, Hoy J (editors). The Use of Antibiotics: A Clinical Review of Antibacterial, Antifungal and Antiviral Drugs. 5th edition. Oxford: Hodder Arnold, 1997. [ISBN-10: 0750601558 ]

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Mulherin D, Fahy J, Grant W, Keogan M, Kavanagh B, FitzGerald M. Aminoglycoside induced ototoxicity in patients with cystic fibrosis. Irish Journal of Medical Science 1991;160(6):173-5.

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Referencias de otras versiones publicadas de esta revisión

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otras referencias

Elphick HE, Tan A, Ashby D, Smyth RL. Systematic reviews and lifelong diseases. BMJ 2002;325(7360):381-4.

Elphick HE, Tan AA. Single versus combination intravenous antibiotic therapy for people with cystic fibrosis. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No: CD002007. [DOI: 10.1002/14651858.CD002007.pub2]

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ir a:

estudios excluidos

Costantini 1982

*Study characteristics*
Methods	RCT. Duration: variable duration of course (mean (SD) 15 (3.4) days). Symptomatic regimen.
Participants	28 pulmonary exacerbations in 19 participants with CF. Age not given but stated that groups similar in age and disease severity. PsA colonised.
Interventions	Single antibiotic group 1: carbenicillin 675 mg/kg/day. Single antibiotic group 2: sisomycin 10.5 mg/kg/day. Combination antibiotic group: carbenicillin 590 mg/kg/day plus sisomycin 10 mg/kg/day.
Outcomes	CXR and symptom scores, bacteriology, development of resistant strains.
Notes	Abstract: no data. No withdrawals.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomly assigned, but no further details given.
Allocation concealment (selection bias)	Unclear risk	Not directly discussed, but referred to as a controlled clinical trial.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not discussed.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not discussed, but appears to be no withdrawals.
Selective reporting (reporting bias)	Unclear risk	Not clear, only published as an abstract and protocol not available.
Other bias	Unclear risk	None identified, but limited information as only published as an abstract.

Huang 1982

*Study characteristics*
Methods	Double‐blind RCT. Parallel design, 3‐arm* Duration: 10‐day course. Symptomatic regimen.
Participants	25 participants randomised. Age not stated. Mixed PsA and non‐PsA.
Interventions	Single antibiotic group (n = 6): ticarcillin 300 mg/kg/day. Combined antibiotic group 1 (n = 10): ticarcillin 300 mg/kg/day plus tobramycin 6 mg/kg/day. Combined antibiotic group 2 (n = 9): carbenicillin 500 mg/kg/day plus tobramycin 6 mg/kg/day.
Outcomes	Lung function, number readmitted within one month, CXR and symptom scores, bacteriology.
Notes	*originally tobramycin plus ticarcillin vs tobramycin vs carbenicillin vs placebo, but due to consent issues using placebo, ticarcillin alone substituted for placebo without breaking the code. Abstract: lung function, CXR and symptom score data not given. No withdrawals.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Mentions randomisation code, but no details given of how it was generated.
Allocation concealment (selection bias)	Unclear risk	Mentions randomisation code, but no details of how this may have been concealed.
Blinding (performance bias and detection bias) All outcomes	Low risk	Stated as double‐blind, but no further details given.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not discussed, but appears to be no drop outs or withdrawals.
Selective reporting (reporting bias)	Unclear risk	Not clear, only published as an abstract and protocol not available.
Other bias	Unclear risk	None identified, but limited information as only published as an abstract.

Master 1997

*Study characteristics*
Methods	Double‐blind RCT. Parallel trial. Duration: 10‐day course. Symptomatic regimen.
Participants	51 participants randomised (combination n = 22, single n = 29). Combination (tobramycin and ceftazidime) group: 21 participants with 51 admissions assessed; mean (SD) age 16 (7) years. Single (tobramycin) group: 23 participants with 47 admissions assessed; mean (SD) age 14 (5) years. 12 participants in the combination (tobramycin and ceftazidime) group and 9 participants in the single (tobramycin) group were eligible for long‐term assessment (at lease 2 admissions in 12 months). Participants in both groups experienced an average of 3.1 and 3.0 admissions, respectively, for IV antibiotic treatment during the study period.
Interventions	Single antibiotic group: tobramycin once daily (9 mg/kg/dose). Combination antibiotic group: tobramycin once daily (3 mg/kg/dose) plus ceftazidime 50 mg/kg/dose 8‐hourly. Participants given 6 syringes/day, in the combination group these were 3 each of tobramycin and ceftazidime, in the single group these were a single syringe of tobramycin and 5 syringes of sodium chloride (placebo).
Outcomes	Lung function, adverse events.
Notes	Full paper. Exclusion criteria stated. The trial was halted for a period of 3 months when one of the trial participants committed suicide by utilizing a trial syringe to administer a lethal substance. The trial was recommenced after the coroner's finding that this was an unrelated death. During this time of suspension, there were 14 admissions of participants previously enrolled. Data from these admissions were not included.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization was stratified for age and disease severity.
Allocation concealment (selection bias)	Low risk	The treatment code was broken only at the completion of the trial.
Blinding (performance bias and detection bias) All outcomes	Low risk	Medical staff, nursing staff and participants were blinded to the treatment. Participants given 6 syringes/day, in the combination group these were 3 each of tobramycin and ceftazidime, in the single group these were a single syringe of tobramycin and 5 syringes of sodium chloride (placebo).
Incomplete outcome data (attrition bias) All outcomes	Low risk	Flow chart showing numbers randomized and included/excluded (with reasons) at each stage in paper.
Selective reporting (reporting bias)	Low risk	Outcomes stated in the methods section were reported in the results section.
Other bias	Unclear risk	Power calculation undertaken to show an absolute difference in FEV₁ % predicted of 2%, but sample size not achieved.

