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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CDC Threat Report: 'We Will Soon Be in a Post-Antibiotic Era'

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Image: CDC

The U.S. Centers for Disease Control and Prevention has just published a first-of-its-kind assessment of the threat the country faces from antibiotic-resistant organisms, ranking them by the number of illnesses and deaths they cause each year and outlining urgent steps that need to be taken to roll back the trend.

The agency’s overall — and, it stressed, conservative — assessment of the problem:

  • Each year, in the U.S., 2,049,442 illnesses caused by bacteria and fungi that are resistant to at least some classes of antibiotics;
  • Each year, out of those illnesses, 23,000 deaths;
  • Because of those illnesses and deaths, $20 billion each year in additional healthcare spending;
  • And beyond the direct healthcare costs, an additional $35 billion lost to society in foregone productivity.

“If we are not careful, we will soon be in a post-antibiotic era,” Dr. Tom Frieden, the CDC’s director, said in a media briefing. “And for some patients and for some microbes, we are already there.”

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News From The Road: No Drugs, Few Strategies, But A Little Good News On Antibiotic Resistance

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So, hi, constant readers. Sorry, didn’t mean to disappear for quite that long. I’ve been on the road, first teaching for a week at the University of Wisconsin as their Science Writer in Residence, and then in New York to attend the annual meeting of the American Society of Journalists and Authors, where I received the June Roth Memorial Book Award for Superbug. (Plus, in between those two, I recorded an episode of the Virtually Speaking Science podcast with Tom Levenson, which you can find here, about the looming post-antibiotic disaster; and an episode of Skeptically Speaking with Marie Claire Shanahan, which you can find here, about the emerging story of H7N9 flu; and got tangentially involved in the Boston bomber manhunt.)

While I was offline, a far amount of news happened. In the next few days, I’ll do my best to catch up. Here’s a start, all on infections and antibiotic resistance.

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News break: First guidelines for treating MRSA

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For my book SUPERBUG: The Fatal Menace of MRSA (came out last March; paperback will be out in February), I spent several years talking to about 100 victims of antibiotic-resistant staph, and family members of victims who did not survive their infections. There were some striking things about their stories.

One was the variability of the bug, which can cause anything from mild one-time skin infections to lethal necrotizing pneumonia, adding up to almost 19,000 deaths, 369,000 hospitalizations and possibly 7 million medical office visits a year. The other was the variability of the patients’ treatment. Some had the good luck to find physicians who knew about the bug, understood the layers of testing needed to determine the best antibiotics to use, and were sensitive to the possibilities of over- and under-treatment. Others were not so lucky: They went to doctors who didn’t recognize the infection, didn’t prescribe drugs that worked, didn’t have anything to offer when the infection recurred — a whole panoply of errors.

It was a lesson for me in how long it can take news of a new medical development to percolate through the clinical community, especially to primary-care practitioners — people who don’t have a channel for new news because they don’t work for an academic medical center or belong to a specialty society that puts out a journal or at least a substantial newsletter. But it was also a lesson on how few agreed-upon standards of practice there were for treating MRSA. For many presentations, there was no evidence refer to; clinicians were thrown back onto poring through the literature, or on making educated guesses based on their past experience.

As of this week, that should change. The Infectious Diseases Society of America has publshed the first-ever clinical practice guidelines for treating MRSA in adults and children. It’s a substantial document, 38 pages (in the advance access section of Clinical Infectious Diseases) and should be a tremendous resource for patients and their physicians. (I know of one patient who printed it out yesterday and took it to an office visit — only to find the physician had just downloaded a copy himself.) [Read more…]

News break: A new type of MRSA spreads in Ohio

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The annual meeting of the Infectious Diseases Society of America is taking place this week in Vancouver. This afternoon, one of the researchers presenting there released a startling bit of news: the spread in Ohio (and likely elsewhere in the United States) of a MRSA strain that is common in the rest of the world but so unusual in the US that it was last seen here in the 1990s and has never caused infections here.

