Maryn McKenna

Journalist and Author

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.

A timely reminder on using antibiotics well (and badly)

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The Infectious Diseases Society of America, the professional organization for ID physicians, is criticizing large grocery store and pharmacy chains for giving antibiotics away for free. (Yes, you read that right: Not generic, not cheap, free. Here is a Wall Street Journal Health blog post explaining the practice, which has become quite common over the past two years.)

IDSA is concerned of course that these antibiotics will be used inappropriately because, being free, they will have a perceived lesser value. The Centers for Disease Control and Prevention has been campaigning for years against inappropriate antibiotic use, via its Get Smart: Keep Antibiotics Working campaign.

(Why is it important to use antibiotics only for the things they work against? All together now: Because if used inappropriately — in too-low doses, too-short courses, or against an illness where they are not useful — they will encourage the development of resistant bacteria, and also may kill your own commensal bacteria, clearing a niche that resistant ones can then occupy. Very good, class, early dismissal today.)

There’s an additional, interesting twist to these campaigns, though, which IDSA very rightly raises: They are taking place now, in flu season. One of the most common inappropriate uses of antibiotics is against viral diseases such as flu; the CDC says:

Tens of millions of antibiotics prescribed in doctors’ offices each year are for viral infections, which cannot effectively be treated with antibiotics. Doctors cite diagnostic uncertainty, time pressure on physicians, and patient demand as the primary reasons why antibiotics are over-prescribed.

IDSA is quite rightly concerned that the launch of these free-pill programs in flu season will reinforce the association between flu and antibiotics, which is precisely the association that causes antibiotics to be most overused. An excellent point.

Final report from ICAAC-IDSA 08 (news from ICAAC, 3)

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The ICAAC-IDSA (48th Interscience Conference on Antimicrobial Agents and Chemotherapy and 46th annual meeting of the Infectious Diseases Society of America) meeting ended a week ago, and I’m still thrashing my way through the thousands of abstracts.

Here’s my final, highly unscientific selection of papers that caught my eye:

* Evidence that the community-strain clone USA300 is a formidable pathogen: It first appeared in the San Francisco jail in 2001. By last year, it had become the sole MRSA strain found in the jail — it crowded out all others. (P. Tattevin, abstract C2-225)
* Another paper from the same UCSF research group finds that the emergence of USA300 has caused a dramatic increase in bloodstream infections, most of which are diagnosed in the ER, not after patients are admitted to the hospital. (B. Diep, abstract C2-226)
* And the CDC finds that USA300 is picking up additional resistance factors, to clindamycin, tetracycline and mupirocin, the active ingredient in the decolonization ointment Bactroban. (L. McDougal, abstract C1-166)
* An example of the complexity of “search and destroy,” the active surveillance and testing program that seeks to identify colonized patients before they transmit the bug to others in a health care institution: Patients spread the bug within hours, often before test results judging them positive have been returned from the lab. (S. Chang, abstract K-3379b)
* In addition to the report from Spain I posted on during the meeting, there is a report of emerging linezolid resistance in France. (F. Doucet-Populaire, abstract C1-188)
* And in addition to the abundant new news about MRSA in pork, and “pork-MRSA” or ST 398, in humans, over the past few days, there were reports of MRSA in milk in Brazil (W. Gebreyes, abstract C2-1829) and Turkey (S. Turkyilmaz, abstract C2-1832), and beef and chicken in Korea (YJ Kim, abstract C2-1831), as well as ST 398 itself acquiring resistance to additional drugs. (Kehrenberg, abstract C1-171)
* Echoing many earlier findings that MRSA seems most common among the poor, the poorly housed and the incarcerated, BR Makos of the University of Texas found that children are more likely to be diagnosed with the bug if they are indigent, or from the South (which I imagine is a proxy for lower socio-economic status, since the South is a more rural, more poor region). (abstract G2-1314)
* And finally, to the long list of objects (ER curtains, stethoscopes) that harbor MRSA, here are more: The ultrasound probes in emergency rooms (B. Wessman, abstract K-3377). Also: Dentures. (Ick.) (D. Ready, abstract K-3354)

New drugs for MRSA, at various experimental stages

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As you might guess by the name, ICAAC (the Interscience Conference on Antimicrobial Agents and Chemotherapy) features much research on the pharma side of things. There were many research reports this past week on drugs at various stages that I was intending to write up for you, but I just noticed that Reuters got there first and did quite a good job. So consider checking this story, which discusses PTK 0796, iclaprim, ceftobiprole, dalbavancin and televancin:

Two experimental antibiotics appear to work safely against an increasingly common and dangerous form of infection called methicillin-resistant Staphylococcus aureus or MRSA, researchers said on Sunday.
Doctors are clamoring for drugs that can fight the so-called superbug infection, which kills an estimated 19,000 people a year in the United States alone. (Reuters)

An important consideration that is not much discussed: It is not enough just to have new drugs; what we need are new classes of drugs. That’s because, when staph acquires protection against one drug, it is likely to be acquiring protecting against all chemically similar drugs — thus, not just methicillin but all the synthetic penicillins; not just Keflex but all the first-generation (and second- and third-generation) cephalosporins.

