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Microbiological and Immunologic Considerations With Aerosolized Drug Delivery
Section snippets
Rationale for Aerosolized Antibiotic Therapy in CF
The primary rationale for the use of aerosolized antibiotics, rather than parenteral antibiotics, in the treatment of PA in CF patients is improved delivery to the site of infection. Table 1 shows the differences in mean peak sputum and serum concentrations of the drug when delivered IV and as an aerosol by means of three different nebulizers.123 While the highest serum concentration is achieved with IV dosing, sputum concentration, which reflects drug delivery to the site of bacterial
Concerns and Questions
A major concern of the long-term delivery of an antibiotic to the lung is the development of resistant forms of PA, the principal organism infecting the airway in CF patients. The following two questions arise from this concern: (1) what is the significance of this resistance for inhaled therapy?; and (2) what are the implications of this resistance for subsequent parenteral therapy using the same antimicrobial?
To address these questions, it is important to understand the concept of minimal
Mechanisms of Resistance
Microorganisms can acquire drug resistance by a number of different mechanisms (Table 3). Some have inactivating enzymes such as aminoglycoside transferases or β-lactamases. Aminoglycoside transferases are enzymes that are generally encoded by plasmids, while β-lactamases can be carried either on plasmids or on a chromosome. Microorganisms also can alter the target for a specific antibiotic. For example, organisms can become resistant to β-lactam antibiotics by altering their penicillin-binding
Chronic Intermittent Inhaled Tobramycin Trial: Microbiological Outcomes at 6 Months
A randomized, placebo-controlled, double-blind study compared 300-mg bid dosing of tobramycin solution for inhalation (TSI) (TOBI; PathoGenesis Corporation; Seattle, WA) and standard CF care to placebo and standard CF care over a 6-month period.34 The microbiological parameters studied during the first 6 months of the trial included the following:
- 1.
the percentage of patients with at least one PA isolate with an MIC ≥ 16 μg/mL (the resistance breakpoint for parenteral tobramycin);
- 2.
changes in
Unpublished Data at 18 and 24 Months
Following the 6-month randomized study, patients were allowed to enroll in three consecutive 6-month open-label extension studies, resulting in up to 24 months of total exposure to TSI, during which microbiology continued to be monitored.
Unpublished data (PathoGenesis Corporation) show an incremental increase in the percentage of patients with an isolate with the highest MIC that would be considered resistant at the parenteral breakpoint (ie, ≥ 16 μg/mL) with each successive 6 months of
Improvement in Pulmonary Function
While changes in bacterial susceptibility to tobramycin did occur over time, the clinical significance of this effect in terms of pulmonary function did not appear to be important. Figure 4 shows the percentage of patients with improvement in FEV1 as a function of MIC. At all time points, even patients with an MIC ≥ 128 μg/mL, which would be considered a resistant value using parenteral breakpoint values, continued to show a clinical response to TSI therapy. This clinical improvement, despite
Immunologic Considerations of Inhaled Therapies
In addition to the concern of altered drug susceptibility in the setting of long-term intermittent therapy with inhaled antibiotics, there is also a concern that inhaling any therapeutic agent may result in host immune reactions to that agent. The concern that such reactions may occur is based on responses to such allergens as grain dust, fungi, and molds, all of which can trigger profound allergic reactions when inhaled.7 While the studies of inhaled tobramycin did not measure these
Conclusions: Microbiology
Lung infection in patients with CF cannot be eradicated with current therapeutic modalities. Rather, repeated courses of antimicrobial therapy are aimed at slowing the lung damage that results from such infection. The experience to date with TSI indicates that long-term, intermittent treatment results in the emergence of PA with increased tobramycin MIC values. This finding is not surprising. Repeated courses of antibiotics, regardless of class or administration route, typically result in the
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Cited by (70)
The effects of cycled inhaled aztreonam on the cystic fibrosis (CF) lung microbiome
2019, Journal of Cystic FibrosisCitation Excerpt :Pseudomonas aeruginosa infects 50–70% of cystic fibrosis (CF) individuals and chronic infection is associated with worse patient outcomes [1]. To manage chronic infections clinicians prescribe inhaled anti-pseudomonal antibiotics [2], enabling targeting of high concentrations of drug specifically to the lungs thereby maximizing potency and minimizing systemic toxicity [3–8]. Commonly used inhaled antibiotics include tobramycin (TIS/TIP) [3] and aztreonam [5–9].
Relevance of multidrug-resistant Pseudomonas aeruginosa infections in cystic fibrosis
2017, International Journal of Medical MicrobiologyCitation Excerpt :Use of tobramycin even with evidence of resistance. It has been shown that patients with CF with highly resistant pathogens detected in sputum cultures may still derive clinical benefit from aerosolized tobramycin (LiPuma, 2001). This may be due to the substantial pharmacodynamic benefits of aerosolized antibiotic: high concentrations of drug (tobramycin concentration in the lung is 900–1000 μg/ml) can be delivered to the site of infection with low risk of toxicity (Lipworth, 1996).
Clinical applications of pulmonary delivery of antibiotics
2015, Advanced Drug Delivery ReviewsCitation Excerpt :Such changes have been characterized for extended inhaled tobramycin treatment [32] but less well-characterized for extended treatment with other inhaled antibiotic classes. Interestingly, although there clearly are inhaled antibiotic treatment-associated shifts in bacterial antibiotic susceptibility, there has yet to be an association demonstrated between reduced in vitro antibiotic susceptibility and reduced clinical efficacy for inhaled or systemic antibiotic treatment in persons with CF [2,33,34]. The inhaled antibiotic treatment regimen used in studies is an intermittent (i.e., month on/month off) strategy; in part because it was observed that in vitro P. aeruginosa tobramycin susceptibilities decrease significantly with continuous exposure to tobramycin but recover after a rest period, and also because initial lung function improvements seen with inhaled tobramycin treatment appear to be limited after a few weeks [28].
Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis
2023, Cochrane Database of Systematic Reviews