Longitude Prize Workshop


Germantown, MD (March 22, 2019). 3i Diagnostics, an innovator in developing novel diagnostics for identifying pathogens from blood directly without culturing announced that its CEO, James Janicki, was invited to present at the Longitude Prize Workshop. The workshop was held in Boston on March 21, 2019. 

The workshop was intended to disseminate information about the Longitude Prize and hear about the latest cutting-edge technologies that might provide a solution to the Antimicrobial Crisis. 


At the workshop, Mr. Janicki described the technology that 3i has been developing and the data demonstrating its feasibility. “Our Biospectrix platform technology is especially well suited to be accessible in all countries and as a point-of-care device because it does not require refrigeration; it is easily miniaturized; and the components are of materials that will result in exponential cost reduction as manufacturing volume Increases," said Jim Janicki 

The Longitude Prize is an inducement prize contest offered by Nesta, a British lottery funded charity, in the spirit of the 18th-century Longitude rewards. It runs a £10 million prize fund, offering an £8 million payout to the team of researchers that develops an affordable, accurate, and fast point of care test for bacterial infection

In order to tackle growing levels of antimicrobial resistance, the challenge set for the Longitude Prize is to invent an affordable, accurate, fast and easy-to-use test for bacterial infections that will allow health professionals worldwide to administer the right antibiotics at the right time.

3i Diagnostics has emerged from 'stealth mode' and have presented details of our technology to the public


At the 70th American Association of Clinical Chemistry Annual Scientific Meeting and Clinical Lab Expo we were awarded the inaugural "Distinguished Abstract" Award by the History of Clinical Chemistry Division.

AACC award certificate.png

The award recognized our work, from among the thousand or more that were submitted, as having the potential to significantly impact clinical chemistry.  The award was presented during the 2018 Annual meeting of the AACC during the History Division luncheon and included a presentation of the work by founder and CTO Rajesh Krishnamurthy. Independently, the poster was also selected by the Annual Meeting Organizing Committee (one of four chosen for this honor) for an Oral Presentation as part of a discussion on Emerging Biomarkers and Technologies. “This is a significant honor for 3iDx said CEO Jim Janicki. The AACC annual meeting showcases the world’s leading clinical laboratory technology, and we’re very happy to have been selected to present here. This is a great event for us because so many of the attendees really understand the challenges in rapid, universal microbial ID and are enthusiastic about the possibilities of Biospectrix.”


3i Diagnostics Awarded Competitive Grant from the National Science Foundation Small Business Innovation Research Program Provides Seed Funding for R&D


3i Diagnostics has been awarded a National Science Foundation Small Business Innovation Research (SBIR) grant for $225,000 to conduct research and development work on a solution for rapid microbial identification. 

3i Diagnostics has developed a revolutionary method to RAPIDLY separate and identify any pathogen from a human blood sample with no need for culturing.   Our technology is designed to help save lives by dramatically reducing the amount of time it takes to diagnose a microbial infection.   3iDx technology gives doctors the chance to improve patient outcomes by prescribing the right antibiotic at the right time. 

“The National Science Foundation supports small businesses with the most innovative, cutting-edge ideas that have the potential to become great commercial successes and make huge societal impacts,” said Barry Johnson, Director of the NSF’s Division of Industrial Innovation and Partnerships. “We hope that this seed funding will spark solutions to some of the most important challenges of our time across all areas of science and technology.” 

“This is a milestone event for 3iDx” said CEO Jim Janicki.  “The funding from the NSF will advance our timetable for the development of the Biospectrix platform.  NSF understood the breakthrough potential of our technology and has provided guidance and support to the company”.  

CEO CFO Magazine Interview


Interview conducted by: Lynn Fosse, Senior Editor CEOCFO Magazine

CEOCFO: Mr. Janicki, would you tell us the idea behind 3i Diagnostics?

Mr. Janicki: We started by studying the problem prior to developing any technology for the solution. The idea behind the company came from looking closely at the actions needed to address the antimicrobial resistance crisis caused by drug resistant infections, also referred to as “super bugs.” We wanted to understand why the crisis was continuing out of control. Why weren’t patients with these infections being isolated sooner? Why were clinical trials so long and expensive for new antibiotics? Why were more of these infections progressing to deadly conditions like sepsis? Why were most antibiotics still given to people who don’t have the bacterial infections that the antibiotics treat? Our conclusion was that these infections needed to be identified in less than an hour with an easy to use affordable method that was also suited to eventually be a portable point of care test. Existing tests for identifying all of these infections took 2 to 6 days, and had to be run in a microbiology lab so physicians were routinely implementing treatment without knowing the identification. They didn’t have time to wait days for the results. So, we focused on developing a solution that would be affordable, easy to use, and identify the organism in less than an hour.

CEOCFO: What have you figured out?

Mr. Janicki: We looked at the field of other potential solutions being developed and we found that the technologies being pursued looked unlikely to ever be able to return a result in less than an hour at an affordable cost while being accessible at the point of care. We noticed what looked like a herd mentality that assumed the answer had to be a DNA focused technology, which we felt blinded many to other possibilities. We realized that even if development was optimistic for those technologies, they would fall short of what was truly needed. Our advantage was to thoroughly suspend our preconceived biases so that our thoughts were free to develop a genuinely new approach to the solution.

CEOCFO: You received Breakthrough Device designation from the FDA. What is the solution?

Mr. Janicki: Our solution is called BiospectrixTM and it’s a new diagnostic platform that removes all the components of a blood sample but isolates the bacteria that needs identification. This removes all the noise and interference that the blood components of the sample would cause when identifying the bacteria. We then scan the bacteria with a proprietary infrared scanner that characterizes the unique molecular structure of that organism. We are then able to identify the organism by looking up the scanning pattern in a database. Our current results suggest we will be able to identify many drug resistant versions of bacteria.

CEOCFO: How does Biospectrix™ get rid of the blood and isolate whatever else is in there?

Mr. Janicki: Finding and isolating the few bacteria in a blood sample is a lot like finding a needle in a haystack. Other technologies that we saw being pursued relied on very sophisticated and expensive ways to essentially reach in and try to grab the “needle” (bacteria) and pull it out of the haystack (blood). We were able to take the opposite approach and essentially burn down the haystack and then sift the “ash” to isolate the needle quickly. This invention came from the mind of our Chief Technology Officer, Rajesh Krishnamurthy.

CEOCFO: How do you “burn down a haystack”; what are you doing?

Mr. Janicki: We created something that had never been done before. We call it the Selective Lysis Chamber. The selective lysis chamber takes advantage of the difference in strength between bacteria and blood cell walls. We are able to uniformly modulate the forces in the Selective License Chamber, so that all of the blood cells are broken down into very small pieces and yet the bacteria are unharmed and intact. After identifying the bacteria, we are still able to grow the bacteria for further characterization and study without having to get another blood sample from the patient, which is an additional advantage of our approach. This fits very well into the existing work flow of clinical labs as well as research labs.

CEOCFO: Are there some types of bacteria you are able to find more easily?

Mr. Janicki: We are focusing on bacteria first and we also expect this to work well for fungi. We may eventually work on applying this to viral infections but we are focused on bacteria first. We believe that it will also work on parasites like malaria.

CEOCFO: How does Biospectrix™ get rid of the blood and isolate whatever else is in there?

Mr. Janicki: Finding and isolating the few bacteria in a blood sample is a lot like finding a needle in a haystack. Other technologies that we saw being pursued relied on very sophisticated and expensive ways to essentially reach in and try to grab the “needle” (bacteria) and pull it out of the haystack (blood). We were able to take the opposite approach and essentially burn down the haystack and then sift the “ash” to isolate the needle quickly. This invention came from the mind of our Chief Technology Officer, Rajesh Krishnamurthy.

CEOCFO: How do you “burn down a haystack”; what are you doing?

Mr. Janicki: We created something that had never been done before. We call it the Selective Lysis Chamber. The selective lysis chamber takes advantage of the difference in strength between bacteria and blood cell walls. We are able to uniformly modulate the forces in the Selective License Chamber, so that all of the blood cells are broken down into very small pieces and yet the bacteria are unharmed and intact. After identifying the bacteria, we are still able to grow the bacteria for further characterization and study without having to get another blood sample from the patient, which is an additional advantage of our approach. This fits very well into the existing work flow of clinical labs as well as research labs.

CEOCFO: Are there some types of bacteria you are able to find more easily?

Mr. Janicki: We are focusing on bacteria first and we also expect this to work well for fungi. We may eventually work on applying this to viral infections but we are focused on bacteria first. We believe that it will also work on parasites like malaria.

CEOCFO: What will you do in terms of testing for the next year?

Mr. Janicki: We are now in the process of raising an investment round and we are going to accelerate development as soon as we close the funding round. We are currently using prototypes in our lab and we expect it will be about 24 months before have the first fully integrated instrument built. We plan to continue to test samples from our suppliers and collaborators to build our database of bacteria identification signatures. We plan to design the first clinical trial around a manageable number of organisms in order to achieve approval of our device as quickly and efficiently as possible. We will then expand the approved signatures in the database with additional trials over time.

CEOCFO: What has been the interest from the investment community?

Mr. Janicki: We are getting a lot of interest especially since the FDA Breakthrough Device designation came out and I anticipate that we will close this funding round before the end of the year. People recognize that we are going after a major need that is now a global crisis, and from an investor’s perspective it is a major opportunity. We look at the healthcare budgets of hospitals and some payors and see that 40% of their expenses go toward managing and dealing with infection. One of the areas that is a significant market segment for us are patients who come down with sepsis that is caused by an infection. Sepsis is a very serious emergency and there are papers suggesting that if you can get the right targeted antibiotic to that patient in less than an hour you might be able to increase their probability of surviving the condition from about 30% to over 80%. Tests today can take two to six days to characterize one of these drug resistant bacteria but the physicians and patients need to know within the first hour what infection they are dealing with, and the physician needs to know what type of strain it is so they can treat it optimally right away. I think the investor interest tends to focus on the value this will provide for the segment of our market made up of sepsis patients because it is probably the most urgent need for specific infection identification, but the overall market size is much larger than just this segment. We believe BiospectrixTM has the potential to create a new market that may be on the order of $20 billion while also taking share from the existing $12+ billion infectious disease testing market.

CEOCFO: You have had lots of experience in the medical industry on many levels. What have you learned from past experience on what to do and what not to do in bringing a product to market?

Mr. Janicki: I have experience leading global diagnostic businesses, and this has shown me just how important it is to focus on the problem-solving process that a physician goes through which is incredibly complex. I look closely at how I can provide clinical utility, which I define as delivering relevant information that is affordable, easy to understand, and fast enough to significantly aid physicians in making treatment decisions that improve patient outcomes. Many people develop cool technologies and many of them come out of respected institutions and have impressive publications and they get significant funding, but I think too many of them look like cool science experiments that are developed without being focused on all the characteristics that create a great product that delvers both clinical utility and economic benefit at the same time. In addition, I look at how to design a product that has a good value proposition for each layer in the healthcare stack. The product needs to have good answers to the following questions. What is the value proposition for the patient? What is it for the physician and what about the hospital or institution that physician works in, and what about the payers? What is the value proposition for each of them as well as some of the organizations that own multiple hospitals. We actually tested all these value propositions for BiospectrixTM before deciding that it fits well into the whole healthcare stack.

CEOCFO: Why pay attention right now to 3i Diagnostics, and what might be overlooked at first glance?

Mr. Janicki: I think that 3i Diagnostics is positioned to launch a genuine new platform technology and that’s a much larger opportunity than just blood testing. We have been talking a lot here about testing blood for bacteria and microbes but it turns out that there are many different applications this will go into for many different types of samples. We are working with an institution now where we are testing tuberculosis, which is going to be a sputum sample instead of blood. We expect to see future tests for biomedical countermeasures, veterinary, food, water, surface contamination, and more. But, for now, we are being careful to stay focused on blood testing and successfully launching the first BiospectrixTM platform.

3iDx received Breakthrough Device Designation from FDA


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3i Diagnostics receives Breakthrough Device designation from FDA for Technology that identifies infection-causing pathogens directly from blood in < 1 hour

GERMANTOWN, Md., March 15, 2018 /PRNewswire/ -- 3i Diagnosticsannounced today that its new technology, called Biospectrix [TM] , for detecting and identifying bacteria directly from whole blood in less than an hour was granted Breakthrough Device designation by the US FDA. The FDA's Breakthrough Device Designation is intended to expedite the development and review of a diagnostic/device that demonstrates the potential to address unmet medical needs for life threatening or irreversibly debilitating diseases or conditions thereby helping patients gain timely access to these medical devices.

Biospectrix does not require culturing and identifies a broad range of bacteria in < 1 hour directly from the patient sample as opposed to the 2-6 days currently needed for culture. Such a system can help initiate treatment using the appropriate antibiotic rapidly, and potentially reduce bacteria-related mortality, complications, and treatment costs. "We view this diagnostic as becoming a vital part of a toolkit that can be used globally to aid physicians in making treatment-related decisions i.e. if an antibiotic is necessary and, if yes, the appropriate antibiotic to use." said Rajesh Krishnamurthy, CTO of 3i Diagnostics, Inc.

"We're pleased to have been granted Breakthrough Device Designation for Biospectrix and look forward to working closely with the FDA to bring this diagnostic to the market as quickly as possible to address the huge unmet need for rapid broad-range bacterial identification without culturing" said James Janicki, CEO of 3i Diagnostics, Inc. "We see Biospectrix as being a key component of the global strategy to combat the antimicrobial crisis"

A Superbug That Resisted 26 Antibiotics


"People keep asking me, how close are we to going off the cliff," says Dr. James Johnson, professor of infectious diseases medicine at the University of Minnesota. The cliffside free fall he is talking about is the day that drug-resistant bacteria will be able to outfox the world's entire arsenal of antibiotics. Common infections would then become untreatable.

Here's Johnson's answer: "Come on people. We're off the cliff. It's already happening. People are dying. It's right here, right now. Sure, it's going to get worse. But we're already there."

His declaration came in response to a report of a woman in Nevada who died of an incurable infection, resistant to all 26 antibiotics available in the U.S. to treat infection. Her death was reported in the Jan. 13 Morbidity and Mortality Weekly Report, published by the Centers for Disease Control and Prevention. That kind of bacterium is known as a "superbug," which belongs to a family of bacteria resistant to antibiotics. In cases like the Nevada woman, who was infected with Klebsiella pneumoniae, the term "nightmare superbug" has been coined because this particular specimen was even resistant to antibiotics developed as a last resort against bacterial infection.

People in the U.S. have died from so-called superbug infections before. The CDC estimates that 23,000 die every year from multidrug-resistant infections. A British report, The Review on Antimicrobial Resistance, estimates that globally, 700,000 people die each year from infections that are drug-resistant. In many of those cases, the infection's resistance was discovered too late, perhaps before a last-line, effective drug was finally initiated. In poor countries, those newer, more expensive antibiotics often are not available.

The Nevada case is different in that resistance was discovered early in treatment, but even the drugs seen as the last line of defense didn't work. "This one is the poster child because of resistance across the board," Johnson says.

The woman described in the report was in her 70s and treated in a hospital in Reno. About two years ago, on an extended visit to India, she broke a thighbone, according to the report. She had several hospitalizations in India because of infections, says Dr. Lei Chen, of the Washoe County Health District in Reno and an author of the MMWRreport. When the patient was admitted to the Reno hospital, health workers discovered that the bacteria specimen tested was resistant to a class of antibiotics called carbapenems — carbapenem-resistant enterobacteria. "Before, we could go to carbapenems, and they could reliably squash the bugs," says Johnson. "This case broke down even our last great gun."

The woman's most recent hospitalization for infection in India had been in June 2016. She was admitted to a hospital in Reno in August, and state health department officials were notified that she had CRE. "Lab results showed she was resistant to all 14 drugs we tested," says Chen. Further tests at the CDC lab showed resistance to 26 antibiotics. She died in September of multiple organ failure and sepsis. "This was my first time to see such a resistant pattern," says Chen.

CRE infections are rare in the U.S. The CDC does not require that hospitals report CRE cases but estimates that some 175 cases have been reported in the states as of January 2017. "The majority of [CRE] cases still respond to one or two classes of antibiotics," says Chen.

CRE infections are more common in India and Southeast Asia. The reasons aren't clear, but all infections spread more easily in parts of the world with inadequate sanitary facilities. Then, as people cross borders and board airplanes, the bacteria spread in the same way that brought CRE to Reno. That's why Dr. Randall Todd, director of epidemiology and public health preparedness at the Washoe County Health District, says all hospitals should double down on preventive efforts, including a travel history. "It's important that health care providers and hospitals keep in mind that our world is ever shrinking," he says. "When someone comes in, it's important to know where in the world they've been."

Then, if CRE or other resistant infections are diagnosed, the hospital can set up appropriate precautions, like isolating the patient, and immediately start lab tests to try to find an effective antibiotic.

But in this case, there was no effective antibiotic. "And we're going to see more of these, from a drip, drip, drip of cases to a steady drizzle to a rainstorm," predicts Johnson. "It's scary, but it's good to get scared if that motivates action."

The action needed is to use antibiotics wisely, in people and in animals, so strains of bacteria don't get a chance to develop resistance, says Johnson. And to continue research into development of new antibiotics. "We do have some new drugs coming along, so there's hope," he says. But as new antibiotics become available, "we have to use them selectively, not willy-nilly."

3iDx voted The Buzz of BIO for the 2017 BIO Investor Forum


3iDx has been voted "The Buzz of BIO" for this year's BIO Investor Forum in San Francisco.  

Physicians have told us that they are completely blind for at least 48 hours when trying to treat patients showing signs of an infection. We realized that what we needed was an easy and inexpensive test that reports the specifics of an infection in less than an hour from the moment a sample is taken so doctors can immediately prescribe the best treatment to stop infections from progressing to life threatening conditions such as sepsis, and to take measures to keep antibiotic resistant infections from spreading.  Anything longer than an hour meant the physician was going to move forward with treatment before results came back from the lab.

2016 Surviving Sepsis Campaign Guidelines


SSC Guidelines

The fourth edition of "Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016" are linked below. The fifth edition is in development. ESICM and SCCM have announced that the fifth edition update will be completed in collaboration with the GUIDE group (Guidelines in Intensive Care, Development and Evaluation) affliated with The Research Institute of St. Joseph's Healthcare and McMaster University, Hamilton, Canada.