Microbes in US meat, but no MRSA

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The ICAAC-IDSA meeting has ended, but there are still many abstracts that I have not been through. While I pore over them, though, an interesting paper has just been published that somewhat contradicts earlier research on the presence of MRSA in meat. (Earlier posts are here, here, here, here, here, here, here and here.)

The researchers, from the Warren Alpert Medical School of Brown University and Rhode Island Hospital, bought ground beef, boneless chicken breasts and pork chops from 10 stores in and around Providence. Two stores offered both conventional and “natural” choices, so they bought both, giving them 36 (=[10+2]x3) samples all told. They cultured for MRSA, vancomycin-resistant Enterococcus, extended-spectrum beta-lactamase producing Gram-negative bacteria and E. coli 0157:H7.

And they found… almost nothing. Only one samples grew a resistant microbe, the ESBL Gram-negative Serratia fonticola. A secnd level of testing, however, uncovered four samples carrying S. aureus — but all methicillin-sensitive, not MRSA.

So are we in the clear? Not necessarily. It is, as they say themselves, as small study, in which only a third of the samples were pork, though pigs are the animals most associated with MRSA via the strain ST398. And the presence of S. fonticola is troubling, because it not only causes disease directly (in animals and in humans), but also harbors a plasmid that can transfer resistance to other bacterial strains.

Nevertheless, it is a comforting reminder that, though MRSA has been found in meat, it has not been found everywhere. (Or at least, not in Providence.) Still, we shouldn’t let our personal vigilance lapse. The hypothetical danger from MRSA in meat is not that we’ll swallow it, but rather that we’ll be colonized if we handle the raw meat without being careful enough about kitchen hygiene. So keep raw meat away from other food, wash your cutting boards and counters, and (say it with me, now), wash your hands, wash your hands, wash your hands.

The cite is: Philip A. Chan, Sarah E. Wakeman, Adele Angelone and Leonard A. Mermel, Investigation of multi-drug resistant microbes in retail meats. Journal of Food, Agriculture & Environment, Vol.6 (3&4), July-October 2008.

Outbreak of Zyvox-resistant staph (breaking news from ICAAC 2)

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Physicians from Madrid reported today on what’s believed to be the first outbreak of MRSA caused by a strain that was resistant to linezolid, usually known as Zyvox, a relatively new and costly drug that is used for complicated MRSA infections and when older drugs fail.

Linezolid resistance in single cases has been recorded before — the first isolate I can see in a quick scan of the literature dates to 2002 — but this appears to be the first outbreak.

Dr. Miguel Sanchez of the Hospital Clinico San Carlos said the outbreak was discovered April 13, 2008 in an ICU patient and subsequently spread to 11 other patients in the ICU and two elsewhere in the hospital. The patients, 8 men and 4 women, had been in the unit for at least three weeks for a variety of reasons; they were intubated, had central venous catheters, and had been receiving broad-spectrum antibiotics. None of them were colonized with MRSA on admission. The outbreak went on for 12 weeks, until June 27.

It was eventually shut down by a combination of strategies: taking the patients off linezolid in favor of other anti-staph drugs (vancomycin and tigecycline); drastically restricting linezolid use, a policy that is already followed by many US hospitals; checking the patients very frequently for colonization; and cohorting them, which means grouping them together physically, away from uninfected patients, and putting them under isolation.

In a quick briefing with reporters, Sanchez seemed to suggest that the hospital does not believe its infection control failed. The hospital swabbed 91 environmental surfaces (such as bed rails and room furniture) and the hands of 47 health-care personnel and found only one sample that grew the linezolid-resistant strain on a culture. A case-control study to find the cause is being conducted, he said.

Half of the patients died, he said, but not as a result of the linezolid-resistant strain.

Sanchez’ data slides were not available to reporters this evening. (More precisely, they were delivered to the press room, but in a format that wasn’t readable). I’ll update with more details if/when we get access to them. Meanwhile, the cite is: M. De la Torre, M. Sanchez, G. Morales et al. “Outbreak of Linezolid-Resistant Staphylococcus aureus in Intensive Care.” Abstract C2-1835a.

