Growing presence of drug-resistant tuberculosis fuels need for faster development of new combination therapies

Johns Hopkins experts in the prevention and treatment of multidrug-resistant tuberculosis are calling for increased screening and more rapid testing of the 9 million people worldwide estimated to be infected each year with TB and now at risk for this form of the highly contagious lung disease.

The call follows results of a survey showing that the harder-to-treat TB variants are much more widespread than previously thought.

Details of the survey, to be published in The online June 7, provide the first-ever, nationwide estimate of the size of the problem in China, where over a million new infections occur each year. The 2007 survey of more than 4,000 Chinese newly diagnosed or recently treated for TB showed that one in 10 was infected with drug-resistant strains of TB, more formally known as Mycobacterium tuberculosis. Among this group, some 0.5 percent (or more than 5,000, annually) were diagnosed with extensively drug- resistant TB, which the experts say is nearly incurable.

TB is spread when uninfected people inhale small numbers of coughed up and spewed into the air by people already infected. Antibiotics can cure the disease, but compliance with the lengthy course of treatment is uncertain and the drugs available in the developing world to treat the disease are limited to fewer than a dozen, mostly older medications.

In an editorial accompanying the study, Johns Hopkins infectious disease specialists Richard Chaisson, M.D., and Eric Nuermberger, M.D., call the proliferation of the drug-resistant organisms an "enormous challenge" to eradicating TB, which now kills 1.5 million people each year, mostly in the .

More worrisome among the study findings, says Chaisson, a professor at the Johns Hopkins University School of Medicine and founding director of its Center for Tuberculosis Research, was that the majority of the estimated 110,000 drug-resistant cases occurred among people newly diagnosed with TB, indicating that these drug-resistant bacteria were transmitted from one person to another. Only 3 percent of all newly detected cases were tested for drug resistance.

This research, Chaisson says, "upsets the old dogma" that drug-resistant organisms occur mostly in people who fail to respond to therapy or in infected people who relapse after drug treatment. In sum, he says, drug resistance appears to be present in new cases on a large scale, and drug-resistance testing should not be limited to previously treated patients.

Chaisson says the study also highlights the urgent need for faster testing of those newly diagnosed to determine drug resistance. Current laboratory testing methods, while relatively cheap (at less than $5 per person), take several weeks to show bacterial growth in sputum samples. Same-day results are available using high-tech molecular assays, but they dramatically raise the test cost to as much as $40 per person, a cost he says is worth it, given the "sobering" scope of the problem.

According to Chaisson, multidrug-resistant strains of TB cannot be effectively treated by either of the two most commonly used antibiotics, isoniazid and rifampin. Extensively strains do not die off in the presence of two other so-called second-line treatments, either.

Both Chaisson and Nuermberger, an associate professor at Johns Hopkins, have tested simpler, shorter regimens of new and existing antibiotics, hoping to streamline treatment and stem the spread of drug-resistant strains. The scientists say, however, that developing new antibiotics is the key to controlling TB in all its drug-resistant forms.

Results from an international study of a new antibiotic called delamanid, published in the same issue of the medical journal, are encouraging, but only "half the answer," they say. In some 400 infected people taking either varying doses of delamanid or a sugar pill in combination with older, second-line antibiotics for two months, TB bacteria were eradicated from sputum samples in at least 42 percent of those taking the new drug combination, and in only 30 percent of those taking the sugar pill version. Delamanid is manufactured by Otsuka Pharmaceutical Inc. of Rockville, Md.

Nuermberger says the delamanid study results are comparable to those published in 2009 in the same medical journal for another new antibiotic, bedaquiline, which showed that after two months of therapy, the drug eradicated sputum TB in 48 percent of study participants.

Nuermberger says the arrival of any new antibiotic drugs is good news, but he stresses that what health care providers really need is better information about what drug combination regimens work best, including guidelines about when to use the newer antibiotics, in what dose and order, and for how long.

"Just as HIV is more effectively treated with potent drug cocktails, the regimens that offer the greatest hope against TB contain two or more effective drugs," says Nuermberger, who adds that further studies need to be done to assess whether delamanid and bedaquiline work better together or separately in boosting the effects of older antibiotics.

Chaisson and Nuermberger point out that individual studies are required by U.S. and global regulatory agencies. But, they say, regulators, pharmaceutical company officials and scientists must accelerate their efforts in evaluating the impact of new drugs - in combination form - if the spread of multidrug-resistant TB is to be contained.

Experts estimate that 2 billion people worldwide are infected with TB, 10 million of whom fall ill each year.

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