CDC report: Antibiotic Resistance Threats in the United States, 2013

CDC_antibiotic_resistance_pathways

Every year, more than two million people in the United States get infections that are resistant to antibiotics and at least 23,000 people die as a result, according to a new report issued by the Centers for Disease Control and Prevention (CDC). Press release here, full report with excellent graphics here.

The report, Antibiotic Resistance Threats in the United States, 2013, presents a first-ever snapshot of the burden and threats posed by the antibiotic-resistant germs that have the most impact on human health. This report is also the first time that CDC has ranked these threats into categories of urgent, serious, and concerning.

  • In addition to the illness and deaths caused by resistant bacteria, the report found that C. difficile, a serious diarrheal infection usually associated with antibiotic use, causes at least 250,000 hospitalizations and 14,000 deaths every year.
  • The loss of effective antibiotic treatments will not only cripple the ability to fight routine infectious diseases but will also undermine treatment of infectious complications in patients with other diseases. Many advances in medical treatment, such as joint replacements, organ transplants, and cancer therapies, are dependent on the ability to fight infections with antibiotics. If the ability to effectively treat those infections is lost, the ability to safely offer people many of the life-saving and life-improving modern medical advances will be lost with it.
  • The use of antibiotics is the single most important factor leading to antibiotic resistance around the world. Antibiotics are among the most commonly prescribed drugs used in human medicine. However, up to half of antibiotic use in humans and much of antibiotic use in animals is unnecessary or inappropriate.

If you think you needn’t worry about the rapid growth of antibiotic resistance, then I suggest you need to do a bit of homework. A starting place: Antibiotic resistance: a return to the pre-antibiotic world is coming faster than you think. This isn’t just an issue to be solved by “them”. We are the victims and the pressure for change has to come from “us”.

Thanks to a tweet from @onemedical One Medical Group for the lead to the CDC report. One Medical looks to me to be a promising crack in the broken US primary care model. Not Your Typical Doctor’s Office indeed!

Antibiotic resistance: a return to the pre-antibiotic world is coming faster than you think

Photo credit: Julian Stratenschulte/EPA/Corbis

We are seeing an alarming increase in new reports on the growth rate of antibiotic resistance. We cannot forecast the future date when we will return to the pre-antibiotic world. But we can be confident that if coordinated global action is undertaken straight away then the costs and social impact will be much lower than coping with the frightening future ahead.

This is a hard problem, possibly a “wicked problem“, thought not quite like the scale of climate change solutions. The costs of effective action to save antibiotics are a small fraction of what is required to decarbonize developing economies. And the required cooperation is not nearly so diffuse.

I will cite a couple of recent links that offer a survey of what is happening and what should be done to prolong our “golden age” of effective antibiotics. First Megan McArdle’s Bloomberg piece  Life Without Antibiotics Would Be Nasty, Brutish and Short(er); second CDC Threat Report: ‘We Will Soon Be in a Post-Antibiotic Era’ by Maryn McKenna, author of Superbug; and third, the key source for the McKenna article Antibiotic Resistance Threats in the United States, 2013, Centers for Disease Control and Prevention. Sept. 16, 2013.

From the press release for the CDC Threat Report 2013:

This report, Antibiotic resistance threats in the United States, 2013 gives a first-ever snapshot of the burden and threats posed by the antibiotic-resistant germs having the most impact on human health.

Each year in the United States, at least 2 million people become infected with bacteria that are resistant to antibiotics and at least 23,000 people die each year as a direct result of these infections. Many more people die from other conditions that were complicated by an antibiotic-resistant infection.

Antibiotic-resistant infections can happen anywhere. Data show that most happen in the general community; however, most deaths related to antibiotic resistance happen in healthcare settings such as hospitals and nursing homes.

For thoughts on some policy solutions I recommend Megan McArdle’s October 2011 analysis. And lastly, become a member of the International Society for Infectious Diseases (we are). Members of the ISID can subscribe to the International Journal of Infectious Diseases at a discount – but note the journal goes open access in 2014.

IBM research: hydrogels of “ninja polymers” to fight drug-resistant bacteria

Most of what I read on antibiotic resistance, hospital-acquired infections (HAI) are very depressing. Humanity seems to be an accelerating train — the destination a pre-antibiotic world — where surgery is often a death sentence.

