Antibiotic Resistance

When antibiotics were discovered almost 100 years ago, they changed the practice of medicine. What followed brought us into a burgeoning antibiotic era in which such infections as pneumonia and syphilis—ones that once would have been highly debilitating or even fatal—became treatable.

But there is also a dark side to antibiotics. The adaptability of bacteria and other microorganisms has driven evolution that enables them to thwart these powerful drugs via a phenomenon known as antimicrobial resistance (AMR). Antimicrobial resistance is a naturally occurring process that happens when bacteria encounter what evolutionary biologists call selective pressure (a force that affects an organism’s ability to survive)—in this case, pressure from an antibiotic. Through random DNA mutations or by sharing resistance genes that lead to adaptive mechanisms, bacteria will evolve in order to survive this selective pressure.

Unfortunately, when antibiotics are overused and misused, as has been the case across the world in health care settings, agriculture, animal husbandry, and beyond, evolutionary pressure on bacteria intensifies. By generating defenses against the antibiotics that were designed to kill them, these microorganisms can multiply and spread antibiotic resistance genes.

AMR is now one of the top global public health threats. It was estimated to have contributed to 4.71 million deaths worldwide in 2021 (with a significant increase in resistant organisms after the COVID-19 pandemic) and is projected to cause 40 million deaths by 2050, according to a paper published in The Lancet last year. Because of a lag in the development of new antibiotics—due in large part to reduced financial incentives for pharmaceutical companies to develop these drugs—this crisis has ushered in what some experts call the post-antibiotic era, marked by a lack of sufficient antibiotic options to treat a wide range of infections.

“Now that we’re in a post-antibiotic era, it puts all those medical advances under a threat,” says Richard Martinello, MD, professor of medicine (infectious diseases) and pediatrics at Yale School of Medicine (YSM), and chief medical officer of Yale Medicine. “Many years ago, we may have been able to easily treat [patients] and cure their infections, but it may not be so easy anymore.”

Certain infections have become almost impossible to treat. Last May, the World Health Organization released its updated Bacterial Priority Pathogens List, which includes four critical priority bacteria (Acinetobacter baumanii, Mycobacterium tuberculosis, and two groups of Enterobacterales) that are resistant to last-line antibiotics. For instance, a class of broad-spectrum antibiotics called carbapenems is highly effective, but physicians can use them only as a last resort when an infection fails to respond to any other antibiotic. And they must be used sparingly to avoid the development of resistance. Thus, the rise of carbapenem-resistant bacteria is especially concerning.

“Every week we have new patients we’re finding in the hospital with bacteria that are resistant to carbapenems, and we have few good options for how we can treat these patients,” Martinello says. In these cases, he says, physicians may seek a newer antibiotic or an antibiotic alternative.

Because AMR is a significant problem on a global scale, an urgent search for solutions is underway. At YSM, researchers are investigating longer-term answers while health professionals at Yale New Haven Health are taking immediate steps to combat this issue on the clinical side.

Founded in the fall of 2022, the Yale Antimicrobial Resistance Network connects researchers from across multiple disciplines and departments for monthly meetings to discuss their AMR-related work.

Members’ research interests span a wide variety of topics. For example, Reza Yaesoubi, PhD, associate professor of public health (health policy) at Yale School of Public Health (YSPH), uses simulation and mathematical modeling to predict trends in antimicrobial resistance patterns and determine the best combinations of antibiotics to use.

“The main advantage of simulation mathematical models is that they allow you to project the long-term impact of different policies, strategies, and interventions,” he says. “The work that we try to do is to have a principled way to make decisions, given that there’s always a battle between these conflicting objectives of wanting to treat as many patients as we can with the newest antibiotic but also protecting the newest antibiotic against the emergence of resistance.”

Another member of the network, Sunil Parikh, MD, MPH, professor of epidemiology (microbial diseases) at YSPH and of infectious diseases at YSM, focuses on malaria in highly vulnerable groups in sub-Saharan Africa. He studies everything from the combinations of malaria drugs that are least likely to lead to resistance at the individual and population levels to continent-wide policy recommendations for surveillance of drug-resistant malaria.

“It’s going to be years before novel drugs are available on the marketplace [for malaria],” Parikh says. “We need to urgently determine how to combat the current emergence of resistance to malaria drugs in Africa, as it could have devastating public health consequences.”