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016 
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Critical Connections Live: New Guidelines for the Management of Sepsis and Septic Shockhttp://guidecanada.org/http://guidecanada.org/GUIDEhttp://guidecanada.org/

We are Running Out of Effective Antibiotics Fast


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Each year, superbugs -- viral bacterial infections resistant to common antibiotics -- infect more than two million Americans, killing at least 38,000. As the list of antibiotic-resistant bacteria grows, so have the extraordinary efforts to prevent the spread of infection from patient to patient. Science correspondent Miles O’Brien and economics correspondent Paul Solman team up for a report.


But, first, we are beginning a special series on the growing concerns around antibiotics, why there is more resistance to the drugs from so-called superbugs that can be dangerous and even fatal, and why it has been difficult to create a newer class of drugs to solve this problem.

It is a story that involves the worlds of science, medicine, business and economics.

So, we asked our science and economics correspondents, Miles O'Brien and Paul Solman, to team up. Their coverage will continue over the next couple of weeks.

We start with Miles' report.

It's part of our weekly series on the Leading Edge of science and technology.

Every Sunday night, I put up the pills for a week at a time.


Thirty times a day.


Amlodipine, that's a blood pressure medicine.


Each and every day.


Prednisone for rejection.


Jane Tecce takes a pill.


This is hydralazine. That's another blood pressure medicine.


No complaints from her. She's just grateful to be alive.


I'm grateful. I wouldn't have gotten to see my grandkids being born and, you know, just see life. So you sacrifice things. So that's how I look at it. It's a tradeoff.


In 2011, after years of battling a rare genetic disease, Jane received the heart and kidney of an 18-year-old man at Tufts Medical Center in Boston. Her daily pill regimen is designed to stop her body from rejecting the organs, but it was another drug, an antibiotic, that fueled an infection that nearly killed her. A month after her transplants, she contracted pneumonia.


They put me back in, and I was very sick. I knew I wasn't doing well at all, and a lot of pain. I had pain as if the ribs were affected and things like that, so they started pumping me through the I.V. with a lot of the antibiotics, and I think that was the beginning. By February, I had been diagnosed with the C. Diff.


C. Diff, clostridium difficile, is a so-called superbug, meaning a bacteria that is not easily stemmed by antibiotics.

In fact, it thrives in people taking the drugs. Each year, superbugs infect more than 2.25 million Americans, killing at least 38,000.


The first thing you do is, you put on your yellow gown.


At Tufts, doctors who come in contact with patients infected with superbugs like C. Diff must take great precautions. As the list of antibiotic-resistant bacteria grows, this has become a much more common routine.

So have some extraordinary efforts to prevent the spread of infection from patient to patient. Here, they bombard rooms with ultraviolet light, which causes genetic damage to bacteria, rendering them unable to reproduce.

Shira Doron is the physician director of the anti-microbial stewardship program at Tufts.

DR. SHIRA DORON, Tufts Medical Center:

We are seeing patients with infections that cannot be treated by any antibiotic on the market. And we're having to tell patients, we don't have anything for you.

And so that makes it really scary and really concerning.


Antibiotics are organic compounds that attack and kill bacteria. They are often derived from microbes found in soil and from mold. That's where Scottish scientist Alexander Fleming discovered the first true antibiotic, penicillin, in 1928.

It, and a host of others developed in the decades that followed, revolutionized medicine. But it was no surprise that these miracle drugs would eventually lose their potency. In fact, when Dr. Fleming received the Nobel Prize, he warned of the danger that the ignorant man may easily underdose himself, and by exposing his microbes to non-lethal quantities of the drug, make them resistant.

Doctors began using penicillin to treat patients in 1942. Only three years later, they encountered the first resistant bacteria.

Helen Boucher is a professor of medicine in the division of infectious diseases at Tufts.

DR. HELEN BOUCHER, Tufts Medical Center:

Resistance happens naturally. So, bacteria have various mechanisms to survive.


It is survival of the fittest, evolution at warp speed. Bacteria adapt very quickly in the face of the assault. They can learn to strengthen their cell walls to repel the antibiotics. They can develop pumps to expel them. Or they can make enzymes that destroy them.


So, they figure out ways to evade the effect of the antibiotic. And this happens in nature, and it happens faster in the presence of antibiotics.


You sort of make it sound like bacteria are smart.


They're very smart.


And they are adapting very fast, creating a big public health crisis.

KIRTHANA BEAULAC, Tufts Medical Center:

Unfortunately, these bugs mutate faster than we can come up with new drugs. So, the only realistic strategy is to use the antibiotics that we have better.


Kirthana Beaulac is the pharmacist director of the Anti-Microbial Stewardship Program at Tufts. We met in the central pharmacy, where they store the vast majority of their medications for patients. Here, they see themselves as a last line of defense.

Prescriptions for antibiotics are carefully scrutinized, particularly the drugs that attack a broad spectrum of bacteria.


It requires constant evaluation of the way we do things, and constant reminders, and really a critical assessment of everything we do every single day to make this — to really make any headway on this battle.


You sound like you're at war.


Kind of. Yes, this is. This is — we call it the arms race.


In her laboratory, Dr. Boucher and her team are constantly analyzing cultures of bacteria from patients in the hospital, always on the lookout for another mutation, another superbug.


The infection preventionists come to our meetings every day at 11:30. And they are tuned in to be looking for anything, any one case that's new that requires them to go do investigation. And that's how we prevent anything from becoming a bigger problem.


The longer bacteria see an antibiotic, the more likely they are to develop resistance. It poses a conundrum for doctors as they weigh the health of an individual patient vs. society as a whole.


I think there has been a general feeling that it's better to err on the side of caution, and that caution equals prescribe. And I am trying to impart the message that caution might actually be not prescribing.


The hunt for new drugs to prescribe is not easy. Scientists say they have already picked the low-hanging fruit. New microbes that lead to new antibiotics are no longer easy to find.

So, we are running out of antibiotics quickly.

My colleague Paul Solman met with a woman in London who could be the poster child for a post-antibiotic world. Eight years ago, Emily Morris was hospitalized with a E. coli superbug, the first of eight serious bouts with resistant bacteria.

EMILY MORRIS, Antibiotic Research UK:

So, I could have had antibiotics when I didn't need them, and also because I had so many.


When she was young, she was prescribed antibiotics frequently because of a hereditary condition that makes her prone to urinary tract infections.


I was just very lucky, very lucky that a last-resort antibiotic did work. A lot of the time, it doesn't work. It kills thousands of people a year. And these superbugs, I have been told, they are going to kill more than cancer by 2050.


After we finished shooting, I sat down with Paul Solman to compare notes.

Emily's story, that's a tough one. And I think our heart goes out to her, anybody watching that, thinking this could happen to any one of us. And as I was shooting the story, I was thinking an awful lot about how close I was getting to these nasty bugs. Were you thinking the same thing?


Yes, I'm a little hypochondriacal to begin with. I was now becoming germophobic, washing my hands all the time. I mean seriously.


As a good American, I assumed going into this series that there had to be some kind of silver bullet solution that will get us out of this. But it's not as simple as that. The drugs just aren't there, are they?


You would think there's enormous, essentially insatiable demand for the product, so, obviously, the market is going to provide it.

But it turns out, it's not anywhere near that simple. And that's what the next installment of this series is about.


All right, we will go to the dismal science next time.

For the PBS NewsHour, I am science correspondent Miles O'Brien.


And I'm economics correspondent Paul Solman.

BioHealth Innovation: Local Startup Developing Technology for Real-Time Detection of Bacteria


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BHI Q&A with 3i Diagnostics, Inc. President & CEO, Jim Janicki & Chief Technology Officer, Rajesh Krishnamurthy

Company: 3i Diagnostics, Inc. “3iDx” www.3iDx.com

Location: Germantown Innovation Center/Launch Labs

Founded: 2013

Overview: 3iDx is an early stage company developing a new technology platform that is able to isolate and analyze microbes directly from samples for the purpose of identifying antimicrobial resistant strains in less than an hour without having to wait for up to a week for blood culture results. Their ultimate aim is to create a 15-minute test that runs in a battery powered handheld device.

Goal: Our goal is to enable true precision medicine for infection. We see this as the largest single global healthcare issue today, as measured in lives and dollars.

Pipeline: We have developed a new technology platform and it provides new information, never before available, to researchers as well as clinicians. We are building a pipeline of assays for this new platform and our first one is for direct testing of whole blood. Our next assay will be for sputum and then urine, swabs, microbiome, etc. We expect assays will be built for this new platform for years to come and we are working with partners who also want to build their own assays on our platform.

Funding: Our funding has mostly been from angel investors and one venture capital firm. We are currently working toward closing a funding round that will enable us to accelerate development.

• Please share the backstory of 3iDx. From the original idea to bootstrapping to today.

Jim - Rajesh deserves all the credit for the original idea, the technology, and the original funding about 4 years ago. He started by wanting to address the antimicrobial resistance crisis which he saw as out of control with no adequate solutions being launched. He started by studying the problem without a bias toward any specific technology, which I think is a rare approach. Most people have a technology they discover and then start looking around for a problem that it might solve. Rajesh went about inventing the technology that not only addressed the problem but created an elegant solution that was easy to use and could be adopted quickly and affordably. There are many cases where the standard of care has been increased by spending a lot more money on large machines or complex procedures, but I think Rajesh has really achieved something extraordinary because 3iDx has the potential to improve the standard of care so significantly and yet it could actually cost less than what is currently spent on this type of testing today.

Rajesh - My background is in the biopharma industry bringing promising drug candidates to the market. There have been several that have made it to the late stages of clinical trials with a couple of commercially successful candidates as well. One of the main elements that motivates most in the pharma/biopharma sector is the opportunity to have an impact on people’s lives. After more than a decade and a half, I started to wonder how I could contribute besides making drugs. This reflection and research led to the recognition that the biggest clinical challenge for many involved bacterial infections. We had drugs that could treat people but we did not have the ability to know which drug to administer. That is, the physician did not have any timely information to complement their clinical intuition, skills, and experience in determining if (i) an infection was caused by a bacteria or a virus, (ii) if it was bacteria knowing which antibiotic would be most effective, and (iii) to have this information in less than an hour. The absence of this information has contributed to the over-use of antibiotics and necessitated the use of “empirical therapy” when it comes to treating infections. 3iDx was started with the goal of introducing a means to provide this information to the physician thereby positively influencing patient outcomes, treatment costs, and reducing the spread of antibiotic resistance.

• What attracted you to the Germantown Innovation Center and Launch Labs?

Jim - The location is great because it’s near the talent that we need. The terms were surprisingly flexible and they allowed us to keep our costs variable to a large degree, which was important while we were raising investment and developing our first product. It allowed us to move development forward in a BSL-2 lab at a very affordable rate, so we could get data and results that would increase the valuation of our company before the time came for a priced funding round. In addition, the location is very scalable because there are larger life science facilities nearby that we can grow into when the time comes for us to expand. It’s much harder to raise capital for early stage companies since 2008 and moving into this lab allows us to develop our technology to a stage where we can more easily attract early stage funding.

Rajesh - Both the GIC and LaunchLabs offered a means to further our development at reasonable cost. At the GIC, their virtual incubator program provides access to several services (e.g. mailbox, meeting rooms, informative meetings with fellow entrepreneurs, etc.) at a good cost. Launch Labs offers access to lab space that is in keeping with the size of the company permitting us to gather data again at a reasonable cost. When one is bootstrapping and trying to stretch every dollar to its maximum, such programs are very helpful. Both are also located in close proximity to our collaborators providing an additional advantage.

• How do you feel about the present startup environment for life sciences companies in Maryland?

Jim - I think Maryland has a chance to really seize a huge opportunity if we are willing to think a little bigger and make a few changes. The start-up environment is ok, but it could be great. The life science start-up environment across the country is in a rut. There is a bolus of extreme early stage technology because of capital constraints created since 2008 resulting in little money being invested in the seed stage of companies. This has created a funding gap that technologies cannot bridge in order to launch commercially, hence we have lost a decade of life- science innovation in the US. I even know people who have left the life- science industry because of the lack of funding and loss of jobs. Meanwhile, traditional life-science innovation locations have skyrocketing costs of living. If Maryland were to: 1. Create more facilities that are flexible and affordable 2. Co-locate funding, innovative people, and affordable facilities 3. Foster a creative environment with a culture that encourages breakthrough innovation 4. Upgrade some key state laws, then I think Maryland could be a major destination for life science innovators who are searching for an affordable and attractive location for their future.

Unfortunately, there are some laws in Maryland that hinder small companies and start-ups "e.g., small business access to health insurance through PEOs". I’m sure these laws had some intended benefit when they were created, but I see them as something that repels entrepreneurs who might otherwise relocate to Maryland. In fact, they forced me to explore if we should re-locate outside of Maryland, and that’s not the conversation you want your entrepreneurs to start having. We should be aware that other locations (i.e. Scotland and Canada) offer major benefits for start-ups by doing things like paying 50% of the cost of R&D employees as well as supplementing facility costs. We need to look at the whole picture, but at a time when people are looking to migrate to more affordable living, why not make Maryland the most attractive place in the world for them to bring their start-up? This is a unique time of migration for these people and once they settle somewhere, they will be less motivated to move again.

Rajesh - I think that the present startup environment is okay but not great; though the state has done a lot to foster the growth of the biotech industry. In my opinion, there is a lot of support structure in this region (once one knows how and where to look for it) like MCCED, BioMaryland, and BHI. But I feel that the area is capital-limited. There is a wealth of technical talent, a small pool of biotech entrepreneurs who have taken companies from nascency to success, and an even smaller pool of investors who are able to seize on the opportunities, evaluate risks, and contribute to a start-up’s growth. However, I feel that we are one or two real big successes away from initiating a virtuous cycle attracting more investors and entrepreneurs to the area. I hope that 3iDx will be one of these successes!

• Where do you see your new technology having the biggest impact?

Jim - I think the biggest immediate impact will be when we rapidly identify microbial strains that cause blood infections for sepsis patients. Patients who present with sepsis could have over an 80% chance of surviving this medical emergency if they can get the correct targeted antimicrobial drug within the first hour. This almost never happens since all technologies today require blood culture before the tests can be run and blood culture takes between 2 and 6 days, which is why we see survival rates like 30% for these patients in the US. Broad spectrum antibiotics are not the silver bullet they once were due to the antimicrobial resistance crisis. People have been contacting me with stories about how family members died or suffered from infections because it took too long to identify the pathogen. Resistant strains and superbugs are now so common that we need to know what the microbe is before we can properly treat it. I think it’s agony for patients and physicians to check the blood culture every day, sometimes checking for 6 days in a row, before finding out what they are dealing with. The stories people tell me are so tragic at times that I have to sit down and take a break after talking to them. Blood culturing is a 150 year old technology and it’s time to find a better way for identifying microbes, and that’s why Rajesh abandoned any thought of using blood culture when he started working on our technology. We are losing the battle against antimicrobial resistance in a big way and it’s mostly because of a failure of imagination.

• What were the main challenges you faced when starting 3iDx?

Jim - I think our biggest challenge was the technology was so new and different that people had a hard time wrapping their head around it. We are launching a technology that identifies the unique molecular structure of a whole microbe, which better represents the behavior of an organism as compared to other molecular techniques. I am personally a huge fan of the genetic revolution and I think a lot of people really want us to just use another DNA assay or a genetic marker since it’s their comfort zone, but we ran into too many limitations exploring that path and we are laser focused on creating clinical utility and not just doing what is easy or convenient to develop. We want what is easy, effective, and affordable to implement.

The immediate benefit wilI come from physicians being able to prescribe the correct targeted antimicrobial for infections within an hour instead of up to 6 days. In addition, our technology will enable new antibiotics to be developed faster and at lower cost because patients can join those clinical trials before they are already treated with other antimicrobials that can confound the statistical data in the clinical trials, which is what makes them long and expensive. I also believe we need to get this technology into research labs. This is truly new information for researchers and can be used in addition to genetic information to accelerate discovery. I’m convinced that we will see scientists discover completely new approaches to fighting resistant strains when they can study how these organisms adapt at the whole-body level without killing the organism they are studying. Our technology is non-destructive so we are able to retain and grow the microbes after we create the molecular fingerprint that identifies them. Give a curious scientist something never before measured and something wonderful will happen.

• What makes 3iDx different from other device companies in the same market space?

Jim - The biggest difference is we don’t require blood culture and we don’t require the lab to guess what they are testing for. Other companies have assays that are made up of small panels and the lab has to keep guessing which panel to test for and they keep buying new panels until they get a positive result. Our database of molecular fingerprints will grow quite large and we expect to provide useful information every time a lab runs our test. Our test will let the lab know if a microbe is present, which is useful for antibiotic stewardship. Meaning, if a microbe is present then it will be rapidly and accurately identified so it can be treated precisely while the patient is still in the waiting room. And in the end the microbes are contained and protected in our cartridge and they are alive and viable so they can be transported to support the current trend of centralization of microbiology labs. The microbes can be grown in culture at a later time without having to take more blood from the patient. This enables longer term confirmatory testing and sample retention for pathogens that need further study.

• What specific advice would you offer to a first-time entrepreneur?

Jim - I think they should constantly invite advice. They should be voracious life-long learners; and they should always remain curious and on the lookout for finding a better way for each challenge or opportunity they encounter or create. Also, I think they should be careful about which advice they choose to implement. Almost all the advice they get will come from someone who knows less than they do about their own business and technology. It’s like the person giving advice is looking through a pin hole when they see your business and even if they are giving you genuinely good advice, it is probably based on limited information and it may therefore not be the best advice to implement without giving it some critical thought first. There are many ways to succeed just like there are many ways to fail. Don’t be so enamored by someone who you admire for being wildly successful such that you just execute their advice because you think it will bring you the same success. The world is a lot more dynamic and a lot more interesting than that. You need to find your own way while actively seeking to improve yourself along the way.

Rajesh - That is difficult to say since every entrepreneur’s circumstances is different. For me, the biggest lesson so far has been the value of persistence. The popular media had me believing that the strength of the idea, data, and market opportunity were all it would take to secure sufficient investment for product development. These elements are absolutely needed but timing (i.e. state of economy and investors), luck, and several other non-objective elements also play a big role. For these elements to align we have needed to exercise a lot of patience and resilience. This appears to be paying off as our collaborations continue to expand and our progress toward a working alpha unit is accelerating. We look forward to more investment that enables us to further accelerate development toward our commercial launch.

