Putting the Pieces Together to Battle Anti-microbial Resistance

Are new technologies and testing strategies needed?

Jen A. Miller

Antibiotic resistant bacteria are not just a $2.2 billion healthcare industry problem: They’re a modern-day health crisis that has continued to build a dangerous momentum.

“Antibiotics have revolutionized medicine and our ability to care for patients because they allow us to treat not just bacterial infections but to make other medical inventions such as surgery, transplantation, childbirth, even just growing up safe,” said Robin Patel, MD, director of the infectious disease research laboratory and chair of the division of microbiology at the Mayo Clinic in Rochester, Minnesota. “When you run into a problem with an infection or, in the case of surgery, when you need to prevent an infection, we use antibiotics for that. We have all just historically assumed that they’re going to work.”

With the growing threat of antibiotic-resistant bacteria, however, that is not always the case. The Centers for Disease Control and Prevention (CDC) estimates that 2 million Americans contract and 23,000 die each year from antibiotic-resistant infections. Calling antibiotic-resistance “one of the biggest challenges of our time,” CDC in September 2018 spearheaded the Antimicrobial Resistance Challenge at the United Nations General Assembly. This year-long campaign encourages international organizations to make formal commitments that further the progress against antimicrobial resistance on a global scale.

New research shows that the danger is not limited to what physicians consider major infections in hospitalized patients, either. Mild conditions easily treated by antibiotics are showing resistance too, and without treatment, could lead to life-threatening illnesses.

Researchers at Alameda Health System Highland Hospital in Oakland, California found that nearly 6% of urinary tract infections (UTI) analyzed during a 1-year period were extended-spectrum beta-lactamases (ESBL) resistant, meaning they are resistant to most beta-lactam antibiotics, including penicillin, cephalosporins, and monobactams aztreonam (Ann Intern Med 2018;72:449-56).

“ESBL has traditionally been considered the kind of resistance you see inside the hospital, not in a community setting like an emergency department,” said Bradley W. Frazee, MD, attending physician at the Alameda Health System Highland Hospital and lead author of the study. “Here, almost half were patients without risk factors for harboring bugs with ESBL.”

A major concern for these patients, he said, is that a mild infection could unexpectedly become extraordinarily dangerous. “A society without working antibiotics would be like returning to preindustrial times, when a small injury or infection could easily become life-threatening,” he said.

LENGTHENING THE RESISTANCE LIFESPAN

Antibiotic resistance may seem like a new problem in medicine, but that’s only because the drugs are still relatively new themselves, compared to billions of years of evolution among bacteria. “We’ve only been using antibiotics in clinical practice since the 1940s,” Patel said. “We’re putting a lot of pressure on bacteria, and they’re just doing what they do naturally when they evolve to be resistant. The more you expose the bacteria to antibiotics, the more they pull out their resistance mechanisms.”

One way to lengthen the life span of antibiotics is to use them only when evidence shows they will be effective, and not when a physician doesn’t know for sure that bacteria and not a virus or fungus is making a patient sick. Better and faster testing can help.

“Diagnosis of bacterial infections by culture and production of susceptibility tests is somewhat time consuming,” noted Sheldon Campbell, MD, PhD, professor of laboratory medicine at the Yale School of Medicine and director of laboratories at the VA Connecticut Healthcare System in New Haven, Connecticut. “Cultures typically take one to two days to grow, and susceptibility testing can take one to two days after that.” That doesn’t seem like a long time, but in practice, four days can seem like an eternity to a sick patient—or the parent of a sick patient—especially one who is used to being given an antibiotic no matter what.

Advances in molecular diagnostics, notably matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, greatly shorten the time to identify organisms and resistance. The disseminating technology also gives quite accurate data—in places where it has been implemented.

“Matching is so precise that it can tell you exactly what that organism is and can tell you not just the name of the bacterium but whether it’s a yeast and the name of the yeast—with one technology,” Patel said. “It takes only five minutes to do, and it requires very minimal consumables to run, so it’s less costly than the way we’re used to identifying bacteria with panels of biochemicals. As soon as we have something growing on a plate, we can submit it to MALDI-TOF and identify what it is and report it out.”

While clinical laboratories can use MALDI-TOF to name the organism that’s growing, it can’t identify which antibiotics will work against it. That takes another day, Patel said, “but knowing what the organism is can give you some hint as to whether it’s a clinically significant organism actually causing the patient’s infection or whether it’s their normal microbiome.”

