Tobramycin

Objectives: This randomized, double-blind, cross-over study evaluated the risk of bronchoconstriction with two preparations of inhaled tobramycin in children with cystic fibrosis (CF) infected with Pseudomonas aeruginosa with and without airway hyperreactivity.

Design: Of 19 children with CF (age range, 7 to 16 years) with mild-to-moderate pulmonary disease, 10 children were at high risk (HR) for bronchospasm (family history of asthma and previous response to bronchodilators) and 9 children were at low risk (LR) for bronchospasm (no family history of asthma or previous response to bronchodilators). Two solutions of tobramycin were administered: (1) 80 mg in a 2-mL vial diluted with 2 mL of saline solution containing the preservatives phenol and bisulfites (IV preparation); and (2) 300 mg in a preservative-free preparation in a 5-mL solution. Following a bronchodilator-free period of 12 h, the patients inhaled either one or the other preparation in random order on two different occasions, 2 weeks apart.

Results: Prechallenge and postchallenge results for the LR group showed a percentage of fall in FE[V.sub.1] ([DELTA]FE[V.sub.1]) of 12 [+ or -] 9% (mean [+ or -] SD) for the IV preparation, compared to 4 [+ or -] 5% for the preservative-free preparation (p = 0.046). An [DELTA]FE[V.sub.1] of > 10% was seen in six of nine patients for the IV preparation and in one of nine patients for preservative-free preparation. For the HR group, the [DELTA]FE[V.sub.1] was 17 [+ or -] 13% for the IV-preparation group, compared to 16 [+ or -] 12% for the preservative-free group (p = 0.4). In this group, equal numbers of patients (8 of 10 patients) had an [DELTA]FE[V.sub.1] > 10% after inhaling each preparation. The largest [DELTA]FE[V.sub.1] was 44% (HR group with the preservative-free preparation that forced the early termination of inhalation).

Conclusions: Both preparations caused significant bronchoconstriction in the HR group, and the preservative-containing IV preparation caused more bronchospasm in LR group than the preservative-free solution. Heightened airway reactivity in children with CF places them at risk of bronchospasm from inhalation therapy.

Key words: bronchial constriction; bronchospasm; cystic fibrosis; inhaled antibiotics; tobramycin

Abbreviations. CF = cystic fibrosis; [DELTA]FE[V.sub.1] = percentage of fall in FE[V.sub.1]; HR = high risk; LR = low risk; mOsm = milliosmole

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The benefits of inhaled tobramycin are well established in the ambulatory treatment of Pseudomonas aeruginosa endobronchial infection in patients with cystic fibrosis (CF). (1-3) A large, multicenter, double-blinded, controlled trial (4) of intermittent treatments of inhaled tobramycin showed a significant improvement in pulmonary function and a decreased frequency of hospitalization. Additional benefits of inhaled tobramycin are that the aerosolized route delivers the medication to the target site of infection with relatively fewer side effects and can be easily used in the home environment. To date, there has been no dose-ranging study, nor has the ideal preparation of tobramycin been established in comparative studies.

Evidence suggesting inactivation of aminoglycosides in CF sputum has been used as an argument for attempting to achieve high intrabronchial concentrations of tobramycin. (5) One of the preparations of inhaled tobramycin that has been used in many studies (1,2,6,7) in patients with CF is an IV form (IV preparation, 80 mg per 2-mL vial) [Eli Lilly; Toronto, ON, Canada] that contains 1.44 mg/mL sodium metabisulphite as antioxidant and 5 mg/mL of phenol as preservative. This preparation is usually diluted with 2 mL of saline solution. It has been widely used by CF clinics in a number of countries. The most recent large, placebo-controlled trial (4) used a preservative-free formulation of 300 mg per 5 mL. Long-term improvements in pulmonary function have been seen with both preparations (1,4) and short-term adverse effects of bronchoconstriction have also been observed with both the preservative-containing solution (7-9) and with the preservative-free solution. (4) There has been no prospective study reporting on the risk of bronchospasm with either preparation. Furthermore, a subpopulation of patients with CF may possess inherent airway hyperreactivity, and therefore may be at more risk of bronchospasm from any inhaled solution. (10)

This study compared potential side effects of the 80-mg IV preparation to a preservative-free solution. There were two objectives of this study. The first was to compare the risk of bronchoconstriction associated with the inhaled IV and preservative-free preparations of tobramycin in children with CF and mild-to-moderate pulmonary disease. The second was to assess whether inherent airway hyperreactivity poses any additional risk for bronchoconstriction in patients with CF inhaling the two preparations.

