The FDA Is On The Side of the Microbes

This should be the golden era of antimicrobial medicine. Molecular biology has over the last two decades created new diagnostic tools like real-time PCR which can isolate and amplify minute quantities of bacterial DNA to identify individual species. Today’s researchers can design antimicrobial drugs that specifically target proteins, RNA, and DNA of individual pathogens.

Existing antibiotics obtained from fungi and plants often interfere with human biology, creating side effects that limit doses. Tomorrow’s antibiotics should defeat pathogens with minimal side effects, by acting only against molecules specific to bacteria, fungi, viruses, and protozoa.

This blog believes that nearly all diseases have an infectious origin. Infections outrun the immune system due to dietary and nutritional inadequacies. Diet, nutrition, and new antimicrobials should enable nearly all diseases to be defeated.

We are on the cusp of enabling nearly everyone to live to age 100 in good health. All we need is a renewed focus on antimicrobial research, and better diets.

Yet nothing is happening.

Via frequent commenter erp comes an excellent story that explains why (Trine Tsouderos, “Arsenal of antibiotics not being restocked: Dispute over rules for approving new drugs stalls production even as concern rises over deadly resistant bacteria,” Chicago Tribune, August 6, 2010):

Drug companies are abandoning the antibacterial business, citing high development costs, low return on investment and, increasingly, a nearly decade-long stalemate with the Food and Drug Administration over how to bring new antibiotics to market.

Soon, doctors fear, we could be defenseless against bacteria that can resist all existing antibiotics, which would mean more victims like Simon, dead from a staph infection that drugs used to conquer easily.

Dr. Brad Spellberg, an expert on antibiotic resistance, called the situation “catastrophic.”

At the core of the problem is a regulatory impasse over whether drug companies seeking FDA approval for antibiotics should be required to run much more stringent clinical trials.

The FDA says yes, citing advances in the science of clinical trial design and a series of humiliations involving trials for drugs the agency had approved, including the antibiotic Ketek….

But the pharmaceutical industry and some infectious-disease doctors say the proposed rules will make it so difficult and expensive to gain approval for new antibiotics that the few remaining companies will abandon the field altogether….

At times the debate has been so heated that the acting chairman of an FDA committee opened a 2009 meeting by warning that he didn’t want to read the next day about police “having to arrest scientists for breaking shop windows and turning over cars.”…

For years, new antibiotics often were approved based on clinical trials that didn’t have to show the new drug was better than an old one. Instead it had to fall within an acceptable margin of efficacy, which meant it could test somewhat worse and still be considered a success.

Just how much worse is OK with the FDA lies at the heart of the debate. The FDA wants the margins for these “non-inferiority trials” to be scientifically justified, and that may result in margins much tighter than before.

Whatever legal considerations may lie behind the FDA’s position, from a medical point of view its planned rules are ridiculous. To be clinically valuable, new antibiotics don’t need to be better than existing ones, just different.  Against most diseases, combinations of antibiotics are the best therapy.  Striking at a bacterium by several independent mechanisms is highly effective at impairing its activity and helping the immune system defeat it.

The fact that bacteria evolve resistance makes the need for a steady stream of new antibiotics even more critical.

Adding to the problem is that it is not feasible to organize clinical trials large enough to evaluate efficacy:

But showing one antibiotic is superior to another is hard because many antibiotics work so well, Spellberg said….

Placebo trials, in which the drug is tested against a look-alike but useless pill or injection, are also unrealistic, according to some experts. It’s nearly impossible to persuade patients with a painful sinus infection to enroll in a study with a 50 percent chance of getting a sugar pill and not a drug, they said….

Some are suggesting that for community-acquired pneumonia, antibiotics trials might require as many as 10,000 patients at a cost of about $50,000 a patient, or $500 million.

The solution is simple. Antimicrobials should be evaluated for safety only. Doctors can work out efficacy quickly through clinical experience.

Dr. David Shlaes, who worked in pharmaceutical antibiotic development for decades and is now a consultant to the industry, said it is absurd to be, in effect, questioning if antibiotics work.

“This is like asking how do I know parachutes work?… Those of us in infectious disease, we are all scratching our heads wondering: What the hell they are talking about?” said Shlaes, whose book, “Antibiotics: The Perfect Storm,” will be published this fall. “It is like proving gravity all over again.”

Soon after reading this story I learned that our next door neighbor, a 62-year-old man in seemingly fine health, died over the weekend from an MRSA infection he contracted while in the hospital for a surgical procedure. The antibiotics that might have saved him were never developed, due to clinical trial requirements that are about to become even more onerous.

“Nobody can run those trials,” said Shlaes. “[FDA administrators] live in a different world. Their world is numbers and logic. It is not patients and life.”

