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Meta-Analysis
. 2021 Jun 23;6(6):CD002007.
doi: 10.1002/14651858.CD002007.pub5.

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

Poppy Holland  1 , Nikki Jahnke  2
Affiliations
Meta-Analysis

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

Poppy Holland et al. Cochrane Database Syst Rev. .

Abstract

Background: The choice of antibiotic, and the use of single or combined therapy are controversial areas in the treatment of respiratory infection due to Pseudomonas aeruginosa in cystic fibrosis (CF). Advantages of combination therapy include wider range of modes of action, possible synergy and reduction of resistant organisms; advantages of monotherapy include lower cost, ease of administration and reduction of drug-related toxicity. Current evidence does not provide a clear answer and the use of intravenous antibiotic therapy in CF requires further evaluation. This is an update of a previously published review.

Objectives: To assess the effectiveness of single compared to combination intravenous anti-pseudomonal antibiotic therapy for treating people with CF.

Search methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search of the Group's Trials Register: 07 October 2020. We also searched online trials registries on 16 November 2020.

Selection criteria: Randomised controlled trials (RCTs) comparing a single intravenous anti-pseudomonal antibiotic with a combination of that antibiotic plus a second anti-pseudomonal antibiotic in people with CF.

Data collection and analysis: Two authors independently assessed trial quality and extracted data. We assessed the certainty of the data using GRADE.

Main results: We identified 59 trials, of which we included eight trials (356 participants) comparing a single anti-pseudomonal agent to a combination of the same antibiotic and one other. There was a wide variation in the individual antibiotics used in each trial. In total, the trials included seven comparisons of a beta-lactam antibiotic (penicillin-related or third generation cephalosporin) with a beta-lactam-aminoglycoside combination and three comparisons of an aminoglycoside with a beta-lactam-aminoglycoside combination. There was considerable heterogeneity amongst these trials, leading to difficulties in performing the review and interpreting the results. These results should be interpreted cautiously. Six of the included trials were published between 1977 and 1988; these were single-centre trials with flaws in the randomisation process and small sample size. Overall, the methodological quality was poor and the certainty of the evidence ranged from low to moderate. The review did not find any differences between monotherapy and combination therapy in either the short term or in the long term for the outcomes of different lung function measures, bacteriological outcome measures, need for additional treatment, adverse effects, quality of life or symptom scores.

Authors' conclusions: The results of this review are inconclusive. The review raises important methodological issues. There is a need for an RCT which needs to be well-designed in terms of adequate randomisation allocation, blinding, power and long-term follow-up. Results need to be standardised to a consistent method of reporting, in order to validate the pooling of results from multiple trials.

Trial registration: ClinicalTrials.gov NCT02781610.

PubMed Disclaimer

Conflict of interest statement

Dr Poppy Holland has no potential conflict of interest to declare.

Nikki Jahnke has no potential conflict of interest to declare.

Figures

1.1
1.1. Analysis
Comparison 1: Single versus combination antibiotics, Outcome 1: FEV1 % predicted (mean absolute values at end of course)
1.2
1.2. Analysis
Comparison 1: Single versus combination antibiotics, Outcome 2: Mean FVC at end of course (% pred)
1.3
1.3. Analysis
Comparison 1: Single versus combination antibiotics, Outcome 3: Mean RV at end of course (% pred)
1.4
1.4. Analysis
Comparison 1: Single versus combination antibiotics, Outcome 4: Mean TLC at end of course (% pred)
1.5
1.5. Analysis
Comparison 1: Single versus combination antibiotics, Outcome 5: Mean RV/TLC at end of course (% pred)
1.6
1.6. Analysis
Comparison 1: Single versus combination antibiotics, Outcome 6: Mean PFR at end of course (% pred)
1.7
1.7. Analysis
Comparison 1: Single versus combination antibiotics, Outcome 7: Mean MMEF at end of course (% pred)
1.8
1.8. Analysis
Comparison 1: Single versus combination antibiotics, Outcome 8: Number of Pseudomonas isolates eradicated at end of course
1.9
1.9. Analysis
Comparison 1: Single versus combination antibiotics, Outcome 9: Mean change Pseudomonas density in cfu/g at end of course
1.10
1.10. Analysis
Comparison 1: Single versus combination antibiotics, Outcome 10: Number resistant strains of Pseudomonas aeruginosa
1.11
1.11. Analysis
Comparison 1: Single versus combination antibiotics, Outcome 11: Number adverse events
1.12
1.12. Analysis
Comparison 1: Single versus combination antibiotics, Outcome 12: Number readmitted to hospital
1.13
1.13. Analysis
Comparison 1: Single versus combination antibiotics, Outcome 13: Mean time to next course of antibiotics (weeks)
1.14
1.14. Analysis
Comparison 1: Single versus combination antibiotics, Outcome 14: Mean Schwachman score at end of course
1.15
1.15. Analysis
Comparison 1: Single versus combination antibiotics, Outcome 15: Mean WBC count at end of course
See this image and copyright information in PMC