Today I read of a possibly optimistic development: Breaking the bacteria barrier. The IBM Research hydrogel uses a novel attack by rupturing the bacteria’s membrane, rendering it completely unable to regenerate or spread. The researchers envision the first healthcare application to be surface decontamination. That’s very important in infection control, so it’s not a small thing if it works as they hope. The following image comes from IBM Research Hydrogels TUMBLR blog, where you can find more background on this research, and hopefully updates as they are announced.

On the left is a mature and healthy MRSA biofilm. After the hydrogel is applied, the biofilm is destroyed as seen on the right. Photo Credit: IBN <

I’ve just followed @IBMResearch  — there will be a a hydrogel chat in a couple of weeks. I’ll be looking for that announcement on Twitter/Tumblr. Since this is the corporate research twitter there will probably be a lot of traffic. I will suggest a #hydrogel hashtag to at least give us a chance of following developments.

It isn’t obvious to me how bacteria will develop resistance to this mechanism of action. Am I missing something there? The IBM team has looked at an injectable application of the gel – e.g., at the site of an infection.

What we all are hoping for is that this research could lead to the equivalent of a broad spectrum antibiotic effective against the growing number of super-bugs.

If you read German, the full paper is available here: Broad-Spectrum Antimicrobial and Biofilm-Disrupting Hydrogels: Stereocomplex-Driven Supramolecular Assemblies.

BTW, CDC has redefined HAI to be “Healthcare-associated infections” which is more accurate.

Antibiotic-resistance: we need better incentives

(…) And going to the hospital has itself become alarmingly risky. Already, 1.7 million people in the U.S. acquire infections in the hospital each year, resulting in 99,000 deaths, according to the Centers for Disease Control and Prevention.

(…) “A lot can happen in the several days that it takes for the doctor and the patient to determine that the first antibiotic that was given didn’t work,” Mellon said.

We were traveling and thus missed Megan McArdle’s Ocober 2011 analysis. I highly recommend a careful read to reflect on the scale of the problem and some possible policy solutions. There are a number of problems contributing to poor investment incentives plus poor incentives to maximize the utility of new molecules.

(…) The problem is, efforts at promoting conservation may discourage innovation—and vice versa. Some hospitals now require infectious-disease doctors to sign off on the use of newer and more powerful antibiotics. But this has a cost. “When a new antibiotic comes out,” Pfizer’s Utt says, “physicians don’t necessarily use it—they tend to hold it in reserve. So by the time it’s being used, it’s already used up part of its marketable patent life.” As a result, fewer large firms may want to spend the time and money to get these drugs approved—according to the IDSA, only two major drug companies (GlaxoSmithKline and AstraZeneca) still have strong active research programs, down from nearly 20 in 1990. Antibiotics are not big moneymakers: Every time a doctor writes a prescription for Lipitor, Pfizer may gain a customer for decades. But short-course drugs like antibiotics sell perhaps a dozen doses.

(…) Those same critics suggest that perhaps we should take this out of the invisible hands of the market. Historically, we’ve solved tragedy-of-the-commons problems either through privatization, as Britain did with its land, or through nationalization, as many nations have done with their military and police. If the market doesn’t work, why not try the government?

Even many libertarian types agree that the commons problem seems to call for stronger state controls over antibiotics. But how far should that go? Government and academia perform vital basic research, but they haven’t delivered a lot of working drugs. “What would be nice,” says Daemmrich, “would be to have free-market mechanisms reward new-drug discovery even as the use of antibiotics was limited to infections that don’t go away on their own.”

One possibility is to have the government buy all the antibiotics on a sliding scale: so many billion dollars for a first-in-class antibiotic, half that amount for a second-in-class, and so forth. The government could then restrict the antibiotic’s use. I’ve posed this possibility to people at pharmaceutical companies and gotten a surprisingly warm reception. Another idea, proposed by Outterson and a colleague, Harvard’s Aaron Kesselheim, is to change the reimbursement system so that companies get paid more when fewer of their drugs are prescribed, as part of a conservation plan. “Let’s say Bayer had a diagnostic test that could quickly tell whether you had a bacterial or viral infection. Right now, the only thing that this would do is knock down their unit sales [of antibiotics]. We should reward companies like Bayer if they bring out a diagnostic like this—their unit sales might decrease by half, but if so, we should quadruple their unit price.” Or we could have special rules for antibiotics patents: instead of a 20-year term, make them renewable annually for drug companies that promote conservation.

