Giving antibiotics regularly to people with cystic fibrosis to prevent lung infection with a germ called

Review question

We reviewed the evidence about the benefits and adverse effects of giving regular antibiotics to people with cystic fibrosis to prevent lung infection with a germ called Staphylococcus aureus.

Background

Cystic fibrosis blocks the airways with mucus and causes frequent airway infections. Over time, these can lead to lung damage and breathing failure. Most deaths in CF are caused by breathing failure. People with cystic fibrosis are sometimes given regular antibiotics to prevent infections from a germ called Staphylococcus aureus. However, antibiotics can also have side effects such as oral thrush or diarrhoea and long term use might lead to other more serious kinds of infection. This is an update of a previously published review.

Search date

The evidence is current to: 27 February 2020.

Study characteristics

The review includes four studies with 401 children; there were no adult studies. The children were put into groups at random and received either an oral antibiotic continuously as a prevention for at least one year or no antibiotic treatment to prevent infection with Staphylococcus aureus. All children could be given additional antibiotics if their doctor thought they needed them, based on symptoms and germs grown in their respiratory secretions. Studies lasted for a maximum of six years.

Key results

The review found some low-quality evidence that giving regular antibiotics to young children (continued up to six years of age) may lead to fewer infections with Staphylococcus aureus. For other outcomes in the review (weight, need for additional antibiotics, side effects or the number of infections with Pseudomonas aeruginosa) there was no difference between giving regular antibiotics or not. Since none of the studies lasted longer than six years, we can't draw any conclusions about long-term use. Also, since all studies were in children, we can not comment on the use of these drugs in adults. Future research should seek more fully to address whether this treatment reduces, increases or has no effect on subsequent rates of infection with Pseudomonas aeruginosa and look at patterns of antibiotic resistance and survival. A large ongoing study called CF-START aims to address these uncertainties.

Quality of the evidence

Overall, the quality of the evidence was concerning. All the studies were of variable quality and we judged the quality of the evidence to be low for the outcomes we assessed. We judged that the two older studies had a higher risk of bias overall compared to the two newer studies. In particular this was because those taking part in the studies (or their parents or caregivers) would be able to guess which treatment they were receiving, and also one study did not state if anyone had dropped out and if so what the reasons were. Only the newest study seemed to be free of bias, although even here we were not certain if the study results were distorted by the way the data were analysed. Given these concerns, if results from future trials confirm the current findings, it would increase our certainty in our conclusions.

Authors' conclusions: 

Anti-staphylococcal antibiotic prophylaxis may lead to fewer children having isolates of Staphylococcus aureus, when commenced early in infancy and continued up to six years of age. The clinical importance of this finding is uncertain. Further research may establish whether the trend towards more children with CF with Pseudomonas aeruginosa, after four to six years of prophylaxis, is a chance finding and whether choice of antibiotic or duration of treatment might influence this.

Read the full abstract...
Background: 

Staphylococcus aureus causes pulmonary infection in young children with cystic fibrosis. Prophylactic antibiotics are prescribed hoping to prevent such infection and lung damage. Antibiotics have adverse effects and long-term use might lead to infection with Pseudomonas aeruginosa. This is an update of a previously published review.

Objectives: 

To assess continuous oral antibiotic prophylaxis to prevent the acquisition of Staphylococcus aureus versus no prophylaxis in people with cystic fibrosis, we tested the following hypotheses to investigate whether prophylaxis:
1. improves clinical status, lung function and survival;
2. leads to fewer isolates of Staphylococcus aureus;
3. causes adverse effects (e.g. diarrhoea, skin rash, candidiasis);
4. leads to fewer isolates of other common pathogens from respiratory secretions;
5. leads to the emergence of antibiotic resistance and colonisation of the respiratory tract with Pseudomonas aeruginosa.

Search strategy: 

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Companies manufacturing anti-staphylococcal antibiotics were contacted.

Most recent search of the Group's Register: 27 February 2020.

Online trials registries were also searched. Most recent search of online trials registries: 15 September 2020.

Selection criteria: 

Randomised trials of continuous oral prophylactic antibiotics (given for at least one year) compared to intermittent antibiotics given 'as required', in people with cystic fibrosis of any disease severity.

Data collection and analysis: 

The authors assessed studies for eligibility and methodological quality and extracted data. The quality of the evidence was assessed using the GRADE criteria. The review's primary outcomes of interest were lung function by spirometry (forced expiratory volume in one second (FEV1)) and the number of people with one or more isolates of Staphylococcus aureus (sensitive strains).

Main results: 

We included four studies, with a total of 401 randomised participants aged zero to seven years on enrolment; one study is ongoing. The two older included studies generally had a higher risk of bias across all domains, but in particular due to a lack of blinding and incomplete outcome data, than the two more recent studies. We only regarded the most recent study as being generally free of bias, although even here we were not certain of the effect of the per protocol analysis on the study results. Evidence quality was judged to be low for all outcomes assessed after being downgraded based on GRADE assessments . Downgrading decisions were due to limitations in study design (all outcomes), for imprecision and for inconsistency .

Prophylactic anti-staphylococcal antibiotics probably make little or no difference to lung function measured as FEV1 % predicted after six years (mean difference (MD) -2.30, 95% confidence interval (CI) -13.59 to 8.99, one study, n = 119, low-quality evidence); but may reduce the number of children having one or more isolates of Staphylococcus aureus at two years (odds ratio (OR) 0.21, 95% CI 0.13 to 0.35, three studies, n = 315, low-quality evidence). At the same time point, there may be little or no effect on nutrition as reported using weight z score (MD 0.06, 95% CI -0.33 to 0.45, two studies, n = 140, low-quality evidence), additional courses of antibiotics (OR 0.18, 95% CI 0.01 to 3.60, one study, n = 119, low-quality evidence) or adverse effects (low-quality evidence). There was no difference in the number of isolates of Pseudomonas aeruginosa between groups at two years (OR 0.74, 95% CI 0.45 to 1.23, three studies, n = 312, low-quality evidence), though there was a trend towards a lower cumulative isolation rate of Pseudomonas aeruginosa in the prophylaxis group at two and three years and towards a higher rate from four to six years. As the studies reviewed lasted six years or less, conclusions cannot be drawn about the long-term effects of prophylaxis.

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