Update of

References

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Riethmueller 2009 {published data only}
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Roberts 1993 {published data only}
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Semykin 2010 {published data only}
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Stack 1985 {published data only}
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    1. Stack BHR, Geddes DM, Williams KJ, Dinwiddie R, Selkon JB, Godfrey RC. Ceftazidime compared with a combination of gentamicin and carbenicillin in cystic fibrosis patients with persistent pulmonary pseudomonas infection and an acute exacerbation of respiratory symptoms [abstract]. In: 9th International Cystic Fibrosis Congress; 1984 June 9-15; Brighton, England. 1984:4.16. [CFGD REGISTER: PI37b]
STOP 2 2018 {published data only}
    1. Flume PA, Heltshe SL, West NE, Vandevanter DR, Sanders DB, Skalland M, et al. Design, enrollment, and feasibility of the STOP-2 randomised study of intravenous antibiotic treatment duration in cystic fibrosis pulmonary exacerbations. Journal of Cystic Fibrosis 2018;17 Suppl 3:S85. [CENTRAL: CN-01746294] [CFGD REGISTER: PI298a] [EMBASE: 622930903]
    1. Heltshe S, West NE, VanDevanter DR, Sanders DB, Skalland M, Beckett V, et al. Design, enrolment, and feasibility of the STOP-2 randomised study of iv antibiotic duration in CF pulmonary exacerbations. Pediatric Pulmonology 2017;52(Suppl 47):388. [CENTRAL: CN-01430878] [CFGD REGISTER: PI298b] [EMBASE: 619069634]
    1. Heltshe SL, West NE, VanDevanter DR, Sanders DB, Beckett VV, Flume PA, et al. Study design considerations for the Standardized Treatment of Pulmonary Exacerbations 2 (STOP2): a trial to compare intravenous antibiotic treatment durations in CF. Contemporary Clinical Trials 2018;64:35-40. [CENTRAL: CN-01668982] [CFGD REGISTER: PI298c] [EMBASE: 624669955] [PMID: ] - PMC - PubMed
    1. Sanders DB, Heltshe S, West NE, VanDevanter DR, Skalland M, Flume P, et al. Update on the STOP-2 randomized study of IV antibiotic duration in CF pulmonary exacerbations. Pediatric Pulmonology 2018;53(S2):324. [CENTRAL: CN-01738944] [CFGD REGISTER: PI298d] [EMBASE: 624049033]
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TORPEDO 2018 {published data only}
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    1. EUCTR2009-012575-10-SE. Trial of optimal therapy for pseudomonas eradication in cystic fibrosis - TORPEDO-CF. www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2009-012575-10-SE (first received 16 November 2016). [CENTRAL: CN-01798235] [CFGD REGISTER: PI299d]
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Turner 2013 {published data only}
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Wesley 1988 {unpublished data only}
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Whitehead 2002 {published data only}
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    1. Whitehead A, Conway SP, Etherington C, Caldwell NA, Setchfield N, Bogle S. Once-daily tobramycin in the treatment of adult patients with cystic fibrosis. European Respiratory Journal 2002;19(2):303-9. [CFGD REGISTER: PI149c] - PubMed
    1. Whitehead A, Conway SP, Etherington C, Dave J. Efficacy and safety of once daily tobramycin in treating acute respiratory exacerbations in adult patients [abstract]. The Netherlands Journal of Medicine 1999;54(Suppl):S36-7. [CFGD REGISTER: PI149a]

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References to other published versions of this review

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