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

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.

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

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 as, not only 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 people with cystic fibrosis with 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 P aeruginosa) or increased adverse effects from drugs, or both. SEARCH METHODS: Randomised and quasi-randomised controlled trials were identified by searching the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, PubMed, MEDLINE, clinical trial registries (Clinicaltrials.gov, WHO ICTRP, ISRCTN Registry), handsearching article reference lists and through contact with experts in the field.Date of the last search of the Group's Cystic Fibrosis Trials Register: 27 July 2017.Ongoing trials registries were last searched: 07 August 2017. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing any combinations of topical, inhaled, oral or intravenous antimicrobials with the primary aim of eradicating MRSA compared with placebo, standard treatment or no treatment. DATA COLLECTION AND ANALYSIS: The authors independently assessed all search results for eligibility. They used the GRADE methodology to assess the quality of the evidence. MAIN RESULTS: The review includes two trials with a total of 106 participants with MRSA infection. In both trials the active treatment was oral trimethoprim and sulfamethoxazole combined with rifampicin; however, 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. In both trials the control arm was observation only.Both trials reported successful eradication of MRSA in people with CF as an outcome; however, the definition used for MRSA eradication differed. The first trial (n = 45) defined MRSA eradication as negative MRSA respiratory cultures at day 28, and reported that, when compared to control, oral trimethoprim and sulfamethoxazole combined with rifampicin may lead to a higher proportion of negative cultures, 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 in the proportion of participants who remained MRSA-negative in either treatment arm, OR 1.17 (95% CI 0.31 to 4.42) (low-quality evidence). In the second trial, successful eradication was defined as the absence of MRSA following treatment (oral co-trimoxazole and rifampicin with intranasal mupirocin or observation) in at least three cultures over a period of six months. At the time of reporting, 40 out of 61 participants had completed follow-up, but results showed no difference between groups. Eradication was achieved in 12 out 29 participants (41%) receiving active treatment, and in 9 out of 32 participants (28%) on the observation arm, OR 1.80 (95% CI 0.62 to 5.25) (very low-quality evidence).With regards to this review's secondary outcomes, these were reported in the first trial only. The trial reports that no differences were observed between the two arms in terms of pulmonary exacerbations (from screening to day 28), nasal colonisation, lung function, weight or participant-reported outcomes. While not a specific outcome of this review, investigators 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 = 0.0102). 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, by six months, the proportion of participants who remained MRSA-negative did not differ between treatment arms in either trial. Moreover, the longer-term clinical consequences in terms of lung function, mortality and cost of care, remain unclear.Using GRADE methodology, we judged the quality of the evidence provided by this review to be very low to low, due to potential biases from the open-label design and unclear detail reported in one trial. Based on the available evidence, it is the opinion of the authors 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.