Lesson 21, Volume 15—Aerosolized Antibiotics

By Guillermo do Pico, MD, FCCP

Objectives

1. Review the indications for aerosolized antibiotics.
2. Understand the advantages of aerosolized antibiotics.
3. Understand the benefits and effectiveness of aerosolized antibiotics.
4. Understand the risks and adverse effects of aerosolized antibiotics.
5. Recognize the disadvantages of aerosolized antibiotics.

Key words

aerosol antibiotics; bronchiectasis; cystic fibrosis; nebulizers; nosocomial pneumonia

Abbreviations

CF = cystic fibrosis; MIC = minimum inhibitory concentration; TSI = tobramycin solution for inhalation

The advantage of aerosolized antibiotics is their ability to provide a greater concentration of antibiotics directly into the target organ, the lung, avoiding systemic complications with a noninvasive method. The disadvantages are the high cost, the inefficiency of the currently available delivery systems in delivering drugs to the lower airways, and the time spent by the patient. This review will focus on the use of aerosolized antibiotics in Gram-negative infections (Table 1).

Delivery systems are, in general, inefficient. It has been estimated by radio tracer studies that only 1 to 10% of an inhaled drug will deposit in the lungs; 15 to 25% remain in the upper airways, 5% is swallowed, 40% is retained in the nebulizer, and 30% is lost into the room air.^1,2 Despite the shortcomings of the current aerosol delivery systems, high concentrations of antibiotics can be measured in expectorated secretions. These high peak levels, 100 to 1,000 mg/g, are far above the minimum inhibitory concentration (MIC) for most organisms and substantially exceed the parenteral breakpoint for antibiotic resistance of 8 mg/mL. Sputum concentration after 300 mg/5 mL of tobramycin was delivered using a Pulmo-Aide Compressor (Sunrise Medical; Somerset, PA) with a Sidestream nebulizer (Airlife Respiratory Care; McGaw Park, IL) was 687 ± 663 mg/g; with a Pari LC (Pari; Midlothian, VA), 490 ± 400 mg/g; and with a DeVilbiss 99/100 (Sunrise Medical), 1,500 ±1,300 mg/g (in 30% of cases, > 2,000 mg/g). The high peak sputum concentrations are usually associated with very low serum concentrations.³ However, sputum concentrations may not adequately reflect the concentration in the lower airways. Furthermore, more severe obstruction of airways is associated with more central deposition. High concentrations of antibiotics have been detected in lung tissue or alveolar fluids in the few studies measuring levels in BAL fluid or lung biopsy specimens after inhalation of antibiotics.^4,5

In addition to the multitude of factors that affect aerosol delivery to the lower airways (eg, nebulizer characteristics and antibiotic formulation), there are other biological factors that affect, interfere with, or antagonize the effect of the antibiotic. The bacteriocidal effect of 100 mg/mL in sputum compares with 4 mg/mL in in vitro culture media. The bacteriocidal in situ effect in airways affected by cystic fibrosis (CF) is influenced by high DNA and ionic concentration of the secretions, the seclusion of the Pseudomonas within a biofilm with low oxygen concentration, and the alginate coat of mucoid strains. There are other factors that may reduce the penetration of the antibiotics into the bronchial epithelium and mucosa.

CF With Pseudomonas Infection

The median survival for patients with CF in the United States has reached 30 years, and one third of patients reach adulthood. This improved survival has been ascribed in part to the aggressive antibiotic and maintenance therapies. Pseudomonas aeruginosa is the most common organism cultured from bronchial secretions of patients with CF-related bronchiectasis, and antipseudomonal antibiotics are a major component of treatment. Infection with mucoid Pseudomonas has been associated with accelerated progression of the pulmonary disease among children with CF.⁶ Earlier in the course of the disease, Staphylococcus aureus and Haemophilus influenzae predominate. Other organisms found in some patients with CF are Stenotrophomonas maltophilia, Burkholderia cepacia, Burkholderia gladioli, Burkholderia pickettii, Alkaligenes xilosoxidans, atypical mycobacteria, and Aspergillus spp.

