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. 2022 Dec 13;12(12):CD009650.
doi: 10.1002/14651858.CD009650.pub5.

Interventions for the eradication of meticillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis

David Kh Lo  1 , Marianne S Muhlebach  2 , Alan R Smyth  3
Affiliations

Interventions for the eradication of meticillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis

David Kh Lo et al. Cochrane Database Syst Rev. .

Abstract

Background: Cystic fibrosis is an inherited recessive disorder of chloride transport that is characterised by recurrent and persistent pulmonary infections from resistant organisms that result in lung function deterioration and early mortality in sufferers. Meticillin-resistant Staphylococcus aureus (MRSA) has emerged not only as an important infection in people who are hospitalised, but also as a potentially harmful pathogen in cystic fibrosis. Chronic pulmonary infection with MRSA is thought to confer on people with cystic fibrosis a worse clinical outcome and result in an increased rate of lung function decline. Clear guidance for MRSA eradication in cystic fibrosis, supported by robust evidence, is urgently needed. This is an update of a previous review.

Objectives: To evaluate the effectiveness of treatment regimens designed to eradicate MRSA and to determine whether the eradication of MRSA confers better clinical and microbiological outcomes for people with cystic fibrosis. To ascertain whether attempts at eradicating MRSA can lead to increased acquisition of other resistant organisms (including Pseudomonas aeruginosa), increased adverse effects from drugs, or both.

Search methods: We identified randomised and quasi-randomised controlled trials by searching the Cochrane Cystic Fibrosis and Genetic Disorders (CFGD) Group's Cystic Fibrosis Trials Register, PubMed, MEDLINE and three clinical trials registries; by handsearching article reference lists; and through contact with experts in the field. We last searched the CFGD Group's Cystic Fibrosis Trials Register on 4 October 2021, and the ongoing trials registries on 31 January 2022.

Selection criteria: Randomised controlled trials (RCTs) or quasi-RCTs of any combinations of topical, inhaled, oral or intravenous antimicrobials primarily aimed at eradicating MRSA compared with placebo, standard treatment or no treatment.

Data collection and analysis: We used standard methodological procedures expected by Cochrane and used the GRADE methodology to assess the certainty of the evidence.

Main results: The review includes three RCTs with 135 participants with MRSA infection. Two trials compared active treatment versus observation only and one trial compared active treatment with placebo. Active treatment versus observation In both trials (106 participants), active treatment consisted of oral trimethoprim and sulfamethoxazole combined with rifampicin. One trial administered this combination for two weeks alongside nasal, skin and oral decontamination and a three-week environmental decontamination, while the second trial administered this drug combination for 21 days with five days intranasal mupirocin. Both trials reported successful eradication of MRSA in people with cystic fibrosis, but they used different definitions of eradication. One trial (45 participants) defined MRSA eradication as negative MRSA respiratory cultures at day 28, and reported that oral trimethoprim and sulfamethoxazole combined with rifampicin may lead to a higher proportion of negative cultures compared to control (odds ratio (OR) 12.6 (95% confidence interval (CI) 2.84 to 55.84; low-certainty evidence). However, by day 168 of follow-up, there was no difference between groups in the proportion of participants who remained MRSA-negative (OR 1.17, 95% CI 0.31 to 4.42; low-certainty evidence). The second trial defined successful eradication as the absence of MRSA following treatment in at least three cultures over a period of six months. We are uncertain if the intervention led to results favouring the treatment group as the certainty of the evidence was very low (OR 2.74, 95% CI 0.64 to 11.75). There were no differences between groups in the remaining outcomes for this comparison: quality of life, frequency of exacerbations or adverse effects (all low-certainty evidence) or the change from baseline in lung function or weight (both very low-certainty evidence). The time until next positive MRSA isolate was not reported. The included trials found no differences between groups in terms of nasal colonisation with MRSA. While not a specific outcome of this review, investigators from one study reported that the rate of hospitalisation from screening through day 168 was lower with oral trimethoprim and sulfamethoxazole combined with rifampicin compared to control (rate ratio 0.22, 95% CI 0.05 to 0.72; P = 0.01). Nebulised vancomycin with oral antibiotics versus nebulised placebo with oral antibiotics The third trial (29 participants) defined eradication as a negative respiratory sample for MRSA at one month following completion of treatment. No differences were reported in MRSA eradication between treatment arms (OR 1.00, 95% CI 0.14 to 7.39; low-certainty evidence). No differences between groups were seen in lung function or adverse effects (low-certainty evidence), in quality of life (very low-certainty evidence) or nasal colonisation with MRSA. The trial did not report on the change in weight or frequency of exacerbations. AUTHORS' CONCLUSIONS: Early eradication of MRSA is possible in people with cystic fibrosis, with one trial demonstrating superiority of active MRSA treatment compared with observation only in terms of the proportion of MRSA-negative respiratory cultures at day 28. However, follow-up at three or six months showed no difference between treatment and control in the proportion of participants remaining MRSA-negative. Moreover, the longer-term clinical consequences - in terms of lung function, mortality and cost of care - remain unclear. Using GRADE methodology, we judged the certainty of the evidence provided by this review to be very low to low, due to potential biases from the open-label design, high rates of attrition and small sample sizes. Based on the available evidence, we believe that whilst early eradication of respiratory MRSA in people with cystic fibrosis is possible, there is not currently enough evidence regarding the clinical outcomes of eradication to support the use of the interventions studied.