McCarty 1988

*Study characteristics*
Methods	RCT. Parallel design (but 3 participants treated on more than one occasion ‐ see below). Duration: minimum of 10 days. Symptomatic regimen.
Participants	17 participants experiencing a pulmonary exacerbation. 3 participants treated on more than one occasion (2 initially in piperacillin group and several months later randomised to combination group; 1 participant enrolled 2x in piperacillin group). 20 data sets. Age, range: 2 to 12 years. Mixed PsA and non‐PsA.
Interventions	Single antibiotic group (n = 8): piperacillin 600 mg/kg/day. Combination antibiotic group (n = 9): piperacillin plus tobramycin 8 to 10 mg/kg/day. All participants also received intense chest physiotherapy and nutritional support.
Outcomes	Lung function, weight, symptom scores (Schwachman scale), adverse events, bacteriology.
Notes	No data for lung function, weight or symptom scores. No withdrawals.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Treatment randomly assigned, no further details.
Allocation concealment (selection bias)	Low risk	Used sequentially numbered envelopes.
Blinding (performance bias and detection bias) All outcomes	High risk	No details on blinding specified, not double‐blind.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Clear explanation of participants in groups, no drop outs occurred.
Selective reporting (reporting bias)	Unclear risk	Some clinical outcomes specified in the methods not directly reported and only summarised with a single narrative sentence.
Other bias	Low risk	None identified.

McLaughlin 1983

*Study characteristics*
Methods	Double‐blind RCT. Duration: 10 days with follow‐up after approximately 4 weeks. Symptomatic regimen. No ITT analysis.
Participants	60 participants originally enrolled and 51 completed. Age, mean (SD): 21 (5) years. PsA in 98%. Schwachman score, mean (SD), range: 60 (14), 36 ‐ 83. Age and Schwachman score similar across groups.
Interventions	Single antibiotic group (n = 16): azlocillin 300 mg/kg/day in 6 divided doses plus placebo (0.85% NaCl) in 3 divided doses. Combination antibiotic group 1 (n = 17): ticarcillin 300 mg/kg/day in 6 divided doses plus plus tobramycin 6 mg/kg/day in 3 divided doses. Combination antibiotic group 2 (n = 18): azlocillin 300 mg/kg/day in 6 divided doses plus tobramycin 6 mg/kg per day in 3 divided doses. All participants also received chest physiotherapy.
Outcomes	Lung function, symptom scores, development of resistant strains, time to next course.
Notes	Only data from the single antibiotic group and the azlocillin plus tobramycin group are presented in the review. Participants were white, of various socioeconomic backgrounds and lived in New England. Exclusion criteria stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Participants randomly selected, but no further details given.
Allocation concealment (selection bias)	Low risk	Hospital pharmacist used consecutively numbered sealed envelopes.
Blinding (performance bias and detection bias) All outcomes	Low risk	Neither participants or clinicians knew which regimen they were receiving.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	9 participants withdrew: 3 participants withdrawn for drug‐related complications (1 participant from single antibiotic group for haemoptysis; and 1 each from single antibiotic and ticarcillin plus tobramycin combination group for urticarial rash); 3 participants (1 from each group) discharged improved before completion of antibiotic course; 3 participants from single antibiotic group 3 withdrawn due to incomplete outcome data.
Selective reporting (reporting bias)	Low risk	Outcomes specified in methods reported in results.
Other bias	Low risk	None identified.

Parry 1977

*Study characteristics*
Methods	Quasi‐RCT (alternate allocation). Parallel trial. Duration: 14 days. Symptomatic regimen.
Participants	28 participants, but some enrolled on multiple occasions giving 42 courses/data sets. Total cohort: 21 male, 21 female, mean age 15.1 years. PsA colonised. 14 participants in each of 3 treatment groups. Group 1 (ticarcillin): 8 male, 6 female; mean (range) age 16.1 (2 ‐ 30) years. Group 2 (ticarcillin & gentamicin): 7 males, 7 females: mean (range) age 16.4 (4 ‐ 30) years. Group 3 (gentamicin): 6 males, 8 females; mean (range) 12.9 (5 ‐ 31) years. This was a control group from the same study period not part of the alternate allocation.
Interventions	Single group 1; ticarcillin 300 mg/kg/day, 4‐hourly. Single group 2: gentamicin 3 ‐ 4 mg/kg/day (adults), 4 ‐ 7 mg/kg/day (children). Combination group: ticarcillin 300 mg/kg/day, 4‐hourly plus gentamicin 3 ‐ 4 mg/kg/day (adults), 4 ‐ 7 mg/kg/day (children). All participants also received chest physiotherapy, bronchial drainage and aerosol therapy with mucolytics.
Outcomes	Lung function, bacteriology, adverse events, CBC, sedimentation rate, urinalysis, serum electrolytes, blood urea nitrogen, creatinine, liver function tests, chest radiographs, blood gas determinations, sputum cultures, change in cough, weight.
Notes	No data available. No withdrawals.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No discussion of how first participant was assigned to which treatment group.
Allocation concealment (selection bias)	High risk	Alternation.
Blinding (performance bias and detection bias) All outcomes	High risk	Drugs administered in different ways so clinicians and participants couldn't be blinded, no discussion of blinding of outcome assessors.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No drop outs or withdrawals.
Selective reporting (reporting bias)	High risk	Paper states that "pulmonary function tests were performed when possible", but no further details or results are given.
Other bias	Low risk	None identified.

