Antibiotic-Resistant Bacteria in meat

The title of this post at Wired's Superbug blog says it all:

Antibiotics and Antibiotic-Resistant Bacteria in Meat: Not Getting Better

The Pew Campaign on Human Health and Industrial Farming (of the Pew Charitable Trusts) has been tracking this data year to year, and this year retrieved some additional data from the human side of the pharma industry to use as a comparison. They found that human-use antibiotics totaled 3.5 million kilograms, or 7.7 million pounds, in 2011.

It’s worth noting that this continued antibiotic use, and continued and rising appearance of resistant bacteria on meat, is happening as the FDA has abandoned attempting to regulate livestock producers’ use of antibiotics, and has switched to a voluntary approach. Given the trend, I think it’s worth asking how well that voluntary approach is going to work.

New antibiotics

A recent Op-Ed in the New York Times addressed the topic of antibiotic resistance and why drug companies aren't developing new antibiotics.
Let’s Gang Up on Killer Bugs.

What makes the rapid loss of antibiotics to drug resistance particularly alarming is that we are failing to make new ones. We are emptying our medicine chest of the most important class of medicines we ever had. 

One of the big problems is the economics of drug development today.

Historically, the drug industry thrived on antibiotics. But if an antibiotic is useful against only one type of bacterium, relatively few people need it during its patent life. And if an antibiotic is “broad spectrum,” meaning it works on many different types of bacteria, wider use shortens its commercial life because it quickens the pace at which bacteria develop resistance. Moreover, antibiotics are designed to cure an acute disease — not to palliate a chronic one — so people need them only for a limited time. Compared with drugs that are used for years to treat widespread conditions like high cholesterol or asthma, antibiotics pale as a corporate investment.

The article contains some suggestions for a better way forward from collaborative drug research to a different economic model.

There are, however, other ways for drug makers to profit beyond using monopoly to protect prices. As Thomas Pogge of Yale and Aidan Hollis of the University of Calgary have pointed out, an intergovernmental fund for drug discovery could reward drug makers for products in proportion to their impact in reducing the loss of healthy years of life. The lower the cost of a lifesaving drug, the greater the number of people who could use it; the more lives protected, then, the greater the monetary reward. An investment of $20 billion a year could encourage more open-lab collaborations to find new medicines in challenging settings like antibiotic discovery and make them accessible to all who need them.

Sampling the antibiotic resistome

Remember the soil bacteria Streptomyces I mentioned as being the source of several of our antibiotics? You will probably not be surprised to find that this bacteria is also the source of resistance genes. A paper from the end of 2006 shocked many people though when it was discovered just how many antibioticsStreptomyces was resistant to.

In the paper, they isolated 480 different strains of the bacteria from soil samples and then exposed them to 21 different antibiotics to see if they could survive. The average strain was resistant to between seven and eight antibiotics and two particularly hardy ones were resistant to 15 drugs. The danger is that these genes will pass from harmless soil bacteria such as Streptomyces into more deadly bacteria. This is known to happen, for example the genes that allow some harmful bacteria to resist vancomycin, one of the last lines of antibiotic defense, originally came from soil-dwelling bacteria.

"The chances that these genes will end up in a disease-causing organism at some future point is high," microbiologist Abigail Salyers, University of Illinois at Urbana-Champaign.

Selman Waksman and streptomycin

Although Mycobacterium tuberculosis has a thick layer of peptidoglycan like the Gram-positive bacteria the mycobacteria are usually considered separately because they have a thick waxy layer surrounding their cell wall. So, unusually, they are classified as Gram-positive because they lack the outer membrane of the gram-negatives but they don't actually retain the Gram stain like the other Gram-positives.

This is actually of considerable significance because they are also not susceptible to beta-lactam antibiotics like penicillin. The first antibiotic to be effective against tuberculosis, streptomycin, was discovered in 1943 by Selman Waksman a Ukrainian-American biochemist and microbiologist. A professor of biochemistry and microbiology at Rutgers University for four decades, he discovered over twenty antibiotics and, in fact, coined the word antiobiotic. He was awarded the Nobel Prize in Physiology or Medicine in in 1952.

Latest 'superbug' - NDM-1

Here's a nice example of how I hope this class can help you understand the science behind the headlines a little better.

If you read the news you may have come across references to the latest 'superbug' NDM-1. But this is misleading, and confusing, because NDM-1 is actually just the name of an enzyme (New Delhi metallo-beta-lactamase-1). Several problematic bacteria have now acquired the ability to manufacture this enzyme (and you now know how they probably acquired this ability - especially if I tell you it is often carried on a plasmid).

