Le Berre and colleagues focused on three extensively studied virulence determinants: quorum-sensing (QS), the type III secretion (TTS) system, and lipopolysaccharide (LPS) O-antigen. aeruginosa produces a potpourri of pathogenic factors, any one of which might or might not be a worthy target for inhibition. But which virulence determinants should be targeted? P. Thus novel agents that target virulence determinants would be a welcome addition to our antipseudomonal armamentarium. It is a frequent cause of nosocomial infections, many of which are responsible for substantial mortality even when treated with appropriate antibiotics. aeruginosa is an opportunistic pathogen familiar to every hospitalist and intensivist. However, it leaves unanswered two important questions: Is the factor critical for virulence in most clinical isolates? And how important is the factor relative to other virulence determinants made by the same bacterium? In this issue of Critical Care Medicine, Le Berre and colleagues address these questions in relation to Pseudomonas aeruginosa. This powerful approach has the benefit of demonstrating a causal relationship between the factor and disease in the model used and has become the gold-standard for identification of virulence factors. To test the importance of a particular bacterial factor in pathogenesis, scientists usually disrupt the gene encoding the factor in a well characterized laboratory strain, and the virulence of the mutant is compared to that of the parental strain in an established animal model of infection. The problem is compounded by the current emphasis on reductionist approaches in microbiology. In other cases, however, the choice is less clear. For example, tetanus toxin is the major virulence determinant of Clostridium tetani, and administration of human tetanus immune globulin attenuates the course of tetanus. In some cases, the choice is straightforward. But which virulence determinants should be targeted? A factor that is highly critical to the organism's pathogenesis, of course. The thought is that such agents could be used by themselves or as adjuncts that would boost the efficacy of conventional antibiotics.
To improve upon the current situation, attempts are being made to leverage our impressive knowledge of bacterial pathogenesis for development of novel therapeutics that block virulence mechanisms rather than simply kill or inhibit growth of bacteria. The ever-increasing burden of resistance erodes the efficacy of conventional antibiotics, while critically ill patients frequently fail to respond to appropriate agents even when infected with susceptible organisms.
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