WHO’s first global report on antibiotic resistance reveals serious, worldwide threat to public health

The nightmare bugs are multiplying because our antimicrobial team has no real leadership and has shockingly inadequate funding. We don’t have much data on what is really happening, but my guess is the deaths-from-resistant-microbes curve is increasing at an increasing rate. Every year more patients discover that the post-antibiotic world has already arrived for them.

A new report by WHO–its first to look at antimicrobial resistance, including antibiotic resistance, globally–reveals that this serious threat is no longer a prediction for the future, it is happening right now in every region of the world and has the potential to affect anyone, of any age, in any country. Antibiotic resistance–when bacteria change so antibiotics no longer work in people who need them to treat infections–is now a major threat to public health.

“Without urgent, coordinated action by many stakeholders, the world is headed for a post-antibiotic era, in which common infections and minor injuries which have been treatable for decades can once again kill,” says Dr Keiji Fukuda, WHO’s Assistant Director-General for Health Security. “Effective antibiotics have been one of the pillars allowing us to live longer, live healthier, and benefit from modern medicine. Unless we take significant actions to improve efforts to prevent infections and also change how we produce, prescribe and use antibiotics, the world will lose more and more of these global public health goods and the implications will be devastating.” 

Globally we are falling further behind. Every year more resistant bacteria are discovered, more people die. The most recent data I have shows 2 million U.S. cases of antimicrobial resistance, resulting in 23,000 deaths. We know the actuals are higher because there is no requirement for hospitals to report cases or even outbreaks of resistance. Here is an example from the transcript of the PBS special “Hunting the Nightmare Bacteria”:

Nationally, most hospitals aren’t required to report outbreaks to the government, and most won’t talk publicly about them. (…snip…)

Dr. BRAD SPELLBERG: It’s not that the government agencies are not aware of the problem and are not— and are not doing anything. It’s that we have not had a comprehensive plan for how to deal with antibiotic resistance. We don’t have reporting mechanisms, like they do in Europe, to know where resistance is occurring, who’s using the antibiotics, are we overusing them?

DAVID E. HOFFMAN: Wait. You’re telling me we don’t know the answers to the extent of the problem?

Dr. BRAD SPELLBERG: That’s correct.

DAVID E. HOFFMAN: We don’t have the data?

Dr. BRAD SPELLBERG: That is correct. I do not know how many resistant infections are occurring right now. I don’t know what the frequency of resistance in different bacteria are. We do not have those data.

NARRATOR: FRONTLINE requested an interview with the secretary of Health and Human Services, Kathleen Sebelius. We wanted to ask about the lack of data and the about the priority the department is giving to the new superbug crisis. But she declined to be interviewed.

The “nightmare bacteria” have caught governments and public health authorities napping. They didn’t seem to notice that over the past twenty years the development of new antibiotics has collapsed. From the 2013 report by the CDC Antibiotic Resistance Threats this graphic illustrates that there is now almost no new antibiotic development.

Antibiotic development collapse

The fundamental reason for the collapse in new antibiotics is the pharma marketplace doesn’t reward developers enough to pay for the R&D and the drug approval process (USD $600 million to $1 billion for a new drug). Those numbers inhibit every kind of drug – but let through those that sell to the chronic patient markets (cholesterol, hypertension, …). A successful new antibiotic may be sold to a patient for 10 days, not 30 years like a hypertension drug.  And sadly there is nearly no high level level focus on the new antimicrobial market failure.

Resistance is an everyday process – microbes begin exhibiting resistance as soon as a new compound is deployed. There was already penicillin resistance when the drug was first commercially introduced. This issue didn’t start making the headlines in at the beginning of the 21st century because there were still a lot of drugs in the cabinet that could be tried when a new resistant bug surfaced. Today, for an increasing number of infectious diseases, the antibiotic cabinet has fewer effective drugs every year. From the  CDC Antibiotic Resistance Threats report, this graphic illustrates key resistance events:

Timeline of antibiotic resistance

The PBS Frontline special is a useful introduction to this subject — with video, audio, transcript and a number of useful resource links. The CDC report Antibiotic Resistance Threats is an excellent, well-researched overview as of 2013. CDC has a Antibiotic / Antimicrobial Resistance websitethat can be your home base for researching and tracking progress on this issue. CDC is asking congress for $160M [Antibiotic Resistance Solutions Initiative — $160M: A Comprehensive Response].

