Review question
We looked for evidence for the effects of different ways of clearing meticillin-resistant Staphylococcus aureus (MRSA), a so-called 'superbug', from the lungs of people with cystic fibrosis.
Background
MRSA is a type of bacteria resistant to some types of antibiotics (medicines that kill or inhibit bacteria). Because MRSA is hard to treat, it is sometimes called a 'superbug'. Infection with MRSA is particularly worrying for people with cystic fibrosis, an inherited condition which, amongst other things, causes thick mucus to build up in the lungs. It is very difficult for people with cystic fibrosis to cough up this thick mucus, making it an ideal breeding ground for bacteria, including MRSA, and making these people more prone to chest infections. It is thought that MRSA can cause more damage than other bacteria which are not resistant to antibiotics. We wanted to identify research evidence to support the best way for treating MRSA infections and also to see if this treatment would improve the lives of people with cystic fibrosis. This is an update of a previously published review.
Search date
The evidence is current to 31 January 2022.
Key results
We found three studies which included 135 people with cystic fibrosis and a diagnosed MRSA infection.
Two studies (106 people) compared treatment given to one group of people versus observation only of a second group of people. In one of these studies, people in the active treatment group were given oral trimethoprim and sulfamethoxazole combined with rifampicin (all three are antibiotic medicines), plus additional decontamination treatment. In the second trial, people in the active treatment group were given two antibiotics orally (co-trimoxazole and rifampicin) and one by nose spray (mupirocin).
The results of these studies showed that clearing MRSA from the airways of people with cystic fibrosis is possible. In both trials, a larger proportion of those who were treated cleared MRSA. However, some people who were untreated also cleared MRSA spontaneously. Also, six months after treatment, the number of individuals who still had MRSA was not different between those who had received treatment and those who had not. We found no differences between treatment groups in quality of life, frequency of exacerbations (that is, flare-ups of the disease), unwanted or harmful effects of treatment, nasal colonisation with MRSA, or in changes in lung function or weight. The studies did not report the length of time until finding the next positive MRSA result in participants. In one of the studies, fewer people who were treated with antibiotics were admitted to hospital in the first 168 days.
The third study compared treatment groups who were given either an inhaled antibiotic or an inhaled placebo (inactive substance). Both groups were also given the same oral antibiotics. In this study, there was no difference between groups in MRSA clearance. There were no differences between groups in lung function, quality of life, unwanted or harmful effects or nasal colonisation with MRSA. The trial did not report on change in weight or frequency of exacerbations.
Treating MRSA early in people with cystic fibrosis has been shown to be possible, but it is not clear what longer-term implications this treatment will have.
Main limitations of the evidence
We had little or no confidence in the evidence we found for the different outcomes. This was due to potential issues from the study designs, where people knew which treatment each participant was receiving (groups were either given medication or just observed), and because there were small numbers of people in each study.
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.
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.
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.
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.
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.
We used standard methodological procedures expected by Cochrane and used the GRADE methodology to assess the certainty of the evidence.
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.