Maryn McKenna

Journalist and Author

Can Antibiotics User Fees Force Down Drug Mis-Use and Overuse?

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image: NeilT (CC), Flickr

Happy new year, constant readers. Here’s the most urgent thing I have to say today: Stop reading and go set your DVRs for 8pm ET tonight. The fantastic The Poisoner’s Handbook, written by Wired colleague and dear friend Deborah Blum, has been adapted by PBS and airs tonight on The American Experience. It’s going to be superb.

Back? OK, on to business. Just before the holidays, the Food and Drug Administration finalized its long-aborning plan to ask the meat-production industry to reduce its use of routinely administered antibiotics. (My posts on the move here and here.) The FDA’s guidance to industry, as it is called, is not a regulation but rather a request for voluntary action on the part of veterinary-drug companies. It has met with skepticism and concerns that manufacturers will redefine the uses of their drugs in such a way that nothing will change.

The FDA action is aimed at the routine use of antibiotics for what is called growth promotion — causing animals to gain muscle faster than they would without the drugs being used — and is modeled on a ban on growth promoters enacted by the European Union in 2005. The goal, as in the EU, is to reduce the drugs’ use, and therefore the antibiotic-resistant bacteria that use stimulates.

In a recent New England Journal of Medicine, University of Calgary economist Aidan Hollis suggests though that a ban may not be the most useful or practical approach to the problem of drug overuse. In its place, he suggests the pocketbook persuasion of having to pay a fee.

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More on 'Nightmare Bacteria': Maybe Even Worse Than We Thought?

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Flickr: CelesteH, CC

In my last post I talked about the under-appreciated emergence of “nightmare bacteria” (those are the Centers for Disease Control and Prevention’s words, not mine) that are widely distributed in hospitals and nursing homes around the world and do not respond to a last-ditch small family of antibiotics called carbapenems. That seemed dire enough, but new research suggests the problem, bad as it looks, has been understated.

There’s an ahead-of-print article in Antimicrobial Agents and Chemotherapy whose authors include David Shlaes, a physician-researcher and former pharmaceutical executive, now consultant, and Brad Spellberg, an infectious disease physician on the UCLA medical faculty and author among other books of Rising Plague, about antibiotic resistance. In a commentary examining the Food and Drug Administration’s promised “reboot” of antibiotic development rules, they analyze privately gathered data on resistance in the United States and conclude the incidence of highly resistant bacteria is greater than the CDC has estimated.

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Drug-Resistant Gonorrhea: WHO Agrees It's An Emergency

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Image: KaptainKobold/Flickr

The World Health Organization has weighed in on the growing threat from antibiotic-resistant gonorrhea, saying in a statement this morning (emailed, and apparently not online):

Millions of people with gonorrhoea may be at risk of running out of treatment options unless urgent action is taken, according to the World Health Organization (WHO). Already several countries, including Australia, France, Japan, Norway, Sweden and the United Kingdom are reporting cases of resistance to cephalosporin antibiotics — the last treatment option against gonorrhoea. Every year an estimated 106 million people are infected.

The statement arrived as an adjunct to the launch of the WHO’s new global action plan for controlling the spread of resistant gonorrhea.

If you’ve been reading here for a while, the problem of resistant gonorrhea won’t be new to you. (Here are some past posts on data from the CDC and a call to action in the New England Journal of Medicine, along with a piece I wrote in Scientific American and a separate post by my SciAm editor Christine Gorman.) But in case you’ve just come in:

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Drug-Resistant Gonorrhea: How We Lost Track

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if I were starting this blog today, I’d be tempted to name it the Department of Unintended Consequences. So much of what I write about seems to belong in that zone: Send U.N. troops to Haiti, start a cholera epidemic. Aim to eradicate wild polio, clear the way for the vaccine-derived kind. Drive down the price of producing animal protein, ramp up antibiotic resistance.

Now add to the list: Develop cheap rapid tests for detecting sexually transmitted diseases, and lose the ability to track that those diseases are becoming resistant to the last antibiotics that work reliably against them.

