Alternative and/or integrative therapies for pneumonia under development

Increasing antimicrobial resistance among common respiratory bacteria has created challenges in selecting appropriate therapy for pneumonia. Fortunately, the analysis of genome sequences has allowed us to find novel, nontraditional targets that are involved in disease pathogenesis or in adaptation and growth in infection sites. The advantage of the nonclassical targets is that targeting these sites could ablate infection without inducing resistance. Interfering with bacterial adhesion, inhibiting, neutralizing and clearing endotoxin, and administering cytokines as immunoadjuvants are the most promising alternative or integrative treatments for pneumonia that are under development.

Interference with bacterial adhesion is possible using inhibitors of sortase or inactivators of the srtA gene against gram-positive bacteria, inhibitors of the periplasmic chaperone or those of usher function against gram-negative bacteria, novel polysaccharides that are present on echinoderm surfaces, antiadhesin vaccines, or the passive administration of antiadhesin antibodies. Inhibition, neutralization, and clearance of endotoxin possibly interferes in the lipid A biosynthetic pathway or using lipid A analogues with reduced or lack of ability to activate the major endotoxin receptors or proteins such as recombinant Limulus antilipopolysaccharide factor, bactericidal/permeability increasing protein, or lipopolysaccharide binding protein. Tumor necrosis factor 70-80, an adenoviral vector that encodes murine tumor necrosis factor alpha, and recombinant interferon gamma seem to be the most promising cytokines for use as immunoadjuvants for the treatment of pneumonia.

Ideally, potential treatment of life-threatening bacterial pneumonia will combine immunoadjuvant and conventional antibiotic therapy. Compounds capable of stimulating early host defense and microbial clearance, but not the later phases of inflammatory tissue injury associated with sepsis, may be advantageous.