Correspondence

Compounded Colistimethate as Possible Cause of Fatal Acute Respiratory Distress Syndrome

N Engl J Med 2007; 357:2310-2311November 29, 2007

Article

To the Editor:

We report a case of pharmacy compounding of the colistin prodrug colistimethate sodium that led to a fatal case of the acute respiratory distress syndrome (ARDS). The patient was a 29-year-old woman with cystic fibrosis who had chronic airway infection with Pseudomonas aeruginosa and moderate lung disease; she was in clinically stable condition. Maintenance therapy was initiated with 75 mg of inhaled colistimethate sodium delivered twice daily by means of an electronic vibrating plate nebulizer. The patient's respiratory symptoms increased within hours after the first dose. Three days after the initiation of treatment, she required urgent hospital admission, with expectoration of large quantities of thin, pink secretions. Progressive respiratory failure developed rapidly, requiring mechanical ventilation, with a bilateral ground-glass appearance on computed tomography of the chest. A clinical diagnosis of ARDS was made. Bronchoscopy on admission and 8 days later identified only the usual cystic fibrosis pathogens. The patient died from multiorgan failure 18 days after the onset of respiratory failure. The Food and Drug Administration was informed by means of a MedWatch submission.

After reconstitution in either water or normal saline, nebulized colistimethate used as maintenance therapy for chronic airway P. aeruginosa infections in patients with cystic fibrosis is approved in the United Kingdom but not in the United States. Although airway reactivity after colistin aerosol therapy has been reported, the development of ARDS has not. The likely cause of both adverse effects is conversion of the colistin prodrug, colistimethate sodium (previously known as colistin sulphomethate and also known as colistin sodium methanesulfonate) to the biologically active form of colistin. It has been reported that, in a single-dose aerosol exposure, the active colistin sulfate is much less likely to be tolerated than its prodrug.1 Conversion of more than 60% of the prodrug to the active form has been reported after 48 hours at 37°C.2 Furthermore, the major active ingredient in colistin, colistin A (polymyxin E1), was investigated as a possible inhaled pharmaceutical agent and was abandoned after inhalational toxicologic studies showed massive inflammation at low doses in both rats and dogs.3 This patient was using a recently made, pharmacy-compounded premixed solution that was 5 weeks old (with the stated expiration date not yet reached). This practice is in contrast to the typical administration of nebulizer solutions of colistimethate sodium that are reconstituted just before use.

This case highlights the risk of pharmacy compounding of unapproved nebulization solutions. If nebulization solutions of colistin are used, the prodrug colistimethate sodium should be reconstituted just before administration in order to avoid excessive conversion to biologically active colistin, which can cause airway or alveolar injury.

Karen S. McCoy, M.D.
Columbus Children's Hospital, Columbus, OH 43205
mccoyk@pediatrics.ohio-state.edu

3 References

1. 1

   Westerman EM, Le Brun PP, Touw DJ, Frijlink HW, Heijerman HG. Effect of nebulized colistin sulphate and colistin sulphomethate on lung function in patients with cystic fibrosis: a pilot study. J Cyst Fibros 2004;3:23-28
   CrossRef | Medline

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   Li J, Milne RW, Nation RL, Turnidge JD, Coulthard K. Stability of colistin and colistin methanesulfonate in aqueous media and plasma as determined by high-performance liquid chromatography. Antimicrob Agents Chemother 2003;47:1364-1370
   CrossRef | Web of Science | Medline

3. 3

   VanDevanter DR, Rose LM, Sprugel KH. 28-Day inhalation toxicology of polymyxin E1, the major active component of colistin in rats and dogs. Presented as a poster at the European Cystic Fibrosis Conference, Vienna, June 6–9, 2001.
   

Citing Articles (9)

Citing Articles

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   Manfred Ballmann, Alan Smyth, David E. Geller. (2011) Therapeutic approaches to chronic cystic fibrosis respiratory infections with available, emerging aerosolized antibiotics. Respiratory Medicine 105, S2-S8
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   Amélie Rognon, Christophe Curti, Marc Montana, Thierry Terme, Pascal Rathelot, Patrice Vanelle. (2011) Efficacité et avenir de l’aérosolthérapie dans le traitement des infections à Pseudomonas aeruginosa chez les patients atteints de mucoviscidose. Thérapie 66:6, 481-491
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   Tareq Abu-Salah, Rajiv Dhand. (2011) Inhaled antibiotic therapy for ventilator-associated tracheobronchitis and ventilator-associated pneumonia: an Update. Advances in Therapy 28:9, 728-747
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   K.W. Leong, S. Ong, H.L. Chee, W. Lee, A.L. Kwa. (2010) Hypersensitivity pneumonitis due to high-dose colistin aerosol therapy. International Journal of Infectious Diseases 14:11, e1018-e1019
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5. 5

   Roger L Nation, Jian Li. (2009) Colistin in the 21st century. Current Opinion in Infectious Diseases 22:6, 535-543
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6. 6

   Stephen Kirkby, Kimberly Novak, Karen McCoy. (2009) Update on antibiotics for infection control in cystic fibrosis. Expert Review of Anti-infective Therapy 7:8, 967-980
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7. 7

   David E Geller. (2009) Aerosol Antibiotics in Cystic Fibrosis. Respiratory Care 54:5, 658-670
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8. 8

   Patrick A. Flume. (2008) A role for aerosolized antibiotics. Pediatric Pulmonology 43:S9, S29-S34
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9. 9

   Matthew E Falagas, Petros I Rafailidis. (2008) Re-emergence of colistin in today's world of multidrug-resistant organisms: personal perspectives. Expert Opinion on Investigational Drugs 17:7, 973-981
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