Pulmonary pathology in CF can be described as a vicious cycle of escalating and mutually reinforcing pathologic events. Initially, there is an abnormal mucus composition as a result of a deficiency in the CFTR gene, which regulates ion transport in the epithelial cells. The abnormal mucus and ionic composition impair clearance and causes inflammation leading to bacterial colonization and activation of the immune system, with an exuberant inflammatory reaction with release of mediators and neutrophils. Destructive proteases are released, causing tissue damage. Pseudomonas stimulates release of a strong neutrophil chemoattractant from epithelial cells. Pseudomonas secretes toxins that paralyze cilia, inactivates antiproteases, and enhances neutrophil oxidative metabolism supporting the importance of eradicating or reducing the burden of Pseudomonas. Temporary eradication of Pseudomonas has been observed.⁷ Bacterial density in sputum does not necessarily decrease with antibiotic therapy, yet clinical improvement can be observed subjectively and objectively. This beneficial effect may be explained by the observation that sublethal doses of aminoglycosides and ciprofloxacin inhibit the production of Pseudomonas virulence factors including proteases.^8,9

Aerosol Antibiotics as Suppressive Therapy

Most studies of aerosolized antibiotics in patients with CF have shown similar beneficial effects to varying degrees.^10-19 In all but one study, FEV₁ and FVC were improved, the sputum Pseudomonas density was reduced, and the frequency of exacerbations, use of IV antibiotics, and hospitalizations were reduced. The results also suggest that aerosol antibiotics improve quality of life and likely prolong life.

The first report of use of inhaled antibiotic therapy in CF using carbenicillin 1 g and gentamicin 80 mg bid was reported by Hodson in 1981.¹⁰ Several studies were published between 1984 and 1989. These were single-center studies with small sample sizes and design flaws. The doses of antibiotic were relatively small: gentamicin 20 mg bid,¹¹ gentamicin 80 mg tid,¹² tobramycin 40 mg and flucloxacillin 25 mg/kg/dose bid,¹³ colistin 1 million units or 35 mg bid,¹⁴ gentamicin 80 mg and carbenicillin 1 g bid,¹⁵ colomycin 35 mg bid,¹⁶ and tobramycin 80 mg.¹⁷ Later, in vitro data indicated that much higher doses were needed to ensure bacterial killing; this led to studies using high doses of tobramycin, 600 mg of tid¹⁸ and 300 mg bid,¹⁹ in a larger number of subjects. The most evidence for a single drug is for tobramycin, which was used in total daily doses of 40 to 1,800 mg (Table 2). The variation in the designs and outcome measures used in the published studies limit metaanalysis. The duration of each trial ranged from 1 to 32 months; 758 patients were enrolled in 10 studies, with 520 of the 758 patients (69%) in a single study.¹⁹ In all but one study, the FEV₁ was better in the treated groups than in the control groups.

A recent, large, multicenter, randomized, placebo-controlled study of 520 patients with CF¹⁹ was designed to assess the effectiveness of 300 mg bid of a preservative-free tobramycin solution for inhalation (TSI) over a 6-month period (Table 2). A subsequent open-label extension allowed patients to continue on TSI or switch from placebo to TSI for up to 24 months. An intermittent regimen of 28 days on and 28 days off was selected because (1) intermittent therapy may reduce the potential for bacterial resistance (P aeruginosa strains with high MICs revert to lower MICs when therapy is discontinued²⁰); and (2) a postantibiotic effect or treatment effect is maintained during the off-drug period.¹⁸

FEV₁ improved in the TSI group by the second week of treatment and values were maintained above baseline for the duration of the study. After 20 weeks, the treatment effect (difference between TSI response and placebo response) was 12%. FEV₁ average increase was 10% over baseline in those taking TSI, vs a 2% decrease in subjects taking placebo. The bacterial density in the TSI group was significantly reduced by an average 0.8 log¹⁰ colony-forming units/g sputum, while in the placebo group there was an average increase of 0.3 log¹⁰ colony-forming units/g. Patients taking TSI had fewer days of IV antibiotics (9.6 vs 14 days), fewer hospital days (5 vs 8 days), and less absenteeism from work (5 vs 7 days), and were 26% less likely to be hospitalized than the placebo group.

