Tobramycin aerosolized

Steinkamp G, Trummler B, Gappa M. Long-term tobramycin aerosol therapy in cystic fibrosis. Pediatr Pulmonol 6 91 98, 1989. 

Coats AL, MacNeish CF, Meisner D. The choice of jet nebulizer, nebulizing flow, and addition of albuterol affects the output of tobramycin aerosols. Chest... 

The use of the aerosol route for delivery of antibiotics for pulmonary infections remains controversial. The majority of pediatric studies have been conducted in children with cystic fibrosis. In these patients distribution of the antibiotic to the desired tissue site is impeded because of the viscosity of the sputum in patients with acute exacerbations of their pulmonary infections [91,92], Long-term studies have demonstrated preventive benefits of aerosolized antibiotics in children with cystic fibrosis who are colonizing Pseudomonas aeruginosa in their lungs but are not acutely ill [93,94], Cyclic administration of tobramycin administered by nebulizer has received FDA approval [95],... 

Patients suffering from cystic fibrosis often use various aerosolized drugs. To reduce the viscosity of the mucus in the airways, recombinant human deoxyribonuclease is used. This enzyme is the first recombinant protein that has been developed for specific delivery to the lungs via the airways. It has a local action on the mucus in the airways and its absorption is minimal. Another drug that decreases the viscosity of the mucus is acetylcysteine. Aerosolized antibiotics are a further group of therapeutics that is widely used by cystic fibrosis patients. Solutions of antibiotics like tobramycin or colistin are used in nebulizers to prevent exacerbation of the disease. Pentamidine has been used for the prophylaxis of Pneumocystis pneumonia in patients infected with HIV virus, while chronic rejection of lung transplants provided a reason to develop an aerosol formulation of cyclosporine A. 

An alternative method which could be used to establish the fraction of protein that actually reaches the alveoli is the so-called co-aerosohzation. If a protein is aerosolized from a solution that also contains another low molecular weight substance (deposition marker), it can be assumed that the fractions of protein and deposition marker reaching the alveoli will be the same. The deposition marker should be a substance with a known alveolar epithelial membrane passage (e.g. tobramycin or a decapeptide) which does not undergo absorption after oral administration. The fraction of the deposition marker that is deposited in the alveoli can be established from plasma (and urine) measurements of the deposition marker. The maximum fraction of protein that can pass the alveolar membrane whl then be known. The ratio between the deposited fraction and the fraction that has been absorbed into the systemic circulation (as can be estabhshed form plasma or urine analysis) will provide an estimation of the protein passage across the alveolar membrane. 

In a randomized comparison of nebulized tobramycin and nebulized colistin in patients with cystic fibrosis, 26 of 53 patients treated with tobramycin had at least one respiratory adverse event, most commonly pharyngitis (3). In 520 patients, inhaled tobramycin (300 mg bd for three 28-day cycles, each cycle being separated by a 28-day period of no treatment) was compared with placebo. Respiratory function was significantly improved as early as the second week and remained so for the rest of the study, even dnring periods withont aerosol treatment. There was also a parallel rednetion in the relative risk of hospitalization, the number of days of hospitalization, and the number of days of intravenous antibiotic treatment (4). 

Geller DE, Pitlick WH, Nardella PA, Tracewell WG, Ramsey BW. Pharmacokinetics and bioavaUabihty of aerosolized tobramycin in cystic fibrosis. Chest 2002 122(l) 219-26. 

Coates AL, Dinh L, MacNeish CF, RoUin T, Gagnon S, Ho SL, Lands LC. Accounting for radioactivity before and after nebulization of tobramycin to insure accuracy of quantification of lung deposition. J Aerosol Med 2000 13(3) 169-78. 

A number of antibiotics have been used as aerosol therapies. Examples include beta lactam agents, polymycin antimicrobials, neomycin, gentamicin, and tobramycin. Many of the early efforts were reported as case studies, and observations and data regarding safety and efficacy were lacking. Controlled clinical trials were not conducted until the middle of the 1980s. More recent evaluations have focused on the role of inhaled tobramycin used as suppressive therapy for cystic fibrosis patients colonized with Pseudomonas aeruginosa. 

Currently, there is a paucity of antimicrobial products delivered by aerosolization. Pentamidine and tobramycin are the only two agents approved for use in the United States as aerosolized antimicrobial therapies. However, interest in using the lung as a site of delivery of therapeutic agents has continued to evolve, and several therapies are under investigation for both local and systemic effects [2],... 

Oral ciprofloxacin has been used in combination with aerosolized colistin as well as a combination of aerosolized colistin and tobramycin to delay the onset... 

Generally, aerosol administration of antimicrobial therapies is considered safe however, respiratory and nonrespiratory side effects occur frequently. Some patients experience bronchoconstriction associated with administration. This has been reported when the parenteral form of gentamicin and tobramycin was aerosolized, and may be attributed to other components of the products, including preservatives [29,30]. Cutaneous rashes have developed rarely, and a sore throat may occur. 

