Ventilator-associated pneumonia (VAP) is an infection of the lung parenchyma developing in patients on mechanical ventilation for more than 48 h. VAP is associated with a remarkably constant spectrum of pathogenic bacteria, most of which are aerobic Gram-negative bacilli (AGNB) and, to a lesser extent Staphyloccus aureus. Most authorities agree that VAP develops as a result of aspiration of secretions contaminated with pathogenic organisms, which appear to be endogenously acquired. These pathogens gain access to the distal airways by mechanical reflux and aspiration of contaminated gastric contents and also by repetitive inoculation of contaminated upper airway secretions into the distal tracheobronchial tree. Persistence of these organisms in the upper airways involves their successful colonization of available surfaces. Although exogenous acquisition can occur from the environment, the rapidity at which critically ill patients acquire AGNB in the upper airways in conjunction with the low rate of AGNB colonization of health-care workers exposed to the same environment favors the presence of endogenous proximate sources of AGNB and altered upper airway surfaces that are rendered receptive. Proximate sources of AGNB remain unclear, but potential sites harboring AGNB prior to illness include the upper gastrointestinal tract, subgingival dental plaque, and the periodontal spaces. Following illness or antibiotic therapy, competitive pressures within the oropharynx favor AGNB adherence to epithelial cells, which lead to oropharyngeal colonization. Similar dynamic changes in contiguous structures (oropharynx, trachea, sinuses, and the upper gastrointestinal tract) lead to the transcolonization of these structures with pathogenic bacteria. Following local colonization or infection, these structures serve as reservoirs of AGNB capable of inoculating the lower airways. As the oropharynx becomes colonized with AGNB, contaminated oropharyngeal secretions reach the trachea, endotracheal tube, and ventilator circuit. Contaminated secretions pooled above the endotracheal tube cuff gain access to the trachea and inner lumen of the endotracheal tube by traversing endotracheal tube cuff folds. Amorphic particulate deposits containing AGNB form along the endotracheal tube and are capable of being propelled into the distal airways by ventilator-generated airflow or by tubing manipulation. Bacteria embedded within this type of amorphous matrix are particularly difficult for the host to clear. If host defenses fail to clear the inoculum, then bacterial proliferation occurs, and the host inflammatory response progresses to bronchopneumonia.(ABSTRACT TRUNCATED AT 400 WORDS)