After the 2-year open-label extension study, patients initially treated with TSI had an FEV₁ 5% greater than baseline, required fewer IV and oral antibiotics, and were less likely to be hospitalized than patients who were initially treated with placebo.²¹ This suggests that irreparable damage that occurred during the initial 6 months of the placebo regimen may have been prevented with TSI. Furthermore, treatment of exacerbations with IV antipseudomonal agents does not seem to arrest the progressive decline in lung function.²² These issues require further clarification but have significant clinical importance to deciding when inhaled antibiotics should be initiated.

While children and adults benefited from TSI therapy, teenagers showed the greatest improvement in FEV₁ with a 16% increase in FEV₁ at week 20, compared with a 7% loss of FEV₁ in those receiving placebo. A 14% increase in FEV₁ was seen in this age group at the end of the open-label 2-year study. In addition, teenagers taking TSI showed a striking positive effect in nutritional status and weight gain. When the placebo group patients joined the open-label study, their weight and FEV₁ improved; however, their mean FEV₁ tended to be lower at the 24-month follow-up.²³

Risks. First, the emergence of resistant organisms is a primary concern with the long-term use of aerosolized antibiotics in patients with CF-related Pseudomonas infection.

Eight studies have examined sputum for drug sensitivity, but the reported results had little detail and interpretation is difficult in cross-over design studies. The presence of organisms susceptible to tobramycin was an entry criterion in the study by Ramsey et al,¹⁸ who found that 14% of patients developed resistant organisms during the 4-month monitoring period; however, no difference was found between antibiotic and placebo groups in this cross-over design study. Carswell et al¹³ found that aminoglycoside resistance developed in three of five subjects who had sensitive organisms on entry to the study. Two studies provided quantitative comparative information for tobramycin. Ramsey et al¹⁹ reported the proportion of isolates of P aeruginosa with an MIC of > 8 mg/mL increased from 25 to 32% in the tobramycin group (n = 258) and decreased from 20% to 17% in the control group (n = 262) between weeks 0 and 24 of the study. The same authors later reported similar results using an MIC of at least 16 mg/mL.²⁴ MacLusky et al¹⁷ used an MIC of > 16 mg/mL to define tobramycin resistance. Resistance developed in 4 of 14 subjects (28.5%) in the tobramycin group and in none of the 12 control subjects during the first 24 months. Jensen et al¹⁴ reported no change in MIC to colistin during a 3-month trial. Two trials used combinations of drugs and reported transient resistance to carbenicillin or ceftazidime in one or two subjects.^10,15

Second,the clinical response to inhaled tobramycin cannot be predicted by Pseudomonas susceptibility to tobramycin. A majority of patients with tobramycin-resistant Pseudomonas (MICs > 8 mg/mL) as defined by parenteral breakpoint showed a mean improvement in FEV₁ after 2 years of chronic intermittent TSI therapy.²¹ Hence, the MIC above which no clinical response to antibiotics occurs has not been determined. Furthermore, the resistance breakpoint for parenteral therapy may not apply to inhaled therapy.

Third, the emergence of intrinsically tobramycin-resistant organisms (eg, Aspergillus spp, B cepacia, S maltophilia) has been a concern because of its potential adverse effect on the course of CF. The emergence of these organisms was reported in one parallel-group trial^19,24 and one cross-over trial.¹⁸ No significant differences were found apart from more frequent isolation of Aspergillus spp in the tobramycin-treated group.^19,24

Adverse effects. Systemic serum levels of tobramycin are very low during aerosolized therapy. No nephrotoxicity or auditory impairment has been reported.^10,17-19 Tinnitus was reported more frequently in the tobramycin-treated group (8 of 258 patients, or 3.1%) than in the placebo group (0 of 262).¹⁹ Tinnitus usually resolves but it can be severe (personal experience). Voice alterations were also found more frequently in the tobramycin group.