These ideas sound elegant and simple in a magazine article. In the real world, they’d be messy and controversial. The government would be getting into the business of fixing prices. Likely, it would overshoot, handing windfall profits to firms, or undershoot, leaving us without enough drugs to treat emerging resistant infections. But the potential for such mistakes shouldn’t stop us from trying to pursue creative public-private solutions. We just need to be prepared to face a lot of yelling.

Especially since the way to reward conservation is not entirely clear. Laxminarayan notes, “Whether resistance develops is not entirely a function of what the manufacturer does—it’s a function of what other manufacturers do as well.” Not to mention doctors, and patients, not all of whom are, ahem, entirely compliant.

If you are not totally depressed, read the June 14, 2011 McArdle analysis “How Superbugs Will Affect Our Health Care Costs. That article is based on “The ‘return of our old enemies in an untreatable form’” by the Remapping Debate. Please read both articles for discussion of the following two figures — these two trends can only end very badly:

Note that the first chart does not include the resurgence of multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis.

New Drugs Cost Even More Than You Think

R&D constant dollar graph.png

The depressing figure above was referenced in McArdle’s “Pharma Spending Less on Finding New Drugs“; Copyright The Boston Consulting Group. NME’s per $B R&D spent (constant dollars), where NME’s are New Medical Entities.

There is a very helpful article where Megan McArdle examines recent studies of the cost of new approvable drug discovery. That US$ 1 billion I’ve been using is low by 4 to 12 times:

(…) The standard figure for drug discovery thrown around by the industry’s most avid critics is the Light and Warburton estimate of roughly $43 million. Most serious analysts think that’s way too low (I agree–their assumptions were bizarre, and their attempt to defend them in the comments to this Tim Noah piece is painful to read).

The industry, and its supporters, prefer Joseph DiMasi’s figure of around $800 million. But critics point out that it was derived using confidential data, which can’t be verified, and they are very critical of the method, which includes opportunity costs–the returns that pharmaceutical firms didn’t earn by spending the money elsewhere.

Now along comes a new method, from Matthew Herper at Forbes. It uses only public, audited data, and it’s breathtakingly simple: over a 15-year period, they divided each company’s R&D spend by the number of drugs they got approved. The result: DiMasi is also way too low. For every approved drug, pharma spent between $4 billion and $11 billion on R&D. Yes, there’s probably some wiggle room on the accounting, but not that much–your auditor is not going to let you reclassify your new delivery trucks, or a Human Resources SVP, as a research expense.

As Herper points out, this isn’t necessarily a vindication of pharma–one could demand to know why they have to spend so much money to develop new drugs. Yes, I know, it’s getting harder to find approvable new drugs, but the industry has been flailing for ten years, and so far, the only answer they have hit on seems to be “more layoffs!” Maybe they’re just trapped in a bad place, but since the layoffs clearly aren’t working, I sure hope they come up with something else.

Still, it’s a useful corrective to the notion that pharma just wanders down to the university labs once a year to harvest the new drugs, then spends the rest of the year sitting back and idly watching the royalty checks pour in through the mail slot. Finding an approvable new drug is a long, expensive process that too often goes awry–and often, the rules we impose make things worse, and even tax policy. We should think about these numbers every time someone like Marcia Angell suggests that really, Big Pharma barely does anything. Unfortunately, Big Pharma is doing a lot, although not necessarily effectively as they could. Even more unfortunately, a dry pipeline hurts us at least as much as it hurts them.

Multi-drug resistant staph in 25% of supermarket meat samples

This should make you very angry – that farmers are still allowed to use unjustified, excessive application of antibiotics in industrial animal husbandry. Maryn McKenna writing for Ars Technica reports on a new study published in Clinical Infectious Diseases: Multidrug-Resistant Staphylococcus aureus in US Meat and Poultry [PDF].

