Fully drug-resistant tuberculosis.

[The Romulan Republic]

http://www.wired.com/wiredscience/2012/ ... -tb-india/

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.

Flickr/Pulmonary_Pathology/CC

So, how worried should I be about this? Could this turn into a major pandemic/global catastrophy, or would such concerns be needlessly alarmist?

Not pleasant news, regardless.

[JME2]

Yeah, my reaction was "oh crap" too. I hope this doesn't go full blown viral either.

[Eulogy]

Don't microbes with resistances require more resources than an otherwise identical microbe that doesn't resist anything? If there is nothing to resist, then the resistant strain gets outcompeted by other microbes and they die off, meaning that socalled superbugs could die off by simply putting in harmless bacteria or something that will simply shut them out.

Or at least, that's what I heard. Am I just talking out of my ass?

[madd0ct0r]

Panemic? mebbe. it kills you slowly though. even with a pandemic we might have time to cure it.

[K. A. Pital]

Tuberculosis is a poor candidate for pandemia. Slow spread, reasonable isolation.

[SpaceMarine93]

Well, bugger.

[someone_else]

Don't microbes with resistances require more resources than an otherwise identical microbe that doesn't resist anything? If there is nothing to resist, then the resistant strain gets outcompeted by other microbes and they die off, meaning that socalled superbugs could die off by simply putting in harmless bacteria or something that will simply shut them out.

It varies from case to case, as "resistence to X" is a general explanation for a mutation in a gene involved in making stuff interacting with substance X.

Quite a few of those do actually require more resources, but just because mutations have much more chances to fuck up things than to make them better.

To have them out-competed and killed off by natural selection you need to remove the selecting agent causing them to outshine their peers. That means not using the drug that kills their peers. Which if my data is correct, results in a 50% death rate among infected with symptoms.

So it would be down to close ill people in quarantine with limited aid and hope they don't die.
Then nuke the site from the orbit.

Then again, tubercolosis is air-borne but not overtly aggressive, with an infected coughing bastard running wild infecting 20 people or so per year.

If everything fails, good old "lock them up until they die or get through it" should work fine to contain any outbreak.


This is more a reminder for anyone. Evolution is still at work. Ain't it cool?

[loomer]

Seems like the kind of thing that could spur on the redevelopment of phages. They might be less flexible, but if they still work, they still work.

[Broomstick]

A couple of things to remember about TB:

1) not all infections produce symptoms. A common figure I see is that only about 1 in 10 infections result in symptoms or risk of death, the rest can only be detected with tuberculin testing. So far as I know, this applies to all strains. Thus, the number of TDR infections is not just those with symptoms, but potentially 9 asymptomatic infections for every active one. The good news is that only active infections are contagious, the latent ones are not. However, latent can convert to active if the person's immune system becomes suppressed, thus, it is entirely reasonable to devote some resources to treating latent infections even if the active ones should take precedence where resources are limited, and where latent infections are of the TDR variety the people should be monitored in case of conversion to active infection.

2) about a quarter of active infections affect parts of the body other than the lungs. If the lungs are not infected the person will not spread the disease by coughing, sneezing, speaking, etc. though they will still be sick and suffering.

3) TDR TB may be incurable, that does not mean it is untreatable. Adequate diet, rest, and supportive care can greatly improve and extend the life of those afflicted. UV light can suppress/kill TB and we can go back to housing such patients in sun-filled facilities. TB does not kill quickly and those afflicted with it should receive humane care and be made as comfortable as possible. As an example of long-term survival, Doc Holliday of OK Corral shoot-out and wild American west fame lived 15-20 years with an untreated, active infection. That's a little unusual, but not unheard of, and modern supportive medicine, if made widely available, should result in more long-term survivors at least among those otherwise healthy (if you have a co-morbid condition like HIV, though, you're sort of fucked). In the 19th Century US sufferers were often encouraged to go west, like Holliday, as it seemed to improve survival - probably due to less sewage in new settlements, more activity outside in sunlight, possibly better diet that eastern city dwellers, and with sparser population fewer other infections to pick up and fight at the same time. Likewise, even today inner city slum dwellers seem to suffer the worst with TB, probably due the environment inhibiting their body's ability to resist the infection.

4) There is a vaccine for TB, although it is not universally used. Perhaps it is time to vaccinate more aggressively against this disease, and certainly anyone working closely with TB patients, especially those with disease-resistant strains, should be offered it.

[mr friendly guy]

In the old days they used to surgically collapse the lung to treat TB patients. I wonder if they are considering that now.

[Fingolfin_Noldor]

In the old days they used to surgically collapse the lung to treat TB patients. I wonder if they are considering that now.

How does that work?

