New Tuberculosis Treatment Uses Old Antibiotics in Novel Ways

Despite the development of vaccines and new diagnostic tools for tuberculosis (TB), it continues to be the deadliest infectious disease in the world. While health officials continue to search for more novel tools to fight TB, a team of researchers has found that a class of antibiotics first introduced in the 1960s may offer an important weapon against the TB outbreaks of today.

The global fight against TB has offered some promising signs, with new tools to diagnose Mycobacterium tuberculosis (Mtb) infections and continued low rates of the disease in the United States and other developed countries. According to the World Health Organization (WHO) though, the worldwide prognosis is still grim, with 10.4 million individuals infected with TB and 1.8 million dying from those infections in 2015 alone. Children account for 170,000 of those deaths. India continues to be the hardest hit by the TB pandemic, followed by Indonesia, China, Nigeria, Pakistan, and South Africa. Together these countries make up 60% of TB cases, and the disease is now the biggest killer of individuals with HIV.

Multi-drug resistant TB affected about 480,000 individuals last year, says WHO, most often causing pulmonary infections. According to the Centers for Disease Control and Prevention, Mtb typically affects the lungs, causing symptoms such as prolonged cough, chest pain, coughing up of blood or phlegm, fatigue, weight loss, fever, and night sweats.

TB infections can occur in any part of the body though, such as the kidney, spine, and brain. Individuals who have TB bacteria in their body but no symptoms of illness have what is called latent TB infection, and still must receive treatment to prevent the onset of disease. TB disease from active and multiplying bacteria can take several months to treat, and up to 24 months for individuals with highly antibiotic-resistant strains of the disease. Individuals with weakened immune systems—such as those with HIV–are at higher risk of developing the active disease.

A recent study, published in the Nature journal, Scientific Reports, tackled the issue of treating today’s contained but virulent TB pandemic. “When it comes to infectious diseases, in our global society we cannot limit our vision to developing and developed world since diseases know no boundaries,” study author Santiago Ramón-García told Contagion. “It is true that there is a misconception in developed societies regarding the real extension of the TB pandemic. However, TB is the most-deadly infectious disease worldwide.” The study authors focused on the issue of lacking new antibiotic drugs and decades-old treatment guidelines for TB, and the continued reliance on the antibiotic rifampicin for these infections. The authors screened commercially available antibiotics, finding that beta-lactam first generation cephalosporins are highly synergistic with rifampicin, and studied how cephalosporins work alone and also paired with other drugs to fight various Mtb strains. In vitro testing found that cephalosporins work well against multiple strains of tuberculosis. When these beta-lactams were not as effective individually, they had high intercellular synergy with rifampicin, becoming more active together and more bactericidal and sterilizing with interaction. Cephalosporins were not as synergistic with rifabutin, another drug in rifamycin group.

“The advantage of cephalosporins over other beta-lactams, such as meropenem, is the ability to administer them orally instead of by parenteral route. However, caution should be exerted by health officials to recommend cephalosporins for TB treatment until properly designed clinical trials have validated their efficacy for TB therapy,” said Dr. Ramón-García.

New antibiotic development has declined markedly since the 1980s, and the authors of this study note that today it costs drug companies $2.6 billion to develop new drugs, urging health officials to do their best with what is already in our arsenal. “Drug development is a long and expensive process,” explained Dr. Ramón-García. “It takes an average of at least 15 years and millions of dollars to bring a single drug to the market. Drug repurposing is a strategy gathering momentum throughout the pharmaceutical industry, driven by the high costs of traditional drug development. Drug development for neglected diseases such as TB, mainly affecting developing countries, is especially complicated by the perception by big pharmaceutical companies that there is insufficient return on their capital investment.”

“In practice, this greatly limits the ability to perform costly clinical trials,” Dr. Ramón-García explained. “In addition, to get to the clinical stage, extensive lead optimization and pre-clinical studies need to be performed and funding is scarce. Because already approved drugs have previously passed all these phases and there is abundant information on safety and human efficacy, the time from bench discovery of in vitro activity to clinic can be greatly reduced. In addition, existing drugs can be used to treat patients that are in desperate need of new effective medications with minimal capital investment from pharma companies.”

The study authors note that by revisiting the use of cephalosporins against TB, they found that these antibiotics—which have gotten little consideration for TB treatment in the past–had good safety profiles and few drug-drug interactions. While they found first generation cephalosporins to be highly effective in their research, they found later generations of these drugs to be less effective. Cephalosporins showed the most promise among the beta-lactam antibiotics tested for synergistic activity with rifampicin.

Only individuals with active TB disease can spread it to others. While the TB vaccine is not commonly used in the United States, infants and children in areas at high risk for TB and healthcare workers treating TB-infected patients may be recommended for the vaccine.