Drug-resistant TB: Should Americans be worried?

Most Americans probably never gave tuberculosis (TB) a passing thought until a case of extensively drug-resistant TB (XDR-TB) recently made national headlines. An American with XDR-TB traveled from the United States to Europe and back in May, potentially exposing hundreds of fellow travelers to the disease. Since then, national public concern about TB has ballooned.

Drug-resistant strains of TB have been increasing over the past few decades. "The driving force in the evolution of the bacterium has been the onslaught of antibacterials it has been exposed to," said Robert C. Reynolds, Ph.D., director of drug discovery technology and manager of medicinal chemistry for the Southern Research Institute in Birmingham, Ala. Because TB organisms hide out in immune cells, they are inherently difficult to eradicate. Multiple antibiotics must be coadministered, and they must be administered for extended time periods-usually six to nine months.

According to the Centers for Disease Control & Prevention, the four first-line drugs for active TB are isoniazid, rifampin, pyrazinamide, and ethambutol. While generally effective, these first-line four have been victims of compliance issues. The size and number of the tablets, adverse effects, cost, and lengthy duration of treatment have all contributed to lack of compliance, according to Reynolds. Unfortunately, he pointed out, these compliance issues have probably contributed significantly to the development of multidrug-resistant (MDR)-TB. According to the World Health Organization, XDR-TB is resistant to any fluoroquinolone and at least one of the three injectable second-line drugs (amikacin, kanamycin, and capreomycin) in addition to MDR-TB.

PA-824 has been active against MDR-TB in preclinical trials. The drug does not appear to interact with liver enzymes, so interactions with other drugs, such as antiretrovirals, are not expected. Since TB is a major opportunistic pathogen in HIV patients, drug interactions have been a major issue in the treatment of TB in people with HIV, Reynolds said. Clinical trials will test how well PA-824 fights TB in humans.

FASgen has come up with a novel series of compounds designed to kill TB more quickly and effectively than currently available drugs. FAS 20013 is the lead candidate in the series, and it appears to be effective in MDR-TB, at least in preclinical trials. FASgen has received funding grants to begin phase I studies of the drug.

Another new class of antimyco-bacterials are the diarylquinolines. "We're excited about the prospect of their coming out," said Josh Schwiesow, Pharm.D., clinical coordinator at National Jewish Medical and Research Center in Denver. (The recent American traveler with XDR-TB is now an inpatient at National Jewish.) One promising diarylquinoline is R207910 (Johnson & Johnson/Tibotec), which performed well in preclinical and phase I trials and has moved to phase II.

Schwiesow said that while he and his colleagues look forward to the availability of new TB drugs, they must use what is currently available. All available antibiotics have been tested at National Jewish for activity against TB. They are then ranked according to efficacy and used accordingly in resistant cases.

Although not a new drug, moxifloxacin (Avelox, Bayer) may be the first drug indicated for TB to hit the market in the near future. It is set for phase III trials for this indication. If successful, the drug could be approved for TB as soon as 2010.

THE AUTHOR is a clinical writer based in the Seattle area.