Other members of the network research a variety of topics both locally and worldwide, including drug-resistant tuberculosis, hookworm infections, skin conditions like acne, pneumococcal disease, and AMR in hospitals. One group is even looking at potential alternatives to antibiotics in the form of microscopic viruses called bacteriophages.

Led by Paul E. Turner, PhD, Rachel Carson Professor of Ecology and Evolutionary Biology, the Center for Phage Biology and Therapy at Yale has been using bacteriophages (phages for short) to treat infections caused by multidrug-resistant bacteria since 2013. This usage was made possible through the Food and Drug Administration (FDA)’s expanded access pathway, which allows for the use of experimental treatments in life-threatening conditions when no other comparable treatments exist.

Phages are naturally occurring viruses that infect and kill specific bacteria. Just as a human cell can be infected with an influenza virus or a cold virus, bacterial cells are infected with phages. Turner’s group, along with those of other researchers worldwide, has capitalized on phages’ specialized ability to kill bacteria for clinical benefit.

Through a process called “phage hunting,” the research team looks for clinically relevant phages both locally and around the world. The researchers categorize and store these phages to create a library of potential candidates for phage therapy. To treat human infections, team members obtain bacterial samples from patients and test them by the phage library to identify which phages are best suited to kill the bacterium in question. Once the team has the right phage or series of phages and obtains FDA approval, the team uses the phage, which can be delivered to the patient through inhalation, injection, or ingestion.

Jon Koff, MD, associate professor of medicine (pulmonary, critical care & sleep medicine) at YSM, is director of the Adult Cystic Fibrosis (CF) Program and the medical director of the Center for Phage Biology and Therapy. Koff has been collaborating with Turner and Benjamin Chan, PhD, scientific director of the Center for Phage Biology and Therapy, to treat both cystic fibrosis patients and those without CF since 2018.

“There are some unique attributes of phages in terms of treating some infections that allow for them to be potentially synergistic with and also potentially independent of antibiotics,” says Koff.

Turner, Chan, and Koff have received requests from their colleagues to use phages to treat infections of the bone, prosthetic joints, the urinary tract, sinuses, and other parts of the body. The center recently completed several clinical trials focusing on phage therapy for cystic fibrosis; found a novel phage to treat methicillin-resistant Staphylococcus aureus (MRSA) that can actually resensitize the infection to antibiotics; and received a number of large National Institutes of Health (NIH) and foundation grants to continue its research.

Despite the success that Turner’s group and others around the world have had, phage therapy has still not been approved by the FDA for use beyond expanded access and clinical trials. Researchers are hopeful that this will change in the next five to 10 years.

“We maintain a unique position at Yale in the center because we can find phages and design their use; we can study them, and we can treat patients and study the bacterial pathogen(s) before and after phage therapy—that’s a unique combination,” says Koff.

While phages might be a promising new treatment, other researchers and clinicians at Yale are working to impede antimicrobial-resistant organisms from infecting patients in the first place. This precaution is especially important in hospital settings, where there is a greater risk of negative health consequences for immunocompromised or otherwise susceptible individuals.

“Most people who are healthy and have functioning immune systems are really not at risk for a lot of these multidrug-resistant bacteria and fungi,” says Scott Roberts, MD, assistant professor of medicine (infectious diseases) at YSM and assistant medical director of infection prevention at Yale New Haven Health (YNHH). “It really impacts the most vulnerable patients.”

In the hospital setting, Roberts sees two different situations in which patients experience multidrug-resistant infections. On the one hand, a patient may come in with a preexisting resistant infection that was contracted outside the hospital. But there are also patients who pick up a bug or become resistant to antibiotics during the course of their hospital stay—a problem that occurs in hospitals everywhere.

This second situation can develop for a number of reasons. For patients who are admitted for extended stays, repeated exposure to antibiotics during the course of their treatment may reduce the drugs’ efficacy over time. But there’s also a problem with the transmission of multidrug-resistant pathogens through such routes as contaminated surfaces, equipment, and human hands.

Handwashing, Roberts and Martinello stress, is one of the most effective measures to reduce the spread of resistant pathogens in the hospital setting—but bacteria can also spread through such medical equipment as thermometers, probes, stethoscopes, catheters, and such nonmedical items as furniture and other surfaces in a patient’s room. Martinello and Roberts have implemented procedures to reduce the spread of pathogens through these routes.

“We focus on handwashing; we focus on disinfection of the environment, disinfection of reusable equipment that gets shared between patients, and ensuring that it’s a safe space,” Roberts says.

