Higher dose antibiotic shown safe in TB patients likely more effective
in treating deadliest form of TB
Date:
March 15, 2022
Source:
Johns Hopkins Medicine
Summary:
A new study in animals suggests that high doses of a widely used
antibiotic called rifampin may safely treat and reduce the duration
of treatment for the deadliest form of tuberculosis that affects
the brain, potentially improving survival rates for patients and
decreasing the likelihood of lasting adverse effects of the disease.
FULL STORY ==========================================================================
A Johns Hopkins Children's Center-led study in animals suggests that
high doses of a widely used antibiotic called rifampin may safely
treat and reduce the duration of treatment for the deadliest form of tuberculosis that affects the brain, potentially improving survival rates
for patients and decreasing the likelihood of lasting adverse effects
of the disease. Additional studies in a small number of people also shed
light on how rifampin moves through the body, including into the brain,
and how rifampin levels could change during treatments, showing how the research could potentially translate to humans.
========================================================================== According to the World Health Organization, an estimated 10 million
people worldwide developed disease by the bacterium that causes TB in
2020. It's also one of the leading infectious disease killers. Previous
studies have shown the deadliest form of TB, TB meningitis, affects more
than 100,000 people each year, damaging brain tissue and even proving
fatal, especially among young children and those with HIV and AIDS due
to a weakened immune system. Treatment generally requires lengthy courses
of antibiotics and monitoring to assure compliance with therapy.
In a study published March 15 in The Journal of Clinical Investigation,
Johns Hopkins Medicine investigators showed that higher doses of rifampin
can treat TB meningitis more effectively by killing bacteria faster
while not increasing brain inflammation.
"Based on what is seen clinically and in previous research, most peope
with TB meningitis will die and, even if treated, may suffer lasting brain damage, since it is difficult to recognize the disease in early, more
treatable stages," according to study first author, Camilo Ruiz-Bedoya,
M.D., pediatric infectious diseases fellow at Johns Hopkins University
School of Medicine.
Treatments for TB meningitis are long and can take up to 12
months. Shorter regimens can lead to better compliance, lower costs,
and better outcomes for patients, adds senior author Sanjay Jain, M.D., professor of pediatrics, and of radiology and radiological sciences at
the school of medicine and a pediatric infectious diseases specialist
at Johns Hopkins Children's Center.
The standard therapy for TB meningitis is a combination of antibiotics, including rifampin, a 50-year-old drug that has been a mainstay in
the global fight against TB and other bacterial diseases. However, the currently recommended dose of rifampin (10-15 mg/kg/day) given orally
does not lead to sufficient rifampin levels in the brain to target and
kill the bacteria. This is because of the blood-brain barrier, which
protects the brain and prevents the entry of infections, toxins, and
drugs, including antibiotics. This limits the drug's effectiveness and can
also lead to the development of antibiotic- resistant strains. Previous clinical studies revealed conflicting results on whether higher doses
of rifampin were a more effective treatment for TB meningitis.
==========================================================================
The team conducted studies in mice and rabbits with TB meningitis
to evaluate a high-dose (35 mg/kg/day) rifampin-containing oral
regimen. "Some animals were given the high-dose regimen, and others
were given the standard regimen. We also used advanced positron emission tomography (PET) and computed tomography (CT) imaging to identify sites of brain infection as well as track the drug penetration and distribution,"
says study co-first author Filipa Mota, Ph.D., former pediatric infectious diseases fellow at the school of medicine.
The researchers found in both animal models of TB meningitis that the
high-dose rifampin regimen killed TB bacteria found in brain tissue
at a rate of 10 times higher as early as two weeks after the start of treatment. Giving a much higher dose of rifampin also achieved much
higher rifampin levels in the brains and cerebrospinal fluid (or CSF)
than the standard dose while not increasing brain inflammation. But
rifampin levels dropped after two weeks of starting treatment.
"The way rifampin kills the bacterium is the more a patient gets, the
faster the bug dies," says study co-first author Elizabeth Tucker, M.D., assistant professor of anesthesiology and critical care at the school
of medicine and pediatric anesthesiology and critical care specialist
at the Children's Center.
"So giving rifampin in the first two weeks of treatment is important
to kill the bugs fast, but it is also important to prevent further
inflammation and subsequent brain damage." The researchers also conducted imaging studies in 12 patients with TB, including one with TB meningitis,
who were enrolled from January 2017 to February 2019 at Johns Hopkins
Health System hospitals. Using PET imaging, the team looked at how
rifampin moves through the body, including the brain, and how those
levels change during treatments in 12 patients with pulmonary TB or
TB meningitis.
In a retrospective analysis, the team reviewed medical records of
four patients at the same hospitals treated between July 2011 to July
2021 with confirmed TB meningitis who underwent MRIs during their TB
treatment. The goal was to see how the patients' blood-brain barrier was affected by TB and treatment. They found that the changes in the patients' blood-brain barrier changes were compartmentalized and changed over time, suggesting that rifampin levels varied in different brain areas and also significantly decreased with treatment over time.
==========================================================================
"One interesting finding was that rifampin levels and markers of
inflammation in the CSF, which acts as a cushion between the brain and
the skull, were substantially different from those within the brain. This
is important as the CSF analysis is commonly utilized in many trials to
study what is happening in the brain, but we now know that studying CSF
may not represent the full picture," Jain says.
Based on their findings, the team believes their animal models of TB
meningitis could be used to evaluate and prioritize promising treatments
before their evaluation in clinical trials and could also be combined
with imaging approaches to provide detailed information on how drugs
penetrate into the brain and through the body.
The investigators noted the limitations of their study. For example,
the team performed their research at different time points early in the treatment regimen, at up to six weeks. "While antibiotic treatment for
TB meningitis is typically for 12 months, most deaths and neurological
damage in TB meningitis occur early in the course of treatment, which highlights the need for early interventions for TB meningitis," Jain says.
If further research validates their findings, the research team believes
the high-dose regimen could prevent deaths from TB meningitis.
Along with Jain, Ruiz-Bedoya, Mota and Tucker, the members of the
research team from Johns Hopkins Medicine include Farina J. Mahmud,
Maria I. Reyes-Mantilla, Clara Erice, Melissa Bahr, Kelly Flavahan,
Patricia de Jesus, John Kim, Catherine A. Foss, Alvaro A. Ordonez and
Carlos A. Pardo. Other study authors were Charles A. Peloquin from
the University of Florida College of Pharmacy and Dima A. Hammoud,
Center for Infectious Disease Imaging, Radiology and Imaging Sciences,
National Institutes of Health.
The study was funded by the U.S. National Institutes of Health
(R01-AI145435- A1, R01-AI153349, Director's Transformative Research Award R01-EB020539 and R01-HL131829 to Jain and K08-AI139371-A1 to Tucker).
========================================================================== Story Source: Materials provided by Johns_Hopkins_Medicine. Note:
Content may be edited for style and length.
========================================================================== Journal Reference:
1. Camilo A. Ruiz-Bedoya, Filipa Mota, Elizabeth W. Tucker, Farina J.
Mahmud, Maria I. Reyes-Mantilla, Clara Erice, Melissa Bahr, Kelly
Flavahan, Patricia de Jesus, John Kim, Catherine A. Foss, Charles A.
Peloquin, Dima A. Hammoud, Alvaro A. Ordonez, Carlos A. Pardo,
Sanjay K.
Jain. High-dose rifampin improves bactericidal activity without
increased intracerebral inflammation in animal models of tuberculous
meningitis.
Journal of Clinical Investigation, 2022; 132 (6) DOI:
10.1172/JCI155851 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/03/220315105606.htm
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