MATERIALS AND METHODS

Nineteen patients with CF with mild-to-moderate pulmonary disease were enrolled from those followed up in the CF Clinic at the Hospital for Sick Children in Toronto, Canada. All were chronically infected with P aeruginosa and were receiving 80 mg of the tobramycin solution containing preservatives diluted with 2 mL of saline solution twice daily, using a breath-enhanced nebulizer at home. (11) This is the current standard in the clinic, with the exception that albuterol is usually added to the preparation. Their ages ranged from 7 to 16 years (mean, 12 years), and they were able to perform spirometry. Patients who had a baseline percentage of predicted FE[V.sub.1] of [greater than or equal to] 50% and had a previously determined bronchodilator response were identified from our CF database. A positive bronchodilator response was defined as either a [greater than or equal to] 12% change (12) in FE[V.sub.1] from baseline on one occasion or a response of [greater than or equal to] 10% change in FE[V.sub.1] from baseline on three or more occasions. The bronchodilator response was determined following the administration of 400 [micro]g of albuterol through a metered-dose inhaler using a valved holding chamber (Aerochamber; Trudell Medical Group; London, ON, Canada). Clinical histories were reviewed, and the presence or absence of a personal or family history of atopy or asthma coupled with clinical symptoms that improved with bronchodilators was assessed. Only those patients who satisfied both the spirometric and the clinical criteria, eg, presence or absence of the above, were approached to participate in the study. No subject was approached if there was any suggestion of allergic bronchopulmonary aspergillosis. Patients were classified into two subgroups. The first group (n = 10), labeled as a high-risk (HR) group for bronchospasm, had the combination of a positive response to bronchodilators and a history suggestive of asthma. The second group (n = 9), labeled as a low-risk (LR) group for bronchospasm, did not possess any of these characteristics. A comprehensive chart review for all patients in both groups was done to ensure that all the clinical criteria were met. Patients were excluded if they had a pulmonary exacerbation requiring a change in antibiotic treatment, either as inpatients or outpatients, within 4 weeks of entry into the study. The ethics committee of the hospital approved the study, and informed consent was obtained from all patients and their parents before participating.

The intervention involved an inhalation challenge test using one of the two tobramycin preparations delivered by Pari LC Star nebulizers driven by the Pari Proneb compressor (Pari Respiratory Equipment; Richmond, VA). One challenge was the IV preparation of tobramycin (80 mg per 2-mL vial; Eli Lilly) diluted with 2 mL of normal saline solution (243 milliosmole [mOsm]/kg). The other challenge was the powdered bulk IV formulation of tobramycin that is preservative free (Eli Lilly). This was prepared by dissolving 300 mg of tobramycin in 5 mL of 0.45% saline solution, which gives an osmolarity of 205 mOsm/kg. This has similar physical characteristics to a commercial preparation (TOBI; Chiron; Seattle, WA). (4) The preparations were inhaled on two separate occasions within a 2-week interval, in random order with the outside of the nebulizer covered to prevent identification of the solution from the fill volume. All studies were done in the pulmonary function laboratory under continuous surveillance for any adverse effects. All the patients were instructed to abstain from using bronchodilator or tobramycin inhalations for 12 h prior to nebulization of any challenge drug. The patients' sex, age, height, and weight were recorded for each visit. A physician assessed the subjects for signs and symptoms of bronchospasm before and after each inhalation challenge.

