A follow-up to Monday's post on the recognition in India of totally drug-resistant tuberculosis, TDR-TB: The fantastic early-warning list ProMED points out that the earliest recorded cases of TDR were not the current 12 known cases in Mumbai or the 15 cases in Iran in 2009, but rather two women from Italy who died in 2003 after being sick for several years.

It's a sad story that was briefly recounted in 2007 in the journal EuroSurveillance, published by the European Centre for Disease Prevention and Control (ECDC).

Both women were middle-aged at most (the journal says only "younger than 50"), born in Italy, from middle class families, and otherwise healthy, with no diseases that would put them at greater risk of TB infection. (Among other things, that means no HIV.) They were both treated at the E. Morelli Hospital, a giant TB sanatorium in the town of Sondalo, north of Milan near the Swiss border. They were both diagnosed by local doctors and treated with repeated rounds of the normal TB drugs — three rounds each — before someone recognized that something unusual was happening. They were separately admitted to the Morelli hospital with what the paper calls "a very severe clinical picture (extended bilateral cavities)," which means the TB infection had eaten away the tissue of their lungs, leaving empty dead zones. (If you'd like to see what that looks like, here are some pathology images, not from these women.)

The first woman actually caught multi-drug resistant TB from her mother and gave it to her 14-year-old daughter (who is not the second case in the paper – more on her below). She was treated in three different hospitals, with 17 different antibiotics, for 422 days, or 14 months — and took TB drugs for 94 months before her untreatable disease killed her.

The second woman – whether she was related to the first, or lived near her, is not made clear – was in one other hospital before being admitted to the TB specialty institution in Sondalo. Her inpatient treatment took 625 days and also involved 17 different drugs. After she was discharged, she was on a drug regimen for 60 months before untreatable TB killed her also.

There are some lessons to pick out from these stories.

The first is that TDR-TB has occurred randomly before. Note, both these women died in 2003, but at that point, one had been under treatment for 5 years and the other for 8 years.

The second is that, as the Indian account from Monday emphasized and this one confirms, these TDR cases are artifacts, created by poorly chosen and insufficient drug treatment. The EuroSurveillance paper says:

In both cases the drug susceptibility tests showed that resistance to new drugs was acquired over time. Case 1 was initially mismanaged, and then admitted at the reference hospital being already resistant to the majority of the available drugs. Case 2 management and adherence to the regimen prescribed was sub-optimal before admission to the reference hospital.

While there may be something molecular going on that makes certain strains more likely to become resistant (or certain patients particularly good hosts for that), the paper emphasizes a second time how much blame should fall on poor health care and bad antibiotic use. Citing a contemporaneous study from Italy and Germany, it says:

All XDR- and about 50% of MDR-TB cases as reported in the study mentioned above were previously treated for TB in the past. This finding, coupled with the unlucky story of the two cases mentioned above, suggests the major role played by mismanagement of TB cases and sub-optimal infection control in determining the emergence of the problem.

Finally, it's important to note both the extraordinary agony that lies behind the dry epidemiological account – imagine living for eight years feeling always starved of oxygen, unable ever to take a deep breath – and the phenomenal amounts of patient care and health expenditure these cases required. And not only them. Case 1's daughter, who caught MDR-TB from her mother before inadequate treatment turned it into TDR, was eventually cured – but only after 3 years of persistent drug treatment, and the surgical removal of part of one lung.

The last thing to say is that, even if TDR-TB emerges from poor treatment, there is no reason to think that it will not spread from person to person – just as drug-susceptible TB does, and MDR-TB and XDR-TB have been demonstrated to do. In other words, the suffering, and spending, contained in the stories above could become much more common, if TDR-TB begins to spread.

Cite: Migliori GB et al. First tuberculosis cases in Italy resistant to all tested drugs. Euro Surveill. 2007;12(20):pii=3194.

TB smear via PHIL, CDC