# Evaluation of novel in vitro and in vivo models to characterize anti-Shigella therapeutic PK/PD relationships

> **NIH NIH R56** · UNIVERSITY OF WASHINGTON · 2021 · $443,174

## Abstract

PROJECT SUMMARY/ABSTRACT
 Enteric infection with Shigella spp. can lead to symptoms ranging from acute watery diarrhea to sudden,
severe dysentery. Approximately 164,000 diarrheal deaths annually are attributed to Shigella (12.5% of total
diarrheal deaths) with a disproportionate impact in low-middle income countries (LMIC). The impact in LMIC was
recently 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 has sex with men (MSM) community confirm that the impact isn’t limited to
LMIC. Moving forward, there are critical gaps in the development of new shigellosis treatments. The long-term
goals of the proposed work are to establish a rigorous pre-clinical framework which can be used to identify
repurposing opportunities or new chemical entities for the treatment of shigellosis.
 Our previous innovative studies on the gut localized pathogen Cryptosporidium demonstrated the
importance of gastrointestinal drug exposure for in vivo anti-Cryptosporidium 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 with in vitro
and in vivo models can be used to establish the relationship between drug exposure and in vivo efficacy for
shigellosis treatments. However, while there currently is no “gold standard” for the treatment of cryptosporidiosis
in humans, there are a set of approved antibacterials with variable clinical efficacy against shigellosis in humans.
Towards our hypothesis, we have initiated the development of in vitro and in vivo models of Shigella infection
which can be used to characterize the efficacy of anti-Shigella therapeutics. The exciting preliminary data from
these models suggest that they can be used to identify PK/PD relationships for antibacterials used to treat
shigellosis. This crucial information will assist in our understanding of why the efficacy of antibacterials differ in
the clinic. We propose to evaluate the PK/PD relationship for antibacterials by undertaking the following three
Specific Aims: (1) To characterize the anti-Shigella efficacy of antibacterials with a panel of in vitro models. (2)
To investigate the in vivo efficacy and pharmacokinetics of antibacterials to treat shigellosis. (3) To identify
associations between antibacterial in vitro efficacy, pharmacokinetics, and in vivo efficacy.
 Taken together, these studies will help us better understand the current treatments for shigellosis and
will provide a series of methods t...

## Key facts

- **NIH application ID:** 10436402
- **Project number:** 1R56AI155421-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Samuel L Arnold
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $443,174
- **Award type:** 1
- **Project period:** 2021-07-23 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436402

## Citation

> US National Institutes of Health, RePORTER application 10436402, Evaluation of novel in vitro and in vivo models to characterize anti-Shigella therapeutic PK/PD relationships (1R56AI155421-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10436402. Licensed CC0.

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