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Review
. 2016 Jul;29(3):581-632.
doi: 10.1128/CMR.00101-15.

Inhaled Antibiotics for Gram-Negative Respiratory Infections

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Free PMC article
Review

Inhaled Antibiotics for Gram-Negative Respiratory Infections

Eric Wenzler et al. Clin Microbiol Rev. .
Free PMC article

Abstract

Gram-negative organisms comprise a large portion of the pathogens responsible for lower respiratory tract infections, especially those that are nosocomially acquired, and the rate of antibiotic resistance among these organisms continues to rise. Systemically administered antibiotics used to treat these infections often have poor penetration into the lung parenchyma and narrow therapeutic windows between efficacy and toxicity. The use of inhaled antibiotics allows for maximization of target site concentrations and optimization of pharmacokinetic/pharmacodynamic indices while minimizing systemic exposure and toxicity. This review is a comprehensive discussion of formulation and drug delivery aspects, in vitro and microbiological considerations, pharmacokinetics, and clinical outcomes with inhaled antibiotics as they apply to disease states other than cystic fibrosis. In reviewing the literature surrounding the use of inhaled antibiotics, we also highlight the complexities related to this route of administration and the shortcomings in the available evidence. The lack of novel anti-Gram-negative antibiotics in the developmental pipeline will encourage the innovative use of our existing agents, and the inhaled route is one that deserves to be further studied and adopted in the clinical arena.

Figures

FIG 1
FIG 1
Representation of the alveolar capillary barrier. The barrier consists of three layers, of which the epithelium constitutes the least permeable layer because of the presence of numerous zonula occludens. Epithelial lining fluid lies in pools on the inside surface of the alveolus. 1,000 Å equals 100 nm. (Republished from reference with permission.)
FIG 2
FIG 2
The airways branch roughly 16 to 17 times before alveolar sacs are encountered. The surface area of the human airways averages ∼2 to 3 m2, compared with roughly 100 m2 for the alveolar surface. In the upper airways, the inertia of the larger particles causes them to break free of the streamlines of the flow and collide with a wall to be deposited. As impaction clears these larger particles in the upper airways, slightly smaller particles are filtered out of the airstream in the middle airways by gravitational sedimentation. Finally, for very small particles, particle motion is determined by Brownian diffusion, which accounts for the dominant mechanism of deposition in the alveolar region. (Reprinted from reference by permission from Macmillan Publishers Ltd.)
FIG 3
FIG 3
Scanning electron microscope image of tobramycin inhalation powder. (Reprinted from reference with permission of the publisher. Copyright 2015 American Chemical Society.)
FIG 4
FIG 4
Colistin concentrations in ELF 1, 4, and 8 h after treatment with 80 mg of inhaled CMS. (Left) Median and interquartile range values; (right) individual concentrations. The dashed line represents the MIC of colistin for A. baumannii and K. pneumoniae. (Republished from reference with kind permission from Springer Science+Business Media. © Copyright jointly held by Springer and ESICM 2012.)
FIG 5
FIG 5
Colistin concentrations in serum 0.16, 0.5, 1, 2, 4, and 8 h after administration of 80 mg of inhaled CMS. (Left) Median and interquartile range values; (right) individual concentrations. The dashed line represents the MIC of colistin for A. baumannii and K. pneumoniae. (Republished from reference with kind permission from Springer Science+Business Media. © Copyright jointly held by Springer and ESICM 2012.)
FIG 6
FIG 6
Mean amikacin concentrations and standard deviations in tracheal aspirates over time on days 1 and 3. q12h, every 12 h. (Republished from reference with kind permission from Springer Science+Business Media. © Copyright jointly held by Springer and ESICM 2011.)
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