Pedersen 1986

*Study characteristics*
Methods	RCT. Cross‐over design ‐ 3 months in between treatment arms. Duration: 14‐day course. Elective regimen.
Participants	20 participants; 3 drop outs, 17 completed trial. Age, mean: 12.6 years. Gender split: 10 male, 10 female. PsA colonised.
Interventions	Single antibiotic: ceftazidime 150 mg/kg/day, 8‐hourly. Combination antibiotic: ceftazidime plus tobramycin 10 mg/kg/day, 8‐hourly.
Outcomes	Lung function, inflammatory markers, development of resistant strains.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Described as randomised, but no details of method given.
Allocation concealment (selection bias)	Unclear risk	Not discussed.
Blinding (performance bias and detection bias) All outcomes	Low risk	Both interventions given with same volume and in same way. NJ: described as an open study ‐ so I interpret this to mean no blinding??
Incomplete outcome data (attrition bias) All outcomes	Low risk	3 participants excluded ‐ reasons given (bacteriological resistance developed between treatment arms in 2 participants and a 3rd withdrew on first day of 2nd treatment arm due to nausea).
Selective reporting (reporting bias)	Low risk	Outcomes stated in the methods section reported in the results.
Other bias	Low risk	None identified.

Smith 1999

*Study characteristics*
Methods	Double‐blind RCT. Parallel trial. Duration: 12 ‐ 14 days (but maximum duration of 31 days) with follow‐up 2 to 8 weeks later. Symptomatic regimen.
Participants	111 participants enrolled, 35 withdrawn. Total cohort (n = 76); mean (range) age 16.3 years (6 ‐ 18 years); 37 male, 39 female; PsA colonised. Single group (azlocillin) (n = 33): mean (SD) age 16.07 (7.4) years; 19 male, 14 female. Combination group (azlocillin plus tobramycin) (n = 43): mean (SD) age 16.53 (6.9) years; 18 male, 25 female.
Interventions	Single group: azlocillin 450 mg/kg/day, 4‐hourly plus placebo (5% dextrose in water), 6‐hourly. Combination group: azlocillin plus tobramycin 240 mg/m²/day, 6‐hourly.
Outcomes	Lung function, time to next admission, symptom scores, adverse events, bacteriology, inflammatory markers, resistant strains.
Notes	No data for symptom scores only narrative.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation balance by FVC and centre.
Allocation concealment (selection bias)	Low risk	Code generated by research pharmacist at the core centre.
Blinding (performance bias and detection bias) All outcomes	Low risk	Participants and clinicians blinded, serum concentrations monitored by unblinded 3rd party (research pharmacist).
Incomplete outcome data (attrition bias) All outcomes	Low risk	35 out of 111 participants withdrawn (21 from azlocillin group), reasons given in a table. SS: should this be unclear or high risk because more than 15% dropped out?
Selective reporting (reporting bias)	Unclear risk	Outcomes described in the methods are reported in the results, but some just brief narrative statements.
Other bias	Low risk	None identified.

CBC: complete blood count
CF: cystic fibrosis
CXR: chest x‐ray
ITT: intention‐to‐treat
PsA: Pseudomonas aeruginosa
RCT: randomised controlled trial