Why is this enzyme important? Because it can break down beta-lactam antibiotics called Carbapenems that were developed to be more resistant to the beta-lactamase enzymes that many bacteria now have. Carbepenem antibiotics are extremely powerful and often used to fight highly resistant bacteria when other antibiotics have failed.

Bacteria that can produce NDM-1 are sometimes referred to as superbugs because infections caused by them are difficult to treat but NDM-1 is the name of the enzyme, not a specific bacteria.

For more information see: NDM-1 — A Cause for Worldwide Concern in the New England Journal of Medicine.

New antibiotics

There's an article in The Daily Telegraph, a British Newspaper, tomorrow about the lack of new antibiotics: The battle to discover new antibiotics.


Most of our antibiotics, and practically all of the different classes of antibiotics (ie the different families with different modes of action) were discovered over a period of three decades from the early 1940's to the late 1960's. No new classes of antibiotics were discovered for over thirty years and only two new classes have been discovered since 1968 - the Oxazolidinones in the late 1990's (although one of them was used against Tuberculosis since 1956) and the Lipopeptides approved in 2003.

The figure to the left is from a similar article in the New York Times in 2010 and shows the steep decline in the number of antibiotics approved for sale over the last three decades. This is the absolute number of antibiotics, not different classes, most of these antibiotics are variations on existing themes.

Interestingly both these articles make the same point that it is not necessarily the science that is lacking but the financial incentive:

While the notion of directly subsidizing drug companies may be politically unpopular in many quarters, proponents say it is necessary to bridge the gap between the high value that new antibiotics have for society and the low returns they provide to drug companies.

Expedited Partner Therapy

Yesterday's LA Times had an article about some new programs to help combat sexually transmitted disease.

They mainly talk about the 'I want the kit' program that supplies free in-home testing kits for three of the most commonly reported STDs, however they also mention the Get Yourself Talking, Get Yourself Tested program and the more controversial  Expedited Partner Therapy  (EPT) which allows those who test positive for certain sexually transmitted diseases to take home antibiotics for up to three partners without a health care provider first examining the partners.

Although this is not legal in all states (see the map at the CDC website) the CDC has reviewed the evidence and concludes that EPT is a useful option particularly for treatment of male partners of women with chlamydial infection or gonorrhea.

(Graphic is from inSPOT a website that allows you to send electronic postcards anonymously or from your email address to your sex partners to inform them that you have an STD).

Tuberculosis Inhalers?

After today's lecture, I looked up information on unique treatments for tuberculosis. Originally, I wanted to find something along the lines of those baffling treatments that people used for cholera (putting bricks in the windows, growing mustaches, smoking, etc.) All I could find were a surprising amount of links to a picture of what I presume to be a doctor (probably the leading physician of his time) curing TB by sticking what looks like a giant gold plunger onto a woman's chest, which is supposed to deliver an electric shock. I hope he remembered to shout "Clear!"

Tuberculosis Treated By Electricity

I did end up finding information on something that might be slightly more useful for TB patients. Researchers at the University of Colorado (as well as University of North Carolina, and Harvard University) have developed a way to inhale antibiotics that fight MDR TB, delivering the antibiotic straight to the deep lung tissue where TB first arises. They have even experimented with aerosols that could deliver this drug through something that is similar to an inhaler used by asthma patients. The hope here is that it would cut down dramatically on cost and treatment time for TB patients, as well as less severe side effects. More information can be found here:

http://www.sciencedaily.com/releases/2010/11/101116150027.htm

and here:

http://www.sciencedaily.com/releases/2010/04/100415134412.htm

This little piggy

You will find a LOT of information on the web about antibiotics and, especially, antibiotic resistance. A lot of people are increasingly concerned about this topic and websites such as SaveAntibiotics.org and KeepAntibioticsWorking.com contain a lot of useful information, videos and links.

Currently the hot topic is pending changes that would restrict the use of antibiotics in the meat industry to when animals are actually sick.
eg New York Times article from last October: Meat industry unhappy over limiting the use of antibiotics
For decades, factory farms have used antibiotics even in healthy animals to promote faster growth and prevent diseases that could sicken livestock held in confined quarters.
The benefit: cheaper, more plentiful meat for consumers.
But a firestorm has erupted over a federal proposal recommending antibiotics only when animals are actually sick.

Better late than never....

Mon Jun 28, 2010 from Reuters: FDA recommends new limits on livestock drugs:

To prevent development of drug-resistant bacteria that could infect people, the U.S. Food and Drug Administration recommended on Monday that livestock farmers use the drugs solely to cure or prevent disease in animals, phasing out their use to promote growth.