Here are the details: A team from the Translational Genomics Research Institute in Flagstaff, Arizona, led by Lance B. Price, Ph.D., bought 136 packages of ground beef, chicken breasts and thighs, pork chops and ground pork, and ground turkey, under 80 brand names, in 26 supermarkets in Flagstaff, Chicago, Fort Lauderdale, Los Angeles and Washington, DC. They analyzed the meat for the presence of staph, because staph has been found in the past in several food-animal species. They did a second round of testing to define which strain of staph was on the meat, and then they did a third round, testing the isolates against five important classes of antibiotics, to see whether the staph they had found was resistant.

Which it was. Very. The antibiotics to which the staph was resistant included: penicillin and ampicillin; erythromycin; tetracycline; oxacillin, the more modern form of the drug methicillin; the drug combination quinupristin/dalfopristin, known as Synercid; the fluoroquinolones levofloxacin (Levaquin) and ciprofloxacin (Cipro); and the last-resort drugs for very serious staph infections vancomycin and daptomycin. One staph isolate was resistant to nine different antibiotics.

Among the types of meat tested, turkey carried the most resistance, with 77 percent of the meat samples showing at least some; that was followed by pork (42 percent), chicken (41 percent) and beef (37 percent). Interestingly, it wasn’t all the same staph. Though there was a great diversity of staph types, each animal species seemed to carry mostly one sequence type or strain of staph: ST1 in pigs, ST5 in chickens and ST398 in turkey. (More on that below.)

I spoke to Lance Price about his team’s work. “This is the first study to show that antibiotic-resistant staph is highly prevalent in the American food supply,” he told me.

He added: “There’s an important second point: We found that each of the meat and poultry types had their own distinctive staph on them. That provides strong evidence that food animals were the primary source of the resistant staph. The source wasn’t human contamination of the meat at slaughter, or when it was packaged for retail sale.”

How much resistant staph is present in food animals and on the meat they become has been an urgent question for about seven years, since a team of Dutch researchers identified an unusual staph strain—MRSA ST398—in a family who operated a pig farm. That strain has since spread to pigs across the European Union and into Canada, and has been found to cause human illness in all those areas. It’s also been found in pigs in the United States, though it has not yet been proven to cause human illness here. (I’ve been covering ST398 for several years, and a long archive of posts is available.)

Read the whole thing. You can follow Maryn at Wired Science/Superbug.

For more background on Denmark’s success in stopping the use of NTA (non-therapeutic antimicrobials), try this Seekerblog search.

Nanoparticles successfully take down MRSA bacteria

These announcements usually turn into a fizzle. I hope this Ars Technica release evolves into a useful therapy because we are in very serious trouble on the antibiotic front.

Traditional antibiotics like doxycyclin and vancomycin—the kind that many bacteria can now resist because of their overuse—work by getting inside the bacterial cell and interfering with essential cellular processes. Charged peptides have been proposed as alternatives, since they work by electrostatically interacting with the negatively charged bacterial cell wall, poking holes in the bacterial cell membrane and thereby killing the bacteria. Because these molecules physically disrupt the bacterial membrane rather than target an intracellular component, bacteria are less able to develop resistance.

However, these agents are expensive to produce, have short circulating half-lives in the body, and tend to kill red blood cells in addition to bacteria. They have thus met with limited clinical success. A report in this week’s Nature Chemistry describes the synthesis of the first biodegradable antimicrobial polymer nanoparticles to help fill the breach.

Antimicrobial resistance: revisiting the "tragedy of the commons"

John Conly is a Professor of Medicine, Microbiology and Infectious Diseases and Pathology and Laboratory Medicine at the Centre for Antimicrobial Resistance at the University of Calgary, Canada. He is also the co-director for the Snyder Institute of Infection, Immunity and Inflammation at the University of Calgary, and the former Chairman of the Board for the Canadian Committee on Antibiotic Resistance.

The November Bulletin of the World Health Organization includes an interview with Prof. Conly. The second interview question is:

Q: Is this the doomsday scenario of a world without antibiotics?

A: Unfortunately yes, with these new multiresistant NDM1-containing strains and their potential for worldwide spread. Doctors will face a terrible dilemma when a pregnant woman develops a kidney infection that spills over into the bloodstream with a pan-resistant strain containing NDM1 and there are no treatment options. We are essentially back to an era with no antibiotics.

The first interview question leads to a good summary of the threat:

Q: What’s special about this new type of resistance labelled as NDM1?