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos

Study	Reason for exclusion
Adeboyeku 2011	Comparison of twice daily vs three times daily antibiotics, not single vs combination.
Al‐Aloul 2004	Comparison of two single IV antibiotics, not single vs combination.
Al‐Aloul 2019	No single IV AB arm, both groups got two IV AB treatments and one group additionally got fosfomycin.
Al‐Ansari 2006	Comparison of once vs multiple daily dosing, not single vs combination.
Aminimanizani 2002	Comparison of single vs multiple daily dosing, not single vs combination.
Balsamo 1986	Comparison of single agent compared with 2 other antibiotics (i.e. drug A vs drug B plus drug C).
Beaudry 1980	Comparison of single agent compared with 2 other antibiotics (i.e. drug A vs drug B plus drug C).
Beringer 2012	Not a comparison of single vs combination antibiotics; a comparison of a single intravenous dose of an antibiotic and multiple oral doses of the same antibiotic.
Blumer 2005	Comparison of two combination regimens.
Bosso 1988	Comparison of single agent compared with 2 other antibiotics (i.e. drug A vs drug B plus drug C).
CFMATTERS 2017	Comparison of 2 antibiotics with the same 2 antibiotics plus a 3rd microbiome‐derived antibiotic treatment.
Church 1997	Comparison of single agent compared with 2 other antibiotics (i.e. drug A vs drug B plus drug C).
Conway 1997	Comparison of colistin with multiple antibiotic combinations.
De Boeck 1989	Comparison of single agent compared with 2 other antibiotics (i.e. drug A vs drug B plus drug C).
De Boeck 1999	Comparison of single agent compared with 2 other antibiotics (i.e. drug A vs drug B plus drug C).
Donati 1987	Home vs hospital therapy, not single vs combination.
Enaud 2017	Comparison of IV antibiotics and control, not single vs combination IV regimen.
Gold 1985	Comparison of single agent compared with 2 other antibiotics (i.e. drug A vs drug B plus drug C).
Hatziagorou 2013	Not a comparison of a single vs combination antibiotics; evaluation of tool to assess treatment response in children.
Hoogkamp 1983	Non‐randomised study: first 7 participants allocated to single treatment; next 7 to combination treatment with marked differences in baseline characteristics.
Hubert 2009	Comparison of intermittent vs continuous infusions, not single vs combination.
Hyatt 1981	Comparison of anti‐staphylococcal drug (oxacillin) vs oxacillin plus 2 anti‐pseudomonal drugs.
Jewett 1985	Comparison of single agent compared with 2 other antibiotics (i.e. drug A vs drug B plus drug C).
Keel 2011	Not a comparison of a single vs combination antibiotic; comparison of intravenous and oral versions of the same agent.
Kenny 2009	Study of eradication of Pseudomonas aeruginosa, not a comparison of single vs combination.
Krause 1979	Pseudo‐randomised study. Treatment and comparison groups were not sufficiently similar at baseline.
Kuni 1992	Not a comparison of single vs combination antibiotics.
Levy 1982	Comparison of 2 single agents.
McCabe 2013	Not a comparison of single vs combination antibiotics; evaluation of a twice‐daily tobramycin regimen.
Moskowitz 2011	Comparison of IV antibiotics using standard vs biofilm susceptibility testing of P. aeruginosa sputum isolates.
NCT01044719	Comparison of duration of antibiotic treatment not comparing single vs combination antibiotics.
NCT01667094	Comparison of intermittent vs continuous IV regimens, not a comparison of single vs combination antibiotics.
NCT01694069	Comparison of timing of administration of the same IV antibiotic combination, not single vs combination.
NCT02421120	Comparison of IV antibiotics, but not randomised.
NCT02918409	Comparison of 2 single antibiotics.
NCT03066453	Single IV vs combination IV antibiotics plus nebulised antibiotic.
Nelson 1985	Review article on single vs combination antibiotic treatment, i.e. not an RCT.
Noah 2010	Inhaled vs systemic antibiotics.
Padoan 1987	Reported number of courses of treatment instead of number of people included. Some participants may have been counted twice or included in both treatment group therefore analysis unclear.
Park 2018	Comparison of oral vs IV antibiotics for treating MRSA not Pseudomonas aeruginosa.
Permin 1983	Comparison of single agent compared with 2 other antibiotics (i.e. drug A vs drug B plus drug C).
Prayle 2016	Not a comparison of single vs combination antibiotics; comparison of morning vs evening intravenous tobramycin.
Riethmueller 2009	Continuous vs intermittent infusions.
Roberts 1993	Randomisation method unclear ‐ participants appeared to have been randomised to single or combination therapy each morning using a cross‐over method.
Semykin 2010	Not a comparison of single vs combination antibiotics; trial of inhaled tobramycin therapy.
Stack 1985	Comparison of single agent compared with two other antibiotics (i.e. drug A vs drug B plus drug C).
STOP 2 2018	Comparison of duration of antibiotic treatment not comparing single vs combination antibiotics.
TORPEDO 2018	An eradication trial comparing oral antibiotics plus inhaled antibiotics to IV antibiotics plus inhaled antibiotics ‐ so not a comparison of single or combination IV antibiotics.
Turner 2013	Not a comparison of single vs combination antibiotics; study of continuous vs intermittent infusion piperacillin‐tazobactam.
Wesley 1988	Comparison of single agent compared with 2 other antibiotics (i.e. drug A vs drug B plus drug C).
Whitehead 2002	Efficacy of once daily tobramycin, not a comparison of single vs combination agents.

