James Heimer
Kate McCoy was out with her 4-year-old son when she got a call from her husband. Their 5-month-old son, Neil, had started having trouble breathing, and they were both now at American Family Children’s Hospital.
McCoy felt a rush of fear when she saw the throng of medical staffers surrounding Neil in the emergency room. He was hooked up to an IV and was wearing a heart monitor and oxygen mask. His heart was racing, and his skin had a strange blue tinge. He was so small, so vulnerable.
After the doctors ruled out a number of possibilities, including a heart defect, brain problem or metabolic disorder, a lab test confirmed that Neil had an E. coli infection that had quickly turned into sepsis. Sepsis causes the body to mount an exaggerated immune response that may continue even after the bacteria have been killed. It can lead to organ damage and death.
Fortunately, once the infection was identified, Neil was promptly given antibiotics; his sepsis responded quickly to treatment. A few hours later, McCoy and her husband, Rob, were relieved to see their infant’s heart rate and breathing become normal again and his healthy color return.
They had their baby back. Neil’s dance with death was over.
It wasn’t until McCoy brought Neil to their family physician for a follow-up visit that she learned just how close she had come to losing her baby: the E. coli strain that infected Neil is resistant to many different antibiotics. Because of this experience, McCoy spoke out publicly last year at a town hall meeting in Madison convened to urge support for new legislation to curb the nontherapeutic use of antibiotics in farm animals.
The overprescription of antibiotics in both farm animals and humans is having deadly consequences. Antibiotics that once effectively fought bacteria, such as E. coli, are no longer doing the job. Nationally, the Centers for Disease Control estimates that more than 2 million illnesses annually are caused by antibiotic resistance, resulting in 23,000 deaths.
Last September, President Obama signed an executive order that declared combating antibiotic-resistant bacteria a national security priority. It has been called public health’s ticking time bomb.
At UW-Madison, a group of researchers are on the front lines of this battle. Buoyed by a $16 million grant from the National Institutes of Health’s Center of Excellence for Translational Research program, the researchers are doing what the pharmaceutical industry has not done since the 1980s — finding new antibiotics.
Eric Tadsen
So far the research team, under investigators Dr. David Andes (left) and Cameron Currie, has found 15 new antibiotics, some of which have already been successfully tested in mice.
Dr. David Andes, chief of the division of infectious disease at UW Hospital, and Cameron Currie, a bacteriology professor at UW-Madison, are co-principal investigators on the project. The team has developed sophisticated screening methods to prioritize the most promising of the compounds that they have found, thus streamlining the journey through testing and production to human trials. So far they have found 15 new antibiotics, some of which have already been successfully tested in mice.
Traditionally, soil was mined to identify antimicrobials that are used to develop antibiotics. But that became a dead end because the same microbes were turning up.
The UW team instead studies ants, plants and marine life to find new antibiotics. And the end game promises to go beyond research papers, leading to new drugs that will one day make it to the marketplace.
“We have a mini-pharmaceutical group here,” says Andes. “We have the capability of taking this all the way to patients.”
Until antibiotics were introduced in the 1940s, infectious diseases were some of the deadliest and most dreaded diseases of all. During the 19th century, cholera, pneumonia, scarlet fever, diphtheria, whooping cough and tuberculosis decimated populations; in America, 25% of children died within their first year.
The widespread availability of antibiotics, along with vaccines and better sanitation, helped curb these deadly diseases.
But the pervasive overuse of antibiotics in humans and livestock during the past 70 years has cause the number of antibiotic-resistant strains of bacteria to proliferate. All of the most common infections of the ear, sinus, throat, skin, lung and urinary tract are resistant to multiple drugs, although they remain treatable by others. With no new drugs in development and antibiotic-resistant bacteria on the rise, experts fear that the current stock of antibiotics is insufficient to meet future needs.
Andes sees this threat daily in his work at UW Hospital. Completely antibiotic-resistant bacteria turn up in patients with alarming frequency, he says.
“Thirty to 40 times per month we grow bacteria from a patient in our microbiology lab and find there’s no antibiotic that we have to treat it,” he says.
“It is getting tough on the front lines to manage resistance,” Andes adds. “Antibiotics have arguably been the biggest advance in medicine over any field. They have doubled life expectancy in different groups and allow us to do transplantation, chemotherapies for cancer and different surgeries.”
