Bronchiectasis: Take a Deep Breath of Tobramycin?
Abstract & commentary
Synopsis: Inhalational administration of tobramycin to patients with bronchiectasis with heavy colonization of their sputum with Pseudomonas aeruginosa was associated with a reduced bacterial load.
Source: Barker AF, et al. Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis. Am J Resp Crit Care Med 2000;162:481-485.
Barker and colleagues, in a multicenter study, examined the safety and microbiologic efficacy of inhaled tobramycin solution (ITS) in adults with chronic bronchiectasis who had grossly purulent sputum containing Pseudomonas aeruginosa in a density of 104 cfu/g or greater. Seventy-four patients were randomized and received, in double-blind fashion, at least one dose of either ITS or placebo. ITS was in the form of tobramycin for inhalational administration (TOBItm); 300 mg tobramycin or placebo were self-administered twice daily for four weeks, using a jet nebulizer.
ITS was associated with significant benefit with regard to the primary efficacy end point of the study—the change in density of P. aeruginosa in sputum. Thus, at the end of treatment, patients given ITS had a mean decrease of 4.54 log10 P. aeruginosa cfu/g, while there was a mean increase of 0.02 log10 cfu/g in placebo recipients (P < 0.01). Two weeks later, there was a modest increase in density in the ITS group.
More ITS recipients than placebo recipients were subjectively assessed by investigators as being improved (62% vs 38%; P < 0.001). Females were more likely to be considered improved than males (62% vs 31%; P = 0.01). Clinical improvement was associated with reduction in P. aeruginosa density and, in particular, with bacterial eradication—a result observed in one-third of ITS recipients. There was no difference in change in pulmonary function.
In a comparison of isolates of P. aeruginosa obtained prior to and two weeks after treatment completion, a 4-fold or greater increase in tobramycin MIC was found in eight of 31 (26%) patients assigned ITS and in four of 29 (14%) placebo recipients (P = 0.25). Four of 36 (11%) ITS patients and one of 32 (3%) placebo recipients had resistant isolates (MIC ³ 16 mg/L) at their last visit.
Adverse events involving the respiratory system were reported in 84% of each group. Dyspnea, chest pain, and wheezing were each reported significantly more often in ITS recipients. Five ITS patients and one placebo recipient were hospitalized because of exacerbations of pulmonary disease; tobramycin-resistant P. aeruginosa was isolated from one of the ITS patients. The median serum concentration of tobramycin in ITS recipients 30-60 minutes after administration was 0.54 mg/L (range, < 0.18-2.64 mg/L). No renal or VIIIth nerve toxicity was reported.
Comment by Stan Deresinski, MD, FACP
Chronic colonization of sputum with P. aeruginosa is associated with poor lung function and more rapid decline in lung function in patients with bronchiectasis.1 However, since patients who become colonized with P. aeruginosa have worse lung function than those colonized with other organisms at the time they first acquire this colonization, causality is uncertain.
P. aeruginosa is difficult to eradicate from patients with bronchiectasis both because of its frequent location in poorly ventilated areas with impaired blood supply and its potential mutability and remarkable phenotypic plasticity. In one longitudinal study of 16 patients with bronchiectasis, 38 distinct antibiotic-resistant phenotypes were detected among 64 isolates obtained over a median period of 10.6 months.2 Clonal analysis found that only a minority of resistance acquisitions over this time were related to acquisition of expogenous strains. Furthermore, as in patients with cystic fibrosis, mucoid forms of P. aeruginosa, indicative of alginate overexpression under the control of a two component environemental sensing system, are commonly present.2,3 These factors frequently make antibiotic therapy incompletely effective. In an attempt to overcome these factors, as well as to avoid the systemic toxicity of prolonged and repeated systemic administration of aminoglycosides, clinicians have increasingly administered drugs such as tobramycin by the inhalational route to patients with bronchiectasis.
TOBItm received FDA approval as an orphan drug at the end of 1997 in the treatment of P. aeruginosa infections in cystic fibrosis patients. This approval was granted on the basis of the results of two randomized clinical trials involving more than 500 patients.4 In these studies, cyclical administration was associated with a significant improvement of FEV1 over baseline. Drug recipients experienced a mean of three fewer days of hospitalization and a mean of 4.4 days fewer of parenteral antibiotic therapy treatment when compared to placebo recipients. The density of P. aeruginosa decreased during treatment periods but returned to baseline during periods when the drug was not administered. Furthermore, the diminution in density of P. aeruginosa in sputum during periods when tobramycin was administered was progressively attenuated during the 24 weeks of cyclical therapy. In addition, treatment was associated with "MIC creep" the proportion of P. aeruginosa MICs ³ 16 mcg/mL increased from 13% at baseline to 23% at the end of six cycles of therapy. However, the high and variable concentrations of tobramycin in sputum, as well as the adverse effects of sputum and its components on the antibacterial activity of aminoglycosides,5 make interpretation of the predictive value of in vitro susceptibility tests problematic.
