Using Old Medications to Defeat Tuberculosis

TastesLikeCoughSyrup writes "Antibiotic resistant tuberculosis is spreading like wildfire in the developing world. While many researchers are looking for new drugs to combat the disease, those efforts could take years to bear fruit. Meanwhile, two scientists at the Albert Einstein College of Medicine have learned how the drug clavulanate can destroy the defenses of tuberculosis, making it vulnerable to medications in the penicillin family. The best part: it has already been approved by the FDA so doctors can start using it immediately."

Links to actual papers for more info ...

Research page at Blanchard Lab [yu.edu] (part of the AE college of medicine) and the ACS paper [acs.org] about their research.

Can't say I understand this stuff, but for those who do, these probably should have been in the story snippet.

Re:Links to actual papers for more info ...

their research works on similar principles to the slashdot article although they work by very different pathways. The slashdot article is about a [penicillin degrading enzyme] inhibitor; penicillin inhibits cell wall synthesis which kills gram-positive bacteria. The research page you linked is about developing inhibitors to several amino acid/nutrient pathways that are common in these kind of bacteria but are very different than the pathway(s) penicillin acts on.

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TB scares the hell out of me. We talk about AIDS being a huge killer in the world, well imagine a disease that is deadly, and spreads by coughing instead of by sex and blood. We should have wiped TB out by the 1980s, but we've been too casual.

Re:Links to actual papers for more info ...

bacteria can be fought nearly indefinitely by bacteriophages which evolve along side the bacteria in a never ending arms race, viruses are far trickier than that. Viruses evolve on very short timespans exceeding bacteria's rate of evolution in many cases so if there's something to fear it's them. Although even HIV has a weakness, one significant one has already been found in populations in Africa. It's an altered gene to be precise, one that alters a cell receptor on the outside of our cells that is a key site for HIV to bind to and gain access to the cell.

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i guess the chemokine receptor 5 (CKR5 or CCR5, depends on where you read from) mutation for HIV infection resistance is quite well-known... but that's what i've read several years back then.

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Bacteriophages are viruses - so called bacteriophages because they infect bacteria.

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TB scares the hell out of me. We talk about AIDS being a huge killer in the world, well imagine a disease that is deadly, and spreads by coughing instead of by sex and blood. We should have wiped TB out by the 1980s, but we've been too casual.

I am a firm

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Yeah, It's specially frightening here on slashdot, where the probability of someone getting a STD is pretty low.

captain obvious

those efforts could take years to bear fruit.

I don't think fruit is going to help against tuberculosis.

beta-lactamase inhibitor

It's a beta-lactamase inhibitor, it stops beta-lactamase from cleaving the 4 atom ring of penicillin-like drugs. This ring is very important in the function of Penicillin which actually prevents the building of cell walls in gram-positive bacteria. these bacteria need a thick cell wall to keep from bursting. this drug in of its self does little, only combined with penicillins does it revive the drug's germ killing power.
http://en.wikipedia.org/wiki/Clavulanate

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i guess that this may or may not be related to the presence of chromosomally encoded, constitutively expressed ESBL (extended-spectrum beta-lactamase) which, when present, would usually indicate extreme drug resistance (sometimes even to big guns like pene

Damn bastards!

You'll see. You'll all see.

Those of us allergic to penicillin will simply evolve and grow gills. So while you all cling to your antibiotics and inhibitors on the poisoned land, me and my brothers and sisters will be ruling the sea!

Re:Damn bastards!

Yep... You'll be sleeping with the fishes one way or another... ;)

Long Term

The developing countries I have visited have very poor infrastructure to handle epidemic of this kind, coupled with lack of hygene and importance of isloation of the infected patients. While hailing these efforts, IMHO, awareness drives in developing natio

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Interesting theory, just so long as you realize that this still leaves *you* in deep shit, since you don't have the "gills" mutation you theorize some people might get. At *best* your kids are the first to develop it. If they're even allergic.

And for the

Think I'm missing something

Isn't that Augmentin [wikipedia.org]? How would this be different?

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Yes, Augmentin is one specific case of a comination of a beta-lactamase inhibitor and a penicillin-like drug [amoxicillin in this case] It is only one of many but that is exactly the kind of drug combo the article is talking about. Unfortunately there are

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augmentin is amoxocillin-clavulante which is not the only clavulanate containing antibiotic. there is also a ticarcillin-clavulanate (timentin - IV only)

piperacillin-tazobactam (zosyn) is another
ampicillin-sulbactam (unasyn)

this said, one can choose to co

FDA???

> ...in the developing world.
> ...The best part: it has already been approved by the FDA so doctors can start using it immediately."

AFAIK, the USA's FDA has no authority over the developing world. Doctors in the developing world can start using any d

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FDA is generally accepted (at least that's how I'm taught and I'm not in the USA) to be the gold standard for drug acceptance. While there is no authority per se, many regulatory bodies will simply stamp and use the FDA data sheet.

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RU-486 is accepted in Europe, not in the US.

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Um, you're incorrect about this. RU-486 has been accepted in the U.S. since 2000 [fda.gov].