A: NDM1 is an enzyme that confers resistance to one of the most potent classes of antibiotics, known as carbapenems, but what has been observed is different in many ways to what we have seen to date. This new resistance pattern has been reported in many different types of bacteria compared to previously and at least one in 10 of these NDM1-containing strains appears to be pan-resistant, which means that there is no known antibiotic that can treat it. A second concern is that there is no significant new drug development for antimicrobials. Third, this particular resistance pattern is governed by a set of genes that can move easily from one bacterium to another. Fourth, NDM1 has been found in the most commonly encountered bacterium in the human population, E. coli, which is the most common cause of bladder and kidney infections. A further concern is that of the two drugs potentially capable of treating an infection due to one of these new multiresistant strains, one of them, colistin, causes toxic effects to the kidney in about a third of people.

For more on NDM-1 and the general topic, just click this query for the tag antibiotic resitance. If you are thinking “no worries, this is just in India and Pakistan” think again:

Does the spread of NDM1-containing strains of resistant bacteria constitute a public health event of international concern? In my opinion the answer is an unequivocal “yes”. We have seen such strains spread internationally. By early September this year, the United States of America (USA) had reported cases in three states and Canada, in three provinces. Australia, Belgium, Japan, Sweden and Viet Nam have all reported cases…

Antibiotic resistance: NDM-1 alarm in the UK

My understanding is that about 16% of infections are now resistant to multiple classes of antibiotics. The Scientist polls readers on the topic (79% real danger, 21% media hype):

The front page of The Guardian featured an article highlighting the apparent waning efficiency of antibiotic efficiency due to the global spread of certain drug-resistant bacteria.

(…)

The Guardian interviews one of the principal authors of The Lancet paper:

A new gene conferring high levels of resistance to almost all antibiotics has been found to be widespread in forms of gut bacteria that can cause potentially life-threatening pneumonia and urinary tract infections.

In just three years, says Professor Tim Walsh of Cardiff University who discovered the gene, it has grown in prevalence from being rarely observed at all to existing in between 1% and 3% in patients with Enterobacteriaceae infections in India.

“It is absolutely staggering,” said Walsh. “Because of international travel, globalisation and medical tourism, [the gene] now has the opportunity to go anywhere in the world very quickly.”

Some of the comments are useful, e.g., this one from UK molecular biology researcher Jim Caryl whose Gene Gym profile reads “Bad bugs, drugs and antibiotic resistance, all in a day’s work at The Gene Gym, brought to you from the gym floor by a researcher (fitness instructor) in bacterial evolution“:

I would find it hard to answer either way. I think multidrug resistance is a serious and potential threat, and there have been recommendations for some time that reports, such as that published by Walsh et al. in Lancet Infectious Diseases, be published and acted upon.

Molecular epidemiological studies are a crucial underpinning to work on predicting antimicrobial resistance (PAR), especially when these elements are associated with, or are in the same ecological niche, as promiscuous mobile genetic elements, and arising in nosocomial environments.

However, whilst the a/biotic pipeline could certainly have been considerably better stocked, the efforts of numerous small biotechs and academic researcher looking at alternatives to the rather poultry introduction of new a/biotic classes, seems to be chronically undervalued. There are valiant efforts to target bacterial virulence, the mechanisms of horizontal transfer, and to inhibit the means by which bacteria resistant antibiotics – in all cases rendering more time for new drug discovery, but crucially more time in clinical therapy.

“Is it likely that we will be dealing with infections in the UK that are completely resistant to antibiotics within 10 years? Or is this simply a case of media hysteria?”

Yes, if the funding is not made available and we rely on the efforts of a (majority) disinterest of large pharmaceuticals to invest in new drug class leads, we will be dealing with increased prevalence of multidrug resistance – as we already are in isolated pockets with some strains of Gram (+)ve bacterial pathogens.

Media hype should be reflective, and not doomsaying. They should be pointing out the threats, but identifying the huge efforts being taken to provide alternative solutions – brought about by the lack of real investment. We know so much more about bacteriology, molecular epidemioloigy and drug discovery now than we did in the heyday of a.biotic discovery. A/biotics were used for years without a full understanding of their mechanisms, nor the mechanisms of resistance. Many instances of a/biotic resistance spread could (and should) have ben predicted and prevented.