[Broomstick]

The idea was to "rest" the lung, allowing it to heal and fight back the infection.

I don't think the efficacy of the treatment has ever been proven, but at the time there were few alternatives and dying patients and their doctors were willing to try something extreme in the hopes of bettering the situation.

[mr friendly guy]

In the old days they used to surgically collapse the lung to treat TB patients. I wonder if they are considering that now.

How does that work?

They used to stick ball bearings into it to collapse it. The process was called plombage. I remember in the pathology library at the University of Western Australia we had a sample of a lung which had undergone such a procedure and we saw the ball bearings still in it.

http://en.wikipedia.org/wiki/Plombage

According to wiki, they used other methods to collapse the lung besides plombage, and it seems that surgeons are occasionally required to surgically treat TB in more modern times but with obviously superior surgical techniques by cutting out the infected tissue. Fun fact, one of the "classical ways" to suspect TB is because it tends to affect the upper lobes of the lung, while say pneumonia from more common organisms rarely do.

http://en.wikipedia.org/wiki/Tuberculos ... _treatment

As to how it works, I had to read wiki for that since surgical management wasn't exactly taught in detail when I was in uni because it had been superseded by antibiotics. But presumably modern surgical techniques involved resecting out the infected part of the lung, which seems straight forward. On older style surgical management here is what wiki has to say.

The first successful treatments for tuberculosis were all surgical. They were based on the observation that healed tuberculous cavities were all closed. Surgical management was therefore directed at closing open cavities in order to encourage healing.

Note they closed by cavities by collapsing the lung.

[madd0ct0r]

Surgical techniques are still in use in less developed areas of the world. One girl I know had 2/3rds of one lung removed at age 18.

[evilsoup]

This is a case of TB 'just' being resistant to our current drugs, right? I'm sure I read something a while back about how no pharmaceutical companies are researching new antibiotics because they aren't profitable (because doctors would hold the new drugin reserve for this kind of situation). If that's the case, then that means we'll be seeing more and more diseases that are fully drug-resistant. What would be the best solution? Government-run research? Maybe something run out of the WHO? Big cash prizes, perhaps, to incentivise companies..?

[Grumman]

The ideal solution would probably be eradication, as was done with smallpox. It can't evolve if it's extinct. In fact, that's just the scaled up version of the approach that would have prevented the creation of these superbugs in the first place.

[Simon_Jester]

Smallpox is a lot easier to eradicate than TB.

TB has ten asymptomatic carriers for every one with any symptoms, and from the figures I've seen something like 30% of humanity are carriers of the bacteria.

TB lasts a long time in the body- curing a patient takes months, even if they respond well to the drugs. Smallpox is different- you catch it, you live or you die in some reasonably short span of time, you don't linger around spreading it into the population for years.

It's easy to vaccinate against smallpox. As far as I know the TB vaccine doesn't work, or doesn't work satisfactorily, on adults.

So all things considered, eradicating tuberculosis would be incredibly hard- you'd need to screen everyone for it (repeatedly, to catch the false negatives in your screening test). You'd need to put them all on long regimens of drugs to kill the bacteria; realistically you'd get the usual problem and just breed more of the drug-resistant types. And you'd be doing this for something like two billion people at once. Prohibitively difficult.

But with smallpox, you can go into an area, vaccinate everyone, keep coming back every few years to vaccinate the children, and that area is now an impassable firebreak for smallpox epidemics. Repeat and you can catch the entire world this way, without needing to rid billions of people of a ubiquitous bacterial infection.

[Grumman]

Fair enough. It makes sense that it would be harder or we might have done it already, but I didn't know the particulars beyond what had been posted here.

[Broomstick]

It's easy to vaccinate against smallpox. As far as I know the TB vaccine doesn't work, or doesn't work satisfactorily, on adults.

It does work, although it would need to be renewed about every 10 years. One of the reasons it isn't more widely used in, say, North America is that once you are vaccinated you will frequently turn up positive on the most common screening test, which then leads to the question of whether or not you are an immune person or a latent infection.

There are alternate tests, but they're more expensive. This would become an issue if you need to screen the entire global population, or even "just" a third.

So all things considered, eradicating tuberculosis would be incredibly hard- you'd need to screen everyone for it (repeatedly, to catch the false negatives in your screening test).

Actually, with the Mantoux test false positives are far more common than false negatives.

TB has one additional problem that smallpox did not, however - it does have animal carriers. The most common domestic carrier is cattle, but wild animals can spread it, too. So even if you eradicated it in humans at a certain point there will continue to be the possibility of re-infection of people. While a couple of countries (Ireland, New Zealand) are attempting to eradicate it in their cattle, they tend to be island countries. Doing this on the mainland may not be possible.