Keeping a lid on an ever-shifting threat

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.

TB treatment has been shadowed by the spectre of drug resistance since the dawn of the antibiotic era. The World Health Organisation estimates there were 425,000 multidrug-resistant tuberculosis (MDR-TB) cases in 2004, with China, India, and Russia accounting for just over 60 per cent.

In a study in the KwaZulu-Natal province of South Africa, of 535 patients who had confirmed tuberculosis, 221 had MDR-TB, a level ten 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 testing. Molecular typing of the isolates indicated that 85 per cent were clonally related, implying epidemic transmission of XDR strains, most likely in HIV clinics and hospital wards.

Resistance to anti-TB drugs arises from selection of naturally occurring mutants with innate resistance to drugs. Poor therapeutic regimen, improper prescribing, 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.

For the past six years, a global effort to treat people with MDR-TB under strict conditions has been under way, reaching thousands with previously untreatable TB. An unfortunate consequence of treating MDR-TB with second-line drugs is the inevitable emergence of further resistance. If the same factors that produce MDR-TB remain in play, then MDR-TB becomes XDR-TB.

Addressing drug-resistant TB cannot be divorced from overall TB control efforts. Moreover, TB control strategies targeted at populations with high HIV burdens are critical. Such strategies include widespread implementation of TB preventive therapy with isoniazid and improved detection in HIV-infected people, many of whom die of TB without a diagnosis. Attention must also be paid to infection control in hospitals and clinics: many of the XDR-TB cases in South Africa were acquired in HIV clinics or wards. Reducing HIV incidence would substantially reduce the TB burden. Moreover, the capacity for prompt, accurate laboratory-based diagnosis of TB and drug resistance must be strengthened.

Enhanced surveillance also is needed. The Global Project on Anti-Tuberculosis Drug Resistance Surveillance has collected information on prevalence, patterns, and trends of drug resistance since 1994, focusing on resistance to first-line drugs and contributing much to our understanding of MDR-TB. But surveillance for XDR-TB has been more limited.

Priorities for XDR-TB surveillance include facilitating access to reliable susceptibility testing to second-line drugs and incorporating this, together with information about HIV testing, into existing TB surveillance activities.

Last, but not least, the importance of effective advocacy for a more vigorous response to the global TB epidemic cannot be overstated. This includes promoting new drugs lines that can enhance the potency of first-line regimens, shortening treatment and preventing the emergence of resistance. But new drugs are not enough. Introducing them into settings where compliance is not assured and drug susceptibility testing is not available would likely lead to even more resistant organisms.

Health systems must be strengthened to enable health-care providers to find TB present in communities with more sensitive and specific tests, treat TB according to the class of the organism with the latest and most potent drugs, and prevent TB among those who are at risk. These steps may ensure that XDR-TB does not engulf the advances made in the past century in the global fight against TB.

• Susan Dorman is a professor of medicine at Johns Hopkins University and a medical director of the Baltimore city health department TB clinic. Richard E Chaisson is professor of medicine, epidemiology and international health, and director of the Centre for Tuberculosis Research at Johns Hopkins University, Baltimore.