All spirometry measurements (Vmax version 4.3a; SensorMedics; Yorba Linda, CA) were performed in accordance with the American Thoracic Society guidelines. (13) After establishing a baseline FE[V.sub.1], the patient inhaled one of the two tobramycin preparations for a total duration of 20 min. Restriction of the time of nebulization to 20 min ensured a standardized exposure to the aerosolized drug, and accounted for the small difference in the charge volume of the nebulizer (4 mL in the IV preparation vs 5 mL in the preservative-free preparation). Postchallenge FE[V.sub.1] measurements were obtained between 1 min and 3 min after completion of the inhalation, and the percentage of fall in FE[V.sub.1] [DELTA]FE[V.sub.1]) from baseline was determined. An [DELTA]FE[V.sub.1] of [greater than or equal to] 10% was considered significant for a positive reaction (bronchospasm). Patients with an [DELTA]FE[V.sub.1] between 10% and 15% were rested for 15 min, and FE[V.sub.1] measurements were repeated to determine if the values dropped further. If there was an initial [DELTA]FE[V.sub.1] > 15%, the patients received 400 [micro]g of albuterol (Ventolin; Glaxo; Toronto, ON, Canada) from a metered-dose inhaler administered through a valved holding chamber (Aerochamber). Spirometry was then repeated after 10 min, and the FE[V.sub.1] values were recorded.

All episodes of coughing or wheezing observed by the technologist or the physician were recorded. Respiratory distress was likewise recorded and, if severe, the test was terminated. Subjective adverse events (persistent cough, wheeze, or chest tightness) were also recorded.

Analysis

The difference in the [DELTA]FE[V.sub.1] between the two preparations of tobramycin was evaluated using paired t tests for the HR group and the LR group. A p value < 0.05 (two tailed) was considered significant. Statistical tests were performed using SigmaStat Version 2.0 (Jandel Scientific; San Rafael, CA).

RESULTS

The patient demographics and baseline pulmonary function data are given in Table 1. In keeping with the coexistence of both asthma and CF in the HR group, there was a trend for the HR group to have a lower FE[V.sub.1] than the LR group. Among the LR group, more patients had bronchospasm following the inhalation of the IV tobramycin than the preservative-free tobramycin preparation (Table 2). The mean [+ or -] SD [DELTA]FE[V.sub.1] from baseline value was 12 [+ or -] 9% for the IV preparation compared to 4 [+ or -] 5% for the preservative-free preparation (p = 0.046; Fig 1). Six of nine patients (67%) had an [DELTA]FE[V.sub.1] [greater than or equal to] 10% from baseline following inhalation of the IV preparation, while only one patient (not one of the six) had a similar drop in FE[V.sub.1] following the inhalation of the preservative-free solution.

[FIGURE 1 OMITTED]

Among the HR group, the mean [DELTA]FE[V.sub.1] from baseline was 17 [+ or -] 13% for the standard IV tobramycin preparation compared to 16 [+ or -] 12% for the preservative-free preparation (p = 0.4; Fig 1). Equal numbers (8 of 10 patients; 80%) of patients had an [DELTA]FE[V.sub.1] of > 10% from baseline following inhalation of the IV preparation and the preservative-free preparation (Table 2). The largest observed [DELTA]FE[V.sub.1] was 44%. This occurred during the inhalation of the preservative-free solution in a patient in the HR group. Coughing and respiratory distress resulted in termination of the test and administration of bronchodilators.

Clinically apparent bronchospasm (subjective symptoms of chest tightness, cough, and audible wheezing) occurred in some patients in both groups. In the LR group, patients had clinical symptoms on three occasions of seven spirometrically determined episodes of bronchospasm ([DELTA]FE[V.sub.1] > 10% from baseline; Table 2). In the HR group, patients had clinical symptoms on seven occasions of 16 spirometrically determined episodes of bronchospasm (Table 2).

DISCUSSION

This study evaluated the risk of bronchospasm in children with CF inhaling two different preparations of tobramycin. Bronchospasm occurred whether the preparation was 80 mg of the preservative-containing IV preparation or 300 mg of the preservative-free preparation. For those judged to be at lower risk for bronchospasm (the LR group), the IV preparation of tobramycin resulted in a higher prevalence of bronchospasm than the preservative-free preparation. For those judged to be at high risk (the HR group), bronchospasm was common and independent of the solution inhaled.

