The discovery of highly virulent XDR-TB

XDR-TB has been in the news quite a bit lately, largely thanks to Andrew Speaker's notoriety. Even though his TB was later re-classified as "just" multi-drug resistant (MDR-TB) instead of the initial extremely drug resistant (XDR) type, it did serve to raise awareness about the issues public health authorities face when dealing with something like tuberculosis--and where the gaps are in the control of its spread. (Indeed, a breaking story out of Taiwan shows how difficult it can be to enforce a travel ban).

However, while XDR-TB is rather new on the radar of the general public (and even many infectious disease folks), it was first recognized over 2 1/2 years ago in Africa. This month's issue of the Yale Alumni Magazine has the story of its discovery; more after the jump.

Researchers, including those from Yale, were doing a study with HIV/TB coinfected patients in South Africa. Most were doing well on their HIV meds, which had decreased the virus to undetectable levels. In the first year of the study, mortality had only been 10%, significantly less than typical coinfected patients who received only TB drugs but nothing to combat HIV. (About 40% of them would die during a typical year). During a routine conference call, however, the investigators noticed something ominous when looking at the deaths that had occurred to date:

One patient had died from an unrelated gastrointestinal bleed. Another had died of drug-resistant tuberculosis. A third patient had been doing well, but had unexpectedly sickened and then died in a matter of weeks. She wasn't the only one. Four or five others had also recently died.

"Whoa, what's this all about?" Friedland remembers asking. "These people have non-detectable viral loads. We know they're not dying of AIDS. What are they dying of?"

"That's when the light bulb started to go on."

Infectious disease specialist Neel Gandhi, on the phone from Emory medical school in Atlanta, remembers going through the possible causes. "This is not about ordinary pneumonia," said Gandhi, a former Yale postdoc. "We're treating for that. And it's not an AIDS-related pneumonia like PCP, because their viral loads were undetectable and their CD4 counts were good. It doesn't add up."

"That's when the light bulb started to go on," says Friedland. He can't recall who said it out loud. But by the end of the call, all five doctors had reached the same chilling conclusion: "They died of MDR TB."

This was a huge problem, because the patients had been screened prior to enrollment for MDR-TB and they excluded those who were at risk for it. So they then decided to get sputum from as many patients as they could and test them more thoroughly for MDR-TB. They ended up with 45 patient samples. Growing them for testing took several months, but by summer of 2005, they had found that 10 of those were resistant to at least 6 drugs--as they note, "a quantum leap worse" than any MDR-TB that had been seen previously.

To put it mildly, this was bad.

Moll did grasp immediately, and viscerally, what the test results meant for his staff. "I could feel something like a cold shiver going through my body," he says. "Working with HIV patients is one thing, because the transmission of HIV from patient to worker is not something to be worried about. But with an airborne disease that is not treatable, it's a completely different ballgame."

And in fact, two of the people whose TB had tested resistant to every drug were hospital staff. Like 20 to 50 percent of the nursing staff, they were HIV-positive. By the time Roux called in May, both were dead.

Of course, they also realized this work had broader implications--how much of this was out there in other patient populations? Collection of samples started quickly.

During the months that followed, Shah and her colleagues collected ultra-resistant bacilli in every region of the world. As alarming as MDR TB is in itself, they had to convey that this newly recognized TB was worse.

On March 24, 2006, the CDC reported their survey results. The researchers had found cases of XDR TB on all six continents, including 74 cases in the United States between 1993 and 2004....Of 5,751 bacillus samples examined by TB laboratories in 2000-2004, 39 percent were MDR TB. Of those, 7 percent were XDR TB. These findings, said the report, raise "concerns of a future epidemic of virtually untreatable TB."

The author covers the fallout from these reports, first publicized at last year's AIDS conference in Toronto. The sad truth is that hospitals, especially in Africa, are ill-equipped to deal with a pathogen like XDR-TB. In addition to simply lacking drugs and expertise, they're overcrowded and frequently lack the type of isolation wards needed to prevent spread to other patients. They--and the rest of the world--need better diagnostics as well, to be able to more quickly identify XDR-TB. The state of things leaves scientists discouraged:

Can they contain the problem, or could it become, asks Friedland, the "slow tsunami" that AIDS has been? He doesn't know. But he feels now what he felt in the early days of AIDS: "a vague and yet very palpable feeling of dread that something very bad was happening."

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I have heard many stories about bacteriophages, as they seem to natural eat bacteria they are in a constant arms race to fight their resistance. I have also heard that, given the phages are continually changing, the FDI is unwilling to support them since they cannot just test one phage and work with that. Are stories of bacteriophages exaggerated? If not, if we wish to help these people are we going to have to move towards them in the future? If what I have read is true, they seem both safer (only attack the specific bacteria, leaving the good bacteria alone) and keep up with drug-resistant strains on their own through evolution.

apy, I wrote a bit about bacteriophage here that might answer some of your questions. They're an interesting idea with potential, but because they're constantly evolving themselves, they're not as easy to deal with as antibiotics.


I'm no expert, but I've done a fair bit of reading on the subject. The stories aren't exaggerated, but they do gloss over some fairly signficant issues. The first is that, for the most part, phage treatment is currently used as a last ditch approach, and often involved growing phages tailored specifically to the patient's bacterial pathogen. There isn't, even in countries where phages are used, a general use, broad spectrum, "take this and call me in a week" phage treatment product. Otherwise, they're a promising alternative, but there is a reason antibiotics took hold in most of the developed world - they are *spectacularly* easy to use in most circumstances when compared to phages. Part of that is development, part of it is history (phage treatments when they first came out were downright dangerous due to impurities), but part of it is innate.

The rapid evolution aspect also ties up regulator's guts in knots.

What about some modern approaches to drug resistant cancers? Has anybody tried packaging toxins in PEG liposomes? Perhaps the PEG is not the right lipo for TB or for disabling its toxin expelling system, but the example in cancers is still an exciting example of combating drug resistance. And P-53 is not likely useful, but decorating nanoparticles to be taken up by TB cells themselves might also include interfering RNA if that mechanism is at work in TB. Or perhaps just a monkey wrench gene if any of them are known. My message: OK try something else.

By Richard Karpinski (not verified) on 07 Aug 2007 #permalink

Part of that is development, part of it is history (phage treatments when they first came out were downright dangerous due to impurities), but part of it is innate.