Pharmacokinetic and pharmacodynamic relationships for antibacterial treatment of shigellosis

Project Summary/Abstract Enteric infection with Shigella spp. can lead to symptoms ranging from acute watery diarrhea to sudden, severe dysentery. Approximately 212,000 diarrheal deaths annually are attributed to Shigella (12.5% of total diarrheal deaths) with a disproportionate impact in low resource countries. The impact in low resource countries was illustrated by a reanalysis of the Global Enteric Multicenter Study (GEMS) which found that Shigella has the highest attributable fraction for diarrhea in children < 60 months. While recent studies have highlighted the burden of the disease, there has been a concurrent reduction in therapeutic options for the treatment of shigellosis as drug resistant strains increase in prevalence. In addition, increasing reports of drug resistant shigellosis cases in the men who have sex with men community confirm that the impact is not limited to children in low resource settings. While there is a clear need for new shigellosis treatments, it is not clear what characteristics of current therapies contribute to their efficacy and emergence of resistance. The goals of the proposed work are to determine exposure-response relationships for antibacterials and to establish a rigorous preclinical framework which can be used to identify and optimize new therapeutics for treatment of shigellosis. Our previous innovative studies on the gut localized pathogen Cryptosporidium demonstrated the importance of gastrointestinal drug exposure for in vivo efficacy. The pharmacokinetic/pharmacodynamic (PK/PD) relationship for anti-Cryptosporidium drugs was characterized with in vitro and in vivo models of cryptosporidiosis. Our central hypothesis for this proposal is that a similar approach can be used to establish the relationship between antibacterial exposure and in vivo efficacy against Shigella. In addition, we believe our models can be used to identify antibacterial concentrations associated with the emergence of resistance. Towards our hypothesis, we will use our established mouse model of Shigella infection to characterize the in vivo efficacy of WHO recommended antibacterial treatments for shigellosis. In addition, we will use an innovative hollow fiber infection model to investigate the emergence of antibacterial resistance. This crucial information will assist in rationalizing dosing regimens for current treatments and will support discovery and development of future therapeutics. We propose to evaluate the PK/PD relationship for antibacterials by undertaking the following three Specific Aims: (1) Determine in vivo exposure-response relationships for antibacterials and (2) Characterize antibacterial efficacy and emergence of resistance with a Shigella hollow fiber infection model. Taken together, these studies will help us better understand current shigellosis treatments and will provide a series of methods to identify and optimize new treatments. In addition, the results of the work will provide fundamental support for drug discovery in infectious disease, especially in the area of enteric infections.