Tuberculosis treatment antibiotics may be more effective when taken daily rather than in larger doses a few times per week, according to a new computer modeling study from the University of Michigan. The findings could help improve outcomes for the roughly 10 million people worldwide who fall ill with tuberculosis each year — and may point the way toward reducing the growing threat of tuberculosis treatment antibiotic resistance.
Why Tuberculosis Treatment Antibiotics Are So Difficult to Use
Active tuberculosis is notoriously hard to treat. Current tuberculosis treatment antibiotic regimens require four different drugs for the first two months, followed by two antibiotics for four additional months. Even with this intensive approach, treatment failure and drug resistance remain serious problems.
Part of the challenge is bacterial behavior. TB bacteria can hide inside tumor like lesions called granulomas, making it difficult for tuberculosis treatment antibiotics to reach them in sufficient concentrations. Once inside, bacteria can enter a passive state where they stop reproducing — reducing the effectiveness of drugs that work by targeting cell division.
“If it’s just sitting there, the drug is not going to have as strong an effect on it, which is why you have to treat for six months,” said Denise Kirschner, U-M professor of microbiology and immunology. “You need to catch those bacteria in the few moments when they divide.”
What the Computer Model Found
Rather than running expensive and time consuming animal experiments, the University of Michigan team developed a computer model capable of testing thousands of tuberculosis treatment antibiotic combinations and regimens quickly.
The model evaluated how standard tuberculosis treatment antibiotics isoniazid and rifampin performed under different CDC approved dosing schedules — including larger doses a few times per week versus smaller daily doses.
The simulations showed that daily dosing with both antibiotics produced the best outcomes. Even so, the drugs struggled to eliminate all TB bacteria, particularly those sheltering inside granulomas.
The team then tested whether increasing dose frequency could raise tuberculosis treatment antibiotic concentrations inside those lesions. They found that raising doses to nine per week — such as morning and evening doses twice per week — reduced the time to bacterial elimination by about 10 days on average.
Tuberculosis Treatment Antibiotics: Modifying the Drugs Themselves
The researchers also explored what changes to the drugs themselves could improve outcomes. One key finding: if the body absorbed about 20% less isoniazid — allowing more of the tuberculosis treatment antibiotic to remain active longer — the treatment failure rate could drop from 1% to nearly 0%.
That single modification could translate to roughly 100,000 more successful tuberculosis treatments per year globally.
The Growing Threat of Drug-Resistant TB
The spread of antibiotic resistant tuberculosis makes this research especially urgent. In 2014, the WHO estimated that 480,000 people developed multi antibiotic resistant TB. The World Health Organization already recommends that patients receive tuberculosis treatment antibiotic doses from a health care professional or designated observer to prevent early discontinuation — a common driver of resistance.
Lead researcher Elsje Pienaar was motivated in part by a 2005 outbreak of extensively drug resistant TB in South Africa that killed more than 50 people. She described the emergence of high level resistance as a potential man made problem — one created by incomplete understanding of the complex dynamics of tuberculosis treatment and control.
Tuberculosis Treatment Antibiotics: What Comes Next
The National Institutes of Health has awarded the team a new grant to incorporate additional antibiotics into their computer model. Researchers from Rutgers University and the University of Pittsburgh will contribute animal study data to expand and refine the model’s predictive capability.
The goal is to speed up the development of new tuberculosis treatment antibiotic regimens and reduce the years typically required to move from laboratory findings to clinical application. Community based research sites play a critical role in that process — translating model based insights into real world trials that reach diverse patient populations.
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For the original source, see the full article at EurekAlert.
Source: EurekAlert | Originally published November 24, 2015