FDA said research showed mixing antibiotics in livestock rations or feedlot water supplies "is not in the interest of protecting or promoting public health." Over-the-counter antibiotics have been routinely used for decades to promote livestock growth and feed efficiency.

Emergence of antibiotic-resistant bacteria poses a serious public health threat, said FDA, so it is looking for ways to reduce overuse of the drugs.

Antibiotics including penicillin and tetracyclines should be used only under the supervision of veterinarians to prevent or treat illness in livestock, FDA said in its 19-page draft.

FDA made its recommendations in a first-round version of a "guidance" document, which represents the agency's current thinking on an issue. Guidance does not carry the weight of law but generally is adopted by industry.

Gram-negative infections

Deborah sent me this link to a New York Times article from last week Rising Threat of Infections Unfazed by Antibiotics .

The article describes the problems caused by the rising prevalence of some gram-negative infections like Acinetobacter.

Doctors treating resistant strains of Gram-negative bacteria are often forced to rely on two similar antibiotics developed in the 1940s — colistin and polymyxin B. These drugs were largely abandoned decades ago because they can cause kidney and nerve damage, but because they have not been used much, bacteria have not had much chance to evolve resistance to them yet.

“You don’t really have much choice,” said Dr. Azza Elemam, an infectious-disease specialist in Louisville, Ky. “If a person has a life-threatening infection, you have to take a risk of causing damage to the kidney.”

Animal antibiotic use

Over the last two nights Katie Couric on CBS News had a two part series on the use of antibiotics on farm animals. You can watch the videos here or read the transcripts.

Part 1: Animal Antibiotics a Threat? (video) and transcript
Public health officials are worried that the widespread use of antibiotics on healthy animals may be putting people at risk. Katie Couric investigates this potential health threat.

Part 2: Antibiotic-free animals (video) and transcript
American farmers use more growth-promoting-antibiotics than any other place in the world. Katie Couric reports on a possible alternative in Denmark, which bans antibiotic use in livestock.

Chronic Lyme Disease

They want ta' legislate the moon
They want ta' legislate the womb
They wanna legislate all the things they hate
They want ta' legislate this tune

Hmm, Whatever happened to Grant Lee Buffalo? Ahh, they broke up in 1999 (thank you Wikipedia) - that explains why they've been quiet.

Anyhow, that brings us to today's topic - should we legislate what are essentially medical issue? Connecticut thinks so. In July last year House Bill 6200 passed through the Connecticut House of Representatives by unanimous approval (137 for, 0 against). What does this bill do? It protect Connecticut licensed Lyme treating physicians from prosecution by the State of Connecticut Medical Examining Board solely on the basis of a clinical diagnosis and /or for treatment of long-term Lyme disease - thus allowing them to provide long term antibiotic treatment for people with chronic lyme disease (and also sufferers from Post-Lyme disease syndrome).

Sounds reasonable? Except that in patients who have non-specific symptoms after being treated for Lyme disease, and no evidence of active infection (so called Post-Lyme disease syndrome or PLDS), studies have shown that more antibiotic therapy is not helpful and can be dangerous.
Read this report from the National Institute of Allergy and Infectious Disease (part of NIH). Read this letter regarding the bill sent by the Infectious Disease society of America.

I write on behalf of the Infectious Diseases Society of America (IDSA) to urge you to oppose the enactment of Connecticut House Bill No. 5625, which sanctions the use of long-term antibiotic therapy to treat Lyme disease and would protect physicians, who administer such therapies, from disciplinary action. In urging your opposition to this legislation, our primary concern is to ensure the best quality in patient care and to protect the public’s health and safety. To this end, we believe it is critically important that you be fully apprised of the widespread consensus within the medical and scientific community about the appropriate treatment of Lyme disease, as well as the medical community’s concerns about unproven, potentially harmful treatments for so called “chronic” Lyme disease that are advocated by a small group of physicians.
.
.
Carefully designed and conducted studies of Lyme disease treatments have failed to demonstrate benefit from prolonged antibiotic therapy. Rather, these studies have demonstrated that there is no difference in the measured improvement between patients receiving placebo and patients treated with antibiotics.

Furthermore, the scientific evidence that long-term antibiotic therapy may be dangerous, leading to potentially fatal infections in the bloodstream as a result of intravenous treatment. Far from improving the patient’s quality of life, prolonged antibiotic therapy may actually increase the patient’s suffering. Also, although the bacteria that causes Lyme disease does not acquire resistance to antibiotics, long-term antibiotic exposure can lead to drug-resistance among other microorganisms, creating “superbugs” that cannot be treated with currently available drugs.

I think we can expect to see more bills like this. It is the government's job to protect us from those who offer false hope and possibly dangerous 'cures' not to enable them.