Antibiotic Resistance: The Last Resort


Health officials are watching in horror as bacteria become resistant to powerful carbapenem antibiotics — one of the last drugs on the shelf.

As a rule, high-ranking public-health officials try to avoid apocalyptic descriptors. So it was worrying to hear Thomas Frieden and Sally Davies warn of a coming health “nightmare” and a “catastrophic threat” within a few days of each other in March.

The agency heads were talking about the soaring increase in a little-known class of antibiotic-resistant bacteria: carbapenem-resistant Enterobacteriaceae (CREs). Davies, the United Kingdom's chief medical officer, described CREs as a risk as serious as terrorism (see Nature 495,141; 2013). “We have a very serious problem, and we need to sound an alarm,” said Frieden, director of the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia.

Their dire phrasing was warranted. CREs cause bladder, lung and blood infections that can spiral into life-threatening septic shock. They evade the action of almost all antibiotics — including the carbapenems, which are considered drugs of last resort — and they kill up to half of all patients who contract them. In the United States, these bacteria have been found in 4% of all hospitals and 18% of those that offer long-term critical care. And an analysis carried out in the United Kingdom predicts that if antibiotics become ineffective, everyday operations such as hip replacements could end in death for as many as one in six1.

The language used by Davies and Frieden was intended to break through the indifference with which the public usually greets news about antibiotic resistance. To close observers, however, it also had a tinge of exasperation. CREs were first identified almost 15 years ago, but did not become a public-health priority until recently, and medics may not have appreciated the threat that they posed. Looking back, say observers, there are lessons for researchers and health-care workers in how to protect patients, as well as those hospitals where CREs have not yet emerged.

“It is not too late to intervene and prevent these from becoming more common,” says Alexander Kallen, a medical epidemiologist at the CDC. At the same time, he acknowledges that in many places, CREs are here for good.

Hindsight is key to the story of CREs, because it was hindsight that identified them in the first place. In 2000, researchers at the CDC were grinding through analyses for a surveillance programme known as Intensive Care Antimicrobial Resistance Epidemiology (ICARE), which had been running for six years to monitor intensive-care units for unusual resistance factors. In the programme's backlog of biological samples, scientists identified one from the Enterobacteriaceae family, a group of gut-dwelling bacteria. This particular sample — of Klebsiella pneumoniae, a common cause of infection in intensive-care units — had been taken from a patient at a hospital in North Carolina in 1996 (ref. 2). It was weakly resistant to carbapenems, powerful broad-spectrum antibiotics developed in the 1980s.

Antibiotics have been falling to resistance for almost as long as people have been using them; Alexander Fleming, who discovered penicillin, warned about the possibility when he accepted his Nobel prize in 1945. Knowing this, doctors have used the most effective drugs sparingly: careful rationing of the powerful antibiotic vancomycin, for example, meant that bacteria took three decades to develop resistance to it. Prudent use, researchers thought, would keep the remaining last-resort drugs such as the carbapenems effective for decades.

The North Carolinan strain of Klebsiella turned that idea on its head. It produced an enzyme, dubbed KPC (for Klebsiella pneumoniae carbapenemase), that broke down carbapenems. What's more, the gene that encoded the enzyme sat on a plasmid, a piece of DNA that can move easily from one bacterium to another. Carbapenem resistance had arrived.

At first, however, microbiologists considered this CRE to be a lone case. Jean Patel, a microbiologist who is now deputy director of the CDC's office of antimicrobial resistance, says that CDC staff were reassured by the fact that the sample had been collected four years earlier and that testing of the remaining archives revealed no further instances of resistance. “It wasn't that there was a lack in interest in looking for these,” Patel says. Instead, the attitude at the time was, “We have a system for identifying these and it's working, and if more occur we'll hear about it”.

But the CDC's surveillance programme was limited: it tracked only 41 hospitals out of some 6,000 and its analyses lagged far behind sample collection. So when carbapenem resistance emerged again, years passed before anyone noticed.

A dire trend

The State University of New York (SUNY) Downstate Medical Center in Brooklyn draws patients from some of the poorest neighbourhoods in New York City, so it tends to be a place where dire health trends surface. It was not part of the CDC's ICARE programme, but physicians there conduct their own bacterial surveillance to scan for emerging infectious threats. In 2003, a review of results from the centre's microbiology lab and some collaborating ones at nearby hospitals picked up something that city physicians had never seen before. Over the previous six years, a handful of patients spread across seven institutions had been diagnosed with Klebsiella infections that were partially resistant to carbapenems. “These had been infrequent and they were flying under the radar,” says John Quale, a medical researcher at Downstate. “And at about the time we picked them up, they just exploded.”

The infections were very serious. In one Brooklyn hospital outbreak, 9 out of 19 patients died. In another, two infections blossomed into more than 30 in just six months, despite stringent infection-control measures. And the organism spread around the city — from Harlem Hospital at the north end of Manhattan to Mount Sinai Hospital on the Upper East Side, and then to Saint Vincent's in Greenwich Village in the south, where one patient died of a Klebsiella infection despite doctors throwing every drug they could at it.

One of the reasons why the resistant strains spread so rapidly was that they were difficult to detect. Most clinical microbiology labs no longer painstakingly culture bacteria over days to determine which drugs they are susceptible to: instead, automated systems, which expose bacteria to graduated dilutions of drugs, can give a result in hours. But these tests, Quale and his collaborators realized, were giving misleading results and were causing physicians to give patients doses or drugs that would not work. And because the infections were not eliminated, the resistant strain could be passed on. By 2007, 21% of all Klebsiella bacteria in New York City carried the carbapenem-resistance plasmid, compared with an average of 5% across the rest of the United States3.

Such a rapid dissemination hinted that CREs were travelling from person to person rather than arising independently in each location. This made sense. Many Enterobacteriaceae, including Klebsiella, reside in the intestines and can easily be carried by an asymptomatic patient. If patients develop diarrhoea, as often happens after the administration of drugs during intensive care, the infectious bacteria can spread far, contaminating equipment or the hands of care-givers inside the hospital and out. So it was easy to imagine how CREs might ride the subway from Brooklyn to Manhattan. But it took a few years, and a much larger outbreak, to illustrate just how far CREs had travelled (see 'The resistance movement').

Rapid spread

In late 2005, one patient at Tel Aviv's Sourasky Medical Center was diagnosed with a KPC-positive infection that was closely related to a New York strain. Within months, CRE infections stormed through the hospital, and then through Israel's small, tight-knit health-care system. By March 2007, there were 1,275 cases nationwide4. They were turning up across a network of hospitals, nursing homes, dialysis clinics and rehab centres.

Israel has a shortage of acute-care beds, explains Mitchell Schwaber, an infection-control physician who was on the Sourasky faculty when the KPC epidemic began. “Whenever a patient can be discharged, especially from internal medicine, they are — which creates a lot of movement from acute-care facilities to long-term care facilities, and then back to either the same hospital or a different one.”

In response, the Israeli Ministry of Health created a national task force on CREs, headed by Schwaber. It demanded daily national-surveillance reports by e-mail, and instituted strict isolation precautions, including dedicated wards, equipment and nurses. The new rules were backed up by surprise inspections and mandatory lab analyses to ascertain where new infections were coming from.

By mid-2008, Israel had reversed its soaring trend of resistant Klebsiella. But control came too late to prevent the pathogen from emigrating: patients, physicians and nurses had brought bacteria carrying the KPC enzyme to Italy, Colombia, the United Kingdom and beyond.

Alarm call

In January 2008, a urine culture performed on a sample from a 59-year-old man hospitalized in Sweden identified a K. pneumoniae strain that was resistant to multiple drugs, including carbapenems5. But rather than using KPC, the bacterium dismantled the antibiotics with a different enzyme, a metallo-β-lactamase. Within three years, more cases involving bacteria carrying this enzyme were identified in the United Kingdom and in the United States. These provoked immediate alarm: they were even more resistant to carbapenems than the KPC-carrying Klebsiella bacteria, and included other Enterobacteriaceae such as Escherichia coli.

Initially, most individuals carrying bacteria with the new resistance factor had some link to clinics in India, through medical tourism or health care needed while abroad. In accordance with taxonomic conventions, doctors named the new enzyme New Delhi metallo-β-lactamase (NDM), after the place where the initial Swedish patient was thought to have picked it up. The name proved unexpectedly controversial: Indian media and the Indian parliament denounced the acronym for stigmatizing India's medical-tourism industry. Further work by the team that first identified NDM only increased the outrage when it established that bacteria carrying the enzyme were present in sewage and municipal water in south Asia6 (see Nature http://doi.org/dgcs33; 2011).

The controversy obscured NDM's real significance: not only had another resistance mechanism emerged, but CREs were now flourishing beyond hospital walls.

Researchers were still struggling to pin down exactly how NDM was spreading. In the second half of 2012, staff at the University of Colorado Hospital in Aurora discovered that their institution had unknowingly hosted eight patients with NDM-positive Klebsiella bacteria, the largest cluster in the United States so far. The first three cases, all in patients with pneumonia, were found during a routine review of clinical specimens. When the hospital escalated its search, it also identified five asymptomatic carriers.

“There was no obvious pattern,” recalls Michelle Barron, the hospital's infection-control physician. “These patients had been in the hospital a long time. They had been on multiple units. There was no single piece of equipment that had been used on all of them.”

Even when the CDC sequenced the bacterial genomes from all eight patients, the data could not explain how the bacterium had spread. Barron hypothesizes that, at some point, the hospital harboured a “ghost patient” — someone who escaped detection despite the surveillance dragnet. She is still looking for that person: the hospital is attempting to call back and sample all 1,700 patients who were treated during the crucial period.

The episode ended well. The five carriers never fell ill, the three who were ill recovered, and once the hospital became aware of the cluster no further spread occurred. They might not be so lucky next time.

Fresh threats are on the way. Researchers have spotted other carbapenem-resistance factors moving around the globe; one has already appeared in the United States, and others are clustered in southern Europe and South America. Because each is genetically different, they are likely to present new challenges to detection. Infectious-disease specialists say that they have learned major lessons from CREs. Drug-resistant bacteria can emerge and spread much faster than patchy public-health surveillance systems and outdated laboratory-detection methods can pick them up, and what seems like adequate infection control cannot always contain their spread.

Some countries are trying to take those lessons on board. Hospitals in Israel now practise 'active surveillance', meaning that if a new patient has been to any other health-care institution in the past six months they are checked for CREs. And anyone who tests positive for such bacteria is flagged as a carrier in national-health records, which are accessible to hospitals, nursing homes and community physicians. France and the United Kingdom follow similar rules, but unfortunately many countries do not. Earlier this month, the European Centre for Disease Prevention and Control in Stockholm published a candid self-assessment by 39 European countries of their CRE burden and ability to counter these organisms7. Only 21 said they have achieved the kind of national coordination that allowed Israel to contain its epidemic.

The United States operates a patchwork of surveillance systems. The CDC looks for CREs through three separate data networks, but none of these covers the entire country. At least nine states have made reporting CRE cases to their health departments mandatory. The CDC has also created a robust tool kit of best practices for health departments and hospitals, such as restricting staff assignments and equipment use in hospitals, and identifying infections in the long-term care facilities that feed patients into hospitals. These measures helped institutions in Illinois and Florida to shut down outbreaks in 2008 and 2009.

Limited options

Meanwhile, lab-detection methods have improved; the CDC's use of whole-genome sequencing to solve the Colorado episode was the first time that the agency deployed that technology to tackle a hospital outbreak. And public-health departments' ability to identify threats has been bolstered by boluses of federal money after the 2001 World Trade Center attack and subsequent anthrax attacks, and in the 2009 stimulus package. But these investments might be rolled back during the current federal budget sequester.

Physicians who treat patients unlucky enough to be caught up in these outbreaks have no better medicines than they did when CREs first emerged. Some organisms respond to two drugs, tigecycline and colistin (also known as polymyxin E). Neither works in every patient, and colistin is notorious for damaging the kidneys. Physicians find themselves caught between using bad drugs or using no drugs at all.

It seems unlikely that new drugs will become available soon. Perversely, the rapid advance of resistance and the consequent need to use these drugs sparingly has convinced pharmaceutical companies that antibiotics are not worth the investment.

That means, say infectious-disease experts, that their best tools for defending patients remain those that depend on the performance of health personnel: handwashing, the use of gloves and gowns, and aggressive environmental cleaning. Yet even research that could improve best practices has been short-changed, says Eli Perencevich, an infectious-diseases physician and epidemiologist at the University of Iowa in Iowa City who studies how resistant bacteria move around hospitals. “We haven't invested in research in how to optimize even standard infection-control practices. We just blame the health-care workers when they go wrong.”

How Can we Stop Antibiotic Resistance?


“The world is heading towards a post-antibiotic era in which common infections will once again kill. If current trends continue, sophisticated interventions, like organ transplantation, joint replacements, cancer chemotherapy, and care of pre-term infants, will become more difficult or even too dangerous to undertake. This may even bring the end of modern medicine as we know it."

That’s what the Director-General of the World Health Organization said last April when she appeared before the United Nations. Dr Margaret Chan wanted to warn of what many deem to be one of the greatest threats to global health today: the increasingly common problem of infections that do not respond to antibiotic treatment.

It sounds alarmist, but it might actually not be alarmist enough.

The efficacy of the world’s antibiotics is quickly decaying – the drugs we’re using to treat infections are working less and less. If we continue at this rate without intervention, we may find that there is not a single antibiotic left to treat any type of bacterial infection.

“This would really change life as we know it,” says Dr David Weiss, director of the Antibiotic Resistance Center at Emory University. “Consider going to back to an era when a minor accident like a scrape could lead to death.” That’s what a world of total antibiotic resistance could lead to.

But there’s good news: we are not likely to continue at this rate. The world is aware of the problem and there are many organisations, governments, and concerned citizens working hard to avoid a worst-case scenario.

The bad news is that the issue is extremely complex and widespread. And thanks to the very nature of bacteria and how they work – and the damage we have already done – the world will never be entirely free from resistance.

What is resistance?

Say you contract a staph infection. In the past that was easily treated with penicillin. But today, it is very possible that your staph infection is actually MRSA – a version resistant to antibiotics (only 10% of current staph infections aren’t MRSA). Penicillin is useless against it. In fact, studies show that two in 100 people are carrying around the MRSA bacteria.

Here’s how resistance develops: just like people, bacteria have DNA. And just like in humans, that DNA can mutate or change. Then, when inputs from the outside world interact with those mutations, survival of the fittest means only the strongest variations live on.

This would really change life as we know it. Consider going to back to an era when a minor accident like a scrape could lead to death – Dr David Weiss

So, when humans use antibiotics to kill off bacteria, in some cases, those bacteria spontaneously mutate their genes, which changes their makeup in such a way that the antibiotics cannot kill them. The bacteria that survive those encounters pass these genes on to other bacteria through simple mating (technically known as 'conjugation') – and those resistant bacteria can spread from one living thing to another.

The tricky part of this is that bacteria can share these genes with each other across bacterial species – so they don’t even have to be that genetically similar to pass along resistance. Humans and animals, who are teeming with trillions of different types of bacteria, then pass the resistant bugs along to each other. And, on top of it all, we introduce those resistant species to each other inside our own bodies. So, even if a human or an animal has been exposed to an antibiotic just once in their lives they can contain mutant bacteria that can be easily spread.

Bacteria, it turns out, don’t care about political borders or immigration policies – for example, researchers have even found drug-resistant bacteria on the rear-ends of seagulls in Lithuania and Argentina.

The most important part of this is that bacterial resistance is essentially a numbers game: the more humans try to kill bacteria with antibiotics, and the more different antibiotics they use, the more opportunities bacteria have to develop new genes to resist those antibiotics. The less we use, the less bacteria can develop and share resistance.

How big is the problem?

It’s hard to say for sure, but the US Centers for Disease Control and Prevention (CDC) estimates that in the US alone there are about 23,000 people who die every year from antibiotic-resistant infections. For example, they estimate that resistance to antibiotics that treat Clostridium difficile (C. difficile) causes almost 500,000 infections in the US every year, which lead to about 15,000 deaths. (But Amanda Jezek, a spokesperson specialising in policy and government relations at the Infectious Diseases Society of America, a group that represents many of the country’s infectious disease doctors and scientists, says the overall number of deaths is a conservative estimate and likely higher.

Meanwhile, a 2015 study published in Nature found that global antibiotic consumption went up 30% between 2000 and 2010.

The WHO estimates that with tuberculosis alone there are about 480,000 people worldwide with drug-resistant strains of the disease. In 2014 they estimated that 3.3% of all new cases of TB were resistant to multiple drugs, and in recurring cases, 20% were resistant. They have also tracked cases of resistance (some very common and some less so) in drugs used to treat E. coli, urinary tract infections, HIV, gonorrhea, malaria, pneumonia, and staph infection (the drug resistant version of which is MRSA).

And according to Public Health England, the “UK government considers the threat of antibiotic resistance as seriously as a flu pandemic and major flooding.” If left unchecked, antibiotic resistance could lead to 10 million deaths by 2050 worldwide, costing some £66 trillion.

How did we get here?

Plain and simple, humanity has drastically overused antibiotics.

Not only have doctors spent decades handing out antibiotics to any patient that asked (regardless of whether or not they were needed), some countries still consider antibiotics to be over-the-counter medicines – as easy to purchase as Anadin or Tylenol. According to Dr Marc Sprenger, director of the antimicrobial programme at the WHO, much of Europe is three times more likely to use antibiotics than their fellow European countries Sweden or the Netherlands, where they are used only occasionally. “This has nothing to do with more people getting sick. This is a cultural phenomenon,” he says.

On top of that, for many decades agricultural pursuits worldwide have fed huge amounts of antibiotics to livestock and food-producing animals – not only as a means to reduce infection, but also as a method to increase growth. And, while humans do not ingest those antibiotics, they do ingest and handle the bacteria that resides within those animals. So if those animals carried drug-resistant bacteria, you potentially could, as well.

This has nothing to do with more people getting sick. This is a cultural phenomenon – Dr Marc Sprenger on antibiotic overprescription

Until recently antibiotics in the US actually listed animal growth as an indication for use on antibiotic labels and a prescription was not required for farmers to obtain them. To illustrate what a problem this is: just last November a strain of E. coli was discovered in Chinese pigs to be resistant to colistin – a last-resort antibiotic that has only been used in the US in the most dire cases of human infection, untreatable by all other antibiotics. In less than six months the CDC detected that strain of E. coli in a patient in Pennsylvania. 