Dr. Shlaes is exactly right. The bureaucrats are not concerned about patients and life. They are concerned about drugs embarrassing them, as Vioxx did.

Without effective antibiotics, the whole medical system falls apart, experts say.

Yes. But when it does, how many will realize that the FDA, and the politicians who wrote their governing legislation, are to blame?

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12 Comments.

  1. Paul,

    I can only especulate if the MRSA you neighbor died from was this “new MRSA” superbug from India that is spreading around the globe?

    http://www.telegraph.co.uk/health/7939687/Can-we-stop-the-Indian-superbug.html

    • I don’t know, Mario, all I heard was MRSA and I would assume they got that right.

      The “new MRSA” isn’t MRSA but some traditional gut bacteria – Escherichia and Klebsiella – which have evolved a new gene for antibiotic resistance. Gene exchange is common among gut bacteria so once this is started it’s liable to spread globally. It’s just another piece of evidence that we have limited time before we need to develop new generations of antibiotics. Since the bacteria evolve quickly, we will need to continually create new antibiotics to keep up.

      The current regulatory model, which slows drug development to a crawl or standstill, is going to lead to many deaths. Do we need to wait for an untreatable pandemic before we fix an obvious problem?

  2. We’ve evolved into a people hamstrung by lawsuits. Practically every governmental rule and reg. is designed to protect from or forestall being sued by “victims,” often in class action suits.

  3. This Blog Is Really Helpful, Thanks A Lot !

  4. Another article on antibiotics, this time from the Guardian.

    I have absolutely no expertise in these areas, but I wonder if slipshod attitudes toward sterile environments and general cleanliness in hospitals hasn’t contributed to the increase in resistant bacteria. Maybe having antibiotics to kill infections, contributed to the lack of concern.

    I was in the hospital for three days a couple of years ago and no cleaning whatsoever took place in my private room and bath. My gown wasn’t changed, neither were the sheets, no floors were mopped, the bathroom wasn’t cleaned — nothing — zippo. I hadn’t been in a hospital since my kids were born forty plus years ago and at that time, there was plenty of cleaning and the smell of soap and bleach.

    When my husband went to use the bathroom, he flipped and called the nurse who said she’d get someone in. No apology — nothing.

    This was in a very expensive private hospital in central Florida associated with a major Christian church.

    • Thanks, erp, I saw that article a few hours ago and decided to work up a post on it, since it goes into detail on the consequences of the new bacterial genes that Mario introduced us to.

      I’m horrified by your hospital story. Maybe I really would rather be a horse than a hospital patient.

  5. Perfect Health Diet » Retroviruses and Chronic Fatigue Syndrome - pingback on August 24, 2010 at 2:35 pm
  6. Hi Paul!

    I ordered your book last week, so it may be a couple of weeks before I can start to read it, so I apologize if you have written about my doubt already there.

    Just wondering… how many of these infections can/should be managed by vitamin C saturation, vitamin D megadoses and healthfully high cholesterol levels? I have no idea of how many illnesses are simply caused by present advice to hide from the sun and lower our cholesterol, but it seems to me that they have to be a lot (99%?).

  7. Hi Andres,

    I wouldn’t say 99%, but all of those are factors.

    Vitamin C saturation mainly helps against some viral infections. Vitamin D is important for maintaining gut and mucosal barriers, so it’s biggest significance is probably for prevention of infection, but also helps against established infections though it’s usually not curative by itself. Statins must be immunosuppressive.

    I think definitely sun-avoidance and statin-ingestion will tend to promote chronic infections and early aging. If lifespan is now shortening, these may be reasons.

  8. http://www.omaha.com/article/20100106/NEWS03/701069926

    Hasn’t Norway virtually eliminated MRSA with more cautious use of existing antibiotics?

  9. Science Based Futurology | Sam Snyder - pingback on August 25, 2011 at 10:01 am
  10. One result of the new PCR tools you mention is that they are revealing whole new vistas of complex microbial communities flourishing in every niche possible, including the numerous crevices and spaces available on and in all multicellular plants and animals. Many of these communities have 500-700 members, both providing nutrients for each other and keeping each other in check.

    It may be argued that the coming revolution in the understanding and treatment of infectious disease will be to view an infection, not as an invasion from some outside pool of disease, but as an overgrowth/virulent transformation of one or several already native species due to a disruption or injury to the normal functioning of a microbial community.

    In that context, while fast-acting anti-microbials will still have their place in the treatment of fast-acting, life-threatening infections, as we gain a better understanding of how our microbial communities work, we will surely look for more sophisticated (and less microbially lethal) tools to re-stock and re-balance them when treating everyday low-level and slow-acting chronic infections.

    That said, I agree with your frustration – this kind of work, while it is already happening in general science labs in many countries, is not translating quickly enough into useful therapy.

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