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Drug resistant TB is found in the US-- in an urban area where conditions are right (lots of uninsured people not getting treated, close proximity for easy transmission etc) it could flare up any time. By the time you know you have an epidemic, it's often w

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If it's gone generic I doubt it will be a problem with insurance companies as they would probably rather you use a proven cocktail not covered by patents than an expensive custom pill covered by patents.

Chest X-Rays required for immigration

My wife is Canadian, and has a US green card. I'm American, and have applied for a Canadian landed immigrant card.

Each of us were required to have chest X-Rays. My understanding is that if they showed that either of us had tuberculosis, our visas would be denied.

However, the doctor who gave me my medical exam - which was rather thorough - told me that I should show my passport to the X-Ray technician, just to make sure someone else wasn't able to stand in for me. I offered it to her, but she didn't bother with it.

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Yeah. Forget the Avian Flu bullshit. TB is one of the most widely destructive and most lethal diseases on Earth. If you're going to be scared of a disease, be scared of TB. It has the lethality, it has the wide distribution, it has the transmission vectors

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It may be too late for the United States. We've been so lax on guarding our borders that we've already seen numerous cases of TB. A disease that we virtually eradicated last century is back.

Here is a link to a story that has received very little attention

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AFAIK Canada has no equivalent of USA case law based on decisions like U.S. v. Wong Kim Ark and Afroyim v. Rusk which has established drive-by citizenship beyond the reach of Congress. Furthermore, there appears to be no potent immigration lobby (unnatural

The Canadian govt encourages immigration

A couple years ago, Nova Scotia established a provincial department of immigration with the aim of encouraging immigrants to settle there.

Immigration is held out as a solution to Canada's aging population - they have baby boomers just like the US, and th

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Wasn't there a kerfuffle a few years back because some part of the government wanted to test people coming to Canada (not sure if it was immigrants or just visitors) from places where TB was common? The politically correct started complaining about racial

Amoxicillin-Potassium Clavulanate Combination

Amoxicillin-Potassium Clavulanate Combination

A fixed-ratio combination of amoxicillin trihydrate, an aminopenicillin, and potassium clavulanate, a beta-lactamase inhibitor, used to treat a broad-spectrum of bacterial infections, especially resistant strains.

from CureHunter [curehunter.com]

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This combination has been used for several decades now. The combination goes under the generic name "Coamoxyclav". It's one of the common antibiotics prescribed for a sinus or a throat infection.

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I'm glad of finding your comment at last: you're right, clavulanic acid usage for penicillin potentiating are not news! The point it is just that someone tried it against Tuberculosis.

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Damn, for a second there I thought that you were referring to Acidachrome Promanganate [panexa.com].

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Amoxicillin-Potassium Clavulanate Combination

As others have noted, this is not a new drug combination. It's currently sold under the brand name of Augmentin [augmentin.com]

In other news...

New Zealand researchers have shown that a (so-far unidentified) compound in Manuka honey kills MRSA and other drug-resistant bacteria. Honey in general has antibacterial properties, but there is an additional substance in Manuka honey which is exceptionally effective. Trials involving using it to treat cuts and abrasions have apparently shown it to be comparable to using more conventional antibacterial ointments. It has also been credited with impacting certain cancers, but people will say that about so many things that that's not one of the more credible claims.

One thing I have done is made Manuka honey mead, which is interesting as it means that either I destroyed the antibacterial agent when using heat to dissolve the honey, or the agent has no significant ability to slow yeast cultures.

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Or the antibacterial agent had no antifungal activity? Keep in mind bacteria are prokaryotic, and yeast eukaryotic...

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Most antibiotics don't have antifungal activity, therefore it wouldn't inhibit yeast cultures. I fact, one of the risks of antibiotic therapy is yeast infection. Long term treatment with antibiotics can disrupt the normal bacteria balance in the body (in

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There really is no need to heat the honey to dissolve it at least not to the point that I'd expect it to denature the mystery agent in the honey. The original ideas behind mead was to get the last bit of honey out of the combs, which is now unnecessary wit

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Lots of things kill bacteria. For something to be an antibiotic, you have to be able to introduce large amounts of it to the human body without too much toxicity. Killing bacteria is easy--it's the second part that's hard.

Cheaper too I presume...

I'm guessing that as an "old treatment" it's a lot cheaper than new drugs, so hopefully the developing countries can afford to treat people quickly and hopefully help stamp out this growing problem...

Here's hoping it actually gets to poor people

Having spent the last couple years living in a developing country where TB is endemic/epidemic (Tanzania), I am usually pretty jaded when it comes to things like this- malaria and TB being "forgotten" by the rich world and all that jazz.

However, I take encouragement from two things about this:

First is that it's an older drug, which means it will probably be off-patent soon (anyone know?). This should guarantee it's fairly affordable. Also, it's a proven drug with a clean track record so far. Both of those mean that governments like Tanzania are more likely to implement it's use for TB.

Second is that it may (and I'm speculating here) shorten the treatment time for TB. That could be big. Current treatment time is on the order of months, if the drugs are more effective then it follows that the treatment might be shorter. That would be good for compliance: In the rich world it's hard to get people to take pills regularly for months on end, and it's no different anywhere else. People forget, or they feel better and don't think they have to continue, it happens.