Ironically, some of the systems biology, high-throughput infrastructures that have been stealing so much of the research funding pot (that could have gone into a/biotic and resistance research), could actually now be of some considerably use in speeding up the whole process of recognising new resistance determinants, tracking their spread and identifying resistance trends that can be exploited to clinical benefit.

Jim’s Gene Gym blog looks to be an excellent resource on antibiotic resistance. Back to the UK NHS brief on NDM-1, who says “not to worry just yet” but:

(…) The NDM-1-positive samples from the UK and India also came from a diverse range of bacterial strains, which means the presence of NDM-1 was not confined to a few common strains of E. coli and Klebsiella pneumonia (the most common types of Enterobacteria carrying NDM-1). Worryingly, this suggests that this was not just a single international outbreak with the same strain of a particular bacterium. This finding supports the fact that the NDM-1 gene, being located on the bacterial plasmid, can be easily transferred to other bacteria. As one of the researchers says, the NDM-1 gene may have “an alarming potential to spread and diversify among bacterial populations.”

The authors say that the emergence of NDM-1 positive bacteria could be a serious global public health concern as there are few antibiotics that are effective against NDM-1. It is also worrying that the isolates in India came from people presenting with common community-acquired infections, suggesting the bacteria with this enzyme may be widespread in the environment, in India at least.

As the researchers conclude, there is the potential of NDM-1 to be a worldwide public health problem, and coordinated international surveillance is necessary.

So don’t be going to India and Pakistan for that cheap surgery. The Lancet paper that is the cause of this UK alarm is Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study (available to the public as a service). From the Summary:

Interpretation: The potential of NDM-1 to be a worldwide public health problem is great, and co-ordinated international surveillance is needed.

Antibiotic resistance: Bugs and drugs…

Jim Caryl at Gene Gym is laboring to make antibiotic resistance understandable by the lay public. In Jim’s post Bugs and drugs… he explains the various resistance mechanisms, and in particular “The worrying cocktail” which we must do everything we can to avoid. This is why the emergence of NDM-1 is a potential nightmare:

(…) Thus what the NDM-1 report (raised in my last post) describes is a heady cocktail ripe for troubled times:

Ecological contact + promiscuous mobile genetic elements + multidrug resistance = not good. These tick all the boxes for a situation that should be carefully monitored, as you would any invading pest species in a zoological sense.

In the previous post Future-proofing antibiotics… Jim attempts the optimist’s perspective on Tim Walsh’s NDM-1 study. He links five commentaries on the Walsh study. One of more accessible of these is by microbiologist Hugh Pennington:

(…) A paper describing this new enzyme was published last September. It is full of technical molecular detail, but it uses plain English to say things that send shivers down the spine. The Klebsiella carrying the new gene was fingerprinted to find its type. It was ST14, a type almost identical to ST 15, which is branded as being the “new MRSA” due to its wide international distribution and carriage of other antibiotic resistance markers. So the Klebsiella was already particularly good at spreading and travelling long distances.

Just as unsettling was the finding in stools from the patient of a strain of Escherichia coli that was also carrying the NDM-1 gene. It was on a plasmid, a small DNA structure that can transfer quite easily from bacterium to bacterium. It is very likely that it had jumped from the Klebsiella to the Escherichia while they were living quietly in the patient’s bowels (vice versa is possible, but the practical consequences would be no different).

The original Klebsiella plasmid carried other antibiotic resistance genes as well. No surprise there; they often do. So more bad news. The paper doesn’t mince its words: “The rapid dissemination of this plasmid throughout clinical bacteria would be a nightmare scenario.”

(…) The nightmare scenario is that NDM-1 producers are close to becoming true superbugs that are resistant to everything. The horror model is XDR-TB – extensively drug-resistant tuberculosis, which broke out in South Africa in 2006, and is a significant problem in Russia, among other regions. It is reasonable to say that such strains, which for all practical purpose are so hard to treat that sufferers from them might as well be living in the 1930s, have evolved because of poorly controlled anti-TB drug prescribing. The same is true for the prescription of antibiotics in the Indian subcontinent. But it is hard to see changes coming there any time soon. Even in the UK we could do better. And hoping for new antibiotics remains just that.