Accumulated experience with tobramycin and colistin indicates that bronchospasm can be a significant adverse effect. It can be prevented or resolved by inhaled bronchodilators but in some cases it precludes the use of aerosol antibiotics. Polymyxins as basic polypeptides can cause mast cell degranulation and histamine release. Hypertonic or hypotonic diluents are more likely to induce bronchospasm than isotonic saline.^25,26 Hence, we recommend using isotonic saline as a diluent when needed; the initial treatment should be observed and the patient pretreated with inhaled bronchodilator. The bronchodilator should not be mixed with the antibiotic; a separate nebulizer or metered-dose inhaler should be used. This is particularly important when using colistin, which tends to foam. It has been postulated, but not proven, that preservatives, eg, phenol, bisulfites, and EDTA, in the parenteral preparations of tobramycin or gentamicin used as aerosols can induce bronchial hyperresponsiveness. In addition, gentamycin preparations have a low pH of about 4, below which bronchospasm can be induced.²⁵ Theoretically, the phenol-free tobramycin preparations should cause less bronchospasm. Inhaled polymyxins have been found to be associated with acute respiratory failure from respiratory muscle weakness.²⁷

Hemoptysis occurred in 27% of the tobramycin group and 31% of the placebo group.¹⁹ Should inhaled antibiotics be withheld when hemoptysis develops? If hemoptysis is moderate to severe, it seems reasonable to discontinue the drug temporarily while treating the patient with IV antibiotics.

During pregnancy, the patient should be apprised of the potential but unknown toxicity of inhaled antibiotics to the fetus.

Summary. There is evidence that suppressive treatment of chronic infection with P aeruginosa in CF patients with nebulized antipseudomonal antibiotics improves lung function and reduces the frequency of exacerbations of respiratory infection. These benefits should lead to an improvement in quality of life, although this has not been demonstrated, and in survival, for which there is limited evidence. The risks of treatment appear minimal, at least up to 2 years of treatment. Some increase in tobramycin resistance by P aeruginosa has been reported and the significance of this for long-term outcome is not established. The drug that has been studied in the largest number of patients is tobramycin. The optimal dose is uncertain; however, the largest trial used a dose of 300 mg bid, alternating 28 days on and 28 days off the drug. Whether smaller doses of tobramycin, eg, 80 to 160 mg bid, are as effective as the larger doses remains to be established.

Aerosol Therapy of Acute Exacerbations

The standard therapy for respiratory exacerbations of Pseudomonas-related infections in CF is IV antibiotic treatment. The use of inhaled antibiotics in place of IV antibiotics has not been studied. However, it is common practice to treat mild exacerbations with aerosol antibiotics in order to delay or avoid hospitalization or home use of IV antibiotics. Another potential use of inhaled antibiotics is as adjuntive to IV therapy. The few studies available demonstrated a reduction or even temporary eradication of Pseudomonas, but the addition of inhaled antibiotics to the standard IV therapy was not associated with greater clinical improvement than when IV antibiotics were used alone.^7,28,29 The dose of inhaled tobramycin or amikacin used in these studies^7,28 was significantly lower than the doses used in more recent studies.^18,19 Despite the lack of studies assessing the role of inhaled antibiotics in mild respiratory exacerbations, it is reasonable to delay or avoid IV antibiotics if the patient has mild symptoms. This may be accomplished by starting inhaled antibiotics or by increasing the dose if the patient is not already taking tobramycin 300 mg bid.