But, says Andes, “Now, we are getting to the point where, for large groups of patients, we can’t do those therapies because the patients are infected with resistant organisms. It’s like going back to the pre-antibiotic era.”
The Center of Excellence for Translational Research project, or CETR, is based out of the shiny new Microbial Sciences Building at the corner of Linden and Babcock drives. Besides Andes and Currie, the team includes Tim S. Bugni, F. Michael Hoffman, Dr. Bruce Klein, Dr. Rod Welch and Harvard researcher Jon Clardy.
Evolutionary biology underpins their work. Currie discovered a number of years ago that ants co-evolved with a bacteria that produced antibiotics. The research team speculated at the start that if these antibiotics evolved with a living animal, such as an ant, they would likely be safe for humans. It turns out they could very well be right.
Eric Tadsen
A fungus garden for an ant colony.
Currie and Bugni travel to such places as Florida, Brazil, Puerto Rico and Hawaii, where they hunt for insects and marine animals such as sponges, which they strongly suspect contain antibiotic-producing microbes.
Back at their labs in Madison they are able to isolate these microbes.
They then test the compounds produced by the microbes to see if they kill pathogens known to be dangerous to humans, including those that have become antibiotic resistant. If the compounds work against these deadly pathogens, the next stage of testing begins.
At the pharmacy school, Bugni, who is also a natural products chemist, isolates large amounts of the antibiotic compound, determines its chemical structure and compares it to known compounds. If it turns out to be something new, the compound is fast-tracked for further study.
“It’s what I refer to as the needle-in-the-haystack test,” Andes says.
In Currie’s lab, the researchers do genomic sequencing on the bacteria, which helps them determine whether they may contain antibiotic-producing microbes. The researchers then prioritize these bacteria for further study.
Once the most promising antibiotic compounds are isolated, Bugni tests them for toxicity to human cells. If they prove nontoxic, the compounds pass to Andes’ lab for testing in mice.
Andes says they may be able to begin human testing with some of the new antibiotics in a couple of years.
Eric Tadsen
Doctoral student Heidi Horn: ‘Cameron [Currie] always jokes that you are not a true field biologist until you’ve bled from an ant bite.’
Heidi Horn, a doctoral student in zoology, has been working with Currie and his ants since her days as a UW-Madison undergraduate. She says she earned her spurs while digging out ant colonies: “Cameron [Currie] always jokes that you are not a true field biologist until you’ve bled from an ant bite.”
Horn began working at the CETR labs last September, and just recently returned from a collecting mission in Brazil.
Horn unlocks the door to the room where the leaf-cutting ants are kept. Because they are non-native species from Central and South America, extra care must be used to keep them confined in the lab. Signs on the door warn: “USDA Containment Area.” “Room must be locked at all times.” “Authorized personnel only.”
Several dozen Sterilite boxes with blue covers contain different ant colonies, distinguished by such names as Evita, Nina, Luna, Regina and Olivia.
These ants are critical to the work of the research team because they are coated with milky white bacteria, a rich source of the precious microbes that produce pathogen-fighting compounds.
In the ant’s natural environment, explains Horn, “these antibiotics protect them from many fungal pathogens. They’re underground most of the time. They’re coming in contact with different pathogens all the time.”
John Maniaci
A leaf-cutter ant is covered with milky, antibiotic-producing bacteria.
The beauty is that the same antibiotics that protect the ants from pathogens in their underground world also act on pathogenic bacteria that infect humans, including bacteria like MRSA, that have grown resistant to the current antibiotics.
Andes says his team has more than 50 new antibiotics at different stages along the research pipeline. So far, the researchers have filed three patent applications and published two papers about their discoveries.
As the threat from antibiotic resistance grows, new legislative and advocacy efforts have been launched to stem the overuse of antibiotics in both humans and livestock.
In April 2014, Madison became the fifth city to go on record in support of the Preservation of Antibiotics for Medical Treatment Act, federal legislation that would regulate antibiotic use in factory farms.
In 2013, the FDA issued proposed voluntary guidelines for ending the use of antibiotics to promote growth in livestock. The final version of the rules is expected this year and will be phased in by late 2016 or early 2017.
