Once‐daily versus multiple‐daily dosing with intravenous aminoglycosides for cystic fibrosis New search for studies and content updated (no change to conclusions)

Abstract

Abstract Background

People with cystic fibrosis, who are chronically colonised with the organism Pseudomonas aeruginosa, often require multiple courses of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations. The properties of aminoglycosides suggest that they could be given in higher doses less often. This is an update of a previously published review.

Objectives

To assess the effectiveness and safety of once‐daily versus multiple‐daily dosing of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations in cystic fibrosis.

Search methods

We searched the Cystic Fibrosis Specialist Register held at the Cochrane Cystic Fibrosis and Genetic Disorders Group's editorial base, comprising references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings.

Date of the most recent search: 31 January 2019.

We also searched online trial registries. Date of latest search: 25 February 2019.

Selection criteria

All randomised controlled trials, whether published or unpublished, in which once‐daily dosing of aminoglycosides has been compared with multiple‐daily dosing in terms of efficacy or toxicity or both, in people with cystic fibrosis.

Data collection and analysis

The two authors independently selected the studies to be included in the review and assessed the risk of bias of each study; authors also assessed the quality of the evidence using the GRADE criteria. Data were independently extracted by each author. Authors of the included studies were contacted for further information. As yet unpublished data were obtained for one of the included studies.

Main results

We identified 15 studies for possible inclusion in the review. Five studies reporting results from a total of 354 participants (aged 5 to 50 years) were included in this review. All studies compared once‐daily dosing with thrice‐daily dosing. One cross‐over trial had 26 participants who received the first‐arm treatment but only 15 received the second arm. One study had a low risk of bias for all criteria assessed; the remaining included studies had a high risk of bias from blinding, but for other criteria were judged to have either an unclear or a low risk of bias.

There was little or no difference between treatment groups in: forced expiratory volume in one second, mean difference (MD) 0.33 (95% confidence interval (CI) ‐2.81 to 3.48, moderate‐quality evidence); forced vital capacity, MD 0.29 (95% CI ‐6.58 to 7.16, low‐quality evidence); % weight for height, MD ‐0.82 (95% CI ‐3.77 to 2.13, low‐quality evidence); body mass index, MD 0.00 (95% CI ‐0.42 to 0.42, low‐quality evidence); or in the incidence of ototoxicity, relative risk 0.56 (95% CI 0.04 to 7.96, moderate‐quality evidence). Once‐daily treatment in children probably improved the percentage change in creatinine, MD ‐8.20 (95% CI ‐15.32 to ‐1.08, moderate‐quality evidence), but showed no difference in adults, MD 3.25 (95% CI ‐1.82 to 8.33, moderate‐quality evidence). The included trials did not report antibiotic resistance patterns or quality of life.

Authors' conclusions

Once‐ and three‐times daily aminoglycoside antibiotics appear to be equally effective in the treatment of pulmonary exacerbations of cystic fibrosis. There is evidence of less nephrotoxicity in children.

Author(s)

Jayesh Bhatt, Nikki Jahnke, Alan R Smyth

Abstract

Plain language summary

Giving aminoglycoside antibiotics intravenously once daily compared to giving them several times per day in people with cystic fibrosis

Review question

We looked for evidence to show the differences between giving intravenous antibiotics once daily compared to giving them several times a day when treating flare ups of disease (pulmonary exacerbations) in people with cystic fibrosis. This is an update of an earlier review.

Background

Most people with cystic fibrosis develop persistent lung infections and they may receive frequent courses of intravenous antibiotics to treat pulmonary exacerbations. Giving the antibiotics just once per day rather than several doses per day reduces the cost of treatment and the time involved.

Search date

The evidence is current to 31 January 2019.

Study characteristics

This review includes five studies with a total of 354 children and adults. All the trials compared once‐a‐day dosing with three times‐a‐day dosing.

Key results

The review found that when treating people with cystic fibrosis for pulmonary exacerbations, giving the antibiotics once per day was just as good at as giving them more frequently in terms of lung function and body mass index. The review also found that giving the antibiotics once per day appeared to be less toxic to the kidneys in children. There were no differences between the different treatment schedules for other outcomes that the studies measured.

While once‐daily treatment can be just as effective and more convenient than three‐times daily treatment, we recommend further studies to look at the long‐term safety of this treatment schedule.

Quality of the evidence

We judged that just one of the five studies carried a low risk that any design factors might affect the outcome results. In the remaining four studies, we thought that the fact that it was obvious whether the antibiotics were given once or three times a day could affect some outcome measures (e.g. lung function). Other risk factors were unclear or at low risk of bias. We assessed the evidence for lung function, body mass index and the evidence for side effects (e.g. toxicity) to be moderate to low quality.

Author(s)

Jayesh Bhatt, Nikki Jahnke, Alan R Smyth

Reviewer's Conclusions

Authors' conclusions

Implications for practice

Moderate‐ to low‐quality evidence found in this review has demonstrated no difference in efficacy between the two treatment regimens, although once daily appears less nephrotoxic in children. Once‐daily aminoglycoside treatment for pulmonary exacerbations of CF may be adopted as it is more convenient for people with cystic fibrosis (CF). For further details of once‐daily aminoglycoside treatment the authors would like to refer readers to the document "Antibiotic Treatment for Cystic Fibrosis" (CF Trust 2009).

Implications for research

Long‐term safety studies (which can be open‐label and non‐randomised) comparing the two regimens are desirable. Acute renal failure has been reported in association with the use of aminoglycosides in CF and the prevalence is 100 times higher in children with CF than in the general population (Bertenshaw 2007). The increased risk of renal failure is associated with gentamicin use, but not with tobramycin (Smyth 2008). Chronic exposure to aminoglycosides has been shown to be associated with reduced creatinine clearance (Al Aloul 2005). Further longitudinal studies are desirable measuring: cumulative effect on renal function; cumulative ototoxic effect; time to the next pulmonary exacerbation; quality of life and longitudinal changes in the antibiotic sensitivity of Pseudomonas aeruginosa.

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