Rationale For Aerosolized Antibiotic Therapy

The continuing interest in inhaled antibiotic therapy is based on several factors, including the following: The lung is a frequent site of infection; achieving adequate antimicrobial concentrations in lung tissue may be difficult; and systemic antimicrobial therapies may have dose-limiting toxicities in other organ systems. The rationale for the use of aerosolized antibiotics is to maximize the therapeutic effect against bacteria in the lung by direct delivery of the agent to the site of infection. This may allow a lower dose to be administered, which may minimize the risk of systemic toxicity while maintaining efficacy.

The search for useful inhaled antibiotics has been driven, in part, by a concern about the adequacy of systemic antimicrobial therapy for respiratory infections. Some agents, including aminoglycoside antibiotics, exhibit limited penetration into respiratory tract secretions. In fact, aminoglycosides may achieve sputum concentrations that are 12% of related serum concentrations. In addition, cystic fibrosis patients are often colonized with mucoid strains of Pseudomonas aeruginosa. This phenotype is associated with a further reduction in penetration of antibiotics.

In some cases, enzymes present in the respiratory secretions inactivate the antibiotic. Based on these factors, systemic aminoglycosides are sometimes dosed aggressively to achieve adequate concentrations in the lung. This increases the risk of systemic toxicity, including nephrotoxicity and ototoxicity. Conversely, concerns about potential toxicities may limit dosage regimens and duration of therapy.

The potential benefit of aerosolized antibiotic therapy is dependent on three factors: characteristics of the disease, aerosol delivery system, and properties of the antimicrobial agent [5]. Diseases that are likely to respond better cause infection in the airway without significant parenchymal or systemic involvement (e.g., cystic fibrosis). There is a significant need for research and scientific advances in the area of aerosol delivery of these therapies. Delivery systems that produce reliable, consistent, and reproducible aerosols are essential. Formulation of drug products requires attention to integrity, stability, tolerability, and overall suitability for aerosolization.

It is important to note that although aerosolization of antibiotic therapy has resulted in significantly higher sputum concentrations, systemic treatment is clearly more effective than this topical route of delivery. This suggests that factors other than sputum concentrations are important in the overall efficacy of therapy.

Although a potential advantage of inhaled antibiotic therapy is the achievement of high concentrations in the sputum, there is substantial variability reported, which may reflect differences in collection and bioassay techniques. There is no clear relationship between systemic and inhaled doses of individual agents. Currently, the decisions about inhaled doses should be made on data specific for an individual agent. In trials with the commercially available inhaled tobramycin product, sputum concentrations of 1200 mg per mL were measured 10 minutes after the dose. Measured concentrations exceeded 25 times the minimum inhibitory concentration (MIC) for the most resistant isolate in 95% of subjects evaluated [7].

Aerosol Deposition of Antimicrobial Agents

Four primary physical factors of an aerosol affect pulmonary deposition. These include particle size, hygroscopicity, viscosity, and surface tension. The characteristics are described in detail elsewhere [8]. This brief overview addresses principles relevant to aerosolized antibiotics.

To achieve benefit from aerosolized antibiotic therapy, an adequate amount of medication must reach the site of infection [3,4,8]. Optimal particle size for deposition in the lower respiratory tract and alveoli lies between 1 and 5 micrometers (mm). For alveolar deposition, particle sizes of 1 -2 mm are optimal. Particle diameters of 3 and 4 mm reach the lower airway, while 5-mm particles deposit in the central airways. Particles below this range are likely exhaled, and larger particles deposit in the oropharynx. Removal of deposited particles from the airway surface occurs by absorption, mucociliary clearance, or expectoration of produced sputum.

The pattern of deposition of inhaled particles in a normal lung is dependent on particle size, flow rate, and airway anatomy (branching). There are also patient specific variables that influence aerosol deposition. These include respiratory rate, tidal volume, and other anatomical features. The presence of airflow obstruction characteristic of some lung diseases will affect deposition.

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