As of March 2014, 25 of the 26 manufacturers of antibiotics for livestock voluntarily agreed to a change in the labeling of antibiotics to eliminate their use for animal growth. If farmers use the antibiotics for nontherapeutic purposes after the new guidelines are fully implemented, they would be violating the law.
The federal government is also prepared to budget more money to fight antibiotic resistance. It currently spends $450 million, or about $1.40 per person, annually, but the 2016 budget proposes a hike to $1.2 billion. The White House estimates the annual economic impact of antibiotic-resistant infections at $20 billion in health costs, with another $35 billion in lost productivity.
In September, the White House issued a national action plan to combat antibiotic resistance that called for increased surveillance of antibiotic-resistant bacteria, better stewardship of existing antibiotics, improved testing for infected patients and an accelerated effort to develop new antibiotics.
Local hospitals have been ahead of the curve on stewardship. As Wisconsin’s largest academic hospital and one of the world’s leading transplant centers, UW Hospital has a 14-year-old antimicrobial stewardship program. At St. Mary’s Hospital and Meriter Hospital, pharmacists supervise antibiotic use.
The Wisconsin Hospital Association in Fitchburg has launched an initiative through its Partners for Patients program to help Wisconsin hospitals of all sizes develop antimicrobial stewardship programs. The association will begin accepting enrollment into this program later this year.
Dr. Barry Fox, director of the antimicrobial stewardship program at UW Hospital, says antibiotic use dropped most dramatically in the first five years of the program.
“Now it has really remained level,” he says. “UW Hospital has one of the lowest rates of antimicrobial-resistant bacteria, when compared with national averages.”
Fox says that under UW Hospital policy, healthcare providers need to get special approval from the stewardship team to use antibiotics. And certain antibiotics are being used very sparingly, he adds. “We are holding some of these antibiotics as a last line of defense, so that they also don’t just fall by the wayside.”
The CDC reports that 50% of hospitalized patients receive at least one antibiotic during their stay that is inappropriate or unnecessary.
But most antibiotics are actually prescribed on an outpatient basis, notes Fox. According to the CDC, antibiotics are prescribed 68% of the time when a patient has an acute respiratory infection; 80% of those prescriptions are unnecessary.
Steven Ebert, infectious diseases and clinical supervisor at Meriter Hospital, says the problem of antibiotic resistance can also be attacked with better testing for bacteria.
“When a patient is treated with antibiotics, whether it’s in the hospital or in the clinic, the physician does not always know if it’s a bacterial or viral infection, and they may or may not be able to collect adequate specimens,” Ebert says. “I would venture to say that about 80% of the time or even more, we’re kind of shooting in the dark with infections.”
Ebert says one new test can check for elevated levels of procalcitonin, a peptide normally found in the human blood stream. In the presence of bacteria, procalcitonin levels rise. The test can help physicians make an accurate diagnosis.
Another new test responds to specific genes in bacteria.
These tests cost a bit more at the outset, but Ebert thinks they are worth it and should be more widely used: “You have to look at the big picture.”
The CETR team’s antibiotic resistance project still has four years to go on its $16 million NIH grant. But CETR is not the only group doing antibiotic research on campus, and Gov. Scott Walker’s proposed $300 million cut to the University of Wisconsin System could affect the extensive work under way on the problem.
The “hub” for that work is the Microbial Sciences Building, says Andes. “There’s everybody from soil microbiology to food microbiology to evolutionary biology, to very practical human microbiology, drug discovery and drug development work. It’s being in this building and seeing seminars and approaches from different people that really brought our group together.”
Andes says the CETR team came together serendipitously because of this environment.
In addition, the annual Antibiotic Discovery and Development Symposium brings together people from departments such as engineering, chemistry, pharmacy, biochemistry and systems engineering, to present their ideas on antibiotic resistance.
“It’s in seminars like that — around this big problem — which allow us to find each other,” Andes says.
Andes says he is glad that the problem of antibiotic resistance is drawing the attention of lawmakers and that the new federal budget proposal calls for more than $1 billion to fight it. But, he warns, “the local cuts will make it challenging to maintain our infrastructure.”
For now, though, his team’s research continues, with promising results.
Says Andes: “Our hit rate, if you will, for finding new antibiotics is about 1,000 times greater than the old way of looking.”
