Incentives for making new antibiotics: What would it take?

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

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

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

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.

Media round-up: recommending MRSA stories

By chance — or is it because interest is really picking up? — a couple of worthwhile stories on MRSA have been published almost simultaneously:

• For when the science gets wonky: Environmental Health Perspectives has an excellent lay-language explanation of how drug resistance emerges and spreads — with gorgeous graphics!
• For when yet another drug doesn't work: Scientific American covers development of new antibiotics, and even more important, development of new ways of creating antibiotics.
• For yet more depressing news about MRSA in meat: Prevention adds to the discussion of MRSA in the food supply with a "special report" review. Constant readers who have been following along as we've drilled into this topic over the past two years won't find a lot new, except for an intriguing account of an outbreak of MRSA in an Arkansas chicken plant (in which the bug went disappointingly untyped, so we don't know whether it was a human strain or ST398). The story hits on issues we have talked about here: Surveillance for MRSA in animals is non-existent, practically speaking, and when the bug is found, investigation falls between human and animal health agencies. It's a longer than usual story for Prevention, and should bring the knotty food-policy questions around MRSA in meat to a new audience.

Even more bad news on new drugs

Via Forbes.com comes news that the Food and Drug Administration has turned back Targanta Therapeutics' application for its new antibiotic oritavancin, which was designed specifically to target drug-resistant staph, and has asked for additional trials. This is a follow-on to a decision by an FDA advisory panel last month that also expressed doubt about the drug.

This comes on the heels of last month's withdrawal of dalbavancin and delay in approval of ceftobiprole.

The long, thin pipeline of new drugs for MRSA just got longer and thinner.

More bad news on new drugs

The Infectious Diseases Society of America (IDSA) has published a new report that fills in the background on last week's news below, and confirms: The landscape for new drugs against MRSA and other multi-drug resistant organisms is bleak. (The organisms, summarized in the acronym ESKAPE, are: E. faecium, MRSA, Klebsiella, Acinetobacter, Pseudomonas aeruginosa and Enterobacter.)

The report, published in the journal Clinical Infectious Diseases, is both an update of surveys of the new-drug landscape done in 2004 and 2006, and also a call to action that asks for broad federal effort to encourage pharma companies to produce new drugs.

Here are the highlights:

• Since the last iteration of the survey in 2006, only one new antimicrobial, doripenem — a very broad-spectrum injectable that is most active against the Gram-negative bacterium P. aeruginosa — has been approved.
• Only three new compounds — ceftobiprole, dalbavancin and Paratek Pharmaceutical's PTK-0796 — are in their final rounds of trials. (The report was obviously written before the latest news about ceftobiprole and dalbavancin.)
• Four of seven efforts to achieve a staph vaccine have been terminated.
  
• Though the pharma industry, through its lobbying arm PhRMA, claims "388 infectious diseases medicines and vaccines and 83 antibacterial drugs in development", that number is misleading:

Careful review of these data reveals that most are preclinical and phase 1 compounds. Also included are topical and nonabsorbable antimicrobials, which we do not consider here, and several compounds for which development has been terminated. Finally, ... many of the listed drugs are previously approved agents that are being studied for new indications.

Just to make sure no one misses the big picture, the authors emphasize:

...The number of new antibacterials that make it through the complete development process and ultimately receive FDA approval has precipitously decreased over the past 25 years. Indeed, we found a 75% decrease in systemic antibacterials approved by the FDA from 1983 through 2007, with evidence of continued decrease in approvals, even during the most recent 5-year period.

What are the answers? IDSA is candid, as in its earlier reports, that it believes incentives for drug companies are the only way to improve the situation: financial boosts, patent extensions and changes in trial requirements. Two things are critical, the group says:

• Novel intravenous and oral drugs to treat both hospitalized and community-based patients are needed, as opposed to “me too” drugs that provide minimal improvement over existing therapies.
• Priority should be given to antimicrobials with the potential to treat serious infections that are resistant to current antibacterial agents.