Resistant Pseudomonas species have been reported with prolonged use or repetitive courses of inhaled tobramycin. After three months of treatment with aerosolized tobramycin 600 mg three times daily, the percentage of patients growing a pseudomonal isolate with a tobramycin MIC of 8 or more increased from 29% to 73% [32]. In studies with the commercially available product where cyclic therapy was administered, the tobramycin MIC = 16 against Pseudomonas aeruginosa was higher in the treatment group compared to placebo (23% vs. 8%) [36]. 

In the studies conducted in support of the commercially available inhaled tobramycin product, aerosol therapies were delivered using a PARI LC Plus nebulizer and a Pulmo-Aide compressor. Currently, the commercial product is labeled for use with the PARI LC Plus nebulizer. 

Initial experiences with aerosolized antimicrobial therapies appeared in the literature more than 50 years ago. Until the early 1990s, the quality of the evidence supporting this strategy in the management of lung infections was poor. Recently, results from well-controlled clinical trials have established a role for inhaled antibiotics, particularly aminoglycosides, as suppressive therapy for patients with cystic fibrosis. Cyclic therapy with inhaled tobramycin reduces the frequency of pulmonary exacerbations and improves lung function. 

Ramsey BW, Dorkin HL, Eisenberg JD. Efficacy of aerosolized tobramycin in patients with cystic fibrosis. N Engl J Med 328 1740-1746, 1993. 

Smith AL, Ramsey BW, Hedges DL. Safety of aerosol tobramycin administration for 3 months to patients with cystic fibrosis. Pediatr Pulmonol 7 265-271, 1989. 

Formulations will increasingly become more complex as the content of the antibiotic is raised within the liposomes [91], and stability is a general concern Dispersions may exhibit aqueous stability of only a matter of days. This issue has partially been addressed through the use of reconstituted lyophilized preps, and a formulation of anamycin has demonstrated over 3 months stability in the solid state [56]. Beauloac et al. [58] have taken this one step further by aerosolizing a dry powder of lyophilized liposome-tobramycin to administer to mice infected with Pseudomonas aeruginosa. [58]. However, the use of powdered preparations does not address the dosing problem. 

Beaulac C, Sachetelli S, Lagace J. Aerosolization of low phase transition temperature liposomal tobramycin as a dry powder in an animal model of chronic pulmonary infection caused by Pseudomonas aeruginosa. J Drug Target 7(1) 33-41, 1999. 

The chronic use of antibiotics to suppress bacteria in CF is controversial because antibiotic resistance may be induced or enhanced. Suppressive therapy is prescribed with the intention of prolonging the time between acute exacerbations and to slow the rate of progression of lung disease. Although attractive intuitively, this practice is not supported by well-designed clinical trials. Moreover, the practice of routine, quarterly administration of intravenous courses of antibiotics used at some European centers still lacks proof of efficacy. Aerosolized tobramycin (TOBI) daily for 1 to 2 months has been shown to eradicate P. aeruginosa from the airways of recently infected patients with CF. 

Oral corticosteroids have also been used to treat the inflammatory process occurring in the lungs of CF patients. Antibiotics that are administered to treat bacterial infections include aerosolized gentamicin and tobramycine. These antibiotics are most effective against P. aeruginosa and S. aureus infections that occur in the CF patients. 

Bronchospasm frequently complicates aerosolized polymyxin therapy as a result of mast cell degranulation and histamine release as such, a bronchial challenge is recommended before initiating therapy. Tobramycin may offer an advantage over gentamicin when used in aerosolized therapy because tobramycin is suspended in neutral pH (a condition similar to the respiratory lining... 

Ramsey BW, Dorkin HL, Eisenberg JD, Gibson RL, Harwood IR, Kravitz RM, Schidlow DV, Wihnott RW, Astley SJ, McBurnie MA, Wentz KM, Smith AL. Efficacy of aerosolized tobramycin in patients with cystic fibrosis. N Engl J Med 1993 328 1740-1746. 

LeConte P, Potel G, Peltier P, Horeau D, Caillon J, Juvin ME, et al. Lung distribution and pharmacokinetics of aerosolized tobramycin. Am Rev Respir Dis 1993 147 1279-1282. 

Baran D, de Vuyst P, Ooms HA. Concentrations of tobramycin given by aerosol in the fluid obtained by bronchoalveolar lavage. Respir Med 1990 84 203-204. 

Aerosol antibiotics in controlled studies improved lung function and reduced the number of acute hospital admissions in patients with cystic fibrosis. Minimal drug hypersensitivity has been reported, and there is no solid evidence that the small increase in resistance to some antibiotics, associated with the use of aerosol antibiotics, is in any way detrimental to the patients (for review, see 161). The drugs used are, for example, tobramycin, carbenicillin, and gentamicin. 

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