CXR: chest X‐ray
IV: intravenous
vs: versus

Data and analyses

Open in table viewer

Comparison 1. Single versus combination antibiotics

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 FEV₁ % predicted (mean absolute values at end of course) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.1 Comparison 1: Single versus combination antibiotics, Outcome 1: FEV₁ % predicted (mean absolute values at end of course)
1.1.1 at 10 to 14 days	2	93	Mean Difference (IV, Fixed, 95% CI)	5.25 [‐9.14, 19.64]
1.1.2 at 2 to 8 weeks	1	41	Mean Difference (IV, Fixed, 95% CI)	0.50 [‐57.36, 58.36]
1.2 Mean FVC at end of course (% pred) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.2 Comparison 1: Single versus combination antibiotics, Outcome 2: Mean FVC at end of course (% pred)
1.2.1 at 10 to 14 days	2	93	Mean Difference (IV, Fixed, 95% CI)	1.84 [‐11.44, 15.12]
1.2.2 at 2 to 8 weeks	1	41	Mean Difference (IV, Fixed, 95% CI)	6.90 [‐50.50, 64.30]
1.3 Mean RV at end of course (% pred) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.3 Comparison 1: Single versus combination antibiotics, Outcome 3: Mean RV at end of course (% pred)
1.3.1 at 10 to 14 days	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.4 Mean TLC at end of course (% pred) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.4 Comparison 1: Single versus combination antibiotics, Outcome 4: Mean TLC at end of course (% pred)
1.4.1 at 10 to 14 days	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.5 Mean RV/TLC at end of course (% pred) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.5 Comparison 1: Single versus combination antibiotics, Outcome 5: Mean RV/TLC at end of course (% pred)
1.5.1 at 10 to 14 days	1	64	Mean Difference (IV, Fixed, 95% CI)	‐1.40 [‐40.68, 37.88]
1.5.2 At 2 to 8 weeks	1	40	Mean Difference (IV, Fixed, 95% CI)	‐5.20 [‐54.27, 43.87]
1.6 Mean PFR at end of course (% pred) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.6 Comparison 1: Single versus combination antibiotics, Outcome 6: Mean PFR at end of course (% pred)
1.6.1 at 10 to 14 days	2	91	Mean Difference (IV, Fixed, 95% CI)	3.21 [‐11.49, 17.91]
1.6.2 At 2 to 8 weeks	1	40	Mean Difference (IV, Fixed, 95% CI)	2.30 [‐60.90, 65.50]
1.7 Mean MMEF at end of course (% pred) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.7 Comparison 1: Single versus combination antibiotics, Outcome 7: Mean MMEF at end of course (% pred)
1.7.1 at 10 to 14 days	2	91	Mean Difference (IV, Fixed, 95% CI)	7.17 [‐8.22, 22.55]
1.7.2 At 2 to 8 weeks	1	40	Mean Difference (IV, Fixed, 95% CI)	‐1.90 [‐73.27, 69.47]
1.8 Number of Pseudomonas isolates eradicated at end of course Show forest plot	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.8 Comparison 1: Single versus combination antibiotics, Outcome 8: Number of Pseudomonas isolates eradicated at end of course
1.8.1 at 10 to 14 days	1	16	Peto Odds Ratio (Peto, Fixed, 95% CI)	6.34 [0.51, 78.02]
1.8.2 2 to 8 weeks	1	18	Peto Odds Ratio (Peto, Fixed, 95% CI)	10.16 [1.44, 71.65]
1.9 Mean change Pseudomonas density in cfu/g at end of course Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.9 Comparison 1: Single versus combination antibiotics, Outcome 9: Mean change Pseudomonas density in cfu/g at end of course
1.9.1 at 10 to 14 days	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.10 Number resistant strains of Pseudomonas aeruginosa Show forest plot	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.10 Comparison 1: Single versus combination antibiotics, Outcome 10: Number resistant strains of Pseudomonas aeruginosa
1.10.1 at baseline	2	140	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.83 [0.38, 1.82]
1.10.2 at 10 to 14 days	2	99	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.44 [0.94, 6.32]
1.10.3 at 2 to 8 weeks	2	76	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.44 [0.17, 1.14]
1.10.4 Difference from baseline at 2 to 8 weeks	1	29	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.27 [0.06, 1.18]
1.11 Number adverse events Show forest plot	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.11 Comparison 1: Single versus combination antibiotics, Outcome 11: Number adverse events
1.11.1 local erythema / irritation	2	131	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.46 [0.09, 2.36]
1.11.2 generalised rash	1	20	Peto Odds Ratio (Peto, Fixed, 95% CI)	6.16 [0.12, 316.67]
1.11.3 fever	1	20	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.81 [0.05, 14.14]
1.11.4 renal impairment (increased creatinine by 50%)	1	80	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.54 [0.15, 15.56]
1.11.5 auditory impairment	1	76	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.86 [0.11, 305.44]
1.11.6 proteinuria	1	63	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.62 [0.68, 19.30]
1.12 Number readmitted to hospital Show forest plot	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.12 Comparison 1: Single versus combination antibiotics, Outcome 12: Number readmitted to hospital
1.12.1 at 2 to 8 weeks	1	16	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.14 [0.01, 1.30]
1.12.2 in 80 days	1	76	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.30 [0.12, 0.73]
1.13 Mean time to next course of antibiotics (weeks) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.13 Comparison 1: Single versus combination antibiotics, Outcome 13: Mean time to next course of antibiotics (weeks)
1.14 Mean Schwachman score at end of course Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.14 Comparison 1: Single versus combination antibiotics, Outcome 14: Mean Schwachman score at end of course
1.15 Mean WBC count at end of course Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.15 Comparison 1: Single versus combination antibiotics, Outcome 15: Mean WBC count at end of course
1.15.1 at 10 to 14 days	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Analysis 1.1

Comparison 1: Single versus combination antibiotics, Outcome 1: FEV₁ % predicted (mean absolute values at end of course)

