# A randomized clinical trial of early empiric anti-Mycobacterium tuberculosis therapy for sepsis in sub-Saharan Africa

> **NIH NIH U01** · UNIVERSITY OF VIRGINIA · 2024 · $659,026

## Abstract

PROJECT SUMMARY/ABSTRACT
Sepsis is a syndrome of critical illness defined as life-threatening organ dysfunction due to a dysregulated host
response to infection and is a leading cause of global mortality. In May of 2017, the World Health
Organization (WHO) made sepsis a global health priority. Yet, little is known about sepsis in the global
South and specifically sub-Saharan Africa where there are at least 1.2-2.2 million cases of sepsis and 6.5
million deaths due to infection annually. The majority of these patients are living with HIV. We have determined
the leading cause of sepsis in this region is tuberculosis (TB) which is responsible for 25-30% of bloodstream
infections in septic patients. TB sepsis is associated with 20-50% mortality rates with the majority of deaths
occurring within the first 4-5 days of admission. However, it is difficult to identify TB sepsis clinically or with
diagnostic tests which are often unavailable and have limited sensitivity. Therefore, TB can be missed and
patients with TB sepsis may not receive anti-TB therapy, or if they do, it may be delayed. However, we have
found that empiric treatment of TB in septic patients without a confirmed diagnosis of TB improves 28 day
survival. We have also studied anti-TB pharmacokinetics/pharmacodynamics in septic patients and discovered
considerably low circulating drug concentrations that are suboptimal for microbial kill. Therefore, our
hypotheses are that immediate anti-TB therapy will improve 28 day survival compared to anti-TB therapy that
is administered only after a diagnosis is made, and that optimized sepsis-specific dosing will improve 28 day
mortality compared to conventional WHO recommended weight-based dosing regardless of the timing of
administration. We will test these hypotheses through a randomized 2x2 factorial clinical trial where
participants with HIV and sepsis will be randomized to 1) empiric immediate initiation of anti-TB therapy plus
standard care or diagnosis dependent anti-TB therapy and standard care and 2) sepsis-specific dose anti-TB
therapy plus standard care or conventional WHO weight-based recommended dose anti-TB therapy and
standard care. This randomized 2x2 factorial clinical trial is strongly endorsed by Tanzanian and Ugandan
community advisory boards and will be the first to determine the optimal content, dosing, and timing of the
antimicrobial regimen for adult sepsis in sub-Saharan Africa.

## Key facts

- **NIH application ID:** 10867331
- **Project number:** 5U01AI150508-05
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Scott K Heysell
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $659,026
- **Award type:** 5
- **Project period:** 2020-09-18 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867331

## Citation

> US National Institutes of Health, RePORTER application 10867331, A randomized clinical trial of early empiric anti-Mycobacterium tuberculosis therapy for sepsis in sub-Saharan Africa (5U01AI150508-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10867331. Licensed CC0.

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