ST 398 in New York City – via the Dominican Republic?

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Here’s a piece of MRSA news from the ICAAC meeting (see the post just below) that is intriguing enough to deserve its own post.

US and Caribbean researchers have found preliminary evidence of the staph strain ST 398, the animal-origin strain that has caused human illness in the Netherlands and has recently been found in Ontario and Iowa, in Manhattan. How it may have arrived: Via the Dominican Republic.

Th researchers (from Columbia University and Montefiore Medical Center in New York, three institutions in the Dominican Republic and one in Martinique) examine the influence of an “air bridge” — very frequent household travel — that is bringing MRSA and methicillin-sensitive staph back and forth between the Dominican Republic and the immigrant Dominican community at the north end of Manhattan. They compared 81 staph isolates from Dominican Republic residents and 636 from Manhattan residents and, among other findings, say that 6 Dominican strains and 13 Manhattan strains were ST398.

It is the first time ST398 has been found in Manhattan or in the Dominican Republic. (Most likely also the first time anyone has looked.)

The authors observe with some understatement:

Given the history of ST398’s rapid dissemination in the Netherlands, its history of methicillin-resistance and its ability to cause infections in both hospital and community, it will be important to monitor its prevalence in these new regions.

It is important to note that these ST398s were not MRSA — they were MSSA, methicillin-sensitive. However: Earlier this year, the Dutch researchers who have delineated the emergence of ST398 in Holland commented on the diversity of ST398 they have found on different pig farms and hypothesized that the resistance element has been acquired several different times by methicillin-sensitive staph. (van Duijkeren, E. et al. Vet Microbiol 2008 Jan 25; 126(4): 383-9.)

So it is possible to hypothesize that this strain arrived in Manhattan from the more rural Dominican Republic, though with the growth of hobby urban farming in NYC, one could also make the case that transmission went the other way. And it is also possible — I emphasize possible — that this could be a precursor to ST398 MRSA emerging in Manhattan. An interesting thought.

(This research is not online, because it is a poster presented at a medical meeting. For reference, the cite is: C. DuMortier, B. Taylor, J. E. Sanchez et al. “Evidence of S. aureus Transmission Between the USA and the Dominican Republic.” Poster C2-224. 48th ICAAC-46th IDSA, Washington DC, 24-28 Oct 2008.)

Breaking MRSA news from the ICAAC meeting 1

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There are 15,000+ people at the 48th Interscience Conference on Antimicrobial Agents and Chemistry (known as ICAAC – yes, “Ick-ack”) and 46th Infectious Diseases Society of America Annual Meeting, and at least half of them seem interested in MRSA. At the keynote address last night, Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases at NIH, referred to MRSA as a “global pandemic.”

Here are some highlights — a few of very, very many — from the first two days:

  • MRSA is truly a global phenomenon: Researchers here are reporting on local epidemics in Argentina, Australia, Botswana, Canada, Colombia, Ecuador, Greece, Japan, Nigeria, Peru, South Korea, Sweden and Taiwan.
  • In the United States, USA300 — the virulent community strain that is crowding out all other community strains — continues its dominance. It first appeared in the San Francisco jail in 2001 and now is the only cause of community MRSA infections there. (Tattevin, P. et al. “What Happened After the Introduction of USA300 in Correctional Facilities?” Poster C2-225.)
  • And MRSA continues to demonstrate its protean ability to cause unexpected forms of illness: The number of cases of sinusitis caused by MRSA seen at Georgetown University tripled between 2001-03 and 2004-06. (I. Brook and J. Hausfeld. “Increase in the Frequency of Recovery of Methicillin-Resistant Staphylococcus aureus in Acute and Chronic Maxillary Sinusitis.” Poster C2-228.)
  • Meanwhile, treatment options are shrinking. Hospitalization for vancomycin-resistant pathogens (that is, resistant to vancomycin, the drug of last resort for MRSA) doubled between 2003 and 2005 according to national healthcare utilization databases. (A.M. Ramsey et al. “The Growing Burden of Vancomycin Resistance in US Hospitals, 2000-2005.” Poster K-560.)
  • But, new drugs are beginning to emerge from the pipeline. Early results from a privately held company called Paratek Pharmaceuticals (co-founded by resistance guru Dr. Stuart Levy) showed that their new tetracycline relative PTK 0796 scored as well or slightly better than linezolid (Zyvox) in safety, tolerability and adverse events, and is advancing to a full Phase 3 trial. (R.D. Arbeit et al. “Safety and Efficacy of PTK 0796.” Poster L-1515.)

More as the meeting goes on.