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Analysis 1.2

Comparison 1: Single versus combination antibiotics, Outcome 2: Mean FVC at end of course (% pred)

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Analysis 1.3

Comparison 1: Single versus combination antibiotics, Outcome 3: Mean RV at end of course (% pred)

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Analysis 1.4

Comparison 1: Single versus combination antibiotics, Outcome 4: Mean TLC at end of course (% pred)

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Analysis 1.5

Comparison 1: Single versus combination antibiotics, Outcome 5: Mean RV/TLC at end of course (% pred)

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Analysis 1.6

Comparison 1: Single versus combination antibiotics, Outcome 6: Mean PFR at end of course (% pred)

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Analysis 1.7

Comparison 1: Single versus combination antibiotics, Outcome 7: Mean MMEF at end of course (% pred)

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Analysis 1.8

Comparison 1: Single versus combination antibiotics, Outcome 8: Number of Pseudomonas isolates eradicated at end of course

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Analysis 1.9

Comparison 1: Single versus combination antibiotics, Outcome 9: Mean change Pseudomonas density in cfu/g at end of course

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Analysis 1.10

Comparison 1: Single versus combination antibiotics, Outcome 10: Number resistant strains of Pseudomonas aeruginosa

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Analysis 1.11

Comparison 1: Single versus combination antibiotics, Outcome 11: Number adverse events

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Analysis 1.12

Comparison 1: Single versus combination antibiotics, Outcome 12: Number readmitted to hospital

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Analysis 1.13

Comparison 1: Single versus combination antibiotics, Outcome 13: Mean time to next course of antibiotics (weeks)

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Analysis 1.14

Comparison 1: Single versus combination antibiotics, Outcome 14: Mean Schwachman score at end of course

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Analysis 1.15

Comparison 1: Single versus combination antibiotics, Outcome 15: Mean WBC count at end of course

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Summary of findings 1. Summary of findings: single compared with combination intravenous anti‐pseudomonal antibiotic therapy for people with cystic fibrosis ‐ short‐term effects

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (trials)	Quality of the evidence (GRADE)	Comments
Single compared with combination intravenous anti‐pseudomonal antibiotic therapy for people with cystic fibrosis ‐ short‐term effects
Patient or population: children and adults with cystic fibrosis Settings: inpatient or outpatient Intervention: combination IV antibiotic therapy Comparison: single IV antibiotic
	Assumed risk	Corresponding risk
	Single IV antibiotic therapy	Combined IV antibiotic therapy
Change in FEV₁ % predicted at end of antibiotic course: absolute post‐treatment values Follow‐up: 10 ‐ 14 days	The mean FEV₁ (% predicted) ranged across control groups from 46% to 50.9%.	The mean FEV₁ (% predicted) in the intervention groups was 5.25% higher (9.14% lower to 19.64% higher).	MD 5.25 (95% CI ‐9.14 to 19.64)	93 (2)	⊕⊕⊝⊝ low^a,b	3 further trials reported on this outcome, but it was not possible to include the data in our analyses. Master reported that the combination antibiotic group had a significantly higher FEV₁ % predicted after 10 days of treatment (P < 0.05) (Master 1997). McCarty reported a "similar improvement" in FEV₁ in both groups but no further detail (McCarty 1988). The elective trial reported higher median values for FEV₁ % predicted in the combination group at baseline and Day 14, but at Day 90 the median was higher in the single antibiotic group (Pedersen 1986).
Change in sputum P aeruginosa density at end of treatment (cfu/g) Follow‐up: 10 ‐ 14 days	The mean (SD) sputum P aeruginosa density was 6.9 cfu/g (15.5) in the control group.	The mean sputum P aeruginosa density in the intervention groups was 1.60 cfu/g lower. (9.51 cfu/g lower to 6.31 cfu/g higher).	MD ‐1.60 cfu/g (95% CI ‐9.51 to 6.31)	76 (1)	⊕⊕⊕⊝ moderate^b	2 further trials looked at bacterial concentration, but used different measures and reported within‐group differences only. McLaughlin reported a significant decrease in bacterial concentration (cfu/mL) in the combination group and a non‐significant decrease in the single antibiotic group (McLaughlin 1983). McCarty reported 5/19 P aeruginosa isolates in the single therapy group decreased in titre by more than 10² cfu/mL compared to 12/19 P aeruginosa isolates in the combination group (McCarty 1988).
Additional treatment required	This outcome was not measured in the short term.
Time to next course of antibiotics	This outcome was not reported in the short term.
Adverse events during treatment Follow‐up: 10 ‐ 14 days	There were no differences between single or combination IV antibiotic therapy: erythema at injection site, RR 0.46 (95% CI 0.09 to 2.36); generalised rash, RR 6.16 (95% CI 0.12 to 316.67); fever, RR 0.81 (95% CI 0.05 to 14.14); renal impairment, RR 1.54 (95% CI 0.15 to 15.56); auditory impairment, RR 5.86 (95% CI 0.11 to 305.44); and proteinuria, RR 3.62 (95% CI 0.68 to 19.30).		N/A	131 (2)	⊕⊕⊝⊝ low^b,c	4 further trials provided narrative information on adverse events. Master reported tinnitus in 2 participants (1 in each group) which was thought to be related to tobramycin (Master 1997). Parry reported phlebitis in 6 participants, eosinophilia in 5 participants and urticaria in 1 participant, all in the single antibiotic group (Parry 1977). The two remaining trials reported no serious adverse events or incidences of auditory problems or nephrotoxicity in either group (Costantini 1982; Pedersen 1986).
Quality of life	This outcome was not measured in the short term.
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). cfu: colony forming units; CI: confidence interval; FEV₁ : forced expiratory volume in 1 second; IV: intravenous; MD: mean difference; RR: risk ratio; SD: standard deviation.
GRADE Working Group grades of evidence High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: 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 certainty: we are very uncertain about the estimate.
a. Downgraded once as there was an unclear risk of bias across some domains across the two trials. In one trial the randomisation methods weren't described adequately and both trials had a high dropout rate. b. Downgraded once due to small sample size or low event rate, or both. c. Downgraded once due to risk of bias within one of the included trials, particularly in the domains of sequence generation and blinding.

