DOI: 10.1097/CCM.0b013e3182a120cd
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PMID: 24346525
Issn Print: 0090-3493
Publication Date: 2014/01/01
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Excerpt
P. aeruginosa uses an arsenal of toxins to target cells of the innate immune system. Of these, ExoU appears to be particularly critical. This protein is injected directly into host cells through a needle-like apparatus called the “type III secretion system” (1). Once in the cytosol, it is targeted to the host cell plasma membrane and activated by host cell factors to become a potent phospholipase. The net result is cleavage of phospholipids in the host cell plasma membrane, which causes lysis and death of the host cell. Recent studies have demonstrated that neutrophils are a prime target for ExoU injection during the early stages of P. aeruginosa pneumonia (2). The subsequent death of these neutrophils results in a localized “neutropenia” in the lungs and creates an environment in which P. aeruginosa thrives (3). Although only one fourth of P. aeruginosa clinical isolates harbor the gene encoding ExoU (4), these isolates appear to be particularly virulent and have been linked to especially severe infections (5, 6).
The credentials of P. aeruginosa in the forum of antibiotic resistance are no less impressive. It has been designated an ESKAPE organism, one of six bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, P. aeruginosa, and Enterobacter spp.) for which novel antimicrobial agents are most needed (7). Loss of susceptibility to the widely used fluoroquinolones is especially problematic, with resistance rates now over 30% in U.S. hospitals (8). This resistance has been linked to worse clinical outcomes (9). Since fluoroquinolone resistance often results from overexpression of efflux pumps, it is frequently linked to multidrug resistance. Thus, the association between fluoroquinolone resistance and poor outcomes is thought to occur because of an increased likelihood of inadequate empiric therapy prior to the availability of antimicrobial susceptibility results.
Interestingly, previous reports indicated that the exoU gene and resistance to fluoroquinolones (as well as other antibiotics) cluster together in the same strains of P. aeruginosa (10–12). These strains therefore have the capacity to both thwart the innate immune response and resist the sterilizing action of one of the most frequently used antibiotics. In this issue of Critical Care Medicine, Sullivan et al (13) present findings suggesting that such strains more frequently lead to pneumonia. In a retrospective analysis of 218 consecutive patients with respiratory cultures that grew P. aeruginosa, the single most significant predictor of pneumonia (as opposed to bronchitis or colonization) in a multivariate regression model was the combined traits of fluoroquinolone resistance and the exoU gene. These findings suggest that strains with both the propensity to produce ExoU and the ability to resist the killing effects of fluoroquinolones are more likely cause progression to pneumonia rather than merely colonize the respiratory tract or cause bronchitis. Sullivan et al (13) go on to suggest that diagnostic tests capable of rapidly identifying such strains could prove clinically useful in allowing clinicians to rapidly intervene to prevent pneumonia or to treat it early in its course.
One of the most interesting questions generated by this study is how the linkage between fluoroquinolone resistance and the exoU gene developed. At first glance, one might assume that fluoroquinolone resistance occurred in an ancestral P.