So why not just develop new antibiotics that the bacteria can’t resist? It has been several decades since a drug company developed and sold a new antibiotic. “You would like to have new antibiotics to treat infections with resistant bacteria, but if you look at the timeline [of new releases] it is empty for almost 30 years,” Sprenger says.

That’s because the process of developing any new drug is extremely expensive and the potential profit in an antibiotic after that massive investment is relatively low. According to Sprenger, “there are no legal instruments to prohibit the use of a new antibiotic.” What that means is if a new antibiotic is released there’s no way to stop the world from overusing it. At current usage levels a new antibiotic, he says, would only have about two years on the market before bacterial resistance to it develops.

How do we get ourselves out of this?

First, the entire world needs to get on board. Two years ago this essentially happened when member states of the WHO agreed to accept a Global Action Plan – by then, antibiotic resistance was a problem that had already been on the radar for many decades. The plan lays out extensive solutions and best practices that all countries can take to reduce resistance. “That’s historic,” says Sprenger. Before then, he says, the only people actively discussing how to reduce resistance were people within medical circles, for the most part. "95% of the worldwide population is now living in a country where they have developed a national action plan. All these countries have increased activities in education, training, and prevention control.”

In the last couple of decades we’ve seen decreases in prescription to children in the US – Dr Katherine Fleming-Dutra

Then, last year, the UN addressed the issue before the General Assembly – only the fourth time in history that a health issue was discussed there. And just this May the G20 leaders signed a declaration on global health that included tackling antibiotic resistance. So it’s definitely a grand challenge that world leaders are taking seriously.

Much of the WHO action plan focuses on hospital stewardship and supervision. The CDC is currently working closely with American hospitals to provide guidelines and education for the safe and reasonable prescription of antibiotics. “We have made some progress,” says Dr Katherine Fleming-Dutra, an epidemiologist at the CDC. “In the last couple of decades we’ve seen decreases in prescription to children in the US. We have seen less progress in adults. The rate in adults has been relatively stable.”

Once hospitals and physicians get on board with reducing prescriptions the next step is to change regulations around agriculture.

Ten years ago the European Union banned antibiotics as growth promoters. And just this January, the US Food and Drug Administration removed growth from the indicated use of antibiotics on drug labelling. According to Dr William Flynn, deputy director for science policy at FDA’s Center for Veterinary Medicine, “There was a real recognition that this was something [farmers] needed to take seriously and respond to. We’re encouraged by the fact that they were engaging and working with us to find ways to make it work.”

But other countries need to follow suit – as evidenced by the recent revelations about antibiotic resistance coming out of China.

One of the most important steps in tackling resistance is tracking it. The CDC have set up a system called the National Antimicrobial Monitoring System (NARMS). “Surveillance for antibiotic resistant bacteria is a big part of our mission,” says Dr Jean Patel, deputy director of the office of Antimicrobial Resistance at the CDC. “We do this to measure the burden of infection and also characterise the types of resistance we see. This helps us strategise how best to prevent resistance.”

We can only really slow the development of resistance. We’re not going to stop it completely. Even appropriate use of antibiotics does contribute to resistance – Amanda Jezek, Vice President for Public Policy and Government Relations, Infectious Diseases Society of America

The CDC funds state health departments around the US (and coordinates with laboratories worldwide) to maintain a network of antibiotic resistant bacteria data and samples. Says Patel: “We can use this to give us national estimates of infection rates to see how bacteria are changing, test new drugs against bacteria, and we also have used the bacteria we collect through this to help with vaccine development.” Though, it should be noted, the continued success of the programme could be in jeopardy as US President Donald Trump’s proposed budget suggests cutting funds to the CDC by 17% (or $1.2 billion).

But there are also some non-traditional methods being attempted. Emory University in Atlanta, Georgia, has established a unique Antibiotic Resistance Center. One of its main goals is to build diagnostic tests using mutated bacteria collected by the national surveillance system and physicians in their own clinic that can spot resistant bacteria.

“The goal is to have scientists, clinicians, and epidemiologists all working together to address this issue. That’s something that hasn’t traditionally happened. There has been division between what the scientists and clinicians are doing,” says the centre’s director David Weiss. “I’m not a doctor. I need to know from the clinicians a lot of what they’re seeing on the front lines to help guide our research to be as relevant as possible.”

A comprehensive, collaborative approach could work: last year, the National Health Service of England announced that in 2015, antibiotic prescribing reduced by 5.3% compared to 2014. Public Health England says that more responsible prescribing is key: it says that it advised the NHS in 2015 on the development of better practices that aim to slash prescriptions by 10% from 2013 to 2014 levels.

Lastly, there need to be incentives that encourage the development of new antibiotics.

The US National Institute of Health and the Biomedical Advanced Research and Development Authority have set up a biopharmaceutical accelerator called CARB-X. The fund is allotting $48 million to support antibiotic drug discovery projects. “They work with companies in the very early discovery stages to give them funding and technical support to get to the point that they have a product they can do clinical trials with,” says IDSA’s Jezek. Along those same lines, the IDSA is also currently working to develop legislation that would provide funding for clinical trials so that companies can avoid those hefty costs and stand a chance of making a profit from new antibiotics.

With all of these programmes working together, and similar efforts taking place around the world, there is a lot of hope that humanity will manage to get a handle on the problem. Still, “we can only really slow the development of resistance. We’re not going to stop it completely,” says Jezek. “Even appropriate use of antibiotics does contribute to resistance.”

And that means the challenge will always be immense. As long as there are humans and those humans carry and transmit disease – which they will – the entire world will have to continue fighting for resistance.

Are State Rules For Treating Sepsis Really Saving Lives?


Doctors can save thousands of lives a year if they act promptly to identify sepsis, an often lethal reaction to infection. Sometimes called blood poisoning, sepsis is the leading cause of death in hospitals.

A 4-year-old regulation in New York state compels doctors and hospitals to follow a certain protocol, involving a big dose of antibiotics and intravenous fluids. It's far from perfect — about a quarter of patients still die from sepsis. But early intervention is helping.

"Intervention has to be quick," says Dr. Howard Zucker, commissioner of the New York State Health Department.

He knows what happens when it isn't. In fact, he says, he has a cousin in the hospital right now who has been struggling to recover from a severe bout of sepsis — hospitalized in another state, he adds.

Doctors didn't immediately realize that he was developing sepsis, and by the time they did, Zucker says it was much more difficult to treat. "That's what we're trying to do. We want people to intervene quickly. That's the regulation, to intervene fast in a situation of this nature."

Indeed, sepsis death rates in hospitals have declined where these rules are in place.

But Dr. Jeremy Kahn at the University of Pittsburgh has mixed feelings about these regulations.

"If we [doctors] were great at doing the right thing — the thing that most people agree on — then we wouldn't need regulation," he says. But in reality, doctors don't all keep up with the latest best practices and follow them, Kahn says, so regulations save lives.

"The downside is that a regulatory approach lacks flexibility," he adds. "It essentially is saying we can take a one-size-fits-all approach to treating a complex disease like sepsis."

That's problematic, because doctors haven't found the best way to treat this condition. The scientific evidence is evolving rapidly, Kahn says. "Almost every day another study is released that shows what we thought to be best practice might not be best practice."

Kahn wrote a commentary about the rapid changes earlier this month for the New England Journal of Medicine.

For a while, medical practice guidelines distributed to doctors called on them to use one particular drug to treat sepsis. It turned out that drug did more harm than good. Another heavily promoted strategy, called goal-directed therapy, also turned out to be ineffective.

And a study presented last week at the American Thoracic Society and published electronically in the New England Journal of Medicine finds that one of the steps required in New York may not be beneficial, either.

The regulations call for a rapid and substantial infusion of intravenous fluids, but that didn't improve survival in New York state hospitals.

Many doctors consider fluids helpful, but "what we haven't learned is the specific type of fluid to give patients, how much and how fast of a rate," says Dr. Christopher Seymour, a critical care researcher at the University of Pittsburgh who co-authored the analysis. "It's been quite controversial."

"There are consequences and adverse effects that can come from too much fluid," Seymour says.

In fact, some doctors believe that most patients are better off without this aggressive fluid treatment. There's a study getting underway to answer that question. Dr. Nathan Shapiro at Harvard's Beth Israel Deaconess Medical Center hopes to enlist more than 2,000 patients at about 50 hospitals to answer this life-or-death question.

But that study will take years, and in the meantime doctors have to make a judgment call.

"It is possible that at present they are requiring hospitals to adopt protocols for fluid resuscitation that might not be entirely appropriate," Kahn says.

There could also be other big changes on the horizon for treating sepsis.

Doctors scattered coast to coast are trying a new protocol that, in addition to limiting fluids, uses high doses of intravenous vitamin C, steroids and vitamin B1. That has generated a great deal of enthusiasm and some startling claims of success, though it remains to be seen whether it is indeed an exciting advance or will become another disappointment in treating sepsis.

Dr. Zucker at the New York Health Department says the current regulations would not stand in the way of advances to treatment.

"If there is a disruptive technology that comes out, or a therapy that comes out, we would adjust accordingly."

You can reach Richard Harris at rharris@npr.org.

Researchers Identify Biomarker that Predicts Death in Sepsis Patients


Runaway immune system response to infection has distinct markers


Duke scientists have discovered a biomarker of the runaway immune response to infection called sepsis that could improve early diagnosis, prognosis, and treatment to save lives.

Sepsis is implicated in half of all hospital deaths and kills nearly a quarter of a million Americans every year.

Practically any type of pathogen -- bacteria, fungi, parasites, and viruses -- can provoke the life-threatening condition, which leads to the body’s immune system overreacting and attacking its own tissues and organs. Sepsis is difficult to diagnose and even more difficult to treat.

The new biomarker, a molecule called methylthioadenosine or MTA, can predict which patients are most likely to die from the illness. The findings, which appear March 8 in the journal Science Advances, could also help determine whether patients could benefit from therapies that either enhance or suppress the immune system, paving the way for new treatments. 

“This area has been a graveyard for the pharmaceutical industry, with more than 100 failed clinical trials of therapies that target the body’s abnormal response to infection,” said Dennis C. Ko, M.D., Ph.D., an assistant professor of molecular genetics and microbiology at Duke University School of Medicine.

“It may be that these failed clinical trials are not actually failures of treatment, but rather failures of diagnosis,” Ko said. “With better biomarkers, we may be able to group sepsis patients into more refined categories to more effectively test and possibly even resurrect old drugs.”

People with sepsis are typically treated with a combination of antibiotics and supportive care, treatments that target the offending germs but do nothing to address the runaway immune response that, ironically, proves more deadly than the infection itself.

In the early stages of sepsis, the immune system churns out prodigious amounts of inflammatory proteins known as cytokines, some of which require activation through another class of proteins called caspases. Caspases can also trigger an explosive form of cell death aptly called pyroptosis (fire falling) that helps destroy pathogens but can exacerbate damage to the host if left unchecked.

In a study published five years ago in the Proceedings of the National Academy of Sciences, Ko searched for genetic variants that might predispose people to higher or lower levels of pyroptosis. His results pointed to some variation between patients in the components of an intracellular recycling system known as the “methionine salvage pathway.”

In this study, Ko and his colleagues focused their search on a molecule called methylthioadenosine or MTA, which feeds into the methionine salvage pathway. They measured levels of MTA in sepsis survivors and sepsis non-survivors from two independent groups of patients, and found that those who died from the disease had elevated levels of the molecule.

They found that measurement of this single molecule was approximately 80% accurate in predicting death, which is comparable to the APACHE II (Acute Physiology and Chronic Health Evaluation II) score, a measurement that is now used in hospitals.

After Ko discovered that MTA could serve as a reliable biomarker of sepsis, he wondered whether he could change the course of infection by manipulating levels of the molecule. His lab found that mice infected with Salmonella lived longer when MTA was administered prior to infection, suggesting that manipulation of the methionine salvage pathway could be used to regulate the inflammatory response that leads to sepsis.

But Ko cautions that much more work needs to be done before a diagnostic or treatment based on MTA could make it into the clinic. It will be crucial to further examine the utility, dosing, pharmacodynamics, and mechanism of tweaking MTA levels in animal models, and if results are promising, to validate them in patients.

“It gets very complicated very fast,” said Ko. “Some people might have too robust of an inflammatory response, some people might not have a robust enough response, and as a result their MTA levels will differ, both between individuals and within an individual over the course of an illness. Biomarkers could determine where individuals fall along that continuum, and what treatments might work.”

The research was funded by the Duke University Whitehead Scholarship, Butler Pioneer Award, National Institutes of Health (R01AI118903, UL1TR001117), Novartis (“Early Detection of Healthcare Associated Infections in the Intensive Care Unit Using the Host Response: A Focus on Healthcare Associated Pneumonia”) and Wellcome Trust (084716/Z/08/Z, 085475/B/08/Z, 085475/Z/08/Z, and 098532).

CITATION:  The full text of the article can be found here in DukeSpace, the university's online repository of open-access research. "Human genetic and metabolite variation reveals that methylthioadenosine is a prognostic biomarker and an inflammatory regulator in sepsis," Liuyang Wang, Emily R. Ko, James J. Gilchrist, Kelly J. Pittman, Anna Rautanen, Matti Pirinen, J. Will Thompson, Laura G. Dubois, Raymond J. Langley, Sarah L. Jaslow, Raul E. Salinas, D. Clayburn Rouse, M. Arthur Moseley, Salim Mwarumba, Patricia Njuguna, Neema Mturi, Wellcome Trust Case Control Consortium 2, The Kenyan Bacteraemia Study Group, Thomas N. Williams, J. Anthony G. Scott, Adrian V. S. Hill, Christopher W. Woods, Geoffrey S. Ginsburg, Ephraim L. Tsalik, and Dennis C. Ko. Science Advances, March 8, 2017. 

Genome Web: Startup 3iDx Raising $5M for Infrared-Based Pathogen ID Platform


Startup 3iDx Raising $5M for Infrared-Based Pathogen ID Platform

NEW YORK (GenomeWeb) – With the long-term goal of commercializing a rapid blood infection test, startup 3iDx is in the midst of raising $5 million to accelerate development of a novel pathogen detection platform.

The platform, whose core technology was invented by 3iDx's Chief Technology Officer and co-founder Rajesh Krishnamurthy, incorporates a fluidics component that isolates whole pathogens from blood samples, and a reader that relies on infrared-based detection. The firm ultimately envisions the system will be battery operated and portable, CEO and co-founder James Janicki said in an interview.

One innovation of the firm's technology is its sample prep method, which first uses microfluidics to concentrate a blood sample, followed by passage through channels that lyse blood cells but not pathogens.

Krishnamurthy devised the strategy after observing that bacteria have a more robust cell wall than mammalian cells. To take advantage of this, he designed silica passages with their shearing properties modulated such that they will break up everything but fungi, bacteria, or parasites.

From the lysis chamber, the resulting mix of debris and whole pathogen cells is filtered, and the pathogens are concentrated by roughly a million times. It takes about 50 minutes to process 10 milliliters of whole blood, but the firm expects to bring that down to as few as 15 minutes.

A poster presented recently at the International Conference on Miniaturized Systems for Chemistry and Life Sciences by a collaborator at University of Maryland noted the device showed bacterial passage rates of nearly 100 percent, suggesting there is little loss to shearing.

Interestingly, the final filter is also transparent to infrared, which enables the pathogen detection step of the platform to happen on the fluidic device, obviating pipetting.

Janicki noted that different pathogens have unique molecular signatures in infrared, which allows them to be distinguished from each other as whole cells, without any further processing. One seminal study showed a similar method could be used to distinguish different bacterial species by comparing them to a database containing 139 reference spectra.

The method also has the potential of being very precise. "The closest you can get to an [antibiotic susceptibility test] and still be a molecular assay is infrared, because we're looking at a unique molecular signature that includes lipids, polysaccharides, proteins, DNA — it's all in that signature," Janicki said.

3iDx's sample prep method is somewhat similar to those of a small number of firms that aim to capture and purify whole pathogens from samples prior to detection. For example, both Qvella and QuantuMDx use electric fields to isolate intact bacteria followed by PCR endpoint detection, while T2 Biosystems uses essentially miniaturized magnetic resonance imaging to detect whole pathogens in samples.

The 3iDx method is also "hypothesis-free," Janicki said, in that a clinician or laboratorian does not need to make a priori assumptions about what pathogens may be present.

This is also the case for Abbott's Iridica, an agnostic pathogen detection platform that uses reverse transcription PCR electrospray ionization mass spectrometry to identify even unculturable pathogens, as well as for a metagenomic sequencing-based method being pioneered by Charles Chiu at University of California, San Francisco.

Syndromic PCR panels can also be considered somewhat agnostic. But Janicki noted that the cost of PCR-based panels is likely to be higher than the small fluidics-and-IR method 3iDx is developing, although he did not comment on pricing and the platform is still under development.

According to Janicki, though, 3iDx's technology could potentially provide cost savings to hospitals. As a basis of comparison, a four-hour blood test for Candida from T2 Biosystems, for example, was recently shown to reduce mortality and antifungal use, and to save about $25,000 per patient. 3iDx sees particular opportunity in the antimicrobial resistance testing market.

Based in Germantown, Maryland, the firm has been essentially in stealth mode since being founded four years ago. Currently, the company is in the final stages of raising $5 million in seed funding, Janicki said. He expects the funding round to close in the first quarter. 3iDx had previously raised $350k from Aaron Capital, Sparksoft, and co-founder Krishnamurthy. It recently received $150,000 from angel investors.

If it is successful in reaching its funding goal, Janicki estimated it would take about 24 months to develop a research-use only instrument and begin beta testing clinical samples with collaborators, followed by about 12 months to create a clinical instrument. He expects the firm will enter clinical trials in about three years, specifically for a blood infection test, since reimbursement for sepsis testing is currently quite clear-cut.

In the meantime, 3iDx may also launch an RUO contamination detection kit, specifically for rapid testing of biologics, for use on cell lines.

The firm is also in talks with several companies interested in using the sample prep technology as a front-end addition to other detection methods. "We're talking to just about every large company in the space right now, and they are interested in the fluidics in front of everything from sequencers to flow cytometers, even mass specs, and certainly PCR," Janicki said. Companies interested in microbiome analysis have also shown interest in the technology, he said, because the system preserves the original ratio of bacteria in a sample.

