Breakthrough in XDR-TB research could lead to two-drug treatment

A combination of two antiobiotics already in use to treat other bacterial infections could potentially treat extensively drug-resistant tuberculosis (XDR-TB), scientists from New York’s Yeshiva University report today in the February 27 edition of Science.

If the results are replicated in human studies due to begin later this year in South Africa and South Korea, “this discovery could be one of the most promising developments in TB research since the discovery of isoniazid – it is very exciting,” said Professor William Jacobs of Yeshiva University’s Albert Einstein College of Medicine.

At present the treatment of multidrug-resistant forms of TB is lengthy and toxic and often results in confinement for the patient. Some treatment courses can last two years. In cases of extensively drug resistant TB the situation is even more difficult. Patients with XDR-TB have either developed or acquired a form of TB that is resistant to the majority of second-line TB drugs, and the chances of a cure are less good than for TB that is resistant only to isoniazid and rifampicin (the standard definition of multidrug resistance).

In recent years extensively drug-resistant TB has been reported in 45 countries, with the highest rates reported in Eastern Europe, Asia and South Africa.

The outbreak in South Africa has caused particular concern due to its emergence in people with HIV and the health professionals caring for them.

The study carried out by Albert Einstein College of Medicine set out to determine whether it was possible to make Mycobacterium tuberculosis susceptible to an antibiotic from the β-lactam class. This class of antibiotic, which includes penicillin, has not proved active against Mycobacterium tuberculosis because mTB contains an enzyme called a β-lactamase that blocks the activity of β-lactam antibiotics.

β-lactamase inhibitors were developed to overcome the effect of this enzyme, which is found in many bacteria and which has been noted to spread since the introduction of antibiotics. The β-lactamase of Mycobacterium tuberculosis is particularly difficult to overcome: two β-lactamase inhibitors are ineffective against it.

However clavulanic acid, the only FDA-approved β-lactamase inhibitor, irreversibly inhibits the enzyme, so the researchers looked at the activity of the β-lactam antibiotic meropenem, in combination with clavulanic acid, against 13 strains of XDR TB and laboratory strains of mTB without drug resistance.

Meropenem was selected after extensive testing of β-lactam antibiotics as the drug with the best potential for inhibiting mTB growth, and tested in cell cultures with clavanulate. A sterilising cure – complete eradication of mTB – was achieved within 9 to 13 days, and the combination was equally effective in drug-susceptible and drug-resistant strains.

If the findings are replicated in humans, the use of these two drugs has the potential to simplify drug-resistant TB treatment from four to six drugs down to two drugs, said Professor John S Blanchard of Albert Einstein College of Medicine.

The US National Institute of Allergy and Infectious Diseases, which co-sponsored the study, is now talking to manufacturers to provide clavanulate in a formulation suitable for studies (it is currently available only as a coformulation with amoxicillin). The first trial is planned in South Korea later this year in 100 patients. Meanwhile Albert Einstein College of Medicine will conduct a second study, in collaboration with the Nelson Mandela School of Medicine in Durban, South Africa.

Current efforts to find better treatments for drug-resistant TB focus on the development of antibiotics in new classes, with several agents with novel mechanisms of action against TB already in phase II trials.

However researchers are also keen to shorten the length of first-line TB treatment. At present, patients must take four drugs for two months and then two drugs for a further four to six months.

“We see tremendous potential for treating not only XDR-TB cases, but also routine TB cases,” said Professor Brian Currie of Albert Einstein College of Medicine, who will lead the planned studies in South Africa.