Non–Cystic Fibrosis Bronchiectasis With Pseudomonas

Based on the experience in CF-related Pseudomonas infections, the use of aerosol antibiotics as suppressive therapy in patients with Pseudomonas infection and bronchiectasis appears justified. Based on the author’s unpublished experience with colistin or tobramycin (Table 2), this suppressive therapy is strongly recommended to reduce exacerbations, hospitalizations, and the frequency of IV therapy, and perhaps to prolong life. A recent short-term study demonstrated that 4 weeks of inhaled tobramycin reduced sputum P aeruginosa density. Clinical improvement occurred in most patients whose treatment eradicated or reduced Pseudomonas density, whereas no clinical response was seen with placebo or when no change in bacterial density was detected with antibiotic therapy.³⁰ In another study, patients received 12 months of inhaled ceftazidime and tobramycin or symptomatic treatment after 2 weeks of IV antibiotics. The number of hospitalizations and days in hospital were significantly less in the treatment group than in the control group (0.6 and 13 days vs 2.5 and 57 days, respectively). FEV₁ and FVC showed similar declines in both groups. No systemic toxicity was observed, but one patient had bronchospasm.³¹

Ventilator-Associated Pneumonia

Ventilator-associated pneumonia (VAP) has been reported in 9 to 60% of patients, with a fatality rate between 20 and 70%. VAP is most frequently caused by Gram-negative organisms. Hence, there is a need to develop preventive and therapeutic strategies to reduce morbidity and mortality.

Prophylactic Aerosol Antibiotics

Studies performed in the 1970s demonstrated that topical antibiotics to prevent VAP could reduce airways colonization and the rate of VAP, but there was an increased risk of fatal pneumonia with resistant organisms.^32-34 Feeley et al³² administered polymyxin for 7 months to patients in a surgical ICU. Bacterial colonization was reduced and the frequency of VAP was reduced from 6% in the control period to 4% in the treatment period. VAP acquired during treatment periods was caused in most cases by multiresistant bacteria. The case fatality rate increased from 48 to 64%. Klastersky et al³³ administered gentamicin endotracheally; colonization was reduced from 80 to 57% and the rate of VAP from 40 to 12%. However, the bacteria in the VAP cases were resistant to gentamicin. Levine et al³⁴ found no effect of inhaled gentamicin in the prevention of nosocomial pneumonia.

Therapy for VAP

The use of aerosolized antibiotics as sole therapy for VAP has not been reported. Brown et al³⁵ published a placebo-controlled study using endotracheal tobramycin. All patients received IV antibiotics. Only half of the patients completed the protocol. There was no intent-to-treat analysis. There was bacterial eradication in 56% of patients treated with tobramycin vs 24% with the placebo, but the clinical response was similar (80 vs 81%).³⁵

Summary

Aerosolized antibiotics to reduce the risk of VAP or to treat it cannot be recommended at this present time for several reasons: (1) The efficacy is unproven; (2) it is a parenchymal as well as a systemic disease; (3) there is increased risk of fatal VAP with multiresistant organisms; (4) the ICU environment may become contaminated by aerosolized antibiotics; (5) delivery systems are inefficient and wasteful; (6) there is unpredictable lung distribution; and (7) criteria for patient selection have not been established.

There are ongoing clinical trials to assess benefits and risks of aerosolized antibiotics to prevent or treat VAP as primary or adjunctive therapy, or perhaps after IV therapy fails.

A potential use of aerosolized antibiotics in the ICU could be to reduce purulent secretions with Pseudomonas that appear to interfere with weaning from the ventilator. However, to the author’s knowledge, there are no studies in such patients to support this application.

Aspergillus fumigatus in Lung Transplant Recipients

Aerosolized amphotericin is safe and feasible, but its role in the prevention and therapy of Aspergillus infections has yet to be defined.

