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The evolution of XDR-TB: A tale of three species
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The trans-Atlantic saga of an attorney from Atlanta has recently focused the world’s attention on tuberculosis.
Originally labeled Extensive Drug-Resistant TB (XDR-TB) and later identified as Multi-Drug Resistant TB (MDR-TB), this one case – of the 425,000 cases of MDR-TB estimated in WHO surveys – became the modern face of “The White Plague.”
Three species
Homo sapiens emerged as the dominant hominid during the past 50,000 years. Mycobacterium tuberculosis has been present in its current phenotype for more than 20,000 years. And the HIV has been associated with disease in Homo sapiens for roughly 50 years. The intersection of these three species in the late 20th Century presents a major challenge to global health in the 21st Century.
Human disease due to TB has been found in the osseous remains from ancient Egypt, South America and China. Labeled “phthisis” by the ancient Greeks and referred to as “consumption” in the Roman era, TB exploded as a highly lethal pandemic in Europe during the past 500 years. TB is spread almost exclusively by the airborne route indoors in confined space, and it is reasonable to speculate that the Industrial Age – with urbanization, crowding, air pollution and the adoption of tobacco use – provided great momentum for the epidemic. Two hundred years ago, TB – then occassionally referred to as “the captain of all these men of death” — was estimated to take the life of one in five adults in Europe.
In the decade around 1950, a potentially curative treatment for TB was devised. The combination of isoniazid, para-aminosalicylate and streptomycin, given for 24 months, resulted in cure rates in the range of 90%. However, it was soon observed that, if substandard treatment was given, the tubercle bacillus could develop resistance to these medications. The chromosome of M. tuberculosis generates spontaneous mutations which have conferred resistance to any of the individual drugs ever demonstrated to be active versus this pathogen. These mutations are not induced by the antimicrobials, but are selected for by exposure to these medications. Because these mutations were rare (about 1 in 106 to 108 replications) and unlinked, “triple therapy” was found to be adequate to prevent the appearance of clinically significant drug resistance.
Drug-resistant strains
Inevitably, though, drug-resistant strains of TB appeared. The rifamycin agents were introduced circa 1970 and it was hoped that by reducing the duration of therapy from 18 to 24 months to 6 to 9 months, rifampin (RIF) would circumvent erratic therapy related to noncompliance.
However, MDR-TB, resistant to both INH and RIF, was soon seen. Notably, though, among a large series of MDR-TB cases treated at the National Jewish Medical and Research Center in the 1970s and 1980s, the drug-resistance was almost exclusively generated in individual patients by sequentially failed treatments. There was little evidence of epidemic transmission.
This is where the third species – HIV – came into play. Large scale, highly-lethal epidemics of MDR-TB appeared in various cities, including New York City, Miami, Buenos Aires and Barcelona, within a few years in the early 1990s. Nearly all of these cases represented recent transmission of fully-formed drug-resistance, and the overwhelming majority of the cases occurred in patients with AIDS.
The epidemics were propelled not only by an exquisitely vulnerable human substrate for disease, but by the practice of cohorting patients with AIDS in hospitals and by the appearance of strains of M. tuberculosis that bore the price of acquired drug resistance with no loss of virulence or transmissibility.
Efforts to make second-line drugs available for the treatment of MDR-TB resulted inevitably in the appearance of the next iteration: XDR-TB. Designated in 2007 by the WHO and CDC as resistance to INH, RIF, the fluoroquinolones and one of the second-line injectable agents (amikacin, kanamycin or capreomycin), XDR-TB may be anticipated to be virtually incurable in the developing nations.
Looking forward
The Darwinistic interplay between these three species provides fascinating insights into the processes of selection and survival. We ignore these at our great peril.
Currently, the primary means of diagnosis for TB in the regions where the disease is most prevalent is microscopic examination of unconcentrated sputum. This is an insensitive tool which misses roughly half of the cases which would be detected by culture. In the absence of culture, drug resistance is inferred only after a patient has failed to improve after four to six months of drug therapy. By this time, it is almost certain there will have been on-going transmissions of drug-resistant TB and possible that there will have been additional acquired resistance.
We must expand diagnostic services to include culture and drug-susceptibility testing. And we must put real “DOT” (Directly Observed Therapy) in the World Health Organization’s “DOTS” programs which have involved very limited supervision of drug administration. The next decade will be a “tipping point” that will dramatically impact our generation’s legacy to the 21st Century. Failure to act is unacceptable.
For more information:
- Michael Iseman, MD, is a professor of medicine in the division of mycobacterial and respiratory infections at the University of Colorado School Of Medicine and at the National Jewish Medical and Research Center, both in Denver.