There are some limitations to this study. It assessed the prevalence of bronchoconstriction induced by the inhaled tobramycin preparations in two subpopulations of children with CF from our clinic population who were believed to be most likely (HR group) and least likely (LR group) to acquire bronchospasm. Because of the selection criteria, these two groups cannot be considered to be a representative sample of the entire clinic. Hence, these data do not allow the assessment of the risk of bronchospasm in the overall CF population, many of whom would fall in between the two groups (for example, no family history of asthma or atopy but a significant response to bronchodilators). Ideally, both groups would have had identical values for FE[V.sub.1] at entrance to the study. However, with the coexistence of asthma and CF in the HR group who had gone at least 12 h without bronchodilators prior to the baseline measurement, it is not surprising to have a trend toward a lower values for FE[V.sub.1] compared to the LR group. However, the differences were relatively modest and not statistically significant, and were unlikely to have influenced the overall results.

While this study was not intended to address the issues of causation of this bronchoconstriction, some inferences may be made when previous work is taken into consideration. The bronchospasm seen in the LR group when exposed to the preparation containing preservatives but with less tobramycin would be in keeping with the earlier suggestions of Beasley et al, (14) that the preservatives rather than the drug were likely to be responsible for the observed bronchoconstriction. Other possible mechanisms that have been previously proposed (7,8,14,15) to explain this bronchoconstrictive effect of inhaled tobramycin appear less likely in this setting. Contrary to suggestions by Nikolaizik et al, (7) the concentration of tobramycin alone seems not to have been a factor, since the tobramycin dose in the preservative-free formulation was threefold higher (60 mg/mL vs 20 mg/mL) than that in the IV preparation, and yet did not induce bronchospasm in the LR group. Given the identical inhalation protocol, the high concentration would be expected to give rise to a much higher lung deposition of tobramycin, suggesting that differences in airway surface tobramycin concentration between the two preparations would not explain the differences. The role of the hypertonicity of the solutions in inducing bronchospasm (8) also seems less likely as both preparations used were hypotonic (243 mOsm/kg for the IV preparation, and 205 mOsm/kg for the preservative-free preparation). While the osmolarity of the solutions would increase due to evaporative losses in the nebulizer, this would be in the order of 1.2 to 1.4 times the initial osmolarity, (11,16,17) and not in the range of hyperosmolarity believed to cause bronchospasm. (8) Finally, data from the HR group lend further credence to earlier speculations on the role of the inherent airway hyperreactivity in patients with CF as a predictive risk factor for bronchoconstriction from inhaled solutions, (10,18) In this group, the prevalence of bronchoconstriction was independent of the preparation administered. A relatively high prevalence of bronchospasm has been demonstrated in patients with CF with advanced lung disease following the inhalation of normal saline solution. (7) Combined with the data of the present study, this suggests that the deposition of droplets in the airway may give rise to bronchospasm in CF independent of the content of the droplet.

The prevalence of bronchoconstriction as a result of the inhalation of tobramycin was higher in this study than previous reports. (2,7-9) There are a number of reasons that may account for this discrepancy. First, the expected total tobramycin pulmonary deposition by the breath-enhanced nebulizer used in this study is at least twice that of the unvented nebulizer (11,19) used by Ramagopal and Lands. (9) The study by Ramsey et al (4) that used the Pari LC Jet nebulizer rather than the more efficient Pari LC Star (11,20) used in the present study found similar ranges of change in FE[V.sub.1], with the exception of the one child who had a fall of 44% in the present study. It is possible that the more efficient nebulizer with greater deposition was part of the explanation, but the number of patients studied with this degree of fall is too small to allow any firm conclusions.

The occurrence of bronchoconstriction, indicated by a fall in FE[V.sub.1], was clinically unapparent in most of the episodes (Table 2). Severe symptomatic bronchoconstriction that forced termination of the tobramycin administration was seen in only one patient who was reacting to preservative-free preparation. In other words, the absence of symptoms following the inhalation of tobramycin should not be interpreted by clinicians as no fall in FE[V.sub.1].

In conclusion, this study found that either of the inhaled tobramycin preparations caused significant bronchoconstriction in children with CF with mild-to-moderate pulmonary disease, in the group identified as having increased airway reactivity. In those children with CF without this additional risk factor, the HD preservative-free tobramycin solution caused less bronchospasm. What remains to be determined is the most appropriate dose of inhaled tobramycin that will be efficacious against pseudomonas infection and yet have the least risk of side effects. Finally, regardless of the preparation, some patients with CF are at risk for significant bronchospasm following the inhalation of tobramycin.