3iDx will be developing a database of IR signatures for different pathogens, potentially with the capacity to identify specific strains and resistance, although it may initially focus on no more than a few dozen of the most prevalent bacterial strains that can cause sepsis, for the purposes of regulatory submissions. The firm has also applied for patents on the manufacturing process for its selective lysis chamber and is in the process of obtaining IP for several other elements of its core technology.

Tackling Antimicrobial Drug Resistance


World Health Assembly addresses antimicrobial resistance, immunization gaps and malnutrition

25 MAY 2015 ¦ GENEVA - The World Health Assembly today agreed resolutions to tackle antimicrobial resistance; improve access to affordable vaccines and address over- and under-nutrition.

Tackling antimicrobial drug resistance

Delegates at the World Health Assembly endorsed a global action plan to tackle antimicrobial resistance - including antibiotic resistance, the most urgent drug resistance trend. Antimicrobial resistance is occurring everywhere in the world, compromising our ability to treat infectious diseases, as well as undermining many other advances in health and medicine.

The plan sets out 5 objectives:

  • improve awareness and understanding of antimicrobial resistance;

  • strengthen surveillance and research;

  • reduce the incidence of infection;

  • optimize the use of antimicrobial medicines;

  • ensure sustainable investment in countering antimicrobial resistance.

The resolution urges Member States to put the plan into action, adapting it to their national priorities and specific contexts and mobilizing additional resources for its implementation. Through adoption of the global plan, governments all committed to have in place, by May 2017, a national action plan on antimicrobial resistance that is aligned with the global action plan. It needs to cover the use of antimicrobial medicines in animal health and agriculture, as well as for human health. WHO will work with countries to support the development and implementation of their national plans, and will report progress to the Health Assembly in 2017.


The Assembly agreed a resolution to improve access to sustainable supplies of affordable vaccines – a key issue for low- and middle-income countries aiming to extend immunization to the entire population. In 2012, the Assembly endorsed the Global Vaccine Action Plan, a commitment to ensure that no one misses out on vital immunization by 2020. A report from WHO’s Strategic Advisory Group of Experts on immunization, warns, however, that progress towards the Action Plan’s targets is slow and patchy.

The resolution calls on WHO to coordinate efforts to address gaps in progress. It urges Member States to increase transparency around vaccine pricing and explore pooling the procurement of vaccines. It requests the WHO Secretariat to report on barriers that may undermine robust competition that can enable price reductions for new vaccines, and to address any other factors that might adversely affect the availability of vaccines. The resolution also highlighted that immunization is a highly cost-effective public health interventions, playing a major role in reducing child deaths and improving health. It recommends scaling up advocacy efforts to improve understanding of the value of vaccines and to allay fears leading to vaccine hesitancy.

Last week, on the margins of the Health Assembly, the Secretariat brought together high-level representatives of 34 countries with low immunization coverage to discuss challenges and explore solutions to overcome them.

Rome Declaration on Nutrition and Framework for Action

Delegates approved a resolution endorsing the Rome Declaration on Nutrition and a Framework for Action which recommend a series of policies and programmes across the health, food and agriculture sectors to address malnutrition. Governments had previously agreed both documents at the Second International Conference on Nutrition (ICN2), organized by WHO and the Food and Agriculture Organization of the United Nations (FAO) in November 2014.

The Health Assembly called upon governments to implement commitments to make policy changes and investments aimed at ensuring all people have access to healthier and more sustainable diets. They requested that WHO report back on progress with implementation every 2 years. Delegates also referred to ongoing discussions in New York on a UN General Assembly resolution to welcome the Rome Declaration on Nutrition and a proposal to declare ‘ten years of sustained action in multiple sectors to improve nutrition’.

Indicators to measure nutrition among mothers, babies and young children

Member States agreed a set of indicators to monitor progress for global nutrition targets set in 2012 when the World Health Assembly endorsed a comprehensive implementation plan on maternal, infant and young child nutrition.

The plan listed 6 global targets to be achieved by 2025 on stunting (low height-for-age), wasting (low weight-for-height), overweight, low birth weight, anaemia, and breastfeeding. The decision called upon Member States to begin reporting on most indicators from 2016, and others from 2018. They recommended a review of the global nutrition monitoring framework in 2020.

The Antibiotic Resistance Crisis


This is the first of two articles about the antibiotic resistance crisis. Part 2 will discuss strategies to manage the crisis and new agents for the treatment of bacterial infections.


The rapid emergence of resistant bacteria is occurring worldwide, endangering the efficacy of antibiotics, which have transformed medicine and saved millions of lives.16 Many decades after the first patients were treated with antibiotics, bacterial infections have again become a threat.7 The antibiotic resistance crisis has been attributed to the overuse and misuse of these medications, as well as a lack of new drug development by the pharmaceutical industry due to reduced economic incentives and challenging regulatory requirements.25,815 The Centers for Disease Control and Prevention (CDC) has classified a number of bacteria as presenting urgent, serious, and concerning threats, many of which are already responsible for placing a substantial clinical and financial burden on the U.S. health care system, patients, and their families.1,5,11,16 Coordinated efforts to implement new policies, renew research efforts, and pursue steps to manage the crisis are greatly needed.2,7


History of Antibiotics

The management of microbial infections in ancient Egypt, Greece, and China is well-documented.4 The modern era of antibiotics started with the discovery of penicillin by Sir Alexander Fleming in 1928.4,13Since then, antibiotics have transformed modern medicine and saved millions of lives.2,5 Antibiotics were first prescribed to treat serious infections in the 1940s.5 Penicillin was successful in controlling bacterial infections among World War II soldiers.4 However, shortly thereafter, penicillin resistance became a substantial clinical problem, so that, by the 1950s, many of the advances of the prior decade were threatened.7 In response, new beta-lactam antibiotics were discovered, developed, and deployed, restoring confidence.4,7 However, the first case of methicillin-resistant Staphylococcus aureus (MRSA) was identified during that same decade, in the United Kingdom in 1962 and in the United States in 1968.4,5

Unfortunately, resistance has eventually been seen to nearly all antibiotics that have been developed (Figure 1).5 Vancomycin was introduced into clinical practice in 1972 for the treatment of methicillin resistance in both S. aureus and coagulase-negative staphylococci.4,5 It had been so difficult to induce vancomycin resistance that it was believed unlikely to occur in a clinical setting.4 However, cases of vancomycin resistance were reported in coagulase-negative staphylococci in 1979 and 1983.4 From the late 1960s through the early 1980s, the pharmaceutical industry introduced many new antibiotics to solve the resistance problem, but after that the antibiotic pipeline began to dry up and fewer new drugs were introduced.7 As a result, in 2015, many decades after the first patients were treated with antibiotics, bacterial infections have again become a threat.7

Benefits of Antibiotics

Antibiotics have not only saved patients’ lives, they have played a pivotal role in achieving major advances in medicine and surgery.2 They have successfully prevented or treated infections that can occur in patients who are receiving chemotherapy treatments; who have chronic diseases such as diabetes, end-stage renal disease, or rheumatoid arthritis; or who have had complex surgeries such as organ transplants, joint replacements, or cardiac surgery.2,3,5,16

Antibiotics have also helped to extend expected life spans by changing the outcome of bacterial infections.13,16 In 1920, people in the U.S. were expected to live to be only 56.4 years old; now, however, the average U.S. life span is nearly 80 years.6 Antibiotics have had similar beneficial effects worldwide. In developing countries where sanitation is still poor, antibiotics decrease the morbidity and mortality caused by food-borne and other poverty-related infections.16



As early as 1945, Sir Alexander Fleming raised the alarm regarding antibiotic overuse when he warned that the “public will demand [the drug and] … then will begin an era … of abuses.” 7,14 The overuse of antibiotics clearly drives the evolution of resistance.5,9 Epidemiological studies have demonstrated a direct relationship between antibiotic consumption and the emergence and dissemination of resistant bacteria strains.10 In bacteria, genes can be inherited from relatives or can be acquired from nonrelatives on mobile genetic elements such as plasmids.9 This horizontal gene transfer (HGT) can allow antibiotic resistance to be transferred among different species of bacteria.9 Resistance can also occur spontaneously through mutation.9 Antibiotics remove drug-sensitive competitors, leaving resistant bacteria behind to reproduce as a result of natural selection.9 Despite warnings regarding overuse, antibiotics are overprescribed worldwide.10

In the U.S., the sheer number of antibiotics prescribed indicates that a lot of work must be done to reduce the use of these medications.12 An analysis of the IMS Health Midas database, which estimates antibiotic consumption based on the volume of antibiotics sold in retail and hospital pharmacies, indicated that in 2010, 22.0 standard units (a unit equaling one dose, i.e., one pill, capsule, or ampoule) of antibiotics were prescribed per person in the U.S.17 The number of antibiotic prescriptions varies by state, with the most written in states running from the Great Lakes down to the Gulf Coast, whereas the West Coast has the lowest use (Figure 2).5,12 In some states, the number of prescribed courses of treatment with antibiotics per year exceed the population, amounting to more than one treatment per person per year.12

In many other countries, antibiotics are unregulated and available over the counter without a prescription.10,15 This lack of regulation results in antibiotics that are easily accessible, plentiful, and cheap, which promotes overuse.15 The ability to purchase such products online has also made them accessible in countries where antibiotics are regulated.15

Inappropriate Prescribing

Incorrectly prescribed antibiotics also contribute to the promotion of resistant bacteria.5 Studies have shown that treatment indication, choice of agent, or duration of antibiotic therapy is incorrect in 30% to 50% of cases.5,18 One U.S. study reported that a pathogen was defined in only 7.6% of 17,435 patients hospitalized with community-acquired pneumonia (CAP).14 In comparison, investigators at the Karolinska Institute in Sweden were able to identify the probable pathogen in 89% of patients with CAP through use of molecular diagnostic techniques (polymerase chain reaction [PCR] and semiquantitative PCR).14 In addition, 30% to 60% of the antibiotics prescribed in intensive care units (ICUs) have been found to be unnecessary, inappropriate, or suboptimal.18

Incorrectly prescribed antibiotics have questionable therapeutic benefit and expose patients to potential complications of antibiotic therapy.11 Subinhibitory and subtherapeutic antibiotic concentrations can promote the development of antibiotic resistance by supporting genetic alterations, such as changes in gene expression, HGT, and mutagenesis.8 Changes in antibiotic-induced gene expression can increase virulence, while increased mutagenesis and HGT promote antibiotic resistance and spread.8 Low levels of antibiotics have been shown to contribute to strain diversification in organisms such as Pseudomonas aeruginosa.8Subinhibitory concentrations of piperacillin and/or tazobactam have also been shown to induce broad proteomic alterations in Bacteroides fragilis.8

Extensive Agricultural Use

In both the developed and developing world, antibiotics are widely used as growth supplements in livestock.5,10,14 An estimated 80% of antibiotics sold in the U.S. are used in animals, primarily to promote growth and to prevent infection.7,12,14 Treating livestock with antimicrobials is said to improve the overall health of the animals, producing larger yields and a higher-quality product.15

The antibiotics used in livestock are ingested by humans when they consume food.1 The transfer of resistant bacteria to humans by farm animals was first noted more than 35 years ago, when high rates of antibiotic resistance were found in the intestinal flora of both farm animals and farmers.14 More recently, molecular detection methods have demonstrated that resistant bacteria in farm animals reach consumers through meat products.14 This occurs through the following sequence of events: 1) antibiotic use in food-producing animals kills or suppresses susceptible bacteria, allowing antibiotic-resistant bacteria to thrive; 2) resistant bacteria are transmitted to humans through the food supply; 3) these bacteria can cause infections in humans that may lead to adverse health consequences.5

The agricultural use of antibiotics also affects the environmental microbiome.5,14 Up to 90% of the antibiotics given to livestock are excreted in urine and stool, then widely dispersed through fertilizer, groundwater, and surface runoff.5,14 In addition, tetracyclines and streptomycin are sprayed on fruit trees to act as pesticides in the western and southern U.S.1 While this application accounts for a much smaller proportion of overall antibiotic use, the resultant geographical spread can be considerable.1 This practice also contributes to the exposure of microorganisms in the environment to growth-inhibiting agents, altering the environmental ecology by increasing the proportion of resistant versus susceptible microorganisms.1

Antibacterial products sold for hygienic or cleaning purposes may also contribute to this problem, since they may limit the development of immunities to environmental antigens in both children and adults.1,15Consequently, immune-system versatility may be compromised, possibly increasing morbidity and mortality due to infections that wouldn’t normally be virulent.15

Availability of Few New Antibiotics

The development of new antibiotics by the pharmaceutical industry, a strategy that had been effective at combating resistant bacteria in the past, had essentially stalled due to economic and regulatory obstacles (Figure 3).14 Of the 18 largest pharmaceutical companies, 15 abandoned the antibiotic field.14 Mergers between pharmaceutical companies have also substantially reduced the number and diversity of research teams.13 Antibiotic research conducted in academia has been scaled back as a result of funding cuts due to the economic crisis.13

Antibiotic development is no longer considered to be an economically wise investment for the pharmaceutical industry.14 Because antibiotics are used for relatively short periods and are often curative, antibiotics are not as profitable as drugs that treat chronic conditions, such as diabetes, psychiatric disorders, asthma, or gastroesophageal reflux.13,13,14 A cost–benefit analysis by the Office of Health Economics in London calculated that the net present value (NPV) of a new antibiotic is only about $50 million, compared to approximately $1 billion for a drug used to treat a neuromuscular disease.14 Because medicines for chronic conditions are more profitable, pharmaceutical companies prefer to invest in them.2

Another factor that causes antibiotic development to lack economic appeal is the relatively low cost of antibiotics. Newer antibiotics are generally priced at a maximum of $1,000 to $3,000 per course compared with cancer chemotherapy that costs tens of thousands of dollars.2,3,13,14 The availability, ease of use, and generally low cost of antibiotics has also led to a perception of low value among payers and the public.13

In addition, microbiologists and infectious-disease specialists have advised restraint regarding antibiotic use.13 Therefore, once a new antibiotic is marketed, physicians—rather than prescribing it immediately—often hold this new agent in reserve for only the worst cases due to fear of promoting drug resistance, and they continue to prescribe older agents that have shown comparable efficacy.1,2 Therefore, new antibiotics are often treated as “last-line” drugs to combat serious illnesses.1,2 This practice leads to the reduced use of new antibiotics and a diminished return on investment.13

When new agents are eventually used, the emergence of resistance is nearly inevitable.2 However, since bacterial evolution is uncertain, the timeline for the development of resistance is unpredictable.2 A manufacturer that invests large sums of money into antibiotic development may therefore discover that profits are prematurely curtailed when resistance develops to a new antibiotic.2 Economic uncertainty related to the Great Recession has also had a restraining effect on the end users of antibiotics.2 Developed countries with well-funded health care systems have applied austerity measures, while developing countries such as China and India still have a large cohort of population that cannot afford expensive new medicines.2 As an additional complication, most antibiotics are currently off-patent and are supplied by manufacturers of generic drugs.3 The result has been access to cheap and generally effective drugs, which is good for the public; however, the downside is that many payers expect all antibiotics to be priced similarly—even new agents that target multidrug-resistant (MDR) pathogens.3

Because of these factors, many large pharmaceutical companies fear a potential lack of return on the millions of U.S. dollars that would be required to develop a new antibiotic.1,2,13 The Infectious Diseases Society of America (IDSA) reported that as of 2013, few antibacterial compounds were in phase 2 or 3 development.11,14 In particular, the IDSA noted that unacceptably few agents with activity against emerging, extensively resistant gram-negative bacteria, such as Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii, were being developed.11 Pharmaceutical companies have also taken a more active interest in developing antibiotics for methicillin-resistant Staphylococcus aureus(MRSA), rather than gram-negative pathogens.2 The most likely explanation for this imbalance is that MRSA is a major problem worldwide, whereas the market for treating gram-negative organisms is smaller, and somewhat more unpredictable given that resistance is rapidly acquired.2

Regulatory Barriers

Even for those companies that are optimistic about pursuing the discovery of new antibiotics, obtaining regulatory approval is often an obstacle.2,13 Between 1983 and 2007, a substantial reduction occurred in the number of new antibiotic approvals.2 Difficulties in pursuing regulatory approval that have been noted include: bureaucracy, absence of clarity, differences in clinical trial requirements among countries, changes in regulatory and licensing rules, and ineffective channels of communication.13

Changes in standards for clinical trial design made by the U.S. Food and Drug Administration (FDA) during the past two decades have made antibiotic clinical trials particularly challenging.3 Studies comparing antibiotics with placebo are considered to be unethical; therefore, trials are designed to demonstrate noninferiority of new agents compared to existing drugs, within a varying statistical margin.3This requires a large sample population and consequently high costs, making the development of antibiotics uneconomical and unattractive.3,13 While small companies have stepped in to fill the gap in antibiotic discovery and development formerly occupied by large pharmaceutical companies, the complexity and high cost of phase 3 clinical trials can exceed the financial means of these companies.13However, in December 2014, Merck acquired the small antibiotic research company Cubist Pharmaceuticals, which is expected to accelerate the study and regulatory approval of new antibiotic agents in the future.19

Shlaes and Moellering have discussed how altering the requirements for trial designs can have a significant impact on the size, and hence cost, of conducting clinical trials.2 Although more work in this area needs to be done, the FDA issued guidance in 2013 that changed the required clinical trial for acute bacterial skin and skin-structure infections.20 These changes included new disease state and endpoint definitions, a schedule for assessing endpoints, guidance on patient inclusion and exclusion, as well as supportive evidence and statistical justification for proposed noninferiority margins.20 Although still in draft form, the updated guidelines have been adopted in some clinical trials and serve as a basis for discussions regarding further study-protocol improvements.20

Additional new regulatory approaches are needed to ensure the continued development and availability of antibiotic medications.2 The IDSA has proposed a new, limited-population antibiotic drug (LPAD) regulatory approval pathway that has drawn positive public comments from FDA officials.14 This model would enable substantially smaller, less-expensive, and faster clinical trials.14 In return for regulatory approval based on smaller clinical trials, the antibiotic would receive a very narrow indication focused only on the high-risk patients for whom benefits were shown to outweigh risks.14 Such limited approvals already exist in other situations, such as orphan drugs for the treatment of rare diseases.2,13