Bad news on the new-drugs front

Via the very robust pharma blogosphere, reports that two much-anticipated new antibiotics will be remaining in the pipeline a while longer:

Fierce Biotech says that Pfizer has withdrawn its US and European applications for dalbavancin, a much-awaited new MRSA drug, and will conduct another Phase III trial.

Pharmalot reports (via Reuters) that the Food and Drug Administration has asked for additional trials for ceftobiprole, another much-anticipated new drug for MRSA, coming from Johnson & Johnson. Shearlings Got Plowed has more detail, speculates that a "new game face" is emerging at the FDA, and notes that J&J's partner in ceftobiprole, Basilea, acknowledged that the FDA raises "issues of data integrity" regarding the current application. J&J's press release is here.

So it's back to vancomycin, again, for now.

Contributing to resistance: fake drugs?

There's news this morning that Interpol has seized $6.65 million of counterfeit medicines in the culmination of a 5-month undercover investigation that stretched across Cambodia, China, Laos, Myanmar, Singapore, Thailand and Vietnam. The fakes included purported antiretrovirals for HIV, anti-TB drugs, antimalarials (especially artemisinin) — and, chillingly for our purposes here, fake antibiotics for pneumonia and other bacterial illnesses.

Bloomberg News says:

Under Operation Storm, which ran from April 15 to Sept. 15, police seized more than 16 million pills...
Asia is the world's biggest producer of all counterfeit products, the Organization for Economic Cooperation and Development said in a report last year. About 40 percent of 1,047 arrests related to fake drugs worldwide last year were made in Asia, according to the Washington-based Pharmaceutical Security Institute.
Counterfeits account for as much as 30 percent of all drugs in developing nations and less than 1 percent of all medicines in developed nations such as the U.S. (Byline Simeon Bennett.)

Counterfeiting medicines is both a huge business — the World Health Organization estimates that "counterfeit drug sales will reach US$ 75 billion globally in 2010, an increase of more than 90% from 2005" — and an appalling crime that attacks the most vulnerable people at their most vulnerable moments. In a recent issue brief, the WHO recounts a number of instances of counterfeiting that led to deaths in a number of countries.

Why should we care here? Because some counterfeits are not complete fakes; they contain a small amount of the active ingredient of the drug they purport to be. That means that, if someone takes a faked version of an antibiotic, they may not be going untreated. Instead, they may be undertreated, the exact situation that can lead to the emergence of resistance. Just last year, according to the Pharmaceutical Security Institute, known counterfeiting episodes involving anti-infective drugs rose 26%.

Now, NB: Activism against counterfeit drugs is politically complicated; it is supported by the pharma industry (PSI is a coalition of 26 manufacturers) and is tangled up with opposition to online pharmaceutical sales and to decisions by developing-world countries to abrogate Western drug patents. But that turf-defending by the pharma industry does not alter the reality that counterfeit drugs are an enormous international problem that imperil not only people unfortunate enough to take them, but anyone who contracts a resistant strain that those drugs helped foster.

And anyone concerned about MRSA will already know that resistant strains do not stay where they are generated. They have already demonstrated their ability to move rapidly around the world.

Despite stewardship efforts, antibiotic use increasing

Well, this is bad news.

I hope we can all agree that antibiotic use creates antibiotic resistance. (Proof, if any were needed, that the universe has a captious sense of humor; but then it has had millennia to practice. OK, sorry for the anthropomorphizing.) The more pressure bacteria are placed under, the more resistant mutants emerge and survive. So the challenge in using antibiotics is to use them sufficiently and not too much: enough to quell infection and save lives, but not so much that the benefit of successful treatment is outweighed by the cost of increased resistance.

That's the theory, anyway. In practice, according to a paper published today in the Archives of Internal Medicine, we're not living up to the plan.

Amy L. Pakyz, Pharm.D. and colleagues at Virginia Commonwealth University surveyed antibiotic use at 22 academic medical centers — tertiary care teaching hospitals, ones that would be most likely to have high awareness of the dangers of resistance and good antibiotic stewardship programs — between 2002 and 2006. And found: Despite all that awareness, antibiotic use is going up, and the use of broad-spectrum agents and vancomycin, MRSA's drug of last resort, is going up most of all.

