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 infections such as pneumonia and syphilis that once would have been highly debilitating or even fatal became treatable.
But there is a dark side too. 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 are faced with what evolutionary biologists call “selective pressure” (a force that affects an organism’s ability to survive)—as from an antibiotic. Through random mutations in DNA 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, the evolutionary pressure on bacteria intensifies. By generating defenses against the antibiotics that were designed to kill them, these microorganisms can develop and spread 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. Because of a major lag in the development of new antibiotics (due in large part to a lack of financial incentives for pharmaceutical companies to develop these drugs), this crisis has ushered in what some experts are calling 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 of pediatrics at Yale School of Medicine (YSM), and medical director of infection prevention at Yale New Haven Hospital (YNHH). “Many years ago, we may have been able to easily treat [patients] and cure their infections, but it may not be so easy anymore.”
How can we ensure our hospital is a safe space where patients come in for one problem and we don’t make things worse by giving them an infection while they’re here?
Scott Roberts, MD
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 types of Enterobacter) that are resistant to last-line antibiotics. For instance, a class of broad-spectrum antibiotics called carbapenems are highly effective, but physicians can only use them 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, Martinello says, physicians may seek a newer antibiotic or an antibiotic alternative.
Because AMR is causing significant problems on a global scale, an urgent search for solutions is underway. At YSM, researchers are investigating longer-term answers, while health professionals at YNHH are taking immediate steps to combat this issue on the clinical side.
Yale’s Antimicrobial Resistance Faculty Network
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 disease at YSM, focuses on malaria in highly vulnerable groups in sub-Saharan Africa. He studies everything from which combinations of malaria drugs are least likely to lead to resistance at both the individual and population level to continent-wide policy recommendations for the surveillance of drug-resistant malaria.
“It’s going to be years before novel drugs are available on the marketplace [for malaria],” he says. “We need to urgently determine how to combat the current emergence 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, hookworms, skin conditions such as acne, pneumococcal disease, and AMR in hospitals. One group is even looking at potential alternatives to antibiotics in the form of microscopic viruses called bacteriophage(s).
Fighting AMR with phage
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 was made possible through the Food and Drug Administration’s (FDA) 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 phage. Turner’s group, along with other researchers around the world, 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. They categorize and store these phages to create a “phage library” of potential candidates for phage therapy. To treat patient infections, a bacterial sample is obtained from patients and tested by the phage library to identify which phages are best suited to kill the bacteria in question. Once they have the right phage or series of phages, and FDA approval is obtained, the phage is used and can be delivered 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 served as director of the Adult CF Program since 2011, and has been collaborating with Turner and Ben Chan, PhD, scientific director of the Center for Phage Biology and Therapy, to treat both cystic fibrosis and non-cystic fibrosis patients 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.
Aside from running clinical trials using phages to treat persons with cystic fibrosis (pwCF), Turner, Chan, and Koff have received requests from their colleagues to use phages to treat bone, prosthetic joint, urinary tract, and sinus and other infections. The center receives multiple requests every week for phage treatments, and recently moved into a new facility to be able to better meet the demand.
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. “I think there will absolutely be a place for phage in treating patients, and I think there probably is a place for phage independent of antibiotics that needs to be more fully explored.”
Reducing the spread of AMR in the hospital
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 is especially true 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 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 pre-existing 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 could happen 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 routes such as contaminated surfaces, equipment, and 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 medical equipment such as thermometers, probes, stethoscopes, catheters, and non-medical equipment, such as surfaces in a patient’s room. Martinello and Roberts have implemented procedures to reduce the spread of pathogens through these routes.
“How can we ensure our hospital is a safe space where patients come in for one problem and we don’t make things worse by giving them an infection while they’re here?” Roberts says. “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 and Martinello have focused on strategically placing hand-sanitizer dispensers in locations that will allow for maximal and convenient hand hygiene for hospital workers. They’ve also begun piloting a 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 certain healthcare associated infections such as catheter associated urinary tract infections and methicillin-resistant Staphylococcus aureus (MRSA) infections. Other researchers at Yale are also beginning to identify additional places where resistant bacteria might lurk, and how to keep them away from patients.
Pathogens in the pipes
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 be splashing resistant bacteria right back into a 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, postdoctoral associate 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 is studying how 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 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 up the sides of the pipe in sticky sheets called biofilms, sometimes even growing as far as the drain cover. Thus, when someone uses the sink, water can hit these biofilms and cause 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. Healy recently tested a foam-based disinfectant that expands inside the pipes, contacting more of the surface inside the pipe than a traditional liquid disinfectant. However, Healy and her team found that while the foam reduced bacterial counts immediately, after about a week, microorganisms returned at higher than initial levels, and with higher proportions of antibiotic resistance.
“This emphasizes how challenging control of these resistant microbes can be,” Healy says. She and her team are continuing to investigate the tradeoffs of lowering microbial loads with selecting for resistant organisms for different disinfections frequencies.
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.
Pathways for 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 decision 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 choice of 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 at 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 electron 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 they 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 regularly review antimicrobial resistance trends.
“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.”