INTRODUCTION

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Gram-negative bacilli are responsible for a significant proportion of nosocomial pneumonia (1). At times, certain pathogens including Pseudomonas aeruginosa may be resistant to many, if not all, currently available antimicrobial agents. A recent study found that the emergence of resistance to antibiotics in isolates of P. aeruginosa was significantly associated with a longer duration of hospitalization and a trend toward increased total charges for patients whose isolates developed resistance (2). Because P. aeruginosa ranks second among gram-negative pathogens reported to the National Nosocomial Infection Surveillance (NNIS) System (1), it is responsible for significant morbidity in addition to its negative economic impact on the health care system. In addition to careful attention to infection control procedures to limit the spread of multidrug-resistant (MDR) P. aeruginosa, there is an urgent need for effective antimicrobial therapies for this ubiquitous nosocomial pathogen.

Since the development of new classes of antibiotics with activity against gram-negative organisms has not kept pace with the increase in prevalence of multiresistant pathogens, there has been renewed interest in reevaluating antimicrobial agents that had previously been abandoned because of problems with toxicity. An example of such an antimicrobial agent is colistin, a polymyxin that has excellent in vitro activity against many species of aerobic gram-negative bacilli (3). The polymyxins are cationic detergents that interact with the phospholipids of bacterial cell membranes and thereby lead to increased cell wall permeability and death (4). Use of intravenous colistin was abandoned in the early 1980s because of problems with nephrotoxicity, neurotoxicity, and neuromuscular blockade. The use of colistin in recent years has been mainly limited to the prevention or supplementary treatment of respiratory tract colonization with P. aeruginosa in patients with cystic fibrosis (5). Aerosolized colistin has also been shown to be effective for the treatment and prevention of recurrent P. aeruginosa pneumonia in patients with underlying human immunodeficiency virus (HIV) infection (8, 9). Following is a description of three patients with nosocomial pneumonia or tracheobronchitis resulting from MDR P. aeruginosa for whom aerosolized colistin proved beneficial as supplemental therapy (summarized in Table 1).

	CASE REPORTS

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Patient 1

A 67-yr-old man was admitted to the hospital on February 13, 1996 with an exacerbation of chronic obstructive pulmonary disease. He was treated with ceftazidime (1 g intravenously every 8 h) and ciprofloxacin (500 mg orally twice a day) for P. aeruginosa bronchitis with initial improvement. He was transferred to a rehabilitation facility on March 11, 1996. His hospital course at the second facility was remarkable for methicillin-resistant S. aureus bronchitis treated with vancomycin. On May 2, 1996 he developed increased respiratory distress and a cough productive of purulent sputum; pulse oximetry revealed decreased oxygen saturation. Sputum culture yielded pure growth of P. aeruginosa that was susceptible only to colistin (Table 1). The patient was initially treated with clarithromycin (500 mg orally twice a day) and ciprofloxacin (750 mg orally twice a day) but his respiratory status continued to worsen with increased sputum production and the development of a new right upper lobe infiltrate on his chest X-ray. A repeat sputum culture yielded two different isolates of P. aeruginosa; one isolate was resistant to all antibiotics except colistin and a second isolate was sensitive to colistin, amikacin, ceftazidime, and aztreonam. Treatment with ceftazidime (1 g intravenously every 8 h), amikacin (500 mg intravenously every 12 h), and aerosolized colistin (150 mg in 2 ml of water diluted in 2 ml of normal saline twice a day) administered with a Respirgard II nebulizer (Marquest Medical Products Inc., Englewood, CO) led to improvement in the patient's respiratory status and clearing of both strains of P. aeruginosa from the patient's sputum.

Peak and trough serum levels of amikacin were monitored every 3 d and were consistently in the therapeutic range. Complete blood counts, serum creatinine, and electrolytes were tested every 3 d and transaminases, total bilirubin, and alkaline phosphatase were evaluated weekly during colistin administration. Based on these tests, there was no evidence of any biochemical or hematological toxicity resulting from the treatment. The patient had no additional respiratory tract infections until the time of his discharge from the hospital, 1 mo after the completion of colistin therapy.

Patient 2

A 45-yr-old-man was originally admitted to the hospital on December 22, 1996 with group A streptococcal toxic shock syndrome complicated by adult respiratory distress syndrome, acute renal failure requiring hemodialysis, disseminated intravascular coagulation, and liver failure. His hospital course was notable for the development of P. aeruginosa pneumonia with bacteremia, prolonged respiratory failure with a tracheostomy, and a severe cutaneous allergic reaction to ceftazidime. His condition slowly improved and he was transferred to a rehabilitation facility on February 25, 1997. His chest X-ray on admission revealed multilobar infiltrates and a sputum culture grew P. aeruginosa that was susceptible to amikacin, gentamicin, tobramycin, and colistin (Table 1).