Lung transplant recipients are particularly susceptible to Aspergillus infection, as the lungs are exposed to this ubiquitous environmental contaminant. Approximately 26% of lung transplant recipients become colonized with Aspergillus without clinical, endoscopic, radiographic, or histologic evidence of Aspergillus disease. Only a small percent (3%) develop invasive disease. The management of airway colonization with Aspergillus has not been well-defined. However, there is evidence to support an aggressive approach to the recognition and treatment of Aspergillus tracheobronchitis with systemic amphotericin or oral itraconazole because it may progress, if untreated, to invasive disease.³⁶

Because established invasive aspergillosis is associated with a high mortality rate, prophylactic postoperative aerosolized amphotericin is used in some lung transplant centers, including the author’s. Three studies have reported a reduced incidence of invasive aspergillosis using aerosolized amphotericin compared with historical controls. Another study showed no clear benefits.³⁶

References

1. Rosenfeld M, Cohen M, Ramsey B. Aerosolized antibiotics for bacterial lowr airway infections: principles, efficacy, and pitfalls. Clin Pulm Med 1997; 4:101–112
2. Ilowite, JS, Gorvoy JD, Smaldone GC. Quantitative deposition of aerosolized gentamicin in cystic fibrosis. Am Rev Respir Dis 1987; 136:1445–1449.
3. Eisenberg J, Pepe M, Williams-Warren J, et al. A comparison of peak sputum tobramycin concentration in patients with cystic fibrosis using jet and ultrasonic nebulizer systems. Chest 1997; 111:955–962
4. LeConte P, Potel G, Peltier P, et al. Lung distribution and pharmacokinetics of aerosolized tobramycin. Am Rev Respir Dis 1993; 147:1279–1282
5. Baran D, De Vuyst P, Ooms HA. Concentration of tobramycin given by aerosol in the fluid obtained by bronchoalveolar lavage. Respir Med 1990; 84:203–204
6. Henry RL, Mellis CM, Petrovic L. Mucoid Pseudomonas aeruginosa is a marker of poor survival in cystic fibrosis. Pediatr Pulmonol 1992; 12:158–161
7. Schaad UB, Wedgwood-Krucko J, Suter S, et al. Efficacy of inhaled amikacin as adjunct to intravenous combination therapy (ceftazidime and amikacin) in cystic fibrosis. J Pediatr 1987; 111:599–605
8. Grimwood K, Semple RA, Rabin HR, et al. Elevated exoenzyme expression by Pseudomonas aeruginosa is correlated with exacerbations of lung disease in cystic fibrosis. Pediatr Pulmonol 1993; 15:135–139
9. Grimwood K, To M, Rabin HR, et al. Inhibition of Pseudomonas aeruginosa exoenzyme expression by subinhibitory antibiotic concentrations. Antimicrob Agents Chemother 1989; 33:41–47
10. Hodson ME, Penketh ARL, Batten JC. Aerosol carbenicillin and gentamicin treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis. Lancet 1981; 8256:1127–1129
11. Kun P, Landau LI, Phelan PD. Nebulized gentamicin in children and adolescents with cystic fibrosis. Aust Paediatr J 1984; 20:43–45
12. Nathanson I, Cropp GJA, Li P, et al. Effectiveness of aerosolized gentamicin in cystic fibrosis. Cystic Fibrosis Club Abstracts 1985; 26:145
13. Carswell F, Ward C, Cook DA, et al. A controlled trial of nebulized aminoglycoside and oral flucloxacillin versus placebo in the out-patient management of children with cystic fibrosis. Br J Dis Chest 1987; 81:356–360
14. Jensen T, Pederson SS, Garne S,et al. Colistin inhalation therapy in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infection. J Antimicrob Chemother 1987; 19:831–838
15. Stead RJ, Hodson ME, Batten JC. Inhaled ceftazidime compared with gentamicin and carbenicillin in older patients with cystic fibrosis infected with Pseudomonas aeruginosa. Br J Dis Chest 1987; 81:272–279
