Overview for healthcare professionals

Regulatory status of colistimethate sodium

Colistimethate sodium powder for nebuliser solution is licensed for treating pulmonary infections caused by Pseudomonas aeruginosa in people with cystic fibrosis. It is available as Colomycin injection (1 or 2 million international units) and Promixin (1 million international units). A dry powder inhaler (Colobreathe, 1.6625 million international units) is also licensed for treating chronic pulmonary infections caused by P. aeruginosa in people with cystic fibrosis, but only in people aged 6 years or older.

Use of nebulised or inhaled colistimethate sodium for non-cystic fibrosis bronchiectasis is off-label. In line with the guidance from the General Medical Council (GMC), it is the responsibility of the prescriber to determine the clinical need of the patient and the suitability of using colistimethate sodium outside its authorised indications.

The manufacturer of Promixin, Profile Pharma, has indicated that it plans to apply for a UK marketing authorisation in 2–3 years for nebulised colistimethate sodium for treating chronic P. aeruginosa infections.

Evidence statements

  • No published randomised controlled trials (RCTs) have investigated nebulised or inhaled colistimethate sodium for non-cystic fibrosis bronchiectasis.

  • Four case series were identified that reported use of nebulised colistimethate sodium in people with non-cystic fibrosis bronchiectasis and bronchial colonisation with P. aeruginosa. Two of the case series also included people with chronic obstructive pulmonary disease.

  • White et al. (2012) (n=30) found that a Pseudomonas eradication protocol that included 3 months of nebulised colistimethate sodium (2 million units twice daily with other oral or intravenous antibiotics) statistically significantly reduced the mean number of exacerbations from 3.93 per year to 2.09 per year (p<0.002), but had no significant effect on hospital admissions or forced expiratory volume in 1 second (FEV1) over a median follow-up of 26.4 months.

  • Dhar et al. (2010) (n=19) found that treatment with nebulised colistimethate sodium (1−2 million units twice daily) for 6 months or more (mean 21.2 months) statistically significantly reduced the mean number of exacerbations from 7.8 per year to 2.7 per year (p<0.001) and the mean number of hospital admissions from 3.0 per year to 0.95 per year (p=0.002), but had no significant effect on FEV1.

  • Steinfort and Steinfort (2007) (n=18) found that long-term (6–116 months) treatment with nebulised colistimethate sodium (30 mg daily, around 375,000 units) had no significant effect on hospital admissions but improved some measures of lung function. Treatment had no significant effect on FEV1 or forced vital capacity (FVC) but reduced the annual decline in FEV1 (from 104 ml per year to 44 ml per year, p=0.035) and FVC (from 110 ml per year to 48 ml per year, p=0.033). A significant improvement in quality of life on a visual analogue scale was seen after colistimethate sodium treatment (score 3.6 before treatment and 6.2 after treatment, p=0.001). However, the scale used has not been validated.

  • Berlana et al. (2011) (n=81) compared post-treatment outcomes in people who received nebulised colistimethate sodium alone (1−2 million units twice daily), tobramycin alone, or both for 3 months or more. There were no significant differences in the mean number of hospital admissions, duration of hospital stay or duration of antibiotic use between colistimethate sodium and tobramycin. Combination treatment reduced these outcomes compared with tobramycin alone.

  • White et al. (2012) and Dhar et al. (2010) did not report on adverse events, and Steinfort and Steinfort (2007) reported that there were no adverse events. In Berlana et al. (2011), drug-related adverse events were reported by 58% of people who took colistimethate sodium, most commonly dyspnoea (shortness of breath), bronchospasm and cough (each affecting 12% of patients), wheezing (10%) and dry mouth (6%). There was no significant difference between colistimethate sodium and tobramycin in drug-related adverse events or withdrawals because of adverse events.

  • According to the summaries of product characteristics, colistimethate sodium is very commonly associated with adverse respiratory effects (affecting at least 1 in 10 people), including cough, dyspnoea, bronchospasm and sore throat. The summary of product characteristics for Promixin states that there have been reports of P. aeruginosa acquiring resistance to colistimethate sodium during clinical use.

  • The 4 case series provide weak evidence for the safety and effectiveness of nebulised colistimethate sodium for treating non-cystic fibrosis bronchiectasis and colonisation with P. aeruginosa.

  • One randomised controlled trial, Inhaled Promixin in the treatment of non-cystic fibrosis bronchiectasis, has been completed but not yet published. Once published and peer-reviewed, this may provide higher level evidence about the safety and efficacy of nebulised colistimethate sodium for treating non-cystic fibrosis bronchiectasis.

Summary of the evidence

This section gives a brief summary of the main evidence. A more thorough analysis is given in the Evidence review section.

Efficacy

Table 1 provides a summary of the 3 case series (White et al., Dhar et al. and Steinfort and Steinfort) that used historical self-controls to compare outcomes before and after treatment with nebulised colistimethate sodium.

The case series by Berlana et al. (2011) (n=81) is not compatible with the 3 case series included in table 1, because it compared the post-treatment outcomes of 3 treatment groups (nebulised colistimethate sodium alone, colistimethate sodium plus tobramycin, or tobramycin alone), rather than comparing outcomes before and after treatment with nebulised colistimethate sodium.

