Inhaled therapeutics for prevention and treatment of pneumonia

Abstract

The lungs are the most common site of serious infection owing to their large surface area exposed to the external environment and minimum barrier defense. However, this architecture makes the lungs readily available for topical therapy. Therapeutic aerosols include those directed towards improving mucociliary clearance of pathogens, stimulation of innate resistance to microbial infection, cytokine stimulation of immune function and delivery of antibiotics. In our opinion inhaled antimicrobials are underused, especially in patients with difficult-to-treat lung infections. The use of inhaled antimicrobial therapy has become an important part of the treatment of airway infection with Pseudomonas aeruginosa in cystic fibrosis and the prevention of invasive fungal infection in patients undergoing heart and lung transplantation. Cytokine inhaled therapy has also been explored in the treatment of neoplastic and infectious disease. The choice of pulmonary drug delivery systems remains critical as air-jet and ultrasonic nebulizer may deliver sub-optimum drug concentration if not used properly. In future development of this field, we recommend an emphasis on the study of the use of aerosolized hypertonic saline solution to reduce pathogen burden in the airways of subjects infected with microbes of low virulence, stimulation of innate resistance to prevent pneumonia in immunocompromised subjects using cytokines or synthetic pathogen-associated molecular pattern analogues and more opportunities for the use of inhaled antimicrobials. These therapeutics are still in their infancy but show great promise.

Conflict of interest statement

Declaration of interest

This research was supported in part by Cancer Center Support Grant CA16672 from the National Institutes of Health.

Figures

Figure 1. Airway epithelium with overlying surface liquid

The conducting airways are lined by approximately equal numbers of ciliated and secretory epithelial cells. Secretory cells contain granules that include peptides and mucins (green), although the intracellular mucins may only be detected in small distal airways by sensitive immunohistochemial techniques or during inflammatory metaplasia when their production is increased [15,19]. The airway surface liquid consists of a periciliary layer 7 μm in depth (blue), and an overlying mucus gel layer (green) that varies from 50 μm in proximal airways of humans. Cilia beat directionally to propel the mucus gel layer cephalad towards the larynx. The mucin glycoproteins MUC5AC and MUC5B are the principal components of the mucus gel layer, and are exocytically released both from the underlying surface epithelium (shown) and from submucosal glands (not shown). While the mucus gel layer is important in clearance of inhaled pathogens (red), excessive mucin production or airway surface liquid depletion can lead to mucus impaction of the airway lumen, providing a sanctuary for microbial infection.

Figure 2. Survival from challenge with Streptococcus pneumoniae (Spn) following treatment with an aerosolized lysate of non-typeable Haemophilus influenze (NTHi)

Mice were pretreated in groups of six with aerosolized NTHi lysate to stimulate innate immunity, then challenged as a single group with a high dose of Spn (6.1 × 1010 CFU/ml). Survival at 7 days is shown as a function of the interval between treatment and challenge (*p = 0.015, ‡p = 0.002, treated versus untreated) [50].