Antibiotic-resistant infections are already widespread in the U.S. and across the globe.1 A 2011 national survey of infectious-disease specialists, conducted by the IDSA Emerging Infections Network, found that more than 60% of participants had seen a pan-resistant, untreatable bacterial infection within the prior year.7 Many public health organizations have described the rapid emergence of resistant bacteria as a “crisis” or “nightmare scenario” that could have “catastrophic consequences.”8 The CDC declared in 2013 that the human race is now in the “post-antibiotic era,” and in 2014, the World Health Organization (WHO) warned that the antibiotic resistance crisis is becoming dire.15 MDR bacteria have been declared a substantial threat to U.S. public health and national security by the IDSA and the Institute of Medicine, as well as the federal Interagency Task Force on Antimicrobial Resistance.1

Among gram-positive pathogens, a global pandemic of resistant S. aureus and Enterococcus species currently poses the biggest threat.5,16 MRSA kills more Americans each year than HIV/AIDS, Parkinson’s disease, emphysema, and homicide combined.1,12 Vancomycin-resistant enterococci (VRE) and a growing number of additional pathogens are developing resistance to many common antibiotics.1 The global spread of drug resistance among common respiratory pathogens, including Streptococcus pneumoniae and Mycobacterium tuberculosis, is epidemic.16

Gram-negative pathogens are particularly worrisome because they are becoming resistant to nearly all the antibiotic drug options available, creating situations reminiscent of the pre-antibiotic era.1,5,16 The emergence of MDR (and increasingly pan-resistant) gram-negative bacilli has affected practice in every field of medicine.1 The most serious gram-negative infections occur in health care settings and are most commonly caused by Enterobacteriaceae (mostly Klebsiella pneumoniae), Pseudomonas aeruginosa, and Acinetobacter.5,16 MDR gram-negative pathogens are also becoming increasingly prevalent in the community.16 These include extended-spectrum beta-lactamase-producing Escherichia coli and Neisseria gonorrhoeae.16

The CDC assessed antibiotic-resistant bacterial infections according to seven factors: clinical impact, economic impact, incidence, 10-year projection of incidence, transmissibility, availability of effective antibiotics, and barriers to prevention.5 The threat level of each bacteria was then classified as “urgent,” “serious,” or “concerning” (Table 1).16 In general, threats that are urgent or serious require more monitoring and prevention activities, whereas those considered concerning require less.5 A summary of information regarding the resistant bacteria mentioned above follows. Information regarding other strains of resistant bacteria that have been identified as threats by the CDC can be found at http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf.5

Methicillin-Resistant Staphylococcus Aureus

MRSA was first identified five decades ago.7 Since then, MRSA infections have spread worldwide, appearing at a high incidence in several countries in Europe, the Americas, and the Asia-Pacific region.16MRSA infections can be very serious and are among the most frequently occurring of all antibiotic-resistant threats.5 In the U.S., 11,285 deaths per year have been attributed to MRSA alone.12

MRSA is resistant to penicillin-like beta-lactam antibiotics.4 However, a number of drugs still retain activity against MRSA, including glycopeptides (e.g., vancomycin and teicoplanin), linezolid, tigecycline, daptomycin, and even some new beta-lactams, such as ceftaroline and ceftobiprole.16 However, MRSA has shown outstanding versatility at emerging and spreading in different epidemiological settings over time (in hospitals, the community, and, more recently, in animals).16 This compounds the epidemiology of MRSA infections and creates a challenge for infection-control systems that focus only on health care–associated infections (HAIs).16 Moreover, although resistance to anti-MRSA agents usually occurs through bacterial mutation, there have been reports of the transfer of resistance to linezolid and glycopeptide antibiotics, which is cause for major concern.16

Fortunately, the incidence of HAI MRSA infections seems to be declining, since aggressive preventive hygiene measures in hospitals in some areas (i.e., the Netherlands and United Kingdom) have had a positive effect.16 Between 2005 and 2011, overall rates of invasive MRSA dropped 31%; the largest declines (around 54%) were observed in HAIs.5 This outcome provides evidence that infection control can be highly effective at limiting the spread of MRSA.16 However, during the past decade, rates of community-acquired MRSA infections have increased rapidly among the general population.5 While there is some evidence that these increases are slowing, they are not following the same downward trends that have been observed for hospital-acquired MRSA infections.5

Vancomycin-Resistant Enterococci

VRE presents a major therapeutic challenge.4 Enterococci cause a wide range of illnesses, mostly among patients in hospitals or other health care settings, including bloodstream, surgical-site, and urinary tract infections.4,5 VRE infections, often caused by Enterococcus faecium and less frequently by Enterococcus faecalis, have a lower prevalence and epidemiological impact than MRSA does worldwide, except for the U.S. and some European countries.16 An estimated 66,000 HAI Enterococci infections occur in the U.S. each year.5 The proportion of infections that are vancomycin-resistant depends on the species.5 Overall, 20,000 (30%) of hospital-acquired enterococcal infections per year are vancomycin-resistant, leading to 1,300 deaths.5

Few antimicrobial options are available to treat VRE.16 Antibiotics used against VRE include linezolid and quinupristin/dalfopristin, while the role of daptomycin and tigecycline needs to be further defined.16 VRE remains a major threat; consequently there is tremendous interest in developing novel drugs that could have bactericidal activity against VRE, such as oritavancin.16

Drug-Resistant Streptococcus pneumoniae

S. pneumoniae can cause serious and sometimes life- threatening infections.5 It is a major cause of bacterial pneumonia and meningitis, as well as bloodstream, ear, and sinus infections.5,12 Resistant S. pneumoniae infections complicate medical treatment, resulting in nearly 1.2 million illnesses and 7,000 deaths per year.5 The majority of these cases and deaths occur among adults 50 years of age or older, with the highest rates among those 65 years of age or older.5 S. pneumoniae has developed resistance to drugs in the penicillin class and erythromycins, such as amoxicillin and azithromycin, respectively.5 It has also developed resistance to less commonly used drugs.5 In 30% of severe S. pneumoniae cases, the bacteria are fully resistant to one or more clinically relevant antibiotics.5

Fortunately, a new version of pneumococcal conjugate vaccine (PCV13), introduced in 2010, protects against infections caused by the most resistant pneumococcus strains, so rates of resistant S. pneumoniaeinfections are declining.5 From 2000 to 2009, an earlier pneumococcal conjugate vaccine, PCV7, provided protection against seven pneumococcal strains, but PCV13 expanded this protection to 13 strains.5 Use of this vaccine has not only prevented pneumococcal disease, it has also reduced antibiotic resistance by blocking the transmission of resistant S. pneumoniae strains.5

Drug-Resistant Mycobacterium Tuberculosis

Drug-resistant M. tuberculosis infections are a serious threat in the U.S., and an even more urgent threat worldwide.4,12 The WHO reported that in 2012, 170,000 people died from drug-resistant tuberculosis (TB) infections.4,12 M. tuberculosis is most commonly spread through the air.5 Infections caused by this bacterium can occur anywhere in the body but most often appear in the lungs.5 Of a total of 10,528 TB cases reported in the U.S. in 2011, antibiotic resistance was identified in 1,042, or 9.9%.5 The major factors driving TB drug resistance are incomplete, incorrect, or unavailable treatment and a lack of new drugs.5

In most instances, TB infections are treatable and curable with available first-line drugs, such as isoniazid or rifampicin; however, in some cases, M. tuberculosis can be resistant to one or more of these first-line drugs.5 Treatment of drug-resistant TB can be complex, requiring longer treatment periods and more expensive drugs that often have more side effects.5 Extensively drug-resistant TB (XDR-TB) is resistant to most TB drugs, including isoniazid and rifampicin, any fluoroquinolones, and any of the three second-line injectable drugs (i.e., amikacin, kanamycin, and capreomycin); therefore, fewer treatment options are available for patients with XDR-TB, and the drugs that are available are much less effective.5 Although drug-resistant TB and XDR-TB infections are an increasing threat worldwide, these infections are uncommon in the U.S. because of the implementation of a robust TB infection prevention and management program.5

Carbapenem-Resistant Enterobacteriaceae (CRE)

Carbapenem-resistant Enterobacteriaceae (CRE) are a group of bacteria that have become resistant to “all or nearly all” available antibiotics, including carbapenems, which are typically reserved as the “treatment of last resort” against drug-resistant pathogens.4,5,12 An enzyme called New Delhi metallo-beta-lactamase (NDM-1) is present in some gram-negative Enterobacteriaceae bacteria (notably Escherichia coli and K. pneumoniae) that makes them resistant to virtually all beta-lactams, including carbapenems.4

Untreatable or difficult-to-treat infections due to CRE bacteria are on the rise among patients in medical facilities.5 An estimated 140,000 health care–associated Enterobacteriaceae infections occur in the U.S. each year; 9,300 of these are caused by CRE.5 Each year, approximately 600 deaths result from infections caused by the two most common types of CRE, carbapenem-resistant Klebsiella species and carbapenem-resistant E. coli.5

MDR Pseudomonas Aeruginosa

P. aeruginosa is a common cause of HAIs, including pneumonia and bloodstream, urinary tract, and surgical-site infections.5 More than 6,000 (13%) of the 51,000 health care–associated P. aeruginosainfections that occur in the U.S. each year are MDR.16 Roughly 400 deaths per year are attributed to these infections.5 Some strains of MDR P. aeruginosa have been found to be resistant to nearly all antibiotics, including aminoglycosides, cephalosporins, fluoroquinolones, and carbapenems.5

MDR Acinetobacter

Acinetobacter is a gram-negative bacterium that causes pneumonia or bloodstream infections, especially in critically ill patients on mechanical ventilation.5 Some Acinetobacter species have become resistant to all or nearly all antibiotics, including carbapenems, which are often considered to be the drug of last resort.5About 12,000 health care–acquired Acinetobacter infections occur in the U.S. each year, and 7,300 (63%) of these are MDR (resistant to at least three different classes of antibiotics), causing 500 deaths per year.5

ESBL-Producing Enterobacteriaceae

Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae carry a broad-spectrum beta-lactamase enzyme that enables them to become resistant to a wide variety of penicillin and cephalosporin antibiotics.5,12 ESBL-producing Enterobacteriaceae cause 26,000 HAIs and 1,700 deaths per year.5 Some ESBL-producing Enterobacteriaceae are resistant to nearly all antibiotics in the penicillin and cephalosporin classes.5 In such cases, the remaining treatment option is an antibiotic from the carbapenem family.5 However, these drugs should be used with caution, since use contributes to resistance.5

Drug-resistant Neisseria gonorrhoeae

In recent years, drug-resistant forms of N. gonorrhoeae, the causative agent for the sexually transmitted disease gonorrhea, have begun to emerge in the U.S.1 Gonorrhea is characterized by discharge and inflammation of the urethra, cervix, pharynx, or rectum.5 While not normally fatal, gonorrhea spreads easily and can cause severe complications in reproductive functions.12 The CDC estimates that more than 800,000 cases of gonorrhea occur annually, making it the second-most-frequently reported infectious disease in the U.S.5 Should drug-resistant N. gonorrhoeae become more widespread, it has been estimated that it would cause 75,000 additional cases of pelvic inflammatory disease, 15,000 cases of epididymitis, and 222 additional human immunodeficiency virus infections over a projected 10-year period.5

Cephalosporin-resistant N. gonorrhoeae is often resistant to other types of antibiotics, such as fluoroquinolones, tetracyclines, and penicillins.5,16 Infections caused by these bacteria will therefore likely fail empiric treatment regimens.5 In response to this challenge, the CDC has updated its treatment guidelines to recommend ceftriaxone, plus either azithromycin or doxycycline, as the first-line treatment for gonorrhea.12


Antibiotic-resistant infections are a substantial health and economic burden to the U.S. health care system, as well as to patients and their families.1 They commonly occur in hospitals, due to the clustering of highly vulnerable patients, extensive use of invasive procedures, and high rates of antibiotic use in this setting.1Nearly two million Americans per year develop HAIs, resulting in 99,000 deaths, most due to antibacterial-resistant pathogens.1 In 2006, two common HAIs (sepsis and pneumonia) were found to be responsible for the deaths of nearly 50,000 Americans and cost the U.S. health care system more than $8 billion.1

Antibiotic-resistant infections add considerable costs to the nation’s already overburdened health care system. When first-line and then second-line antibiotic treatment options are limited or unavailable, health care professionals may be forced to use antibiotics that are more toxic to the patient and frequently more expensive.5,11 Even when effective treatments exist, data show that in most cases patients with resistant infections require significantly longer hospital stays, more doctors visits, and lengthier recuperations and experience a higher incidence of long-term disability.5 The duration of hospital stays for patients with antibiotic-resistant infections was found to be prolonged by 6.4 to 12.7 days, collectively adding an extra eight million hospital days.1

Estimates regarding the medical cost per patient with an antibiotic-resistant infection range from $18,588 to $29,069.1,14 The total economic burden placed on the U.S. economy by antibiotic-resistant infections has been estimated to be as high as $20 billion in health care costs and $35 billion a year in lost productivity.1 Antibiotic-resistant infections also burden families and communities due to lost wages and health care costs.1,15


Rapidly emerging resistant bacteria threaten the extraordinary health benefits that have been achieved with antibiotics.14 This crisis is global, reflecting the worldwide overuse of these drugs and the lack of development of new antibiotic agents by pharmaceutical companies to address the challenge.14 Antibiotic-resistant infections place a substantial health and economic burden on the U.S. health care system and population.1 Coordinated efforts to implement new policies, renew research efforts, and pursue steps to manage the crisis are greatly needed.2,7 Progress in these areas, as well as new agents to treat bacterial infections, will be discussed in Part 2 of this article.

PCAST Releases New Report on Combating Antibiotic Resistance



Today, the President’s Council of Advisors on Science and Technology (PCAST) released a report, Combating Antibiotic Resistance. The report was released simultaneously with a National Strategy on Combating Antibiotic Resistant Bacteria as well as with a Presidential Executive Order, emphasizing to the Nation the importance of addressing this growing challenge.

Today, the President’s Council of Advisors on Science and Technology (PCAST) released a report to the President, Combating Antibiotic Resistance. The report was released simultaneously with a National Strategy on Combating Antibiotic Resistant Bacteria as well as with a Presidential Executive Order, emphasizing to the Nation the importance of addressing this growing challenge.

The evolution of antibiotic resistance in bacteria is occurring at an alarming rate and is outpacing the development of new countermeasures. According to the Centers for Disease Control and Prevention (CDC), the annual domestic impact of antibiotic-resistant infections to the U.S. economy has been estimated at $20 billion in excess direct health care costs, with additional costs to society for lost productivity as high as $35 billion per year and 8 million additional days in hospitals. The safety of many modern medical procedures – including cancer chemotherapy, complex surgery, dialysis for renal disease, and organ transplantation – relies on effective antibiotics. These interventions become significantly more dangerous as bacterial resistance rises. Indeed, the World Health Organization recently warned that we risk entering a “post-antibiotic” era unless we act now.

Bacteria and other microbes evolve in response to their environment and inevitably develop mechanisms to resist antibiotics. In his 1945 Nobel Prize address, Alexander Fleming (recipient of the Nobel Prize for his discovery of penicillin) warned that the inappropriate use of antibiotics would cause human infections to become resistant to these drugs. As bacteria evolve resistance to widely used antibiotics, it is crucial to stay one step ahead of the problem. PCAST recommends measures to strengthen antibiotic stewardship, boost surveillance, and facilitate the development of new drugs, diagnostics, and vaccines to combat this growing crisis.

Responsible stewardship of antibiotics requires identifying the microbe responsible for disease (ideally with rapid and inexpensive diagnostics); administering the most effective antibiotic at the appropriate dose, route, and time; and discontinuing antibiotic therapy when it is no longer needed.  Optimizing the use of our current antibiotics in human healthcare and animal agriculture will extend the longevity of these life-saving medicines and maximize their benefits.  

Increased surveillance for antibiotic-resistant bacteria will enable more effective responses to resistant strains, support earlier identification of outbreaks, and limit the spread of resistant organisms. Improved surveillance will help address fundamental questions of where resistant infections originate, practices that contribute to emergence, and how resistant microbes are being transmitted.

Even with improved stewardship and surveillance, it is critical to develop new antibiotics, diagnostics, vaccines, and other interventions at a rate that outpaces the emergence of resistant microbes. A robust antibiotic pipeline is essential for creating new antibiotics to replace those being steadily lost to antibiotic resistance. Establishing this pipeline and successfully addressing the rise in antibiotic resistant bacteria will require coordination across governmental, academic, health-related, agricultural, and private sectors.

In the fight against microbes, no permanent victory is possible: as new treatments are developed, organisms will evolve new ways to become resistant. This reality underscores how essential it is to embark on a course of action that will ensure an effective and enduring arsenal of antibiotics. Committing to combating antibiotic-resistant microbes will support patient care, economic growth, agriculture, and economic and national security.  By taking the recommended steps, the United States and global community will continue to reap the benefits of these essential medicines.

  • Read the full report here.

  • Read the President's Executive Order here.

  • Read a White House Fact blog post here.

  • Read the Administration's National Strategy here.

Eric Lander and Christopher Chyba are members of PCAST and co-chairs of the PCAST Antibiotic Resistance Working Group.

Superbug: An Epidemic Begins


LESS THAN A CENTURY AGO, the age-old evolutionary relationship between humans and microbes was transformed not by a gene, but by an idea. The antibiotic revolution inaugurated the era of modern medicine, trivializing once-deadly infections and paving the way for medical breakthroughs: organ transplants and chemotherapy would be impossible without the ability to eliminate harmful bacteria seemingly at will.

But perhaps every revolution contains the seeds for its own undoing, and antibiotics are no exception: antibiotic resistance—the rise of bacteria impervious to the new “cure”—has followed hard on the heels of each miracle drug. Recently, signs have arisen that the ancient relationship between humans and bacteria is ripe for another change. New drugs are scarce, but resistant bacteria are plentiful. Every year, in the United States alone, they cause two million serious illnesses and 23,000 deaths, reflected in an estimated $20 billion in additional medical costs. “For a long time, there have been newspaper stories and covers of magazines that talked about ‘The end of antibiotics, question mark,’” said one official from the Centers for Disease Control and Prevention (CDC) on PBS’s Frontline last year. “Well, now I would say you can change the title to ‘The end of antibiotics, period.’”