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Goodbye, Magic Bullet: Hello, Highly Resistant Gonorrhea

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One hundred years and some months ago — on March 16, 1911 — a publication called the Boston Medical and Surgical Journal printed a description of the treatment of 20 men at Walter Reed General Hospital in Washington, D.C. The men were members of the U.S. Army. Because medical privacy rules were a lot looser 100 years ago, we know most of their names, because the journal gave them: Cornwell, 22 years old; Smith, 24; Randall, 29; Simerly, 27; Brown, 23; Davis, 26; Waits, 22; Allen, 19; Kimmitt, 27; Megee, 29; Laird, 40; Brinson, 34; Franklin, 29; Clements, 34; Johnson, 24; Lorah, 23; and Crabbe, 27.

The men were in Walter Reed, which we now know as Walter Reed Medical Center, because they all had the sexually transmitted disease syphilis. A century later, it seems absurd to be hospitalized for an STD — but in the years before antibiotics, syphilis and gonorrhea were fantastically destructive of productivity. The men’s records, excerpted by the journal, capture that: They had arthritis, ulcerated skin, heart-valve failure, necrosis of the skull. Cornwell had been “on sick report” — unable to report to duty — for 4 months and 10 days; Simerly, for 5 months and 23 days; Kimmitt, for 11 months; Johnson, for 1 year.

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Not Enough Antibiotics: Just an Incentives Problem?

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My college boyfriend and I used to have this conversation:

Me: “I’m so broke.”

Him: “Yeah, me too.”

Which was almost always followed, a few days later, by this conversation:

Him: “Let’s go get a beer.”

Me: “I thought you said you were broke?”

Him (after a puzzled pause): “Well, yeah, I was. But then I went to the bank.”

How is this relevant, you ask? Like this. When it comes to antibiotic resistance — that is, to the increasing number of infections against which many drugs are no longer effective — people seem to think like my ex: When we’re out, we go back to the bank for more. The problem is, when it comes to antibiotics, we’re not temporarily out. We’re broke for real.

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Incentives for making new antibiotics: What would it take?

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Let’s play a thought experiment. Imagine that you’re a major pharmaceutical company, a public company, with shareholders that you answer to, and market analysts looking over your shoulder to see whether this quarter’s earnings are up to projections. Imagine that you want to make a new drug. Let’s make it an antibiotic, because — as we talk about here all the time (and SUPERBUG explores in detail) — new antibiotics that can leapfrog over existing drug resistance are very needed. Thus, you imagine, a new antibiotic ought to sell well, even though any individual course of that antibiotic will only be a few weeks by mouth, or maybe a few months by IV if the patient is very sick. You know there’s a big market out there.

But: Imagine — as is generally accepted to be true — that it will take about 10 years, and about $1 billion dollars, to get that novel antibiotic through the development pipeline and into the marketplace. And then imagine that — as has been shown for a number of drugs, most recently the new antibiotic daptomycin — bacteria begin developing resistance to your drug within a year of its deployment in patients. And after that, imagine — as has been cited in a number of papers — that once local resistance to your antibiotic appears in approximately 20% of isolates, physicians will cease prescribing your antibiotic, for fear their patient will be one of that 20%.

So, to recap: 10 years, $1 billion; short course; short market life; rapid obsolescence.

Would you make that investment? Or would you, if you were a pharma company, opt instead to make insulin, which Type 1 diabetics will take every day for the rest of their lives? Or statins, which at this point we’re practically ready to put in the water supply? Or a cancer drug that costs $10,000 per dose? Or Viagra, or Cialis?

If you’re a company that is responsible to its shareholders, or listening to its analysts — or even capable of doing basic math — the answer’s obvious: Antibiotics lose. Which goes a long way to explaining why so many companies have backed off from making antibiotics, and why many of the few antibiotics in the pipeline are “me too” formulations, rather than new compounds with truly new mechanisms of action.

How to respond to this impasse has been an active debate for a while, largely focused on proposals to give market incentives, changes in tax credits, or patent extensions to pharma companies to persuade them to stay in or re-enter the marketplace. The Infectious Diseases Society of America, the specialty society for infectious-disease physicians (many of whom are also academic researchers), has been addressing this through its campaign “10x 20”, which has a goal of getting 10 new compounds into if not through the pipeline by the year 2020.

But, as a new article in the British Medical Journal points out, good incentivizing demands complexity — not just in developing both “push” and “pull” mechanisms (say, tax incentives to fund research v. prizes and wildcard patent extensions), but also in making sure that the incentives can be taken advantage of by companies of all sizes, not just the international mega-pharmas:

The characteristics of an ideal incentive mechanism and the desire for an equitable approach that engages developers of all sizes would suggest that neither push, pull, nor lego-regulatory mechanisms would be optimal to spur the desired investment in antibiotics …. Rather, elements of each should be combined. The exact shape of the ideal package is, however, as yet unclear. (Morel et al.)