Tanzania has a TB control program which provides free medicine and Tanzanians can take medicine just as well as the rest of us. Sadly, rural clinics often don't have enough drugs to give out a whole course of treatment to everyone, so people have to return for more pills, and again for check-ups. That often means a large disruption in daily life (imagine walking an entire day to get to a clinic, then going back), and the decisions presented are not easy: skipping work regularly to go get your medicine/checkup could impact your crop, your herd, get you fired etc. I wonder how many cases of TB have relapsed or spread due to this sort of coerced non-compliance? Less disruption is a win on all fronts.

On a less serious note, I am reminded of a particularly bad cross-country trip where I was crammed in the back of a ricketty Land Rover 110 with at least 12 people (just in the back compartment, I think the total headcount was over 20, not counting chickens). I was directly across a man who was a textbook case of kifua kikuu (TB), and the ride was almost 12 hours, with breakdowns. At a certain point, I just resigned myself to catching it.

Amazingly, I didn't. I didn't get malaria once either.

But in the end, malaria, TB and HIV were about the only things I didn't get at some point.

Any other RPCV Slashdoters?

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Amoxicillin is out of patent, was first marketed early 1970's. Would be interesting if anyone rushes for a Swiss Claim patent, could potentially make money if a local industry managed it...

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My understanding was that beta-lactam type antibiotics were not very effective against TB in vivo because those drugs kill the cells when they try to replicate, and TB replicates very, very slowly in humans. I'm not entirely convinced that beta-lactamase

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I guess it remains to be seen. TB is one tough bugger, the way it forms cysts can make it hard for any drug to even get close enough to work. But since it is already treated with a cocktail, adding this might be cost effective: kill cells with the usual dr

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...and the Seattle Health Department made sure I took the drugs.

You bet they did. I'm sure you are aware of this, but others should know a doctor and judge can have a person locked up in JAIL and forced to take the meds if they decide to be non-compliant w

This article seems to be missing something...

The FA mentions use of clavulanate, if you read the abstract for the ACS article linked to by the FA you will see there are three beta lactamase inhibitors - sulbactam, tazobactam, and clavulanate - trialled.

Apparently nobody really has tried beta-lactam antibiotics in this indication, but it seems suprising that any medical professional would consider this a "one-two punch strategy". Realistically this would be one combo of a multi hit process. Modern day TB therapy always includes a specifically chosen 3-4 drug combination. This combination depends on where the infection was contracted along with any characterisation of the strain that is possible. This is simply because if you feed a drug that's not killing it, you're selecting for resistance to that drug. If physicians start using beta-lactamase inhibitors they'd better be careful because there are already several examples of other infections resistant to clavulanic acid (just google search).

Whilst the article reports this as if it is a major breakthrough, this is purely sensationalism. It is a minor breakthrough in a major problem.

No money in old medicines

There's no money in using old medicines, this is why they drug companies are always inventing new ones. Once a drug has been copied and sold by other companies then the price comes right down.

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There's no money in using old medicines, this is why they drug companies are always inventing new ones. Once a drug has been copied and sold by other companies then the price comes right down.

Yeah, it has nothing to do with the fact that there are illnesses that we don't have a good treatment for. That's why nobody makes aspirin or penicillin anymore. Oh wait, lots of companies produce both.
Drug companies develop new drugs because there is a

Interesting, but no guarantees here.

It's an interesting study, and they're doing it right, but there's no particular breakthrough yet. This is an in vitro study with no clinical implications yet. TB is a significant problem where I work (I'm a doctor in the Western US), but there are some hurdles to get over before I can start using clavulanate.

Clinical utility is the Holy Grail here - the biochemical activity of a drug is critical, but the effect of the drug on the infection in an infected person is a lot more complicated. You have to get an effective concentration of the antibiotic into the area of the organism, get the bug to take up appropriate quantities of it, and not injure the patient in the process. Every step of this can kill an otherwise promising use of the drug.

In the case of clavulanate, we know that it causes significant side effects. I use it a LOT in kids (Augmentin is your friend for a variety of conditions, and clavulanate is what makes Augmentin Augmentin), and it causes pretty impressive diarrhea at fairly low doses. Diarrhea, especially if it involves altered intestinal flora, is a set-up for C. difficile colitis, which can be deadly. If we need high concentrations of clavulanate, we may not be able to give enough of it to patients. Or there may be other toxicities, although it's been quite benign in widespread use to date.

Another problem is that the bacterium can mutate proteins to avoid drugs, and TB is pretty good at this. MDR TB didn't happen by accident, and mutation of beta-lactamases to avoid clavulanate is not unheard of. Overproduction of the enzyme is also possible, and would then increase the required dose of the drug (and see above).

A final problem is the physical defenses of the bug. The cell wall for TB is quite effective and strong, and the bacterium has a variety of transport mechanisms to get antibiotics out of the cell. Again, we may not be able to get enough clavulanate into the cell long enough to kill it.

Having said all of that, I'm delighted both that the work is being done and that these initial results are promising. It will be fun to see what happens clinically.