If the end is here, it has been a relatively long time coming. Its complex roots are evident in the lengthy relationship between humans and Staphylococcus aureus, a resilient species that has met each antibiotic challenge with new, more resistant incarnations. If the gains of the antibiotic revolution are to be preserved, the lessons to be learned lie in this relationship as well. S. aureus, after all, was present at the antibiotic era’s very beginnings.

Newton meets Darwin

IN AUGUST 1928, Scottish scientist Alexander Fleming had just returned to his London laboratory from vacation when, amid the usual clutter, he found a petri dish that gave him pause. At the edge of the dish was a colony of mold, and around it, a halo within which the Staphylococcus bacteria that dotted the rest of the dish were conspicuously absent.

“That’s funny,” Fleming is said to have remarked to his assistant. Fleming was no stranger to compounds that could kill bacteria; seven years earlier, he had discovered the enzyme lysozyme, which inhibits bacterial growth, by culturing his own nasal mucus. Suspecting another antibacterial compound, he set about investigating the mold, Penicillium notatum, and the substance he later named penicillin.

After 10 years in obscurity, the compound caught the attention of Oxford researchers Howard Florey and Ernst Chain. In 1941, the scientists conducted the drug’s first clinical trial. The patient, a policeman suffering from a severe staphylococcal infection, died a month later—supplies of penicillin had run out after just five days—but his initial improvement had been remarkable. The drug shot to prominence against the backdrop of World War II. In the Allied countries, penicillin production increased exponentially, and the compound helped save thousands of solders’ lives. “Thanks to penicillin…he will come home!” promised an advertisement in Life magazine in 1944, when the drug became available to the general public.

For all of prior human history, minor injuries carried the threat of severe illness and even death: the first recipient of penicillin, for instance, developed his deadly infection after being scratched by a rose bush. Staphylococcus aureus, named for its colonies’ golden color, was a frequent culprit. Though it resides harmlessly in the noses and on the skin of some 30 percent of the population, S. aureus has long exploited scrapes and cuts to cause ailments ranging from boils and abscesses to life-threatening sepsis. But with the beginning of the antibiotic age, humanity gained a powerful, almost miraculous, new weapon—a “magic bullet” that fulfilled Nobel laureate Paul Ehrlich’s vision of a chemical that would specifically eliminate pathogens, without harming patients.

Yet wrapped up in penicillin’s serendipitous beginnings were hints of challenges to come. “It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them,” Fleming warned in 1945 when he received the Nobel Prize in medicine or physiology, together with Florey and Chain, “and the same thing has occasionally happened in the body.”

His remarks proved ominously prescient: penicillin-resistant strains of S. aureus began appearing in hospitals just years after the drug was introduced. “It’s Newton meets Darwin,” says Michael Gilmore, Osler professor of ophthalmology at Harvard Medical School and Massachusetts Eye and Ear Infirmary, and director of the Harvard-wide Program on Antibiotic Resistance (HWPAR). “For every biological action, there’s an equal and opposite reaction.”

What Fleming understood was that antibiotics confer an unfortunate advantage on those bacteria that happen to be naturally resistant through some mutational twist of luck. Penicillin, for instance, kills bacteria by binding to and incapacitating an enzyme that maintains the cell wall, a critical barrier between the cell and its surroundings. By chance, one bacterium might have a mutant enzyme that the drug cannot recognize, allowing the organism to escape the compound’s effects. As Fleming warned: given a sufficiently large number of bacteria, at least one is bound to survive.

But even Fleming did not anticipate the magnitude of the resistance problem to come. In the 1950s, amid postwar outbreaks of dysentery, Japanese researchers led by Tsutomu Watanabe began to encounter bacteria simultaneously resistant to multiple drugs—impossibly unlikely for pathogens acquiring random mutations. By 1955, researchers were reporting several strains of Shigella dysenteriae resistant to the same four antibiotics at once. Even worse, the resistance itself was contagious. Related species, when mixed with multidrug-resistant S. dysenteriae, also became resistant to multiple antibiotics.

“Resistance works differently in the bacterium,” explains Stuart Levy, director of the Center for Adaptation Genetics and Drug Resistance at Tufts University School of Medicine. Drug resistance itself is common in all microorganisms: bacteria, viruses, and parasites alike can gain mutations or otherwise adapt to escape the toxic effect of drugs. But bacteria have an added feature, says Levy, who studied with Watanabe. “Their resistance can be transferred.”

What was happening, Watanabe and others later deduced, was that bacteria were exchanging small, circular pieces of DNA called plasmids, which happened to carry genes for resistance. Most genetic material is transmitted only from parent to offspring, but plasmids can be transferred horizontally—from neighbor to neighbor. This unique ability makes bacteria an even greater threat. Many resistance genes can gather on a single plasmid and spread to different species as the host bacterium moves through the environment; in clinical settings, horizontal gene transfer is by far the most common mechanism through which bacteria become drug-resistant. “It’s a little frightening,” says Levy, “to realize that you’re running after something that can transfer its football to somebody else right away.”

In the case of penicillin, plasmids helped spread naturally occurring resistance genes. In 1940, before the compound had even undergone its first clinical test, Chain and his colleagues were studying Escherichia coli, one of many bacterial species unaffected by penicillin, when they found an enzyme, penicillinase, capable of destroying the drug altogether. Indeed, as scientists began to uncover more natural molecules with antibiotic effects, they likewise encountered more enzymes seemingly dedicated to those molecules’ destruction.

In retrospect, the discovery is unsurprising. As Fleming’s serendipitous discovery suggests, most antibiotics derive from naturally occurring compounds that likely evolved to aid in inter-microbial warfare, as different species compete to colonize limited spaces. In response, some bacteria evolved to harbor natural resistance mechanisms—enzymes that pump hostile compounds out of the cell, for instance, or chemically alter drugs to render them ineffective. Recent studies have found soil bacteria that are naturally resistant to most known antibiotics; some of these species can even use antibiotic molecules as food.

As penicillin’s popularity grew, therefore, S. aureus did not have far to look for a means of defense. Unbeknown to scientists at the time, plasmids carrying penicillinases entered the staph population, and resistant strains spread rapidly. In one English hospital, the proportion of resistant staph infections quadrupled from 14 percent in 1946 to 59 percent just two years later. By mid century, the world was in the midst of its first pandemic of antibiotic-resistant infections. As a commercially available drug, penicillin was not yet 10 years old.


The hunt for new drugs

HELP CAME in the form of new antibiotics. In the wake of penicillin’s immense impact, drug companies rushed to search for new compounds. The 1940s and 1950s marked the golden age of antibiotic discovery: streptomycin, chloramphenicol, tetracycline, and erythromycin were isolated within a 10-year span. The molecules expanded the antibiotic arsenal with new classes of chemical compounds that employed distinct strategies to achieve their deadly effect.

In the meantime, another drug-discovery strategy helped scientists make better use of existing compounds. Early penicillin production involved growing enormous vats of the fungus that made the precious molecule; in the hope of improving production, chemists embarked on a decade-long quest to synthesize the compound from scratch. It was no easy task—molecules produced in nature, and antibiotics in particular, are often far more complex than what can readily be produced in labs. As MIT chemist John Sheehan remarked to The New York Timesafter achieving the first successful total synthesis, “Nature designed the penicillin molecule to teach organic chemists a little humility.”

Nevertheless, Sheehan’s method ushered in a new wave of drug development. Scientists synthesizing the molecule could now make chemical modifications to improve drug activity—and, in doing so, develop molecules able to combat resistance. “Widespread germ succumbs to a new synthetic penicillin,” declared the Times in 1961 after new treatments saved the life of actress Elizabeth Taylor, who had developed penicillin-resistant staphylococcal pneumonia on the set of Cleopatra. To avoid being destroyed by penicillinases, the new drug had an extra chemical group: a methyl tail, which earned it the name methicillin.

Methicillin was introduced in 1960, and strains of methicillin-resistant S. aureus, better known as MRSA, appeared two years later. Since methicillin was mostly immune to the enzymes that could destroy penicillins, MRSA acquired a different resistance mechanism: a mutant target protein, borrowed from another Staphylococcus species, that was unaffected by the drug. Within a few years, strains of MRSA began spreading in hospital wards around the world, mirroring the rise of penicillin-resistant S. aureus less than two decades earlier.

But even as the danger of MRSA intensified in the 1970s and 1980s, drug development began to slow down. New antibiotics were developed, but they, like methicillin, were closely related to drugs that had come before. Chemical modifications could breathe new life into older drugs, but rarely more than a few years’ worth: the bacteria adapted. “It’s a Red Queen race,” says Cabot professor of biology Richard Losick. “We’re running as fast as we can just to stay in the same place.”

Meanwhile, the risks from MRSA have grown steadily worse. Early on, infection occurred almost entirely in hospitals, among patients already weakened by other illnesses, and by 2002, nearly 60 percent of S. aureus cases in American hospitals were methicillin-resistant. Adding to the toll, a new, more virulent MRSA strain began circulating in communities in the early 1990s, sickening otherwise healthy people. In 2005, an estimated 100,000 Americans suffered severe MRSA infections, and nearly 20,000 of them died—more than from HIV and tuberculosis combined.

Drug discovery has yet to catch up. “All the low-hanging fruit has been picked,” says Levy. Following the introduction of synthetic quinolones in 1962, no new chemical classes of antibiotics were developed until 2000. Most large pharmaceutical companies have abandoned antibiotic research and discovery altogether because of its unfavorable economics: drug development is risky and expensive, and antibiotics do not generate revenue the way drugs for chronic infections do (see “Encouraging Antibiotic Innovation,” page 48). “We have, at this point, a perilously thin pipeline,” warns John Rex, head of infection development at AstraZeneca, one of the few pharmaceutical companies still pursuing antibiotic discovery. “There are very few new drugs coming.”

Part of the problem is that, more than 80 years after Fleming’s serendipitous discovery, there are still no hard and fast rules for what makes a good drug. Antibiotic discovery remains largely a matter of chance: in high-throughput screens, pharmaceutical companies test hundreds of thousands of molecules on live bacteria or key enzymes and look for evidence of inhibitory effects. But finding a hit is just the beginning. An antibiotic is the exceedingly rare molecule that survives a gauntlet of contradictory requirements—killing a broad spectrum of bacteria while being absorbed harmlessly by the human body—and there is no way to predict where a compound might fail. Sifting through early leads is expensive, risky, and time-consuming: it takes approximately 10 years and a billion dollars to bring a new drug to market.

Consequently, the responsibility for research is falling increasingly to academic researchers. Michael Gilmore organized Harvard’s Program on Antibiotic Resistance in 2009: a multimillion-dollar project grant from the National Institutes of Health (NIH) currently funds the collaborative effort of HWPAR’s seven independent laboratories to study antibiotic-resistant S. aureus. The goal of the academic program is less to develop new drugs—a task better suited to companies, given their superior financial resources and specialized pharmacological knowledge—than to develop innovative approaches to finding them. “We explore new drug targets that are higher risk than those a company would work on,” explains professor of microbiology and immunobiology Suzanne Walker, one of Gilmore’s collaborators. “It’s hard to beat a company at developing a compound, and there’s no reason to do that. But I think it’s up to academics to lay the groundwork.”

In 2009, Walker’s lab discovered the compound targocil, which prevents bacterial growth by interfering with a cellular pathway that creates a critical component of the S. aureus cell wall. Targocil is potentially useful for treating drug-resistant strains like MRSA: the compound restores the lethal effect of antibiotics like penicillin and methicillin by disabling bacterial modes of resistance. Other such molecules have been clinically useful; to combat the naturally penicillin-resistant species E. coli, for instance, some treatments like augmentin combine a penicillin-like antibiotic with a second compound that inhibits the enzyme that confers resistance, and targocil combination treatments have likewise succeeded in overcoming MRSA in mice. Moreover, targocil has proven to be a useful tool for understanding S. aureus biology. “The more we understand about the physiology of MRSA, the more likely we are to find new ways to intervene,” says Walker.

Some researchers are looking beyond Ehrlich’s magic bullet. That paradigm of treatment has dominated medical research since penicillin’s discovery, in part because it perfectly suits the setting of a lab. A good drug molecule kills bacteria in a petri dish—an effect that, as Fleming’s discovery evidenced, is easy to observe. But the realities of an infection are far more complex. In its interactions with a host or with other bacteria, a microbe takes on distinct properties that can diminish an antibiotic’s success—or provide new avenues for drug discovery.

Many bacteria, S. aureus included, form dense communities called biofilms that are difficult to eradicate, particularly on devices, like catheters, that are inserted into the body. Sticking together helps bacteria shield each other from an antibiotic’s effects, however susceptible they may be when isolated in a lab. “There is no genetic change, but the physiology has changed,” explains professor of microbiology and immunobiology Roberto Kolter, who, with Richard Losick, studies the genetic basis of biofilm formation as part of HWPAR. “A few bacteria might survive antibiotic treatment because they were in the right physiological state.”

Other scientists are delving deep into the intricacies of infection, targeting biological properties that may not be apparent in lab settings. “If we learn more about the host-pathogen interaction, we can be more surgical about our intervention,” says Deborah Hung, associate professor of microbiology and immunobiology. Her lab searches for molecules that interfere with a pathogen’s ability to cause disease. For infections like diphtheria and botulism, for instance, antitoxins are often prescribed alongside antibiotics to neutralize the pathogen’s toxic proteins.

Natural immune processes may provide additional opportunities for targeted intervention. “I think it’s important to understand pathogenesis—not just from the pathogen’s point of view, but also from the host’s point of view,” says professor of genetics Fred Ausubel, another of Gilmore’s collaborators. Using the nematode Caenorhabditis elegans as a model, he has identified more than a hundred compounds that he describes as anti-infectives: they cure a range of infections in the worm without killing the bacterial pathogens, some by modulating natural immune processes. “If you really understand how a pathogen causes disease and how a host resists,” he says, “then you can intervene a lot more easily with a targeted therapeutic, or a vaccine.” Such novel approaches may soon become a standard part of antibiotic therapy. Small companies are beginning to make use of recent academic discoveries, and last year, HPWAR and AstraZeneca brought together experts from academia and industry to discuss collaborative approaches to combatting antibiotic resistance.

After its long stasis, drug discovery shows signs of picking up. The approvals of linezolid in 2000, daptomycin in 2003, and tigecycline in 2005 have introduced three new chemical classes of drugs, more than in the previous three decades combined. The Infectious Diseases Society of America (IDSA) has launched an initiative to develop 10 new antibiotics by 2020, and new public-private partnerships are helping draw large pharmaceutical companies back into antibiotic discovery. Even so, treatments for some pathogens remain worryingly sparse, and the continually evolving nature of bacteria means that constant cycles of drug discovery will be necessary for the foreseeable future if medical care is to remain ahead of antibiotic resistance. Yet the entire 2013 budget for the NIH, at just under $30 billion, falls short of the CDC estimate of the yearly cost of antibiotic-resistant infections—as high as $35 billion, when accounting for lost productivity.

“I’m not pessimistic about the science,” says Losick. “But it needs the proper investment.”

Societal drugs

SINCE THE 1970s, vancomycin has been the last-line drug against MRSA. Isolated in 1953 from a soil sample collected in the forests of Borneo, vancomycin never gained the widespread popularity of penicillin and its derivatives. Impurities in its early production (its discoverers at pharmaceutical company Eli Lilly nicknamed initial preparations “Mississippi mud”) had toxic effects, and even after the drug was refined, it was mainly given intravenously rather than orally.

Perhaps because of its more limited early use, vancomycin has enjoyed a relatively lengthy life. Resistance to most antibiotics has historically become widespread within one to three years of their introduction. Vancomycin, by contrast, has been in clinical use since the 1960s, but resistance was not observed until the mid 1980s, when it emerged in Enterococcus, a group of gut bacteria that frequently cause hospital-acquired infections, typically of the urinary tract and blood. Vancomycin-resistant S. aureus, or VRSA, did not appear until 2002, and as of 2013, there had been only 14 reported cases in the United States.

Concealed behind vancomycin’s apparent longevity, however, are concerns about antibiotic use and abuse. As a last-line drug administered only in hospitals, vancomycin’s use was strictly limited, in turn limiting the selective pressure for bacteria to become resistant. In the late 1970s, though, two changes took place. Avoparcin, a closely related drug, was approved for use on farms in Europe. And in the United States, vancomycin usage grew exponentially with the escalating MRSA epidemic, increasing 100-fold in the next 20 years.

The farm use of avoparcin and other antibiotics has drawn fierce criticism. For decades, scientists have called agricultural antibiotic use unnecessary and harmful, because the main function of antibiotics on farms is to promote animal growth, not treat disease. For reasons still poorly understood, small amounts of antibiotics regularly mixed into feed make young animals gain weight up to 8 percent more quickly, which can help farmers cross the line from loss to profit. The practice benefits both the agricultural and pharmaceutical industries: the Food and Drug Administration (FDA) estimates that 80 percent of American antibiotic use today takes place on farms.

In 1976, Stuart Levy of Tufts led perhaps the only prospective study to investigate whether small amounts of antibiotic use in livestock could lead to the spread of resistant bacteria to humans. His team began feeding tetracycline to some chickens on a small farm in Sherborn, Massachusetts, that had never before used antibiotics in animals. Within a week, tetracycline resistance appeared in the chickens’ gut bacteria, and then in untreated chickens in neighboring pens—and, a few months later, in the intestinal flora of the farmers. Even more alarming was the fact that with time, the tetracycline-resistant bacteria also developed resistance to other, unrelated antibiotics to which they had never been exposed. The finding was attributed to the aggregation of resistance genes on mobile plasmids, as described in Japan, that then spread to other bacterial species. The farm acted as an incubator for multidrug resistance.

In 1981, Levy founded the Alliance for the Prudent Use of Antibiotics, a global nonprofit group that disseminates information about and sponsors advocacy for the proper management of antibiotics. His call for a ban on antibiotic use in agriculture has been echoed by many other groups, including the IDSA, the Union of Concerned Scientists, and, recently, the Pew Charitable Trusts. “We have a lot of good antibiotics, we just haven’t known how to use them,” says Roberto Kolter of HWPAR, who is also past president of the American Society for Microbiology. “We have abused them.”