ACKNOWLEDGMENT: The authors thank Eli Lilly Canada, Inc. for the supply of all medications.

REFERENCES

(1) MacLusky IB, Gold R, Corey ML, et al. Long-term effects of inhaled tobramycin in patients with cystic fibrosis colonized with Pseudomonas aeruginosa. Pediatr Pulmonol 1989; 7:42-48

(2) Steinkamp G, Tummler B, Gappa M, et al. Long-term tobramycin aerosol therapy in cystic fibrosis. Pediatr Pulmonol 1989; 6:91-98

(3) 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

(4) Ramsey BW, Pepe MS, Quan JF, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl J Med 1999; 340:23-30

(5) Mendelman PM, Smith AL, Levy J, et al. Aminoglycoside penetration, inactivation, and efficacy in cystic fibrosis sputum. Am Rev Respir Dis 1985; 132:761-765

(6) Weisemann HG, Steinkamp G, Ratjen F, et al. Placebo-controlled, double-blind, randomized study of aerosolized tobramycin for early treatment of Pseudomonas aeruginosa colonization in cystic fibrosis. Pediatr Pulmonol 1998; 25: 88-92

(7) Nikolaizik WH, Jenni-Galovic V, Schoni MH. Bronchial constriction after nebulized tobramycin and saline in patients with cystic fibrosis [abstract]. Am J Respir Crit Care Med 1996; 153:A707

(8) Chua HL, Collis GG, LeSouef PN. Bronchial response to nebulized antibiotics in children with cystic fibrosis. Eur Respir J 1990; 3:1114-1116

(9) Ramagopal M, Lands LC. Inhaled tobramycin and bronchial hyperreactivity in cystic fibrosis. Pediatr Pulmonol 2000; 29:366-370

(10) Mellis CM, Levison H. Bronchial reactivity in cystic fibrosis. Pediatrics 1978; 61:446-450

(11) Coates AL, MacNeish CF, Lands LC, et al. A comparison of the availability of tobramycin for inhalation from vented vs unvented nebulizers. Chest 1998; 113:951-956

(12) Lung function testing: selection of reference values and interpretative strategies; American Thoracic Society. Am Rev Respir Dis 1991; 144:1202-1218

(13) Standardization of spirometry, 1994 update: American Thoracic Society. Am J Respir Crit Care Med 1995; 152:1107-1136

(14) Beasley R, Rafferty P, Holgate ST. Adverse reaction to the non-drug constituents of nebuliser solutions. Br J Clin Pharmacol 1988; 25:283-287

(15) Nikolaizik WH, Jenni-Galovic V, Schoni MH. Bronchial constriction after nebulized tobramycin preparations and saline in patients with cystic fibrosis. Eur J Pediatr 1996; 155:608-611

(16) Coates AL, MacNeish CF, Lands LC, et al. Factors influencing the rate of drug output during the course of wet nebulization. J Aerosol Med 1998; 11:101-111

(17) Kwong E, MacNeish CF, Meisner D, et al. The use of osmometry as a means of determining changes in drug concentration during jet nebulization. J Aerosol Med 1998; 11:89-100

(18) Boushey HA, Holtzman MJ, Sheller JR, et al. State of the art: bronchial hyperreactivity. Am Rev Respir Dis 1980; 121:389-413

(19) Katz SL, Ho SL, Coates AL. Nebulizer choice for treatment of cystic fibrosis patients with inhaled colistin. Chest 2001; 119:250-255

(20) Ho SL, Kwong WTJ, Coates AL. Evaluation of four breath-enhanced nebulizers for home use. J Aerosol Med 2001; 14:467-475

* From the Division of Respiratory Medicine, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada. Supported by the Canadian Cystic Fibrosis Foundation.

Manuscript received June 29, 2001; revision accepted April 26, 2002.

Correspondence to: Allan L. Coates, MD CM, Division of Respiratory Medicine, Hospital for Sick Children, 555 University Ave, Toronto, ON, Canada M5G IX8; e-mail: allan.coates@sickkids.ca

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