The strain is ST239, sometimes called the Brazilian clone, and it’s serious stuff: It causes major epidemics and is responsible for something like 90 percent of all the MRSA infections in hospitals in Asia. Its hallmark is that it very multi-drug resistant — including to just about all the oral antibiotics that are used against MRSA.

Brief recap — disease geeks, go on ahead and we’ll catch up: MRSA stands for methicillin-resistant Staphylococcus aureus, the most common drug-resistant infection in the world (and, shameless self-promotion alert, the subject of my recent book). All MRSA strains, at a minimum, are indifferent to the beta-lactam antibiotics, a group of drugs that share a four-cornered arrangement of atoms at the center of their base molecule. That structure allows the beta-lactam drugs to disrupt staph’s cell membrane, killing the bacterium. When staph evolved a work-around for that attack, it became resistant not just to methicillin, which hasn’t been sold for years, but to all the other beta-lactams as well — of which there are dozens; they are the fundamental, basic antibiotics used in medicine every day. Over the years, MRSA has also gained the ability to defuse the attack of additional drugs and drug families, by exchanging with other bacteria bits of DNA containing additional resistance genes. At the same time, the pace of new-drug approvals has slowed dramatically.

OK, back to today’s news.

At IDSA this afternoon, Dr. Shu-Hua Wang, an assistant professor of medicine at Ohio State University, revealed the results of an analysis of MRSA strains that showed up in a surveillance network that links Ohio State and seven rural hospitals nearby. Between January 2007 and January 2010, 7 percent of the 1126 MRSA strains they found in sick patients turned out to be ST239 — the first ST239 infections ever recorded in the US.

The infections were serious: half of the patients had bloodstream infections and one-fourth had pneumonia. And they were unusually difficult to treat: The bacterial samples were indifferent not only to the beta-lactams, but to a wide array of additional drugs: clindamycin, tetracycline, trimethoprim/sulfamethoxazole (TMP/SMX, usually called Bactrim or Septra), moxifloxacin, and gentamicin. They were susceptible only to vancomycin, the MRSA drug of last resort for decades, and one newer drug, linezolid (Zyvox).

That is a dismaying list. Here’s why: In the search for drugs that still work against MRSA, medicine has increasingly turned to older drugs — ones that until recently were never been used against the bug, because there were newer, better drugs available. Tetracycline and TMP/SMX are two of the great remaining hopes for treating MRSA infections without rolling out the really big-gun drugs that should be reserved for life-threatening emergencies. If the resistance factors carried by ST239 knock out the older generics, MRSA infections will become yet harder to treat. As appears to have happened in Ohio:

“Twenty-two percent of the patients experienced relapse and failure of their drug regimens,” Wang said in a briefing for the media. “Another 22 percent died within 30 days.”

The 77 patients infected with ST239 tended to be male and older, and they were apparently already ill: 74 percent had been hospitalized before, 44 percent had had surgery, 29 percent had been in a nursing home, 17 percent had been on dialysis. Where the ST239 first came from and how it spread isn’t clear, Wang said, except that the surveillance network results show the earliest cases to have been treated at Ohio State. It may have spread to the rural hospitals from there.

The most worrisome implication of today’s news may not be the appearance of ST239 itself — it is so common in the rest of the world that its return to the US may just have been a matter of time — but rather the possibility that public health may not be able to keep track of it. In everyday medicine, isolates are tested enough to identify the organism and to determine its susceptibility to antibiotics; those results deliver enough information to determine a patient’s  best treatment. Multi-locus sequence typing, the test that identified ST239 in the Ohio patients, is expensive and complex and delivers more information than a clinician really needs; it’s most used in academic research labs. So it is entirely possible that patients could become infected with this strain without the strain being detected, unless the physician treating them happened to put together the puzzle pieces of the unusual resistance pattern.

This possibility seems to have been on Wang’s mind in Vancouver. To track the spread of ST239, “Increased molecular surveillance is needed,” she said. But she offered some workarounds — less expensive, more commonly used assays — whose results could be used to cast a net of detection for the spread of this new strain.

MRSA image from the Public Health Image Library, CDC; poster previously sold by Threadless, original design by Olly Moss

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.

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.