16. Day AJ, Williams J, McKeown C, et al. Evaluation of inhaled colomycin in children with cystic fibrosis. In: Proceedings of the 10th International CF Conference, 1988; 106
17. MacLusky IB, Gold R, Corey M, et al. Long-term effects of inhaled tobramycin in patients with cystic fibrosis colonized with Pseudomonas aeruginosa. Pediatr Pulmonol 1989; 7:42–48
18. Ramsey BW, Dorkin HL, Eisenberg JD, et al. Efficacy of aerosolized tobramycin in patients with cystic fibrosis. N Engl J Med 1993; 328:1740–1746
19. Ramsey BW, Pepe MS, Quan JM, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl J Med 1999; 340:23–30
20. Gilligan PH. Microbiology of airway disease in patients with cystic fibrosis. Clin Microbiol Rev 1991; 4:35–51
21. Nickerson B, Montgomery AB, Klystra JW, et al. Safety and effectiveness of two years treatment with intermittent inhaled tobramycin in cystic fibrosis patients [abstract]. Pediatr Pulmonol 1999; 19(suppl 18):S243
22. Quan JM, Vasiljev M, Schaeffler B, et al. Treatment for exacerbation only does not arrest progressive lung function decline in cystic fibrosis [abstract]. Neth J Med 1999; 54(suppl):S84
23. Moss R, Klystra JW, Montgomery AB, et al. Who benefits more? An analysis of FEV₁ and weight in adolescents (age 13 - <18) CF patients using inhaled tobramycin (TOBI) [abstract]. Pediatr Pulmonol 1999; 19(suppl 18):S243
24. Burns JL, Van Dalfsen JM, Shawar RM, et al. Effect of chronic intermittent administration of inhaled tobramycin on respiratory microbial flora in patients with cystic fibrosis. J Infect Dis 1999; 179:1190–1196.
25. Lowry RH, Wood AM, Higenbottam TW. Effects of pH and osmolarity on aerosol-induced cough in normal volunteers. Clin Sci 1988; 74:373–376.
26. Fine JM, Gordon T, Thompson JE, Sheppard D. The role of titratable acidity in acid aerosol-induced bronchoconstriction. Am Rev Respir Dis 1987; 135:826–830
27. Wilson FE. Acute respiratory failure secondary to polymyxin-B inhalation. Chest 1981; 79:237–239
28. Stephens D, Garey N, Isles A, et al. Efficacy of inhaled tobramycin in the treatment of pulmonary exacerbations in children with cystic fibrosis. Pediatr Infect Dis 1983; 2:209–211
29. Huang NN, Hiller EJ, Macri CM, et al Carbenicillin in patients with cystic fibrosis: clinical pharmacology and therapeutic evaluation. J Pediatr 1971; 78:338–345
30. Barker AF, Couch L, Fiel SB, et al. Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis. Am Rev Respir Crit Care Med 2000; 162:481–485
31. Orriols R, Roig J, Ferrer J, et al Inhaled antibiotic therapy in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection with Pseudomonas aeruginosa. Respir Med 1999; 93:476–480
32. Feeley TW, du Moulin GC, Hedley-Whyte J, et al. Aerosol polymyxin and pneumonia in seriously ill patients. N Engl J Med 1975; 293:471–475
33. Klastersky J, Huysmans E, Weerts D, et al. Endotracheally administered gentamicin for the prevention of infections of the respiratory tract in patients with tracheostomy: a double-blind study. Chest 1974; 65:650–654
34. Levine BA, Petroff PA, Slade L, et al. Prospective trials of dexamethasone and aerosolized gentamicin in the treatment of inhalation injury in the burned patient. J Trauma 1978; 18:188–193
35. Brown RB, Kruse JA, Counts GW, et al. Double-blind study of endotracheal tobramycin in the treatment of Gram-negative bacterial pneumonia. Antimicrob Agents Chemother 1990; 34:269–272
36. Mehrad B, Paciocco G, Martinez FJ, et al. Spectrum of Aspergillus infection in lung transplant recipients Chest 2001; 119:169–175

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