Summary of findings 1. Summary of findings: single compared with combination intravenous anti‐pseudomonal antibiotic therapy for people with cystic fibrosis ‐ short‐term effects

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Summary of findings 2. Summary of findings: Single compared with combination intravenous anti‐pseudomonal antibiotic therapy for people with cystic fibrosis ‐ long‐term effects

Outcomes	*Illustrative comparative risks (95% CI)**		Comments
Single compared with combination intravenous anti‐pseudomonal antibiotic therapy for people with cystic fibrosis ‐ long‐term effects
Patient or population: children and adults with cystic fibrosis Settings: inpatient or outpatient Intervention: combination IV antibiotic therapy Comparison: single IV antibiotic
	Assumed risk	Corresponding risk
	Single IV antibiotic therapy	Combined IV antibiotic therapy
Change in FEV₁ (% predicted) Follow‐up: 6 months	This outcome was not reported.		1 trial reported that there was no significant difference in pulmonary function tests, with mean follow‐up time of 20 months; but further commented that sample size restricted statistical power (Master 1997).
Change in sputum P aeruginosa density at end of treatment (cfu/g)	This outcome was not reported in the long term.
Additional treatment required	This outcome was not reported in the long term.
Time to next course of antibiotics	This outcome was not reported in the long term.
Adverse events during treatment Follow‐up: 10 ‐ 14 days	This outcome was not reported in the long term.
Quality of life Follow‐up: 6 months or more	1 trial reported no statistically significant difference in NIH scores between treatment groups at the long‐term follow‐up (mean 20 months for both groups) (Master 1997).
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). cfu: colony forming units; CI: confidence interval; FEV₁ : forced expiratory volume in 1 second; IV: intravenous; NIH: National Institutes of Health.
GRADE Working Group grades of evidence High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: 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 certainty: we are very uncertain about the estimate.

Summary of findings 2. Summary of findings: Single compared with combination intravenous anti‐pseudomonal antibiotic therapy for people with cystic fibrosis ‐ long‐term effects

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Table 1. Lung function results (median (range)) from Pedersen 1986

Time point	Outcome	Combination antibiotics	Single antibiotic
Day 1	FEV₁ % predicted	56 (35 to 74)	53 (33 to 68)
Day 1	FVC % predicted	57 (39 to 79)	54 (38 to 67)
Day 14	FEV₁ % predicted	69 (56 to 83)	66 (52 to 81)
Day 14	FVC % predicted	72 (60 to 85)	64 (53 to 83)
Day 90	FEV₁ % predicted	53 (27 to 70)	55 (33 to 75)
Day 90	FVC % predicted	67 (33 to 76)	59 (45 to 80)
FEV₁: forced expiratory volume at 1 second FVC: forced vital capacity

Table 1. Lung function results (median (range)) from Pedersen 1986

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Comparison 1. Single versus combination antibiotics

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

1.1.1 at 10 to 14 days	2	93	Mean Difference (IV, Fixed, 95% CI)	5.25 [‐9.14, 19.64]
1.1.2 at 2 to 8 weeks	1	41	Mean Difference (IV, Fixed, 95% CI)	0.50 [‐57.36, 58.36]
1.2 Mean FVC at end of course (% pred) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.2.1 at 10 to 14 days	2	93	Mean Difference (IV, Fixed, 95% CI)	1.84 [‐11.44, 15.12]
1.2.2 at 2 to 8 weeks	1	41	Mean Difference (IV, Fixed, 95% CI)	6.90 [‐50.50, 64.30]
1.3 Mean RV at end of course (% pred) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.3.1 at 10 to 14 days	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.4 Mean TLC at end of course (% pred) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.4.1 at 10 to 14 days	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.5 Mean RV/TLC at end of course (% pred) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.5.1 at 10 to 14 days	1	64	Mean Difference (IV, Fixed, 95% CI)	‐1.40 [‐40.68, 37.88]
1.5.2 At 2 to 8 weeks	1	40	Mean Difference (IV, Fixed, 95% CI)	‐5.20 [‐54.27, 43.87]
1.6 Mean PFR at end of course (% pred) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.6.1 at 10 to 14 days	2	91	Mean Difference (IV, Fixed, 95% CI)	3.21 [‐11.49, 17.91]
1.6.2 At 2 to 8 weeks	1	40	Mean Difference (IV, Fixed, 95% CI)	2.30 [‐60.90, 65.50]
1.7 Mean MMEF at end of course (% pred) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.7.1 at 10 to 14 days	2	91	Mean Difference (IV, Fixed, 95% CI)	7.17 [‐8.22, 22.55]
1.7.2 At 2 to 8 weeks	1	40	Mean Difference (IV, Fixed, 95% CI)	‐1.90 [‐73.27, 69.47]
1.8 Number of Pseudomonas isolates eradicated at end of course Show forest plot	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