And an accompanying editorial emphasizes that new antibiotics are not the only things needed; new diagnostic tests, for instance, need funding as well:

Catchy as 10×20 sounds, the public sector strategy for funding such research and development must prioritise among different health technologies, such as diagnostics and vaccines, to combat antibiotic resistance. For example, three million children die each year from acute respiratory bacterial infections in developing countries, but penicillin sensitive pneumococcal strains have declined to a half, even a quarter, in some countries. A diagnostic test for bacterial pneumonia would save an estimated 405 000 lives a year, by targeting treatment and avoiding overprescription of antibiotics. New vaccines may also reduce reliance on drugs as the use of pneumococcal vaccine has suggested. (So et al.)

This is a hard discussion. I confess, as a longtime reporter, I flinch reflexively at the thought of handing more money to the pharmacos. At the same time, the state of the market demonstrates that the current model is not working. And though I would much prefer we focus on the ecological model of preserving antibiotics as a resource — dialing back on overuse and encouraging rigorous stewardship — it’s clear that we’ll always need new drugs for the most serious, most resistant infections.

So some sort of incentivizing seems necessary. And the multi-layered approach recommended in the BMJ, with appropriate attention paid to incentivizing the development of tests and vaccines as well, seems worth heeding.

Another resistant bug rising: Acinetobacter

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From the excellent and forward-thinking research team at Extending the Cure comes a dismaying report: over 7 years, a more than 3-fold increase in resistance in the Gram-negative bacterium Acinetobacter baumanii to its drug of last resort, imipenem.

Because MRSA is a Gram-positive, we don’t talk much here about the Gram-negatives — the two categories of bacteria have different cell-wall structures and thus are treated using different categories of drugs. (That structural difference causes them to react in different ways to a stain invented by a scientist named Gram in the 19th century.) But the resistance situation with Gram-negatives is at least as dire as with MRSA, possible more so, because there are fewer new drugs for Gram-negatives in the pharmacology pipeline (as discussed in a New Yorker article by Dr. Jerome Groopman last year.)

And Acinetobacter is one nasty bug, as science journalist Steve Silberman ably documented in Wired in 2007 when he traced the spread of the organism through the military medical-evacuation chain from Iraq, demonstrating that the vast increase in resistant Acinetobacter among US forces was due to our own poor infection control.

The Extending the Cure paper (which will be published in February in Infection Control and Hospital Epidemiology) puts hard numbers to the Acinetobacter problem. Drawing on data from the private Surveillance Network, which gathers real-time electronic results from 300 US hospitals, they find:

  • full resistance to imipenem rose from 4.5% of isolates in 1999 to 18.2% in 2006 — a 300% increase
  • intermediate resistance rose from 1.3% of isolates to 9.4 — a 623% increase
  • susceptible isolates declined from 94.1% to 72.4% — a 23% decrease.

The authors write:
Our results demonstrate substantial national and regional increases in carbapenem resistance among clinical isolates of Acinetobacter species over the period 1999–2006. Increasing carbapenem resistance among Acinetobacter species is particularly troubling, because it is very often associated with multidrug resistance and because it is occurring in the context of increases in the incidence of Acinetobacter infection.

There’s a further point to be made that is not explicit in the paper that I can see (though it is often made by Extending the Cure researchers). Acinetobacter needs attention, just as MRSA does — but if we focus just on the individual organisms, we are not going far enough. Antibiotic resistance is a system problem: It is an issue of infection control, of drug development, of agricultural organization, of federal priorities. It needs sustained attention and comprehensive, thoughtful, wide-ranging response. Now would not be too soon.

Guest Q&A: Dr. Brad Spellberg and RISING PLAGUE

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I’m thrilled today to present another guest blogger: Dr. Brad Spellberg, associate professor of medicine at the David Geffen School of Medicine at UCLA and author of the new book Rising Plague: The Global Threat from Deadly Bacteria and Our Dwindling Arsenal to Fight Them (Prometheus Books). This new book is important reading for anyone concerned, as all of us are here, about the narrowing pipeline for new antibiotics against MRSA and other resistant pathogens. That pipeline problem is something Dr. Spellberg knows well: He is not only a practicing infectious-disease physician, but also a member of the Antimicrobial Availability Task Force of the Infectious Diseases Society of America, the specialty society that produced the “Bad Bugs” reports that I’ve posted on before.

