Well, this is a bad way to start the year.

Over the past 48 hours, news has broken in India of the existence of at least 12 patients infected with tuberculosis that has become resistant to all the drugs used against the disease. Physicians in Mumbai are calling the strain TDR, for Totally Drug-Resistant. In other words, it is untreatable as far as they know.

News of some of the cases was published Dec. 21 in an ahead-of-print letter to the journal Clinical Infectious Diseases, which just about everyone missed, including me. (But not, thankfully, the hyper-alert global-health blogger Crawford Kilian, to whom I hat-tip.) That letter describes the discovery and treatment of four cases of TDR-TB since last October. On Saturday, the Times of India disclosed that there are actually 12 known cases just in one hospital, the P. D. Hinduja National Hospital and Medical Research Centre; in the article, Hinduja's Dr. Amita Athawale admits, "The cases we clinically isolate are just the tip of the iceberg." And as a followup, the Hindustan Times reported yesterday that most hospitals in the city – by extension, most Indian cities – don't have the facilities to identify the TDR strain, making it more likely that unrecognized cases can go on to infect others.

Why this is bad news: TB is already one of the world's worst killers, up there with malaria and HIV/AIDS, accounting for 9.4 million cases and 1.7 million deaths in 2009, according to the WHO. At the best of times, TB treatment is difficult, requiring at least 6 months of pill combinations that have unpleasant side effects and must be taken long after the patient begins to feel well.

Because of the mismatch between treatment and symptoms, people often don't take their full course of drugs – and from that (and some other factors I'll talk about in a minute) we get multi-drug resistant and extensively drug-resistant, MDR and XDR, TB. MDR is resistant to the first-choice drugs, requiring that patients instead be treated with a larger cocktail of "second-line" agents, which are less effective, have more side effects, and take much longer to effect a cure, sometimes 2 years or more. XDR is resistant to the three first-line drugs and several of the nine or so drugs usually recognized as being second choice.

As of last spring, according to the WHO, there were about 440,000 cases of MDR-TB per year, accounting for 150,000 deaths, and 25,000 cases of XDR. At the time, the WHO predicted there would be 2 million MDR or XDR cases in the word by 2012.

That was before TDR-TB.

The first cases, as it turns out, were not these Indian ones, but an equally under-reported cluster of 15 patients in Iran in 2009. They were embedded in a larger outbreak of 146 cases of MDR-TB, and what most worried the physicians who saw them was that the drug resistance was occurring in immigrants and cross-border migrants as well as Iranians: Half of the patients were Iranian, and the rest Afghan, Azerbaijani and Iraqi. The Iranian team raised the possibility at the time that rates of TDR were higher than they knew, especially in border areas where there would be little diagnostic capacity or even basic medical care.

The Indian cases disclosed before Christmas demonstrate what happens when TB patients don't get good medical care. The letter to CID describes the course of four of the 12 patients; all four saw two to four doctors during their illness, and at least three got multiple, partial courses of the wrong antibiotics. The authors say this is not unusual:

The vast majority of these unfortunate patients seek care from private physicians in a desperate attempt to find a cure for their tuberculosis. This sector of private-sector physicians in India is among the largest in the world and these physicians are unregulated both in terms of prescribing practice and qualifications. A study that we conducted in Mumbai showed that only 5 of 106 private practitioners practicing in a crowded area called Dharavi could prescribe a correct prescription for a hypothetical patient with MDR tuberculosis. The majority of prescriptions were inappropriate and would only have served to further amplify resistance, converting MDR tuberculosis to XDR tuberculosis and TDR tuberculosis.

As their comment suggests, the other TB challenge is diagnosis, especially of resistant strains, and here again the news is not good. The WHO said last spring that only two-thirds of countries with resistant TB epidemics have the lab capacity to detect the resistant strains. As a result, only one MDR patient out of every 10 even gets into treatment, and when they do, cure rates range from 82 percent down to 25 percent. That's for MDR. None of the TDR patients have been recorded cured, and at least one of the known Indian patients has died.

Meanwhile, health authorities estimate that one patient with active TB can infect up to 15 others. And thus resistant TB spreads: XDR-TB was first identified just in 2006, and it has since been found in 69 countries around the world.

Cite: Zarir F et al. Totally Drug-Resistant Tuberculosis in India. Clin Infect Dis. advance access Dec. 21, 2011. doi: 10.1093/cid/cir889.

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