Trial registration: ClinicalTrials.gov NCT01594827 NCT01349192 NCT01746095 NCT03181932.

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Conflict of interest statement

David Lo: none known.

Marianne Muhlebach is one of the principle investigators for a randomised controlled trial evaluating early treatment of meticillin‐resistant Staphylococcus aureus (MRSA) (Muhlebach 2017). She has acted as a consultant for Nabriva Therapeutics (who produce an antibiotic for use in community‐acquired pneumonia) and participated in an advisory group meeting in 2021. This included a preview of material provided by the company and participation in a three‐hour online meeting.

Alan Smyth is the Co‐ordinating Editor of the Cochrane Cystic Fibrosis and Genetic Disorders Group and declares holding a patent for alkyl quinolones as biomarkers of Pseudomonas aeruginosa infection and uses thereof; however, he has not benefited from this financially.

Figures

1
1
PRISMA study flow diagram
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
1.1
1.1. Analysis
Comparison 1: Active treatment versus observation only, Outcome 1: Eradication of MRSA
1.2
1.2. Analysis
Comparison 1: Active treatment versus observation only, Outcome 2: FEV1 (L) ‐ absolute change from baseline
1.3
1.3. Analysis
Comparison 1: Active treatment versus observation only, Outcome 3: FEV1 (L) ‐ relative change from baseline
1.4
1.4. Analysis
Comparison 1: Active treatment versus observation only, Outcome 4: FEV1 (% predicted) ‐ absolute change from baseline
1.5
1.5. Analysis
Comparison 1: Active treatment versus observation only, Outcome 5: Overall antibiotic use
1.6
1.6. Analysis
Comparison 1: Active treatment versus observation only, Outcome 6: QoL measured using CFRSD Chronic Respiratory Infection Symptom Score (absolute change from baseline)
1.7
1.7. Analysis
Comparison 1: Active treatment versus observation only, Outcome 7: QoL measured using CFQ‐R Respiratory Symptom Score (absolute change from baseline)
1.8
1.8. Analysis
Comparison 1: Active treatment versus observation only, Outcome 8: Participants positive for Pseudomonas aeruginosa
1.9
1.9. Analysis
Comparison 1: Active treatment versus observation only, Outcome 9: Weight (kg) (absolute change from baseline)
1.10
1.10. Analysis
Comparison 1: Active treatment versus observation only, Outcome 10: BMI (change from baseline)
1.11
1.11. Analysis
Comparison 1: Active treatment versus observation only, Outcome 11: Adverse effects of treatment
1.12
1.12. Analysis
Comparison 1: Active treatment versus observation only, Outcome 12: Number of participants with pulmonary exacerbations
1.13
1.13. Analysis
Comparison 1: Active treatment versus observation only, Outcome 13: Mean number of pulmonary exacerbations
2.1
2.1. Analysis
Comparison 2: Treatment with oral antibiotics plus nebulised vancomycin versus oral antibiotics plus placebo, Outcome 1: Eradication of MRSA
2.2
2.2. Analysis
Comparison 2: Treatment with oral antibiotics plus nebulised vancomycin versus oral antibiotics plus placebo, Outcome 2: Adverse effects of treatment
2.3
2.3. Analysis
Comparison 2: Treatment with oral antibiotics plus nebulised vancomycin versus oral antibiotics plus placebo, Outcome 3: Elimination of MRSA carrier status (number of participants with negative nasal swabs for MRSA)
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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Dodd 1997 {published data only}
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EUCTR2007‐005346‐20‐GB {published data only}
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EUCTR2007‐006276‐11‐GB {published data only}
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EUCTR2009‐013660‐39‐FR {published data only}
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EUCTR2010‐023533‐34‐FR {published data only}
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EUCTR2016‐004033‐25‐ES {published data only}
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EUCTR2019‐003178‐25‐HU {published data only}
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Flume 2015 {published data only}
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Flume 2016 {published data only}
    1. Flume P, VanDevanter DR, Cohen F, Fleming R, Elborn JS. Safety profile of levofloxacin inhalation solution from 3 controlled cystic fibrosis trials. Journal of Cystic Fibrosis 2015;14 Suppl 1:S87. [ABSTRACT NO: 117] [CENTRAL: CN-01077213] [CFGD REGISTER: PI240f // PI283c // PI284c]
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References to other published versions of this review

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