So what can you do? Most important is to make it clear to your representatives that you expect them to support a major government focus.  In the U.S. there should be at least an NIH Assistant Secretary devoted to antimicrobial resistance, whose mission should be new antimicrobial drug research and development, high-efficiency testing to fast-track diagnosis of new cases, case tracking/reporting, and OBVIOUSLY to radically slash the agricultural misapplication of antibiotics at sub therapeutic doses (about 80% by mass of US antibiotic sales).

To give you an idea of how inadequate the US response is read Can a New White House Plan Catch Up to the “Superbug” Threat?

Although that initiative represents the government’s first-ever attempt to broadly address the issue of antibiotic resistance, the plan has been quickly dismissed by some scientists and lawmakers for not going far enough. In an interview with Politico, Rep. Louise Slaughter (D-N.Y.), the only microbiologist in Congress, said that goals set for 2020 are too far off to make up for lost ground.

“I’ve said to people, ‘Right now your government is not going to protect you,’” said Slaughter. “They’re about 10 years behind.”

PS – if you have some elective surgery on your horizon, say a knee or hip replacement, you might want to think about getting that done while there are still a few antibiotics that could help save your life (or your leg).

Re-Examining the FDA Antibiotics Decision: Banning Growth Promoters Won’t Be Enough

Denmark weaner pigs experience

Chart via Hagan Vigre, Danish Technical University, 2009

Further to the Denmark experience, Maryn McKenna has a new essay at Wired

The object lesson in changing antibiotic patterns is Denmark, which in 2000 made farm antibiotics prescription-only, and banned nontherapeutic uses altogether. It’s often pointed out, on the ag side, that Denmark had an increase in deaths among weaner pigs immediately after that ban was rolled out; but within 3 years, weaner pig survival improved and returned to where it had been before the ban.

What reversed the trend was Danish farmers’ understanding that it wasn’t enough just to remove antibiotics from meat production. What was necessary was to change the conditions in which meat animals were raised, so that the welfare threats which the antibiotics had addressed no longer existed.

That seems to me to be the lesson that meat production in America needs to learn, if the FDA’s intention to remove growth promoters is going to be meaningful. Simply reducing antibiotic use (if that does indeed happen) isn’t adequate; by itself, it may even be a threat to welfare. Changing the livestock practices that made antibiotic use necessary will improve animal and human health both.


How to protect effective antibiotics: a conversation with Doc Ricky

MRSA

I believe that the rapid spread of antibiotic resistance should be recognized as an urgent public health priority – possibly the #1 priority. E.g., CRE [1].

After reading Betsy McCaughey [2] “U.S. Lacks Will to Fight Superbugs” [3] I tweeted the citation for her op-ed

CRE the “nightmare bacteria”: U.S. Lacks Will to Fight Superbugs j.mp/1au0EbR

Shortly Doc Ricky replied:

@stevedarden I’m kind of perplexed by the media repetition of “fighting superbugs” – what do ppl expect anyway? Some secret weapon?

What an excellent framing question! I replied with some suggestions:

  1. Transparency of hospital performance on sanitation standards.
  2. No excuses policy on resistance cases e.g. Israel
  3. Strict limitation of agriculture use to disease, no routine NTA dosing
  4. Transparency on physician prescribing by doctor

Shortly Doc Ricky replied:

“@drricky: @stevedarden but problem is most of these are preventative, what is expected when MDR {Multi Drug Resistance} is detected?”

I replied over several tweets: By #2. what I meant is that the CDC publishes “best practice” on procedures to execute upon every identified case of MDR[4]– beginning with effective quarantine and decontamination. The “best practice” level of response is mandated to be the minimum response. It should be the top priority of the hospital to eliminate the detected microbe from the institution. I appreciate that is a statistical goal, as we have no way to validate that “we killed it”.

For examples of such best practices consider the 2011 NIH Clinical Center response to a CRE outbreak [5], and of Israel 2006 (from Betsy McCaughey):

When CRE invaded Israel’s hospitals in 2006, public health authorities launched a military-style campaign requiring reports from all hospitals, which were ordered to test patients and undergo rigorous cleaning efforts. This reduced CRE by 70 percent in one year. Israeli researchers just announced a drug that may protect patients exposed to CRE from becoming infected.

My personal bias is that regulation is a blunt and ineffective tool in complex, fast-changing domains like this one. My question: How to incentivize hospitals to succeed?