Saving not just lives...

A child bomb-victim receiving penicillin treatment by Ethel Gabain. Painted 1944 and part of the Imperial War Museum Collection it is currently part of an exhibit at the Canadian War Museum.

Gabain's image of the child being treated with penicillin shows her isolated, amid weights and levers and drips that balance and sustain her. However, the overall impression here is of someone safe, protected and, as she engages the viewer, hopeful. Penicillin saved her leg from amputation. This was one of a series of paintings commissioned to display scientific developments. Gabain had lost a child during the war and was herself in poor health when she undertook the commission.

It's important to remember that Penicillin saved not just lives but also numerous limbs which no longer needed to be severed to avoid the potentially fatal effects of infection. Not just in soldiers but in anyone who sustained serious (or sometimes not so serious) wounds from accidents, surgery or any of a dozen other causes.

Penicillin synthesis

A number of magazines and newspapers have now put most, if not all, of their archive material online. This means that Google searches now throw up original news reports from decades ago, way before the internet.

I was looking for some details about the development of synthetic penicillin and found this report from Time magazine in 1957 describing the discovery of the first practical method of synthesizing Penicillin. There's a nice description of why the problem was so hard:

The molecule is not unusually complicated, but extremely fragile. Any kind of rough treatment, such as heat or acids, makes it fall into fragments that cannot kill any kind of germ. To use the customary chemical methods on penicillin, says Dr. Sheehan, "would be like attempting to repair a fine watch with a blacksmith's sledge and anvil." The critical problem was to find a way to bond a carbon atom and a nitrogen atom to form a chemical ring in the heart of the molecule. Avoiding many standard reagents as too violent, and keeping his solutions at room temperature or lower, Dr. Sheehan finally found a reagent that would do the job.

Summer re-runs - part 6

The Daily Show With Jon StewartM - Th 11p / 10c

Bubonic Plague

Daily Show Full Episodes
Important Things With Demetri Martin

Funny Political News
Joke of the Day

Some nosocomial infection and antibiotic resistance favorites:

• Almost inevitable
• Patients flee, drawing attention to quarantine dilemma
• Meet the Clostridiums
• XDR-Tb in California

Quote

Here's a quote I skipped in lecture for time. Nothing new, but it really brings home to me exactly how unpleasant the side effects from some second line Tuberculosis drugs are:

Nesri Padayatchi, deputy director of the Centre for the AIDS Programme of Research in South Africa, tells of 35 patients treated with a second-line drug that causes intense nausea. Eight of them, she says, "tried it and said, 'I would rather die.'"

Just a Bill

Although unanimously endorsed by public health and medical organizations, federal bills aimed at phasing out the non-therapeutic use of antibiotics in US food animal production have repeatedly failed to make it out of committee. The current version is still in committee - the 'Preservation of Antibiotics for Medical Treatment Act of 2009'.

Govtrack.us is a pretty neat site for tracking legislation. If you click on 'related legislation' you can see that legislation with the same title was introduced to the previous 3 Congress's but has never made it out of committee despite having bipartisan support (at least the sponsors include both Republicans and Democrats).

110^th Congress: S. 549Dead

110^th Congress: H.R. 962Dead

109^th Congress: S. 742Dead

109^th Congress: H.R. 2562Dead

108^th Congress: S. 1460Dead

108^th Congress: H.R. 2932Dead

You can read the FDA's Statement before the House Committee on Rules on July 13th this year, here. A statement read into Congressional record by Rep. Jerry Moran (The expanding power of the federal government and its intrusion into America's business) gives some idea of why this Bill has trouble getting anywhere.

Other countries have, however, acted, the European Union banned the use of antibiotics as growth promotional agents in 2003.

More Pork

Nicholas Kristoff continues the Pork/MRSA story in another Op-Ed piece for the New York Times today entitled 'Pathogens in our Pork'.

“We don’t give antibiotics to healthy humans,” said Robert Martin, who led a Pew Commission on industrial farming that examined antibiotic use. “So why give them to healthy animals just so we can keep them in crowded and unsanitary conditions?”

The answer is simple: politics.

Legislation to ban the nontherapeutic use of antibiotics in agriculture has always been blocked by agribusiness interests. Louise Slaughter of New York, who is the sole microbiologist in the House of Representatives, said she planned to reintroduce the legislation this coming week.

“We’re losing the ability to treat humans,” she said. “We have misused one of the best scientific products we’ve had.”

Fleming would be proud

Biophysicist Herbert Levine's Petri dishes look like an exhibit at a modern art museum. His beautiful images are actually made from bacteria similar to the ones that cause deadly diseases.

 You can watch a video and read the story here.