Because of the presence of fever, cough, and copious purulent sputum production, therapy with gentamicin (90 mg intravenously every 12 h) for probable P. aeruginosa pneumonia was initiated on February 28, 1997. On March 3, 1997 the patient still was producing copious purulent secretions and had not progressed in being weaned from the ventilator so therapy with twice daily aerosolized colistin (100 mg in 2 ml of water diluted in 2 ml of normal saline administered with a Respirgard II nebulizer via the tracheostomy tube) was initiated. Gentamicin levels were therapeutic. During the following 2 wk, the patient's pulmonary secretions became progressively less purulent and his overall respiratory status improved to such an extent that he could be weaned off the ventilator and have his tracheostomy removed. Renal function and hematological indices (monitored two to three times per week) remained stable throughout the course of colistin therapy.

Patient 3

A 59-yr-old man with chronic renal insufficiency, hypertension, and coronary artery disease was admitted to the hospital with a cerebrovascular accident on November 5, 1996. His hospital course was notable for the development of pneumonia with respiratory failure requiring intubation and eventual tracheostomy placement. He was transferred to a rehabilitation facility on February 27, 1997. Initial evaluation revealed evidence of P. aeruginosa tracheobronchitis. Sputum culture grew P. aeruginosa that was susceptible to ceftazidime, piperacillin, gentamicin, and tobramycin. The patient was treated with ceftazidime (500 mg intravenously every 12 h) with gradual resolution of his fever and purulent sputum production.

On March 24, 1997 the patient developed recurrent fever, dyspnea, and cough productive of purulent sputum. There was no radiographic evidence of pneumonia. Sputum culture again yielded P. aeruginosa that was susceptible to ceftazidime, piperacillin, gentamicin, and tobramycin. The isolate was also found to be susceptible to colistin (Table 1). The patient was treated with ceftazidime (500 mg intravenously every 12 h) and gentamicin (50 mg intravenously every 12 h) but the latter agent had to be discontinued after 4 d because of deteriorating renal function and high trough levels of gentamicin. Due to the presence of persistent fever and purulent sputum production, treatment with aerosolized colistin (150 mg twice a day via a Respirgard II nebulizer through the patient's tracheostomy) was initiated on March 31, 1997. During an 11-d course of therapy with colistin (in conjunction with ceftazidime), the patient's respiratory distress, fever, and purulent sputum production all resolved. Twice weekly monitoring of complete blood counts, serum creatinine, electrolytes, and transaminases revealed no evidence of renal or hematological toxicity during treatment with colistin. The patient had no further episodes of respiratory tract infections during the subsequent 3 wk of his hospitalization.

	DISCUSSION

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Aerosolized colistin was used successfully as an adjunct in the treatment of nosocomial pneumonia in all three patients described. Patients 2 and 3 clearly showed evidence of improvement in the signs of pneumonia or tracheobronchitis resulting from MDR P. aeruginosa after the addition of aerosolized colistin. Because of the high attributable mortality in patients who have nosocomial pneumonia caused by P. aeruginosa, the use of two antibiotics with in vitro activity against this pathogen is recommended (10). The three patients in this small series all had isolates of P. aeruginosa that were multiply resistant and therefore only a limited number of antimicrobial agents were available to treat their infections. The addition of colistin provided a greater range of possible therapeutic combinations and, in the case of Patient 2, obviated the need for monotherapy with an aminoglycoside.

Although one study found that nearly one-third of patients with cystic fibrosis who were treated with aerosolized colistin were unable to tolerate this intervention because of chest tightness (11), none of the patients described in this report experienced any adverse effects from this treatment. Although pulmonary function testing was not performed during treatment with colistin, all three patients had progressive improvement in their overall respiratory status during therapy. Nevertheless, because inhaled colistin can potentially cause bronchoconstriction, patients who receive this form of therapy must be carefully monitored for evidence of respiratory distress and should be treated with ₂ agonists if they develop signs or symptoms of bronchoconstriction.

A recent report from Brazil that described the use of colistin given intravenously for the treatment of hospital-acquired infections resulting from MDR P. aeruginosa and Acinetobacter baumannii found that colistin given parenterally was beneficial in 58% of 60 patients with nosocomial infections although therapy was frequently complicated by renal toxicity (12). However, only 25% of patients with hospital-acquired pneumonia had a good outcome during treatment with colistin given intravenously. The relative lack of efficacy and its systemic toxicities generally preclude the use of colistin given intravenously for the treatment of nosocomial pneumonia. Although only small numbers of patients have been studied in uncontrolled studies, aerosolized colistin appears to be effective for the treatment of respiratory tract colonization and infections resulting from P. aeruginosa. Because colistin has good in vitro activity against a wide range of commonly encountered nosocomial pathogens and is generally well tolerated when given by the aerosol route, its role in the treatment of nosocomial pneumonia caused by MDR gram-negative rods merits further evaluation.