Berlana et al. (2011) found no significant differences between colistimethate sodium alone and tobramycin alone in the mean number of hospital admissions, duration of hospital stay, or duration of antibiotic use in people with non-cystic fibrosis bronchiectasis or chronic obstructive pulmonary disease with P. aeruginosa bronchial colonisation. Compared with tobramycin alone, the combination of colistimethate sodium and tobramycin was associated with a significant reduction in hospital admissions (0.4 compared with 1.9 per person per year, p<0.05), duration of hospitalisation (2.8 days compared with 22.5 days per person per year, p<0.05), and duration of antibiotic use (2.0 days compared with 14.8 days per person per year, p<0.05). Reliable lung function measures were available for only 32% (31/97) of all treatment courses.

Table 1 Summary of the case series

Before treatment

After treatment

Analysis (before to after treatment difference)

White et al. (2012)

Patients

30 people with non-cystic fibrosis bronchiectasis who received Pseudomonas eradication therapy that included nebulised colistimethate sodium (2 million units twice daily for 3 months)

Outcomes

Pseudomonas eradication from sputum

Not applicable

80%

(24/30)

54% (13/24) remained Pseudomonas-free at their latest follow-up (median 14.3 months)

46% (11/24) subsequently re-cultured Pseudomonas (median time to re-infection 6.2 months)

Exacerbations (mean)

3.93 per year

2.09 per year

p<0.002

Hospital admissions (mean)

0.39 per year

0.29 per year

NS, p value not reported

Lung function (mean percentage predicted)

FEV1 62.1%

FEV1 64.1%

NS, p value not reported

Safety

NR

NR

Adverse events were not reported.

10% (3/30) withdrew because of intolerance to colistimethate sodium

Dhar et al. (2010)

Patients

19 people with non-cystic fibrosis bronchiectasis and Pseudomonas colonisation who received nebulised colistimethate sodium (1−2 million units twice daily) for at least 6 months (mean 21.2 months)

Outcomes

Pseudomonas-positive sputum samples (mean)

4.2 per year

0.5 per year

p<0.001

Exacerbations (mean)

7.8 per year

2.7 per year

p<0.001

Hospital admissions (mean)

3.0 per year

0.95 per year

p=0.002

Lung function (mean)

FEV1 1.13 litres

FEV1 1.14 litres

NS, p value not reported

Safety

NR

NR

Adverse events were not reported

Steinfort and Steinfort (2007)

Patients

18 people with non-cystic fibrosis bronchiectasis or severe COPD and chronic bronchial sepsis who received nebulised colistimethate sodium (30 mg daily, around 375,000 units) long term (6 to 116 months)

Outcomes

Hospital admissions1

1.1 per year

0.84 per year

p=0.493 NS

Lung function1

FEV1 1.07 litres

FEV1 1.02 litres

p=0.400 NS

FVC 2.0 litres

FVC 1.9 litres

p=0.295 NS

Lung function (annual decline)

FEV1 104 ml per year

FEV1 44 ml per year

p=0.035

FVC 110 ml per year

FVC 48 ml per year

p=0.033

Quality of life (VAS)

3.6

6.2

p=0.001

Safety

NR

NR

Reported that there were no adverse events

Abbreviations: COPD, chronic obstructive pulmonary disease; NR, not reported; NS, non-significant; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; p, p value; VAS, visual analogue scale (not validated).

1 These are assumed to be mean values, although this is not stated in the paper.

Safety

According to the summaries of product characteristics, colistimethate sodium (Colomycin injection and Promixin powder for nebuliser solution, and Colobreathe dry powder for inhalation) is very commonly associated with adverse respiratory effects (affecting at least 1 in 10 people) including cough, dyspnoea (shortness of breath), bronchospasm and sore throat. Colobreathe also very commonly (in at least 1 in 10 people) causes dysphonia (hoarseness and difficultly speaking) and dysgeusia (distorted taste). It is also associated (in at least 1 in 100 people) with nausea and vomiting, tinnitus, balance disorder, headache, arthralgia and fatigue.

The case series Dhar et al. (2010) and White et al. (2012) did not report adverse events. Steinfort and Steinfort (2007) reported that there were no adverse events in the 18 people who received long-term nebulised colistimethate sodium.

In Berlana et al. (2011) drug-related adverse events were experienced by 58% of people (29/50) who took colistimethate sodium alone and 28% of people (20/72) who took tobramycin alone (no significant difference, p=0.24). There was no significant difference between the colistimethate sodium and tobramycin groups in the number of withdrawals because of adverse events (26% with colistimethate sodium compared with 13% with tobramycin, p=0.06). The most common adverse events seen with colistimethate sodium were shortness of breath, bronchospasm and cough (each affecting 6/50 patients, 12%), wheeze (5/50, 10%) and dry mouth (3/50, 6%).

Cost effectiveness and cost

According to MIMS (November 2013), the costs of preparations of colistimethate sodium for inhalation (excluding VAT) are as follows:

  • Colobreathe costs £968.80 for 56 capsules containing 1.6625 million units and a Turbospin inhaler.

  • Colomycin injection costs £18.00 for 10 vials containing 1 million units of colistimethate sodium and £32.00 for 10 vials containing 2 million units of colistimethate sodium.

  • Promixin costs £138.00 for 30 vials containing 1 million units of colistimethate sodium. The price includes the cost of the nebuliser, training, support service and all related consumables.