1.8.1 at 10 to 14 days	1	16	Peto Odds Ratio (Peto, Fixed, 95% CI)	6.34 [0.51, 78.02]
1.8.2 2 to 8 weeks	1	18	Peto Odds Ratio (Peto, Fixed, 95% CI)	10.16 [1.44, 71.65]
1.9 Mean change Pseudomonas density in cfu/g at end of course Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.9.1 at 10 to 14 days	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.10 Number resistant strains of Pseudomonas aeruginosa Show forest plot	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

1.10.1 at baseline	2	140	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.83 [0.38, 1.82]
1.10.2 at 10 to 14 days	2	99	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.44 [0.94, 6.32]
1.10.3 at 2 to 8 weeks	2	76	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.44 [0.17, 1.14]
1.10.4 Difference from baseline at 2 to 8 weeks	1	29	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.27 [0.06, 1.18]
1.11 Number adverse events Show forest plot	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

1.11.1 local erythema / irritation	2	131	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.46 [0.09, 2.36]
1.11.2 generalised rash	1	20	Peto Odds Ratio (Peto, Fixed, 95% CI)	6.16 [0.12, 316.67]
1.11.3 fever	1	20	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.81 [0.05, 14.14]
1.11.4 renal impairment (increased creatinine by 50%)	1	80	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.54 [0.15, 15.56]
1.11.5 auditory impairment	1	76	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.86 [0.11, 305.44]
1.11.6 proteinuria	1	63	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.62 [0.68, 19.30]
1.12 Number readmitted to hospital Show forest plot	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

1.12.1 at 2 to 8 weeks	1	16	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.14 [0.01, 1.30]
1.12.2 in 80 days	1	76	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.30 [0.12, 0.73]
1.13 Mean time to next course of antibiotics (weeks) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.14 Mean Schwachman score at end of course Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.15 Mean WBC count at end of course Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.15.1 at 10 to 14 days	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 1. Single versus combination antibiotics

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Referencias

Referencias de los estudios incluidos en esta revisión

Costantini 1982 {published data only}

Huang 1982 {published data only}

Master 1997 {published data only}

McCarty 1988 {published data only}

McLaughlin 1983 {published data only}

Parry 1977 {published data only}

Pedersen 1986 {published data only}

Smith 1999 {published data only}

Referencias de los estudios excluidos de esta revisión

Adeboyeku 2011 {published data only}

Al‐Aloul 2004 {published data only}

Al‐Aloul 2019 {published data only}

Al‐Ansari 2006 {published data only}

Aminimanizani 2002 {published data only}

Balsamo 1986 {published data only}

Beaudry 1980 {published data only}

Beringer 2012 {published data only}

Blumer 2005 {published data only}

Bosso 1988 {published data only}

CFMATTERS 2017 {published data only}

Church 1997 {published data only}

Conway 1997 {published data only}

De Boeck 1989 {published data only}

De Boeck 1999 {published data only}

Donati 1987 {published data only}

Enaud 2017 {published data only}

Gold 1985 {published data only}

Hatziagorou 2013 {published data only}

Hoogkamp 1983 {published data only}

Hubert 2009 {published data only}

Hyatt 1981 {published data only}

Jewett 1985 {published data only}

Keel 2011 {published data only}

Kenny 2009 {published data only}

Krause 1979 {published data only}

Kuni 1992 {published data only}

Levy 1982 {published data only}

McCabe 2013 {published data only}

Moskowitz 2011 {published data only}

NCT01044719 {published data only}

NCT01667094 {published data only}

NCT01694069 {published data only}

NCT02421120 {published data only}

NCT02918409 {published data only}

NCT03066453 {published data only}

Nelson 1985 {published data only}

Noah 2010 {published data only}

Padoan 1987 {published data only}

Park 2018 {published data only}

Permin 1983 {published data only}

Prayle 2016 {published data only}

Riethmueller 2009 {published data only}

Roberts 1993 {published data only}

Semykin 2010 {published data only}

Stack 1985 {published data only}

STOP 2 2018 {published data only}

TORPEDO 2018 {published data only}

Turner 2013 {published data only}

Wesley 1988 {unpublished data only}

Whitehead 2002 {published data only}

Referencias adicionales

Cantin 1995

Castellani 2018

Cheng 1996

Elbourne 2002

Farrell 2018

Flume 2008

Gibson 2003

Higgins 2003

Higgins 2017

Hoiby 1993

Katbamna 1998

Kucers 1997

Levy 1998

Mulherin 1991

Prayle 2010