# PK/PD Optimized Cephalosporins Based Treatment Regimens for Children With MDR-TB

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH CTR AT TYLER · 2022 · $306,226

## Abstract

Project summary/Abstract
Children exposed to tuberculosis (TB) bacterium have a greater risk of progressing to active TB disease. Younger
children (<2 years) are especially susceptible to developing disseminated disease due to ineffective immunologic
containment. As per World Health Organization 2017 report, ~1 million children become ill with TB each year
representing nearly 10% of the total TB cases. In 2016, ~3% of the reported cases in children diagnosed to have
multi-drug resistant (MDR) TB (defined as being resistant to the two most potent first-line anti-TB drugs, isoniazid
and rifampin). One of the hurdles in pediatric TB management is the availability of a safe and effective treatment
regimen for MDR-TB designed specifically for children considering the age specific pharmacokinetic variability.
Our broad objective is to use our hollow fiber system model for TB to streamline TB drug development. Given
that the pipeline for novel TB drugs is still slim, there is renewed interest in repurposing old drugs for new use.
β-lactam antibiotics are the backbone of many antibacterial treatment regimens; however, their efficacy against
Mycobacterium tuberculosis (Mtb) have not been fully explored. We screened 13 drugs from the β-lactams class
of the antibiotics including the cephalosporins sub-class, against drug resistant clinical strains of Mtb. In this
grant application we will advance 6 cephalosporins to the next phase of investigations. Cephalosporins have an
advantage because the pharmacokinetic and safety profile in children is well defined. We will combine the leading
cephalosporins with two other oral drugs—moxifloxacin, an integral backbone of MDR-TB treatment regimens
in people of all ages, and tedizolid, a new oxazolidinone effective against gram-positive pathogens as well as
Mtb to create a potent regimen effective against MDR-TB in children. Our drug and combination regimen
development approach apply pharmacokinetic/pharmacodynamic science using our validated hollow fiber
system model for intracellular Mtb (HFS-TB). We have information on each drug’s optimal exposure target for
maximal Mtb kill as monotherapy from the HFS-TB studies performed to collect preliminary data. The workflow
of the current application will be - (1) use of checkerboard studies to evaluate additivity, synergy or antagonism
of each cephalosporin with moxifloxacin, (2) add tedizolid at concentration to achieve optimal exposure target to
the cephalosporins-moxifloxacin drug pair(s) to test in the HFS-TB comparing Mtb kill rates with a second-line
MDR-TB regimen of five drugs (amikacin-levofloxacin-ethionamide-cycloserine-pyrazinamide) using MDR-TB
clinical strains, (3) mathematical modeling of the HFS-TB results to predict Mtb time-to-extinction that will inform
optimal duration of therapy with the proposed novel drug combination regimens, (4) in silico clinical trial
simulations incorporating pediatric-specific pharmacokinetic variability as well as Mtb-strain min...

## Key facts

- **NIH application ID:** 10449269
- **Project number:** 5R01HD099756-04
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH CTR AT TYLER
- **Principal Investigator:** Shashi Kant
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $306,226
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10449269

## Citation

> US National Institutes of Health, RePORTER application 10449269, PK/PD Optimized Cephalosporins Based Treatment Regimens for Children With MDR-TB (5R01HD099756-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10449269. Licensed CC0.

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