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The incidence of ventilator-associated pneumonia ranges between 8% and 28% in patients receiving mechanical ventilation for more than 48 hours, and between 34% and 70% in patients with acute lung injury or acute respiratory distress syndrome.1 It prolongs the duration of stay in the intensive care unit and hospital, and increases costs.2 Associated mortality ranges from 24% to 76%, and appears far greater than the mortality resulting from other nosocomial infections. It may even exceed 85% when high-risk gram-negative bacteria, such as Pseudomonas aeruginosa or Acinetobacter baumannii, are the causative pathogens.3 Many studies demonstrate that early intravenous administration of appropriate antibiotics improves the prognosis. Lung deposition of antibiotics, however, administered by the intravenous route is either limited or poorly documented and treatment failure is common, leading to increased dosage and risk of systemic toxicity. Despite antimicrobial therapy and adequate supporting treatment, the mortality rate from ventilator-associated pneumonia remains high, indicating a need for a more effective route of administration. Inhaled antibiotic therapy may represent such an alternative.

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At least three major theoretical arguments support the administration of inhaled antibiotics in critically ill patients with ventilator-associated pneumonia: the very pathogenesis of lung infection that originates in the tracheobronchial tree, the possibility of obtaining high lung-tissue concentrations by bypassing the alveolar–capillary barrier, and the potential for decreasing systemic toxicity.

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Deep Lung Infection Originates in the Upper Airways

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The normal human respiratory tract possesses efficient defenses against bacteria colonizing the pharynx. The glottis and larynx serve as natural anatomic barriers. The cough reflex, mucociliary clearance, and regional immunity contribute to elimination of invading pathogens and prevention of infection deep in the lungs. Endotracheal and tracheostomy tubes bypass the natural barrier between the oropharynx and tracheobronchial tree. Bacteria penetrate into the trachea by leakage of infected secretions and/or contaminated gastric contents around the low-pressure cuff of an endotracheal tube.4 In ventilated patients, deep sedation depresses the cough reflex whereas endotracheal intubation inhibits the ciliary escalator.5,6 In addition, the internal wall of the endotracheal tube rapidly becomes coated with an antibiotic-resistant bacterial biofilm, which then can become fragmented and disseminated into the deep lung during tracheal suctioning or fiber-optic procedures.7,8 Consequently, it appears reasonable to hypothesize that antibiotics administered by the inhalational route may reduce bacterial inoculum by stopping the continuous bacterial seeding from the upper airways.

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Bypassing the Alveolar–Capillary Barrier May Provide High Antibiotic Tissue Concentrations

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Killing bacteria infecting the lung parenchyma requires that an antibiotic achieve a pulmonary concentration at least five times greater than minimal inhibitory concentrations for the infecting pathogen. Reaching concentrations lower than mutant prevention concentrations in the infected parenchyma may trigger the emergence of resistant bacterial strains.9 When antibiotics are intravenously administered, the alveolar–capillary barrier imposes a difficult-to-cross obstacle, which impairs lung deposition even if lung inflammation increases capillary permeability. Pulmonary vasoconstriction and regional thrombosis, two pathophysiologic abnormalities ...

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