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The staphylococci are perhaps the preeminent opportunistic pathogens in that they exist as commensal inhabitants of a significant proportion of the healthy human population yet retain the capacity to cause serious and even life-threatening disease. This is particularly true of Staphylococcus aureus, which is capable of producing a diverse array of virulence factors and causing a correspondingly diverse array of infections. At the same time, the coagulase-negative species S. epidermidis is of increasing medical significance owing largely to its remarkable capacity to colonize indwelling medical devices. The continuing emergence of antibiotic resistant strains of both species is a major concern; indeed, recent years have seen the appearance of vancomycin-resistant S. aureus (VRSA) and even strains that are resistant to new drugs (e.g. linezolid, daptomycin) introduced in response to the appearance of VRSA. This emphasizes the urgent need to identify new targets for anti-staphylococcal therapy, and identification of such targets is a primary focus of our research. We are particularly interested in those virulence factors that are most relevant to musculoskeletal infection, and we have placed a specific emphasis on biofilm formation because we believe biofilms play a particularly important role in many of these infections both in terms of native tissues (bone and cartilage) and indwelling medical devices (catheters, orthopaedic implants). This biofilm, which consists of multiple layers of bacterial cells encased in an extracellular matrix, not only protects bacteria from host defenses but also impedes delivery of at least some antibiotics. Perhaps more importantly, the phenotype of biofilm-associated bacteria confers intrinsic resistance to specific antimicrobial agents at least within a subset of the population of bacterial cells. For instance, such bacteria grow very slowly if at all, and this limits the efficacy of antibiotics that target cell wall biosynthesis (e.g. the beta-lactams). Based on this, we are actively investigating the mechanisms of biofilm formation in S. aureus and the nature of the adaptive response to the sessile lifestyle. Owing at least in part to formation of a biofilm, many staphylococcal musculoskeletal infections, including those associated with indwelling medical devices, cannot be resolved without surgical intervention. It is important to emphasize that, while antibiotic resistance among the staphylococci is a primary concern, the recalcitrance of these infections is not a function of acquired resistance. Indeed, in many cases, the offending bacteria are found to be fully susceptible once they are removed from the biofilm and tested under in vitro conditions. Based on this, we believe it is also important to develop better ways to diagnosis infection in a timely manner (i.e. before the formation of necrotic bone and/or a biofilm). Indeed, we believe early detection would greatly facilitate treatment, possibly to the point that surgical debridement would become an option rather than an imperative. Based on this, we are investigating noninvasive imaging methods (e.g. FDG-PET) for the diagnosis and management of staphylococcal musculoskeletal infection. We also believe that a more effective means of antibiotic delivery would facilitate the efficacy of both existing and newly developed antimicrobial agents. To address this issue, we are evaluating the efficacy of different antimicrobial agents in the specific context of musculoskeletal and biofilm-associated infection as well as novel methods of delivering those antibiotics to the site of infection. Importantly, while our experiments focus on the staphylococci, the methods we develop will be directly applicable to other bacterial pathogens that cause similar infections. These experiments will also compliment our ongoing studies focusing on the staphylococcal virulence factors that are most relevant in the pathogenesis of musculoskeletal and biofilm-associated infection. Questions about this page? Send us an email. |
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