# Pharmacokinetic and pharmacodynamic relationships for antibacterial treatment of shigellosis

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $436,309

## Abstract

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 f...

## Key facts

- **NIH application ID:** 10821450
- **Project number:** 5R01AI170784-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Samuel L Arnold
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $436,309
- **Award type:** 5
- **Project period:** 2023-04-06 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10821450

## Citation

> US National Institutes of Health, RePORTER application 10821450, Pharmacokinetic and pharmacodynamic relationships for antibacterial treatment of shigellosis (5R01AI170784-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10821450. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*