Advice

Key points

Key points

The content of this evidence summary was up-to-date in April 2017. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Regulatory status: Tobramycin is an aminoglycoside antibiotic. Inhaled (nebuliser solution and inhalation powder) preparations, TOBI, Bramitob, Vantobra and TOBI podhaler are licensed for the management of chronic pulmonary infection caused by Pseudomonas aeruginosa in patients with cystic fibrosis aged 6 years and older. Use of inhaled tobramycin for treating infective exacerbations caused by Pseudomonas aeruginosa in non-cystic fibrosis bronchiectasis is off-label.

Overview

This evidence summary includes 3 randomised controlled trials that investigated the efficacy of nebulised tobramycin, 300 mg twice daily compared with placebo for treating infective exacerbations caused by P aeruginosa in people with non-cystic fibrosis bronchiectasis. The treatment duration varied across the studies from 4 weeks to 6 months.

Compared with placebo, statistically significant reductions were seen with 4 weeks to 6 months treatment with nebulised tobramycin in:

  • sputum P aeruginosa density (1 study)

  • number of hospital admissions and days in hospital (2 studies).

Compared with placebo, no statistically significant improvements were seen with nebulised tobramycin in:

Of the 2 studies that reported number of exacerbations as an outcome, when compared with placebo, 1 study found no statistically significant reduction in the number of exacerbations per person over 6 months treatment with tobramycin, and 1 study found a statistically significant reduction in the number of exacerbations over 3 months of treatment with tobramycin. One study found that more participants in the tobramycin group were classified by the investigators as having improved medical condition compared with placebo. However, this finding was limited as it was based on a subjective assessment that did not use a validated tool.

The studies included in the evidence summary had many limitations that affect their application to clinical practice. All studies included small numbers of participants (n=30 to 74) in the US or Spain. The study populations varied and it is unclear which patients might benefit most from treatment and for how long to treat infective exacerbations caused by P aeruginosa in people with non-cystic fibrosis bronchiectasis.

The adverse events seen in the studies reflect those listed in the SPC for TOBI (nebuliser solution). These include dyspnoea, chest pain, cough and bronchospasm.

The improvement in some of the reported outcomes in the studies must be balanced with the risk of experiencing adverse effects and the development of bacterial resistance. In current practice, when nebulised treatment is indicated for P aeruginosa infections in people with non-cystic fibrosis bronchiectasis, inhaled tobramycin is considered when treatment with other commonly used nebulised therapies is not tolerated, if the condition is deteriorating while on other nebulised antibiotics, or if cultures are sensitive to tobramycin.

A summary to inform local decision-making is shown in table 1.

Table 1 Summary of the evidence on effectiveness, safety, patient factors and resource implications

Effectiveness

  • At 12-month follow-up, Orriols et al. (2015) (n=35) found that 3 months' treatment with nebulised tobramycin showed a statistically significant reduction in the number of exacerbations compared with placebo (p=0.04).

  • Drobnic et al. (2005) (n=30) reported a statistically significant reduction in the number of hospital admissions with tobramycin compared with placebo (p=0.038). Orriols et al. (2015) also found a statistically significant reduction in the same outcome (p=0.04).

  • Drobnic et al. (2005) reported a statistically significant reduction in the number of days in hospital with tobramycin compared with placebo (p=0.047). Orriols et al. (2015) also found a statistically significant reduction in the same outcome (p=0.03).

  • After 4 weeks' treatment, Barker et al. (2000) (n=74) found a statistical significant mean decrease in sputum P aeruginosa density in the tobramycin group compared with placebo (p<0.01).

  • The optimal duration of treatment with inhaled tobramycin for treating non-cystic fibrosis bronchiectasis exacerbations caused by P aeruginosa has not been established. The risk of contributing to the emergence of bacterial resistance needs to be considered with prolonged antibiotic therapy.

Safety

  • According to the SPC for TOBI (nebuliser solution), very common adverse effects (incidence 1 in 10 or more) include lung disorder, rhinitis, dysphonia (difficulty in speaking), discoloured sputum and decreased pulmonary function test. Common adverse effects (incidence between 1 in 100 and 10 in 100) include laryngitis, tinnitus, myalgia and malaise.

  • The incidence of adverse effects varies between the different inhaled tobramycin preparations, see individual SPCs for Bramitob, Vantobra and TOBI podhaler for further information.

  • Four deaths in people using tobramycin and 1 death in a person using placebo caused by respiratory failure were reported during the studies, however it was not clear if the deaths were considered to be related to the study medication.

  • Eleven withdrawals caused by adverse effects were reported with tobramycin in the studies (mainly because of bronchospasm) compared with 2 withdrawals in the placebo groups.

  • Most common adverse effects reported in the studies included bronchospasm, cough, dyspnoea, chest pain, wheezing, haemoptysis and mild transient tinnitus.

Patient factors

  • Current clinical practice suggests baseline renal function should be assessed and urea and creatinine levels should be reassessed after every 6 complete cycles of inhaled tobramycin therapy (180 days total of aminoglycoside therapy; SPC: TOBI [nebuliser solution]).

  • The first dose of tobramycin should be given under medical supervision because bronchospasm can occur following inhalation of tobramycin and has been reported with inhaled preparations (SPC: TOBI [nebuliser solution]).

  • Some people may find it difficult or inconvenient to use a nebuliser.

  • Inhalation of nebulised solutions may induce a cough reflex (SPC: TOBI [nebuliser solution]).

  • The included studies did not investigate the efficacy and safety of inhaled tobramycin in children.

Resource implications

  • Two of the 3 studies in this evidence summary used the TOBI brand of tobramycin nebuliser solution. Costs for 28 days' treatment for TOBI at a dose of 300 mg twice daily as used in the studies would be £1,305.92 (Drug Tariff; March 2017).

  • Bramitob and Vantobra nebuliser solutions are also available in the UK; 28-day treatment costs for them based on the dose used for their licensed indications would be; £1,187.00, and £1,305.00 respectively (MIMS; March 2017).

  • One of the 3 studies in this evidence summary used tobramycin solution for injection as a nebulised therapy at a dose of 300 mg twice daily. However, specialists involved in the production of this evidence summary suggested that when the injection is used as a nebulised therapy, a dose of 80 mg to 160 mg twice a day is used in practice. Costs of 28 days' treatment using this preparation at a dose of 80 mg to 160 mg twice daily would cost £211.12 to £422.24 (BNF; March 2017).

  • These costs are for the medicine only and do not include VAT, any local procurement discounts or other costs incurred, such as dilution and administration or standard supportive therapy.

  • The acquisition cost of nebulised tobramycin is more than that of other inhaled antibiotics that are recommended by the British Thoracic Society for non-cystic fibrosis bronchiectasis.