Clinicians can also look at data generated by other labs to identify what has traditionally worked against that specific infection and guide drug deployment. “There’s no one single test that will be the solution. They’re all just pieces that will do better,” she said.

A SYSTEM-WIDE APPROACH

Combating antibiotic resistance will take a combination of wide access to quick, effective testing and a paradigm shift away from treating antibiotics like a never-ending resource, according to experts. “We haven’t had perfect ways of differentiating these different types of infections. We’ve come to expect that when we’re sick with something that looks like an infection, we’ll take an antibiotic because that’s what’s been done in the past,” said Campbell.

Frazee sees multiple pieces forming the solution, including wider use of culture in relatively mild disease, monitoring trends by geographic site, publishing hospital antibiograms stratified by clinical site (emergency departments versus intensive care units, for example), and developing rapid testing for resistant organisms. “Of course, there is a need to develop new drugs. How do you incentivize pharma to develop new oral drugs for resistant UTI pathogens that do not cost $5,000 for a course?”

Frazee also said that clinical laboratories can work on creating systems that automatically alert clinicians “on resistant bugs, perhaps even checking themselves whether a patient was prescribed an active drug.”

Campbell sees a need to build more efficient systems, “not just doing one-offs but working through antibiotics stewardship programs, infectious disease experts, and laboratories, and optimizing both the reporting of the data and the use of it,” he said. “There’s pretty good data now that shows a system-wide approach is having an impact on antibiotic overuse. It’s not just the laboratory saying this, but a data-driven institutional process for reporting in a way that results in appropriate antibiotic use.”

The one thing we cannot do is go back. The days of antibiotics working in every case, every time, are over. “There is no way to get rid of antibiotics resistance permanently or go back to an era where all we have is fully susceptible bacteria, because we’re dealing with evolution,” Patel commented. “There are infections for which we need antibiotics, and if that wasn’t the case, we wouldn’t be in this crisis.”

CAN AN IMMUNOASSAY SYSTEM COMPETE WITH PCR FOR RAPID TESTING?

Rapid molecular tests for flu and other viruses are potential game-changers for encouraging more appropriate antibiotic use, especially when they are available at the point of care. The most recent technological advances from in vitro diagnostics manufacturers have focused on making polymerase chain reaction simple and fast enough for use in doctors’ offices and clinics. MeMed, a young private company, aims to break into this market with a different take on rapid, molecular testing.

The company’s MeMed BV is a new, blood-based, multiplex immunoassay platform that promises to distinguish between bacterial and viral infections within 15 minutes of testing. Eran Eden, PhD, co-founder and CEO of MeMed, believes this testing system can play an important part in fighting antibiotic resistance infections because it can tell physicians within minutes what they’re dealing with.

“We’re trying to tackle a seemingly simple problem. You go to the doctor with your child, and they’re sick and they have a fever—or maybe it’s you or one of your parents. Often, physicians are trying to figure out if it’s a bacterial or viral infection and how to treat you,” he said.

A big problem with the current approach is that “many of the solutions we have today take hours or even days, which is not fast enough,” said Eden. He said that current rapid testing isn’t available for all kinds of infections, and that there’s a high rate of false alarms due to colonization. “Sometimes you identify a bacteria in a 2-year old, and every 2-year old is going to have it whether they’re sick or not. We carry these bacteria when we’re healthy,” he said. Pathogens can change quickly, too.

MeMed believes it can work around these issues in two ways. The first is MeMed BV, an immune-system instead of pathogen-based test for distinguishing between bacterial or viral infections. “The immune system is perfect machinery, so we decided to just listen to the immune response,” said Eden. “We knew we were probably not going to find one magic bullet, one biomarker. Instead, we combined several biomarkers together to measure the immune response.”

That leads to the second part of testing: MeMed Key, a proprietary point-of-care protein measurement platform that runs the MeMed BV test.

MeMed, a private medtech company, received a new round of funding in September, bring-ing total financing of the project to $70 million. That influx builds on two grants MeMed has already received from the U.S. Department of Defense for test development. So far, the system has been evaluated in double-blind studies in 13,000 patients with results published in The Lancet, Pediatrics, and PLOS One.

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