Unlabeled Uses of Nebulized Medications

Mary Beth Shirk; Kevin R. Donahue; Jill Shirvani


Am J Health Syst Pharm. 2006;63(18):1704-1716. 

In This Article


One of the greatest concerns among several patient populations is chronic pulmonary infection with Pseudomonas and other gram-negative bacteria.[49] These organisms can be difficult to treat as resistant strains commonly develop, and treatment-related toxicities present a concern. This has led researchers to look for alternatives in patients with gram-negative pulmonary infections. Nebulized colistin sulfomethate, or polymyxin E, is used increasingly to manage Pseudomonas infections in cystic fibrosis patients. In Europe, nebulized colistin is commonly used in long-term management of Pseudomonas. I.V. colistin had been used to treat a variety of bacteria but became less common because of its nephrotoxicity and neurotoxicity and the development of safer antimicrobials.

One of the early studies that suggested nebulized colistin could be of benefit was conducted by Jensen et al.[50] who reasoned that colistin resistance was rarely found among Pseudomonas aeruginosa infections, so treatment with nebulized colistin that limited systemic absorption could potentially be helpful. In a randomized study, 40 cystic fibrosis patients with chronic P. aeruginosa infections were enrolled after a two-week course of i.v. antibiotic treatment. Twenty patients were assigned nebulized colistin (colistimethate sodium) and 20 received a placebo. Patients in the colistin group received 1 million units of colistin twice daily for 90 days, where 33.3 mg of colistin base equals 1 million units, in 3 mL of 0.9% sodium chloride. Twenty-nine patients completed the study, 18 of whom were in the colistin group. In the placebo group, four dropped out because of treatment failure requiring i.v. therapy for acute infection. Two dropouts were reported in the treatment group. One patient required surgery and the other developed a severe asthma attack. Adverse effects included one instance of a burning sensation of the tongue in the colistin group and one of irritating cough due to inhalation therapy in the placebo group. Clinical scores monitored during treatment, including cough, expectoration, dyspnea, and general conditions, strongly favored the colistin group (p < 0.01). FVC and FEV1 decreased during therapy, but the decrease was less severe in the colistin group (p < 0.05). In addition, the minimum inhibitory concentration of colistin did not change during treatment. The treatment was within safety guidelines, no drug was detected in the urine, and no superinfection with colistin-resistant organisms had developed.

A retrospective study conducted by Berlana et al.[51] reviewed nebulized colistin in the treatment of multidrug-resistant organisms. Seventy-one hospitalized patients received inhaled colistin (colistimethate sodium) over a 10-month period in 2001. Sixty of those were infected with Acinetobacter baumannii and 11 with P. aeruginosa. A majority of the patients had previously received oral or i.v. antimicrobial treatment and were given i.v. antimicrobials during colistin therapy. Dose regimens included 16.67 mg every 6 or 8 hours and 33.3 mg every 8 or 12 hours of nebulized colistimethate sodium, with an average treatment duration of 12 ± 8 days. Of the 40 patients with follow-up cultures, 37 showed the organism had cleared. Mortality over the course of the review was 18%, including those receiving i.v. and intrathecal therapy. No adverse effects were reported. Berlana et al. concluded that nebulized colistin was within safety margins and appeared to be efficacious for the treatment of multidrug-resistant A. baumannii and P. aeruginosa infections.

Hodson et al.[52] compared the effects of nebulized tobramycin with nebulized colistin in patients with cystic fibrosis, who had chronic P. aeruginosa infections. The randomized study lasted four weeks, and the primary outcome measure was FEV1. During the course of the study, no other antimicrobials were given, but other drug therapies were continued. Patients received colistimethate sodium 80 mg (equivalent to 33.3 mg of colistin base) twice daily dissolved in 3 mL of 0.9% sodium chloride or 300 mg of tobramycin in 5 mL 0.9% sodium chloride twice daily. Sixty-two patients received colistin during the study. The change in FEV1 was not significant in the colistin group (p < 0.473); however, 16% reported an improvement in their overall health status over baseline. Respiratory-related adverse effects resulting from the nebulization were reported by 50% of the patients. Nebulized colistin produced a significant decrease (p < 0.007) of P. aeruginosa density in sputum, but it did not appreciably improve lung function.

A case series examined the efficacy of nebulized colistin as part of the treatment plan for nosocomial pneumonia and tracheobronchitis due to a resistant strain of P. aeruginosa.[53] Two patients received colistin 150 mg twice daily and one received 100 mg twice daily to treat nosocomial pneumonia for 11, 13, and 14 days, respectively. Respiratory conditions and fever improved in all three patients. The patient who received 150 mg for 11 days had both strains of P. aeruginosa cleared from the sputum.

Another treatment avenue being examined is colistin’s use in cystic fibrosis patients awaiting lung transplantation. [54] This patient population is at high risk for infection following transplantation due to a compromised immune system; one-year survival for cystic fibrosis patients who had Pseudomonas before the operation was only 34%. Because of this, many centers will not transplant patients with Pseudomonas. The new approach involves treating with nebulized colistin before surgery, selecting for less resistant strains to be present after the operation. Bauldoff et al.[54] treated 20 patients with resistant Pseudomonas strains with 75 mg of nebulized colistin sodium in 1 mL 0.9% sodium chloride twice daily before transplant. All of the patients had sensitive strains of Pseudomonas in their sputum after inhalation therapy was started. Because colistin is unlikely to be used systemically after surgery, the researchers believed selecting for colistin-resistant strains was not of great concern.

Concern with colistin use comes from the potential for harmful adverse effects and the loss of antimicrobial activity with nebulization. However, neither jet nor ultrasonic nebulization altered the properties of colistin.[55] The colistin solution turns foamy but retains its antimicrobial properties. Of more importance is the possibility of bronchoconstriction when using inhaled colistin. Alothman et al.[49] suggested that because bronchospasm and chest tightness occurred with both hypotonic and isotonic solutions, airway problems are related to the colistin molecule. Their study compared the effects of inhaled colistimethate sodium with placebo in high-risk and low-risk patients for airway toxicity. Patients in the high-risk group were found to have a greater mean ± S.D. fall in FEV1 compared with placebo (17 ± 10%) (p < 0.002), and four patients had a fall of greater than 15%. In the low-risk group, the mean ± S.D. fall in FEV1 was 13 ± 8%. Bronchospasms were successfully treated with bronchodilators. Alothman suggested that the patients with an FEV1 less than 50% of the predicted value should be pretreated with a bronchodilator, and the risk of bronchospasm should not preclude a patient from receiving nebulized colistin if deemed necessary.[49] Since all tonicities of nebulized colistin cause approximately equal levels of chest tightness and reduction in pulmonary function, a pretreatment with a bronchodilator should be used to help minimize the bronchoconstricting effects of colistin.[56]

The nebulized form of colistin appears to limit systemic toxicity and if the risk of bronchospasm is overcome by the benefit of colistin therapy, it may be therapeutically viable. Further studies are necessary to determine the most effective ways to use the potential benefits of inhaled colistin in managing bacterial infections.


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