Below, Dr. Spellberg thoughtfully answers some questions about the difficulties of treating resistant infections and of developing drugs to control them.

From your point of view as a practicing ID physician, why is it so difficult to prevent resistant infections?

It’s difficult to prevent all infections period. Not more difficult to prevent infections caused by resistant organisms than any other organisms. However, also difficult to prevent the spread of resistance among bacteria that are causing infections.

So, why is it difficult? People have this crazy belief that hospital acquired infections are the result of sloppy medicine. Not so. They are the result of very sick people with tremendously sophisticated levels of intensive medical care being delivered in a concentrated environment (i.e., a hospital). Crowd a bunch of sick people together with plastic catheters, mechanical ventilators, and nasty bacteria, and such infections are inevitable. What we are learning is that we have to go above and beyond normal to stop these infections from happening. Research is needed on how best to do this. It’s not as simple as people think.

You can’t stop the spread of the resistance itself. It is inevitable.

You say in Rising Plague that physician misuse and overuse of antibiotics is not the cause of antibiotic resistance. What do you consider the primary driver?

This is by far the biggest misperception among the public. Let’s start from first principles. Who invented antibiotics? Who invented antibiotic resistance? When were both invented?

Humans did NOT invent antibiotics. Bacteria did…about 2 billion years ago. And they invented antibiotic resistance at the same time. So, bacteria have been creating and defeating antibiotics for 20 million times longer than humans have even known that antibiotics exist (about 78 years, as the original sulfa compound was developed in late 1931 by Gerhard Domagk). Over the past 2 billion years, bacteria warring among themselves have learned to target virtually every targetable biochemical pathway with antibiotics, and have learned to create defense mechanisms to defeat virtually all such antibiotics. They are already resistant to drugs we haven’t even developed yet. It is bacteria that cause antibiotic resistance, not humans.

What humans do, is we apply natural selection when we use antibiotics. We kill off susceptible bacteria, leaving behind already resistant bacteria to replicate and spread their resistance genes.

This may seem like a subtle distinction: We don’t create antibiotic resistance, we just increase its rate of spread. But, from the perspective of effective response planning, this is a critical distinction. If inappropriate antibiotic use caused antibiotic resistance, all we would have to do to defeat resistance is never prescribe drugs inappropriately. Unfortunately, that won’t work. All antibiotic prescription, even appropriate antibiotic prescription, increases selective pressure, which increases the rate of spread of resistance.

Eliminating inappropriate antibiotic use, and always using antibiotics appropriately is indeed critical, because it will slow the spread of resistance, buying us time to develop new antibiotics. But if 100% of our efforts are focused on antibiotic conservation, all we will achieve is a slowing of the inevitable exhaustion of the antibiotic resource. What is needed is to marry antibiotic conservation with antibiotic restoration. That is, we need new drugs to be developed. Just conserving what we have is not enough.

Why are “antibiotic stewardship” policies not a sufficient remedy for controlling resistance?

See above. Stewardship leads to conservation. That is half the battle, but by itself it will only lead to a slowing of the inevitable exhaustion of the resource.

Furthermore, the initial calls for stewardship were made by people like Max Finland in the late 1940s and early 1950s. This is not a new call. It’s more than a half century old. It just doesn’t work very well. An analogy is the temptation to say that we don’t need condoms to stop the spread of STDs, we just need abstinence. It is true that abstinence will stop the spread of STDs. But, an abstinence-only policy just doesn’t work. You’ve got to have the condoms too. Well, stewardship, by itself, just hasn’t worked after more than 60 years of calls for it. It is too hard to change behavior, and the pressures on physicians not to be wrong about their patients’ illnesses is too great.

What do you consider the chief impediments to developing newer/better antibiotics?

The two major impediments are: 1) economic, and 2) regulatory.

The primary economic impediment is that antibiotics have a lower rate of return on investment than other classes of drugs. You make a lot more money back on your R&D investment if the drug is taken every day for the rest of the patient’s life (e.g. cholesterol, hypertension, dementia, arthritis) than if it is taken for 7 days and then the patient stops because he/she is cured.