The third significant observation is the marked increase in vancomycin use during the 5-year period such that it became the single most commonly used antibacterial in this sample of hospitals from 2004 to 2006. ...
The reasons for the continued increase in vancomycin use are likely multifactorial, including the increasing numbers of hospital-acquired infections caused by MRSA and the emergence of community-associated MRSA, all of which encourage greater empirical use of vancomycin.

With only a few new drugs of comparative effectiveness on the market, and none that are significantly better, this is bad news, the authors underline:

Vancomycin use is a risk factor for emergence of vancomycin-intermediate S aureus and vancomycin-resistant S aureus, although these strains are rare in the United States. Of greater concern may be the emergence of low-level resistance in MRSA to vancomycin, referred to as minimum inhibitory concentration (MIC) “creep,” and this is far more common. Strains of MRSA having vancomycin MICs of 2.0 μg/mL are associated with longer median times to clearance of bacteremia compared with strains having MICs of 1.0 μg/mL or less, as well as frank treatment failures.

The cite is: Pakyz, AL et al. Trends in Antibacterial Use in US Academic Health Centers 2002 to 2006. Arch Intern Med. 2008;168(20):2254-2260.

New report and recommendations, "Why Infectious Diseases Are a Threat to America"

I'm still catching up post-ICAAC - and in addition am on the road reporting, again. But I'm trying to keep all y'all informed. (That's a clue to my destination. Where in the US is "y'all" a single noun and "all y'all" the plural? Hint: It's the same place where "barbecue" is only made of beef... Oh, OK, I'm in Texas, enough with the quiz already.)

While the ICAAC-IDSA meeting was happening, the very good nonprofit organization Trust for America's Health released a report that, just in time for the election, proposed a policy framework for emerging infections and infectious diseases generally. "Germs Go Global: Why Emerging Infectious Diseases Are a Threat to America" lists five major, ongoing, under-appreciated threats:

• Emerging infectious diseases that appear without warning (SARS, H5N1)
• Re-emerging infectious diseases (measles, pertussis/whooping cough)
• "Neglected” infectious diseases (dengue)
• Diseases used as agents of bioterrorism (smallpox, anthrax)
• Rising/spreading antibiotic resistance.

The report makes a number of important, well-argued recommendations for the next administration to consider. Several concern us particularly:

The U.S. government, professional health organizations, academia, health care delivery systems, and industry should expand efforts to decrease the inappropriate use of antimicrobials in human medicine, agriculture and aquaculture.
The U.S. Congress should amend the Orphan Drug Act to explicitly address infectious diseases like MRSA, or create a parallel incentive system to address the unique concerns in this area.

The entire report is worth reading. (If you're short on time, there is an executive summary that covers the main points.) I recommend it.

Breaking MRSA news from the ICAAC meeting 1

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.

Non-pharm prevention alternative for MRSA skin infections

Longtime reader and botanical-medicine expert Robyn spotted this new story and study this morning and pointed it out in the comments to a previous post. It's about a product, but it's a product with science to back it, so under my rules regarding commercial products, I am moving it up to post status. (Robyn didn't say, but given the internals of her post I assume, that she has no commercial interest in this. Right, Robyn?)

The product under investigation is an over-the-counter cream called StaphASeptic that contains the natural antimicrobials tea tree (Melaleuca alternifolia) oil and white thyme (Thymus vulgaris — the "white" refers to the preparation not the species) oil, along with the commercial antiseptic benzethonium chloride. That product's effect on isolates of CA-MRSA was compared against two common OTC first aid creams, one containing the topical antibiotic polymyxin B and the other containing both polymyxin B and the topical antibiotic neomycin.

The authors found that the botanical-containing cream did a better job of killing CA-MRSA in a time-kill analysis, finding specifically that it went on killing longer — up to 24 hours — than the other two creams. The assumption obviously is that this non-antibiotic cream would do a better job of protecting superficial wounds and scrapes from MRSA infection than the antibiotic-containing ones, while presumably not promoting resistance.

