A. J. Benjamin1, G. An1 1University Of Chicago,Surgery,Chicago, IL, USA
Introduction: Acinetobacter baumannii is a microbe of growing importance in trauma related soft tissue infections (STIs), and is currently one of the most common causes of late mortality following combat injuries. It has also become a significant cause of multi-drug resistant infection in the intensive care setting. Injury and ischemia have been shown to enhance A. baumannii virulence, both directly and by altering the fitness function of any microbes present in the wound. Characterizing for the ecological dynamics of host-pathogen interactions (HPIs) in the wound milieu will provide insight into tipping points that lead to A. baumannii STIs (AbSTIs). Towards this end we have adapted a prior agent-based model (ABM) of STI to incorporate virulence activation mechanisms of A. baumannii in order to characterize the dynamics of wound HPI and identify conditions that promote AbSTI.
Methods: Our prior muscle wound ABM (MWABM) was extended by adding known A. baumannii virulence mechanisms and host tissue responses to hypoxia and inflammation. The resulting ABM incorporates muscles cells, neutrophils, macrophages, avirulent commensal bacteria, and the detailed representation of A. baumannii. Parameter sweeps were performed to evaluate dynamic patterns of of injury, microbial community composition, virulence activation and host mediator levels in relation to the generation of non-healing and the development of AbSTI. Simulation interventions included differing levels of wound debridement and topical antibiotic therapy.
Results: Simulation experiments identified a series of interconnected thresholds of microbial population composition, degree of initial injury and residual damaged tissue leading to AbSTIs. We demonstrated the role of free iron in the activation of virulence in relation to A. baumannii’s ability to sequester iron via siderophore production. Decreased free iron increased accumulation of HIF1α and decreased iNOS dimerization, which improved with greater debridement. Paradoxically, early topical antibiotic therapy demonstrated decreased microbial populations but increased relative rates of AbSTIs, suggesting the importance of microbial ecological suppression of A. baumannii virulence.
Conclusion: The modified MWABM effectively provides dynamic knowledge representation of A. baumannii virulence in the pathogenesis of AbSTI, demonstrating the effect of debridement, and also the unexpected result that topical antibiotic therapy may have adverse microbial ecological effects on the development of AbSTIs. These findings suggest the importance of incorporating intact microbial communities in future experimental wound healing STI studies in order to make them more clinically relevant. This type of model can serve as a framework to add more detailed mechanistic knowledge as well as investigate novel anti-virulence strategies.