The regulatory problem is a startling degree of confusion at the FDA regarding what types of clinical trials should be conducted ot lead to approval of new antibiotics. There has been a total rethinking of antibiotic clinical trials at the FDA over the past 5 years. Right now, companies don’t know what trials they are supposed to do to get drugs done, and increasingly the standards are calling for infeasible study designs that simply can’t be conducted. This revisionist thinking is being driven by statisticians who know nothing about clinical medicine or patient care. They are asking for things to be done that can’t be done to human beings. The balance of clinical and statistical concerns is totally out of whack, and must be restored if this problem is to be solved.

What types of policies are needed to kick-start development of new antibiotics?

Simple. Solutions follow the problems above.

For the economic problem, we need Congress to pass legislation that creates special economic incentives for companies to re-enter the antibiotic R&D market. The return on investment calculation must be changed. Antibiotics are a unique, critical public health need. Congress should recognize this. Examples of programs that would work include increase in funding to scientists (e.g. via NIH) who study bacterial resistance and antibiotic development. Increased small business grants to help translate basic science discoveries to lead compound antibiotics. Tax credits, guaranteed markets, patent extensions, and prizes to serve as pull strategies to help companies improve the return on investment for antibiotics.

For the regulatory problem, Congress needs to stop hammering the FDA into a state of paralysis, where fear permeates every decision to approve a drug. We should be encouraging a balance between statistical concerns and clinical concerns, and we need to restore a sense that the agency is regulating drugs used by physicians for patients, and that trials showing those drugs are safe and effective must be feasible to conduct and relevant to how the drugs will be used in clinical medicine after they are approved.

Antibiotics – the EU pipeline is empty too

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We’ve talked before about the shrinking number of drugs available to treat MRSA and about the challenges of getting new drugs to market. Well, it’s not just a problem in the United States.

A new report from the European Centre for Disease Prevention and Control (ECDC) and the European Medicines Agency (EMEA) — that’s the CDC and the FDA of the European Union — analyzes the bench-to-market “pipeline” of new drug development in the EU and finds… not good news. Out of 167 antibacterial agents that are somewhere in the pipeline of development, only 15 look likely to improve treatment of resistant organisms over drugs that already exist — and 10 of those 15 are in early-stage trials and will not come to market anytime soon.

That leaves 5 potential new drugs, for an epidemic of antibiotic resistance that, just in the EU, causes 25,000 deaths and $1.5 billion Euros ($2.27 billion) in extra healthcare spending each year.

(Within that epidemic of resistance, by the way, the single most common organism is MRSA.)

It’s worth understanding how the agencies conducted their analysis. When we look for new drugs to treat resistant organisms, we ideally need several things:

  • a formula or molecule that is new (and not just an improved version of an existing one, because if bacteria have developed resistance against the existing one, they have a head start in developing resistance against the new one)
  • a new mechanism or target on the bacterial cell, and not an improved version of an existing one (ditto)
  • evidence that it works in living organisms, and not just in lab dishes (in vivo, not just in vitro)
  • evidence that it can be given internally, not just topically (necessary for addressing the most serious infections)
  • and some indication that it is making its way through the regulatory approval process in time to achieve some practical good.

Here’s what the EU pipeline looks like:

  • 167 agents in process
  • 90 that have shown effectiveness in vivo
  • 66 that are new substances
  • 27 that have a new target or mechanism
  • 15 that can be administered systemically

If you’re wondering whether you should be depressed, the answer is Yes.

… it is unclear if any of these identified agents will ever reach the market, and if they do, they may be indicated for use in a very limited range of infections.

The agencies call for a concerted government effort to turn this around, and ask for quick action because it takes years to get drugs through the pipeline:

…a European and global strategy to address this serious problem is urgently needed, and measures that spur new antibacterial drug development need to be put in place.

This echoes a call that has already been made in this country by the Infectious Diseases Society of America, which has asked for changes in incentives to drug-makers, and has backed what’s known as the STAAR Act (STrategies to Address Antimicrobial Resistance). With this latest EU report — which comes on the heels of a US-ER agreement to work cooperatively on resistance — the IDSA is asking for an international commitment to bringing forth 10 new drugs in 10 years, what they are calling 10 x ’20.