But the important question, which Robyn raises, is whether the essential oils are not in fact acting as natural antibiotics, possibly synergistically. Let's remember that the majority of antibiotics — including, for instance MRSA drug-of-last-resort vancomycin, and its replacement daptomycin — were initially isolated from natural substances (fungi, in both those cases). Overall, however, botanical products receive much less research attention that pharmaceuticals, so their action and their therapeutic potential remain unexplored.

The cite is: Bearden, DT, Allen GP and Christensen JM. Comparative in vitro activities of topical wound care products against community-associated methicillin-resistant Staphylococcus aureus. Journal of Antimicrobial Chemotherapy (2008) 62, 769–772. NB: The research was supported by an unrestricted grant from StaphASeptic 's manufacturers, Tec Laboratories Inc., and JM Christensen, of the Oregon State University College of Pharmacy, disclosed a consultant relationship with Tec.

Gram-negatives need love too

Britain's Health Protection Agency warns today that the supply of new drugs for resistant Gram-negative infections — Acinetobacter, Pseudomonas, Burkholderia — is in even worse shape that the drug pipeline for MRSA and other Gram-positives.

"Over the last ten years the pharmaceutical industry has significantly invested in antibiotic treatments for bacteria such as Staphylococcus aureus (including MRSA). There is however a big public health threat posed today by multi-resistant gram-negative bacteria and therefore there is an urgent need for the pharmaceutical industry to work towards developing new treatment options to tackle infections caused by these bacteria, in the same way as they did for bacteria like MRSA." (Dr. David Livermore, HPA press release)

The announcement comes between two important events: the release of the HPA's annual survey of antibiotic prescribing patterns in England, Wales and Northern Ireland (report .pdf here, 2mb); and the start next week of the HPA's annual scientific conference, which will have a full-day symposium on resistant infections (agenda here).

Interesting: The meme "MRSA's taken care of, let's get on to the gnarly Gram-negatives" has picked up traction in the past few months. While I'd certainly agree with the second proposition — pharmaceuticals for resistant Gram-negatives are the next big task — I reject the first, that the MRSA problem is solved and all we have to do is wait for the drugs to roll down the pipeline. Doesn't exactly square with all those posters at the last ICAAC and IDSA exploring emerging resistance to daptomycin and other new compounds.

For a full and thoughtful exploration of the Gram-negatives problem, see this recent New Yorker article, written by the inestimable Dr. Jerome Groopman. (True story: When Groopman's first book came out, I interviewed him by phone - I was working in Atlanta - and wrote a complimentary piece about it. Fast-forward several years, he has at least one more book out, has become a writing rockstar - in addition to being a hugely respected Harvard clinician and professor — and I am doing a journalism fellowship on genomics at Harvard Medical School. I'm standing in line at the Longwood area Starbucks, and I spy Groopman about four people ahead of me. And I'm too shy to say anything. So much for reportorial moxie.)

Natural remedies - upsides and downsides

For obvious reasons there is a lot of interest in finding new sources for antimicrobial compounds that work against MRSA, and in finding non-drug remedies as well. There's been a small upsurge in reports of such research recently, which may be coincidence or may simply be due to the timing of certain scientific meetings.

Notably there was the report of "four or five super-active peptides" found in the blood of alligators and reported at the American Chemical Society's annual meeting a few weeks ago (first author Lancia Darville. Louisiana State University; Science News' take on the story is here), and another report at the same meeting of antimicrobial compounds in clay (authors Lynda Williams and Shelley Haydel of Arizona State University; press release here).

And just a few days ago, the journal Clinical Infectious Diseases posted ahead-of-print a study from the Netherlands on a "medical-grade honey" named Revamil that reduced skin colonization by resistant bacteria 100-fold.