Indeed, evidence now suggests that agricultural use of avoparcin shortened the lifespan of vancomycin, the last-line drug. Gilmore’s lab established that the strains of vancomycin-resistant Enterococcus (VRE) that cause an estimated 20,000 hospital infections in the United States each year are descended not from relatively innocuous strains in the human gut, but rather from strains that live in the guts of livestock. From VRE, they found, the DNA trail leads to the dozen known American cases of VRSA, each of which occurred when MRSA acquired resistance genes from its Enterococcus neighbors. “This is a real issue,” Gilmore says of continued antibiotic use on farms. “Agricultural companies are externalizing their costs—antibiotic-resistant hospital infections are not their problem.” The European Union banned agricultural use of avoparcin and other antibiotics in the late 1990s, but the United States has yet to follow suit. Last December, the FDA announced a new policy to phase out the use of antibiotics for growth promotion, but the regulation is a relatively small step compared to what many scientists have been demanding for decades.

The controversy over farm use of antibiotics illustrates their complex role as what Levy described in his book The Antibiotic Paradox as “societal drugs.” Antibiotic resistance begins with a random mutation or chance transfer of genes, but without the selective pressure of antibiotic exposure, a mutant never comes to dominate the bacterial population. It is human society, through antibiotic misuse and overuse, that gives a rare event its pandemic potential. “Each individual use,” Levy wrote in 1997, whether human or animal, “contributes to the sum total of society’s antibiotic exposure. In a broader sense, the resistance problem is ecological.”

No other medications carry the same societal consequences for abuse. Yet in the United States, an astonishing half of antibiotic use in humans is estimated to be unnecessary. Drugs are often prescribed needlessly for ailments like the common cold and the flu, which are not even caused by bacteria, but by viruses—which are not susceptible to the same drugs.

“It’s bewildering,” admits Jeffrey A. Linder, associate professor of medicine and associate physician at Brigham and Women’s Hospital. Opponents of agricultural antibiotic use can point to specific culprits, but antibiotic over-prescription has complex roots. Physicians often follow medical recommendations when responding to hypothetical scenarios, but may act otherwise in reality. Linder and colleagues have found, for instance, that even though medical guidelines state that antibiotics are never needed for acute bronchitis, they are prescribed 70 percent of the time.

Often, he says, the over-prescription results from miscommunication. Patients are often confused about when antibiotics are effective and concerned by how long symptoms last, even though one or two weeks is normal for a cold, three for a cough. Doctors, in turn, may prescribe antibiotics in hope of avoiding a patient confrontation. “I think there’s a role for educating patients” about what antibiotics can and can’t do, Linder adds. “There’s stuff doctors can do to help people feel better and get a good night’s sleep, but antibiotics won’t make the duration of a cold or cough any shorter.” In fact, their over-prescription can make patients worse. Antibiotic overuse has societal and personal side effects: diarrhea, allergic reactions, drug interactions, and unnecessary cost.

Though common ailments account for most instances of antibiotic over-prescription, the problem extends to severe infections in hospital settings as well. In the case of last-line drug vancomycin, for instance, skyrocketing usage in the 1980s likely helped spread strains of the vancomycin-resistant Enterococcus that had emerged on farms, creating the current epidemic. Most of this antibiotic use was unavoidable, a consequence of MRSA’s rapid spread, but public-health officials still see considerable room for improving treatment practices. According to a CDC report released in March, approximately one-third of vancomycin prescriptions include potential errors: the drug is given without proper testing or evaluation, or given longer than necessary.

The errors reflect a significant and longstanding information gap. When a hospital patient is admitted, doctors prescribe treatment based on an initial clinical diagnosis, but microbiological information about the infection—the organism that causes it and its resistance profile—does not become available until two days later. In the interim, physicians are forced to guess. Unnecessarily prescribing a last-line drug like vancomycin can decrease its long-term efficacy, but treating an infection with methicillin could be deadly if the pathogen turns out to be MRSA.

In response, many hospitals have set up infection-control units that track patterns of disease and resistance within their wards—critical measures for promoting responsible antibiotic use. “With few antibiotics in the pipeline, we have to be even more careful about preserving the ones we have,” says David Hooper, professor of medicine and chief of the infection-control unit at Massachusetts General Hospital, and another HWPAR researcher. “Antimicrobial stewardship is important to help doctors select the right drugs, and infection control is important to make sure we don’t amplify infections by allowing them to be passed from patient to patient.”

In northern Europe, proactive infection control and vigilant surveillance have kept MRSA rates low: less than 5 percent of staph specimens isolated in Denmark and the Netherlands are methicillin-resistant, compared to nearly 50 percent in the United States. But even in the United States, increased hospital vigilance is beginning to have an effect. Between 2005 and 2011, national MRSA rates fell by nearly one-third, with rates of hospital-acquired infections dropping by more than half, and Congress is considering an act that would strengthen disease surveillance at a national level.

Nevertheless, MRSA continues to kill more than 11,000 Americans every year, and approximately a quarter of infections occur in the community, outside healthcare settings. Hospitals can play critical roles in curbing drug-resistant strains, but their role is limited: agriculture and the wider community remain bigger drivers of antibiotic use. By the time drug resistance reaches hospital wards, an epidemic is already under way.

A new normal

ANTIBIOTIC RESISTANCE raises the grim specter of a return to the medicine of a century ago. Last year’s emergence of plasmid-mediated resistance to carbapenems, last-line drugs against a variety of pathogens, set off alarms throughout the public-health community. Before long, officials warned, resistance might become so common that physicians will run out of treatment options altogether.

In fact, we are already in the post-antibiotic era. It is not that drugs have lost all efficacy: the handful of truly untreatable superbugs has, so far, been contained. But decades of antibiotic use have altered, perhaps irrevocably, the relationship between humans and the microbial world.

Traditional, broad-spectrum antibiotics cause significant collateral damage. “Antibiotics not only select for resistance in the bacteria you are trying to treat, but also wreak havoc among the bacteria in the environment,” says Stuart Levy. “We don’t know how large that domino effect is.…A bacterium that might have been a minor participant in the previous environment now finds an environment so changed that it can become a major participant.”

Ironically, therefore, antibiotics can foster serious infection. One of the most deadly cases is Clostridium difficile, a natural gut inhabitant whose hardy spores proliferate following antibiotic treatment. Without a normal microbial ecosystem to keep it in check, C. difficile can cause symptoms ranging from mild diarrhea to life-threatening colitis; in the United States, it now causes 14,000 deaths and at least $1 billion in additional medical costs a year. Antibiotics may have subtler effects as well: some studies now suggest that, by altering the balance of bacteria in the body, the drugs contribute to weight gain, perhaps bulking up humans as they have long fattened livestock.

By eliminating susceptible bacteria, decades of antibiotic use have also made drug resistance more common, even in nonpathogenic species. As Levy has observed, “The antibiotic susceptibility profile of bacteria on the skin of people today, and in the environments of hospitals and homes, is very different from what it was in the pre-antibiotic era, and even 10 years ago.” In the bacterial community at large, it is no longer unusual for organisms to carry one or more resistance genes, even in the absence of obvious antibiotic exposure. Microbiologists once hoped that antibiotic-resistant bacteria—both within a single patient, and in the broader environment—would die off after drug treatment stopped. But in large swaths of the microbial world, it seems, antibiotic resistance is the new bacterial normal.

It may be time, therefore, for antibiotics themselves to evolve. Michael Gilmore draws an analogy to ecological control: “What we’re talking about now is human ecology management,” he says. “The antibiotics we first discovered were clear-cutters—they killed everything. They were broad-spectrum, they wiped everything out.” Now, he says, researchers are exploring ways to fine-tune antibiotics’ lethal potential.

A holy grail for researchers and clinicians is the development of reliable rapid diagnostics, tests that identify both the microbial cause of an infection and its drug resistance profile within hours, rather than the current standard of two days. “Patients come in with a clinical disease—a urinary tract infection, or pneumonia—but the cause of that infection could be one of many different things,” explains Scott Evans, senior research scientist in biostatistics at Harvard School of Public Health. “Currently, we often have to initiate treatment of clinical disease based on unknown causes and antibiotic susceptibility. If we could get rapid diagnostics, then we could better tailor patient treatment.”

In fact, rapid diagnostics are already becoming a reality. As director of the Statistics and Data Management Center for the Antibacterial Resistance Leadership Group, a nationwide clinical research network created in 2013 by the National Institutes of Health, Evans helps evaluate the effectiveness of existing tools. He and collaborators have found that some genomics-based rapid diagnostics are able to accurately detect resistance to certain drugs like penicillins, cephalosporins, and carbapenems.

“I think that rapid diagnostics are a very solvable problem, in the very near future,” says Deborah Hung. “And once we solve that, it completely changes the landscape of what we do.” Reliable rapid diagnostics would pave the way for more precise incarnations of Ehrlich’s magic bullet: narrow-spectrum drugs that target a few bacterial species, rather than the broad spectrum of bacterial diversity that current antibiotics are designed to eliminate. Such possibilities would also open new avenues of drug discovery. “If we get to the point of narrow-spectrum drugs—say we’re looking for a staph-only drug—then you have a lot more potential targets, because a drug doesn’t have to kill as many bacteria as possible,” says Suzanne Walker.

A more radical antibiotic future may cut back the role of antibiotics altogether by using normal bacteria to counter relatively minor infections. A growing area of research explores how to alter microbial interactions to promote human health. Fecal transplants, for instance, have occasionally proven effective against recurrent C. difficile infections. Such probiotic treatments that use live microbes are in their infant stages—no one knows exactly how normal gut bacteria keep C. difficile in check—but evidence is beginning to suggest that humans’ future with bacteria will depend, at least in part, on careful coexistence.

An epidemic begins

NEARLY 80 years after the antibiotic revolution, the human relationship with S. aureus is again on the verge of change. Genes for vancomycin resistance are increasingly prevalent, and on at least 12 separate occasions, they have entered MRSA to create new, vancomycin-resistant strains. Resistance to last-line drugs is brewing in many other bacterial species as well. Chance will determine when resistance finally catches on, and resistant strains spread through the bacterial population—taking the place of what has come before, once again transforming the game of survival that humans and microbes play.

Can humans evolve first? Bacterial evolution occurs with barely imaginable rapidity. But the antibiotic revolution that transformed our ancient relationship started not with a gene, but with an idea. This idea, once harnessed and spread through society at scale—the human version, perhaps, of horizontal gene transfer—has enabled our species to remain ahead.

The pieces are in place for change. We have our own means of resistance, and they are already common in parts of the human population. Activism and awareness are ancient, while the seeds of scientific innovation are new. What has been missing is the impetus for change, the pressure that causes an idea to spread.

“How big does this problem have to get for us to do something about it?” asks Michael Gilmore. “The challenge is, there’s a lag between when we realize a problem is big enough and when we can come up with a solution.”

The cause may be a gene or an idea. But sometime soon, an epidemic will begin. 

Latest Report from the CDC: Antibiotic Resistance Threats in the United States


Antibiotic resistance is one of the biggest public health challenges of our time. In 2013, CDC published a comprehensive analysis outlining the top 18 antibiotic-resistant threats in the U.S., titled Antibiotic Resistance Threats in the United States, 2013 (AR Threats Report). The report sounded the alarm to the danger of antibiotic resistance, stating that each year in the U.S., at least 2 million people get an antibiotic-resistant infection, and at least 23,000 people die.

The report ranked the 18 threats (bacteria and fungi) into three categories based on level of concern to human health—urgent, serious, and concerning—and identified:

  • Minimum estimates of morbidity and mortality from antibiotic-resistant infections

  • People at especially high risk

  • Gaps in knowledge about antibiotic resistance

  • Core actions to prevent infections caused by antibiotic-resistant bacteria, and slow spread of resistance

  • What CDC was doing at that time to combat the threat of antibiotic resistance

The data below is pulled from the 2013 Threats Report. CDC is working towards releasing an updated AR Threats Report in fall 2019.

Urgent Threats

Clostridioides difficile

Type: Bacteria

Also known as: C. difficile or C. diff, previously Clostridium difficile

About: C. difficile causes life-threatening diarrhea and colitis (an inflammation of the colon), mostly in people who have had both recent medical care and antibiotics

Infections per year: 500,000*

Deaths per year: 15,000*

Learn more: CDC’s C. difficile website

Carbapenem-resistant Enterobacteriaceae (CRE)

Type: Bacteria

Also known as: Nightmare bacteria

About: Some Enterobacteriaceae (a family of germs) are resistant to nearly all antibiotics, including carbapenems, which are often considered the antibiotics of last resort

Drug-resistant infections per year: 9,000

Deaths per year: 600

Learn more: CDC’s CRE website

Drug-resistant Neisseria gonorrhoeae

Type: Bacteria

About: N. gonorrhoeae causes the sexually transmitted disease gonorrhea, and has progressively developed resistance to the antibiotic drugs prescribed to treat it

Infections per year: 246,000

Learn more: CDC’s antibiotic-resistant gonorrhea website

Serious Threats

Multidrug-resistant Acinetobacter

Type: Bacteria

About: People with weakened immune systems, including hospitalized patients, are more at risk of getting an Acinetobacter infection, which is resistant to many commonly prescribed antibiotics

Multidrug-resistant infections per year: 7,300

Deaths per year: 500

Learn more: CDC’s Acinetobacter website

Drug-resistant Campylobacter

Type: Bacteria

Also known as:  Campy

About: Campylobacter usually causes diarrhea, fever, and abdominal cramps, and can spread from animals to people through contaminated food, especially raw or undercooked chicken

Drug-resistance infections per year: 310,000

Learn more: CDC’s Campylobacter website

Fluconazole-resistant Candida

Type: Fungus

About: Candida yeasts normally live on skin and mucous membranes without causing infection; however, overgrowth of these microorganisms can cause symptoms to develop

Fluconazole-resistant Candida infections per year: 3,400

Deaths per year: 220

Extended-spectrum Beta-lactamase (ESBL) producing Enterobacteriaceae

Type: Bacteria

Also known as: ESBL, or extended-spectrum β-lactamase 

About: ESBL-producing Enterobacteriaceae are resistant to strong antibiotics, including extended spectrum cephalosporins

  • ESBL is an enzyme that allows bacteria to become resistant to a wide variety of penicillin and cephalosporin drugs

  • Bacteria that contain this enzyme are known as ESBLs or ESBL-producing 

Drug-resistant infections per year: 26,000 

Deaths per year: 1,700

Vancomycin-resistant Enterococcus (VRE)

Type: Bacteria

Also known as: VRE

About: Enterococci cause a range of illnesses, mostly among patients receiving healthcare

Drug-resistant Enterococcus infections per year: 20,000 

Deaths per year: 1,300

Learn more: CDC’s VRE in Healthcare Settings website

Multidrug-resistant Pseudomonas aeruginosa

Type: Bacteria

Also known asP. aeruginosa

About: Serious Pseudomonas infections usually occur in people with weakened immune systems, making it a common cause of healthcare-associated infections 

Multidrug-resistant Pseudomonas infections per year: 6,700 

Deaths per year: 440

Learn more: CDC’s P. aeruginosa in Healthcare Settings website

Drug-resistant non-typhoidal Salmonella

Type: Bacteria

  • Non-typhoidal Salmonella includes serotypes (a subdivision of a species) other than Typhi, Paratyphi A, Paratyphi B, and Paratyphi C 

About: Salmonella spreads from animals to people mostly through food, and usually causes diarrhea, fever, and abdominal cramps 

Drug-resistant Salmonella infections per year: 100,000

Learn more: CDC’s Salmonella website

Drug-resistant Salmonella Serotype Typhi

Type: Bacteria

Also known as: typhoid fever

About: Salmonella Typhi causes a serious disease called typhoid fever, and is spread by contaminated food and water

Drug-resistant Salmonella Typhi per year: 3,800

Learn more: CDC’s Typhoid Fever website

Drug-resistant Shigella

Type: Bacteria

About: Shigella spreads in feces through direct contact or through contaminated surfaces, food, or water, and  most people infected with Shigella develop diarrhea, fever, and stomach cramps

Drug-resistant infections per year: 27,000

Learn more: CDC’s Shigella website

Methicillin-resistant Staphylococcus aureus (MRSA)

Type: Bacteria

Also known as: MRSA, resistant staph (short for Staphylococcus), resistant S. aureus

About: MRSA is S. aureus that has become resistant to certain antibiotics called beta-lactams, including methicillin

  • Patients in healthcare settings frequently get severe or potentially life-threatening infections, and people can also get MRSA in their community

Severe MRSA infections per year: 80,461 

Deaths per year: 11,285 

Learn more: CDC’s MRSA website

Drug-resistant Streptococcus pneumoniae

Type: Bacteria

Also known as: S. pneumoniapneumococcus

About: S. pneumoniae causes pneumococcal disease, which can range from ear and sinus infections to pneumonia and bloodstream infections 

Drug-resistant infections per year: 1.2 million 

Hospitalizations per year: over 19,000 

Deaths per year: 7,000 

Learn more: CDC’s S. pneumoniae website

Drug-resistant Tuberculosis

Type: Bacteria

Also known as: TB, multidrug-resistant TB (MDR TB), or extensively drug-resistant TB (XDR TB), Mycobacterium tuberculosis (M. tuberculosis)

About: TB is caused by the bacteria M. tuberculosis, and is among the most common infectious diseases and a frequent cause of death worldwide 

Drug-resistant TB cases in 2011: 1,042 

Learn more: CDC’s TB website

Concerning Threats

Vancomycin-resistant Staphylococcus aureus (VRSA)

Type: Bacteria

Also known as: VRSA, resistant staph (short for Staphylococcus), resistant S. aureus

About: VRSA is S. aureus that has become resistant to the antibiotic vancomycin, the antibiotic most frequently used to treat serious S. aureus infections 

Cases 2002-2013: 13 in 4 states 

Learn more: CDC’s VRSA website

Erythromycin-resistant Group A Streptococcus

Type: Bacteria

Also known as: resistant group A strep, GAS 

About: Group A strep can cause many different infections that range from minor illnesses to very serious and deadly diseases, including strep throat, scarlet fever, and others 

Drug-resistant infections per year: 1,300 

Deaths per year: 160 

Learn more: CDC’s GAS website

Clindamycin-resistant Group B Streptococcus

Type: Bacteria

Also known as: resistant group B strep, GBS

About: Group B strep can cause severe illness in people of all ages 

Drug-resistant infections per year: 7,600 

Deaths per year: 440 

Learn more: CDC’s GBS website