In addition to strategically placing hand sanitizer dispensers in locations that allow for maximal and convenient hand hygiene for hospital workers, Roberts and Martinello have also begun piloting UV light disinfection technology to sanitize entire patient rooms. The efforts have paid off, as YNHH is currently experiencing better than national average rates for such health care-associated infections as catheter-associated urinary tract infections and MRSA infections.

While hand hygiene is one of the most important measures a hospital worker can take to reduce the spread of multidrug-resistant bacteria, there’s a good chance that the very sink where they wash their hands could splash resistant bacteria right back into the patient’s room.

“Pathogens in sink drains have been increasingly tied to nosocomial [originating in a hospital] infections, and a lot of antibiotic-resistant nosocomial infections,” says Hannah Greenwald Healy, PhD, assistant professor of environmental health and exposure science at Harvard T.H. Chan School of Public Health, and previously a postdoctoral associate at Yale in the lab of Jordan Peccia, PhD, Thomas E. Golden Jr. Professor of Environmental Engineering. “I think we’re just beginning to recognize the importance of plumbing systems and how big a problem they are.”

Healy’s research focuses on the ways in which bacteria from hospital drains can cause these infections, as well as how to stop contamination routes. Bacteria thrive in wet environments, which makes the liquid stuck in the P-trap (a bend in the sink pipe that prevents sewer gases from coming up through the drain), the perfect place for them to grow. Once in the P-trap, bacteria can grow along the sides of the pipe in sticky sheets called biofilms, sometimes even extending as far as the drain cover. Thus, when someone uses the sink, water can strike these biofilms, causing bacteria to disperse and enter the patient’s room through droplets of water or even through the air, Healy says.

Hospital sink basins are disinfected on a daily basis, but disinfecting inside the drains and pipes is a bit more challenging. While at Yale, Healy tested a foam-based disinfectant that expands inside the pipes, contacting more of the surface inside the pipe than a traditional liquid disinfectant. Healy and her team found, however, that while the foam reduced bacterial counts immediately, microorganisms returned at higher than initial levels after about a week, and with higher proportions of antibiotic resistance—especially bacteria that are carbapenem-resistant. “This emphasizes how challenging control of these resistant microbes can be,” Healy says. Beyond these measures to reduce the spread of resistant pathogens in the hospital, Yale physicians and researchers are also working to combat the AMR problem in general through responsible use and stewardship of antibiotics.

One of the main contributors to the antibiotic resistance crisis is the overuse and misuse of antibiotics. The Yale New Haven Health System has more than 600 clinical pathways, called Care Signature Pathways, built into the electronic health record system to guide clinical decision-making, including decisions involving antibiotics.

“In the busy moment of caring for a patient in the hospital or in the ambulatory space, one often doesn’t have time to look up the optimal choice and duration of treatment or to access the antibiogram, which is the pattern of antimicrobial resistance specific to our institution that may influence the choice of an antibiotic agent,” says Deborah Rhodes, MD, professor of internal medicine (general medicine), and enterprise chief quality officer of Yale Medicine, who launched the Care Signature Pathway program in the health system and oversees the Care Signature team. “The pathways integrate up-to-date evidence, the consensus of our clinician and research experts, and access to precise orders and resources at the point of care, and the pathway is suggested to the care provider within the electronic health record when relevant to a patient they are evaluating.”

Rather than prescribing a commonly used antibiotic that might be too broad for a particular patient, a clinician can use these pathways to quickly and easily prescribe what might be a less well-known antibiotic, but ultimately one that would be more appropriate for their patient and less likely to lead to the development of antibiotic resistance.

“Somebody who may not have that degree of expertise can use [the algorithms] to help guide them to make sure that not only are they picking the best antibiotic for a patient, but also that they are minimizing any risk that patient may incur,” Martinello says.

The pathways are regularly updated with the expert knowledge of Yale pharmacists and physicians who review antimicrobial resistance trends. The team also recently convened an expert group to create new pathways for recognizing, isolating, and treating patients for measles—a disease that many providers in Connecticut have never seen before.

“These pathways are built by faculty representing all different specialties literally volunteering their time to come to meeting after meeting, and to refine these pathways so that they are concise, accurate, and up-to-date,” says Rhodes. “I think it’s an extraordinary tribute to the collective commitment that this school and system have to excellence in patient care.”