That study's authors raise a red flag: that while honey has an antibacterial reputation that reaches back into prehistory, most investigations of honey as an antimicrobial have tripped up on the lack of product standardization, with batches from different areas, or even the same area at different times, showing significant variations in antibacterial activity. (Standardization of active ingredient is a long-standing problem for herbal remedies as well; regulatory authorities in Europe, where herbal preparations are more mainstream, are far ahead of the US on tackling this.)

It's important to remember that, naturally-sourced or not, antimicrobials are antimicrobials and must be handled with care, or they may invoke the sort of unintended consequences that brought us resistant organisms in the first place. For an excellent example of this, see a little-noticed paper from Irish researchers published last year in the the Journal of Antimicrobial Chemistry. That group found problems with the well-researched natural antimicrobial tea tree oil (Melaleuca alternifolia), which is commonly used in "natural" toiletries and cleaning products (and which I have in my own medicine cabinet). When tea tree oil was applied to bacterial colonies at a lower-than-lethal dose, the surviving bacteria developed resistance not only against the oil's active ingredient, but also against a range of antibiotics including vancomycin.

A staph vaccine: How much would it help?

One more post on research from the meeting of the Society for Healthcare Epidemiology of America: Many MRSA researchers believe that the only way to truly control the pathogen — especially out in the community — will be through a vaccine.

Lay aside for the moment how problematic introducing a new vaccine can be these days, since the cost issues, along with shifts in the public's willingness to accept new vaccines, are ferocious hurdles. And lay aside also the difficulties that pharma companies have already faced in attempting to develop a staph vaccine.

But if such a vaccine were achieved, how many people could it help? Researchers from the Centers for Disease Control and Prevention attempted to answer that question in research presented at SHEA.

Background assumptions, part 1: The number of invasive MRSA infections now tops an estimated 105,000/year (a recalculation of the 94,000/year estimate from last October); more than 40% of invasive infections occur in those over 65; more than 50% are associated with a recent hospitalization; and 15% of MRSA infections recur at least once. And background assumptions part 2: A vaccine would have an efficacy rate of 40-75%, and an acceptance rate similar to flu-vaccine uptake: 20-50% among those 15-44, 35-70% among those 45-64, and 50-70% among those 65 and older.

Given those assumptions, Cynthia Lucero, MD and colleague predicted:

• If given only to those 65 and older, a vaccine would prevent from 12,720 to 32,270 invasive MRSA infections;
• If given to those over 65 and also those 15 and older who have already had an invasive infection, a vaccine would prevent 14,130 to 38,310 invasive MRSA infections;
• And if given to those over 65 and also anyone over 15 who is being discharged from a hospital, a vaccine would prevent from 17,240 to 49,940 invasive MRSA infections.

The best bang for the buck, the agency said, would be the middle strategy: It would prevent from 660 to 1,170 cases for every million doses of vaccine used. And since the vaccine would also cover methicillin-sensitive staph, it would likely prevent an equal number of serious MSSA cases as well.

The CDC is not by law allowed to lobby — or even, for the most part, allowed to offer a professional opinion unless Congress has asked it to do so. So these numbers are purely a thought experiment. But they're also a strong argument for the broad usefulness of a staph vaccine if one could be achieved.

Got (wallaby) milk?

Researchers in Melbourne, Australia report finding a broad-spectrum antimicrobial compound in the milk of the Tammar wallaby, which lives on islands off Australia's south and west coasts. Like other young, wallabies are born with an undeveloped immune system yet seem notably resistant to infection; the compound, AGG01, may be why.

Using advanced computer systems, researchers at the state of Victoria's Department of Primary Industries in Melbourne, Australia, found more than 30 potential bug-fighting compounds in the milk of the Tammar Wallaby (Macropus eugenii). One compound, known as AGG01, was particularly potent said lead researcher and animal geneticist, Ben Cocks.

Some experiments showed small amounts of a synthetic form of the drug were able to kill all bacteria in 30 minutes. "We found in lab tests that AGG01 is very effective against multidrug-resistant gram negative bacteria, including those that are most difficult to treat," he said.

Next research step: Designing a wallaby-milking machine.

Full text: Anti-superbug weapon developed from wallaby milk

(Hat tip to Boing Boing.)