Suggestion: first try transparency. E.g., if the Johns Hopkins data, such as MDR cases, hand hygiene and infection-control scores are published on the web every month – that is a powerful incentive to improve – to be ranked among the very best institutions globally.

Meanwhile Doc Ricky tweeted a critique of my first try on agriculture:

@stevedarden The agriculture issue is more nuanced than that, after all, how does one exactly limit the use?

Exactly:

@drricky Legislating detailed Rx rules not practical. How about transparency of farm usage per animal-KG? Is public shame effective?

I am thinking of the Denmark experience beginning 1999 where they succeeded to eliminate NTA use in agriculture. See my 2010 Denmark: results of stopping NTA (non-therapeutic antimicrobials)

Doc Ricky moves the discussion to the next level, biology:

@stevedarden only skirts around the real problem, which is biology. We culture animals with similar physiology to ours

The microbes shared by humans and pigs, chickens, beef are why we are so concerned about agricultural applications of antibiotics. Agriculture uses roughly 80% of the antibiotics effective in the human population – but in vastly larger quantities. If we were all vegetarians that would eliminate the whole worry about agriculture.

Doc Ricky is truly the expert in this topic – I’m looking forward to learning from him. We agreed to shift the conversation from Twitter to a long-form-friendly fora.

@stevedarden clearly a complicated topic, and hope you’ll continue to discuss.

NOTES:


  1. The CDC on CRE Carbapenem-Resistant Enterobacteriaceae.  ↩

  2. Betsy McCaughey founder of Committee to Reduce Infection Deaths  ↩

  3.  (…snip…) CRE was first uncovered in North Carolina in 1999. By 2008, it had spread to 24 states and was “routinely” seen in certain New York and New Jersey hospitals. But hospitals kept quiet. Now it’s in at least 43 states.
    (…snip…) Two months ago at a press conference, CDC Director Thomas Frieden dubbed CRE the “nightmare bacteria,” warning that “without urgent action now,” superbugs like CRE will prevent patients from getting joint replacements, cancer therapy and other treatments. The risk of incurable infections will make these treatments too dangerous. Yet, where’s the urgent action?
    The CDC doesn’t even have accurate data on how many CRE infections are occurring and where, because according to the director of the CDC’s Office of Antimicrobial Resistance, Steven Solomon, the government agency has never reached out to state officials to make CRE a reportable disease. Only 12 states require hospitals to report cases. Astoundingly, New York State did not require reports until July 2013, despite CRE menacing some of its hospitals for a decade.  ↩

  4. I am using the shorthand MDR to represent all the emerging multi-drug resistant microbes.  ↩

  5. This is what happened at the National Institutes of Health Clinical Center in Maryland in 2011. A 43-year-old woman known to have CRE was admitted from a New York City hospital. The NIH treated her, using CDC infection-control precautions, but three weeks later, a male cancer patient who had had no contact with her came down with CRE. Week after week, more and more patients contracted the infection introduced by the New York woman. Six of those patients ultimately died, one of whom was a 16-year-old boy. To stop the outbreak, NIH investigators double-cleaned rooms with bleach and misted hydrogen peroxide in measures far beyond what the CDC recommends.  ↩

The File Drawer Effect

This is not an academics-only esoteric debate. It is about whether new, effective drugs are released. It is about how accurate is our knowledge of reality. Here is astronomer Phil Plait quoted in this excellent essay on Survivorship Bias:

For far too long, studies that fizzled out or showed insignificant results have not been submitted for publication at the same level as studies that end up with positive results, or even worse, they’ve been rejected by prominent journals. Left unchecked, over time you end up with science journals that only present the survivors of the journal process – studies showing significance. Psychologists are calling it the File Drawer Effect. The studies that disprove or weaken the hypotheses of high-profile studies seem to get stuffed in the file drawer, so to speak. Many scientists are pushing for the widespread publication of replication, failure, and insignificance. Only then, they argue, will the science journals and the journalism that reports on them accurately describe the world being explored. Science above all will need to root out survivorship, but it won’t be easy. This particular bias is especially pernicious, said Plait, because it is almost invisible by definition. ”The only way you can spot it is to always ask: what am I missing? Is what I’m seeing all there is? What am I not seeing? Those are incredibly difficult questions to answer, and not always answerable. But if you don’t ask them, then by definition you can’t answer them.”

We subscribe to the AllTrails network – I can’t recommend their work highly enough. See also Publication bias in Wikipedia and All Results Journals.

 

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…