The inhalational route has a number of theoretical benefits, including the potential for achievement of extremely high antibiotic concentrations in respiratory secretions while limiting systemic toxicity. Other investigators have reported that gentamicin levels in sputum after a single 5 mg/kg intravenously-administered dose of gentamicin failed to exceed the MIC of P. aeruginosa.6 In contrast, a single inhalation of 160 mg of either dry powder gentamicin or liquid gentamicin by nebulization resulted in high concentrations of the antibiotic in sputum in the majority of individuals and was associated with a significant decrease of P. aeruginosa in sputum.6 The tobramycin concentration in sputum approximately 10 minutes after inhalation of a 300 mg dose is, however, remarkably variable, ranging from 35 to 7414 mcg/g (mean, 1237 mcg/g) and exhibits a rapid decline to approximately one-seventh of these early levels after two hours. As reported in the study reviewed here, as well as in patients with cystic fibrosis, systemic absorption is minimal. It is of interest that administration by inhalation of antibiotics in liposomes is associated with greater persistence in respiratory secretions.
The results of the study of patients with bronchiectasis reviewed here are encouraging but mixed. ITS clearly was effective with regard to the primary end point of the study (i.e., a decrease in the density of P. aeruginosa in sputum). In fact, the microbiologic effect reported here was significantly better than that reported in patients with cystic fibrosis, in whom the mean reduction in bacterial density was only 1.7-2.0 log10 cfu/g and in whom there was a rebound to baseline by two weeks after discontinuation of ITS. Furthermore, based on Barker et al’s subjective assessments, administration of ITS was associated with improved clinical status. On the other hand, ITS was associated with an increased frequency of symptoms suggestive of airways reactivity, and an increased frequency of emergence of apparent tobramycin resistance. While objective evidence of clinical improvement in association with ITS was lacking, the study was of short duration and was not powered to detect such an effect.
While systemic toxicity was not observed, there appeared to be increased local toxicity, albeit insufficiently severe to require discontinuation of treatment, in these patients with bronchiectasis. Presumably, the increased incidence of dyspnea, chest pain, and wheezing in the ITS recipients reflects airway reactivity to the antibiotic, an effect we have seen with inhalational administration of colistin, an antibiotic that has been reported to be of benefit in cystic fibrosis when administered by inhalation.7 Whether pretreatment with bronchodilators would improve tolerability was not addressed by this study.
The clinical manifestations of lung disease in cystic fibrosis and widespread bronchiectasis are similar and raise frequent questions concerning the possible relationship of the two diseases. A recent study found an increased prevalence of mutations in the cystic fibrosis transmembrane regulator gene among white adults with chronic rhinosinusitis.8 Similar mutations have been reported in some patients with bronchiectasis not known to have cystic fibrosis.9 The diagnosis of cystic fibrosis should be considered in adults with radiographic evidence of widespread bronchiectasis that is predominantly cylindrical and most severe in the upper lobes.10
A number of adjunctive therapies for patients with bronchiectasis have been the subjects of recent metaanalyses. A Cochrane review concluded that there is insufficient evidence for evaluation of the routine use of mucolytics, although high doses of bromhexine (a mucolytic not approved for use in the United States) together with antibiotics, "may help with sputum production and clearance."11 Recombinant human DNase, which is beneficial in cystic fibrosis, is ineffective in bronchiectasis. Inhaled corticosteroids were associated with a short-term trend toward improved lung function, that did not, however, achieve statistical significance.12 Finally, the evidence for the value of bronchopulmonary hygiene physical therapy is felt to be inconclusive.13,14
Overall then, it appears that the efficacy of commonly used adjunctive therapies in bronchiectasis have not been adequately demonstrated. In patients with purulent sputum and heavy colonization with P. aeruginosa, ITS has the potential for benefit with lesser toxicity than seen with systemic administration, but this also requires further studies of greater size and longer duration.
References
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