Tuberculosis, one of the most deadly infectious diseases, is back with a vengeance, especially in Africa. Extensively drug-resistant tuberculosis (XDR-TB) is a difficult-to-treat strain of TB which attacks where health systems are historically weak, especially in areas of high HIV prevalence.
Failure to contain local outbreaks, develop tools and strategies for identifying and treating XDR-TB and invest in longer-term improvements in TB control could transform our pharmacological magic bullets for TB into blanks.
The development of TB chemotherapy from the 1940s through the 1970s transformed the once deadly "white plague" into a curable disease. But TB treatment has been shadowed by the specter of drug resistance since the dawn of the antibiotic era.
Fifteen years ago, an epidemic of multidrug-resistant tuberculosis (MDR-TB) in New York City induced near panic, before a massive infusion of funds into the public health infrastructure turned the tide in the US and public interest waned. However, the problem of drug resistance has persisted and efforts to contain it globally have not been sufficient.
Enter XDR-TB. The WHO estimates that there were 425,000 new MDR-TB cases in 2004, with China, India and Russia accounting for just over 60 percent. But it was an outbreak of XDR-TB among HIV-infected people in KwaZulu-Natal, South Africa, that turned the global spotlight on issues of extensively drug-resistant organisms.
In a study at the Church of Scotland Hospital in rural KwaZulu-Natal of 535 patients who had confirmed tuberculosis, 221 had MDR-TB, a level 10 times greater than in the province as a whole. More alarmingly, 53 of the 221 had a strain that was also resistant to the two most clinically useful classes of second-line TB drugs. Fifty-two of the 53 died in a median of just 16 days from the time of sputum collection. Molecular typing of the isolates indicated that 85 percent were clonally related, implying epidemic transmission of XDR strains, most likely in HIV clinics and hospital wards.
How did this localized outbreak of XDR-TB emerge? Are similar localized outbreaks going unrecognized elsewhere? More importantly, can XDR-TB be controlled?
Resistance to anti-TB drugs arises from selection of naturally occurring mutants with innate resistance to drugs. Poor adherence to the therapeutic regimen, improper prescribing by clinicians and drug interactions or malabsorption can result in partial suppression of bacterial growth and the emergence of resistant organisms. Once this resistance develops, treatment is compromised, further resistance can evolve and resistant organisms can be transmitted to other people, leading to primary drug resistance that may fail to respond to standard therapy.
Effective treatment and cure of MDR-TB requires prolonged use (typically two years) of a combination of drugs, including second-line drugs that for the most part are less potent than first-line agents, more toxic, or both. For the past six years, a global effort (called DOTS-Plus) to treat people with MDR-TB under strict conditions has been underway, reaching thousands with previously untreatable TB. An unfortunate consequence of treating MDR-TB with second-line drugs, however, is the inevitable emergence of further drug resistance. If the same factors that produce MDR-TB remain in play, then MDR-TB becomes XDR-TB.
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