Breakthroughs Blog: Antimicrobial resistance

In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. An English springer spaniel has been trained to sniff out Clostridium difficile, a drug-resistant bacterium that infects nearly half a million Americans and costs the US health system an estimated US$1 billion annually. The two-year-old pup—Angus—was tapped for the job after Teresa Zurberg, who normally trains dogs to sniff out bombs and drugs, almost lost her life to C. difficile. Zurberg’s husband, a nurse, had read about a now-retired beagle in the Netherlands that had been trained to smell the bacteria on patients, and the couple approached the local health authorities, suggesting their new pup would be a prime candidate for such a job. Now, after extensive training, Angus is an official employee of Vancouver General Hospital, where he moves from room to room, searching for traces of the bacteria, which are then destroyed using ultraviolet light. As nearly two-thirds of C. difficile cases are acquired in hospitals, dogs like Angus could have a significant impact in not just detecting, but preventing, new cases of C. difficile. Launched last week at the World Economic Forum in Davos, the Coalition for Epidemic Preparedness Innovations (CEPI) seeks to develop vaccines against the diseases most likely to cause the next major pandemic. The coalition was established by the governments of Norway, Japan, and Germany in partnership with philanthropic organizations the Wellcome Trust and the Bill & Melinda Gates Foundation. Collectively, these partners have pledged US$460 million to the initiative, half of what is needed for CEPI’s first five years of operation. During its initial phase, CEPI will focus on advancing two experimental vaccines for each of the three viruses that have been identified by the World Health Organization as leading contenders for the next major pandemic: Lassa fever, Middle East respiratory syndrome (MERS), and Nipah virus. Carbapenem-resistant Enterobacteriaceae (CREs), a class of deadly, drug-resistant bugs that have been deemed “nightmare bacteria” by the director of the Centers for Disease Control and Prevention may be more prevalent and virulent than previously realized. These bacteria often contain specific genes that enable them to evade different types of antibiotics, including carbapenems, potent drugs that are often reserved as the last line of treatment against drug-resistant infections. To better understand their evolution and spread, researchers at Harvard University and the Massachusetts Institute of Technology sequenced the genomes of 263 CREs, collected from patients at four hospitals. The results revealed that carbapenem resistance is emerging across diverse types of bacteria and that the genes that confer resistance can be transferred between distinct bacterial families. Even more alarming: some CREs don’t have any of the known resistance genes, meaning that there are either more, unidentified resistance genes than we are aware of or that CREs have developed other ways to resist antibiotics. The study also indicates that CREs can be carried and transmitted asymptomatically, making surveillance of these dangerous infections all the more difficult.

Scientists at the University of Oklahoma are looking for the next breakthrough drug in an unusual place: roadkill. Every animal hosts a unique microbiome—a community of microorganisms, including bacteria, fungi, and molecules with antibacterial and antifungal properties. The research team is collecting swabs from dead animals found along a state highway and has already discovered two compounds (taken from an opossum’s ear) that could prevent the spread of yeast infections. Hypothermia is a significant driver of morbidity and mortality among babies born prematurely, even though the condition is easy to detect and treat. Detection relies on temperature monitoring, and current standard of treatment is Kangaroo Mother Care (skin-to-skin contact). Now, an electronic alert bracelet is being used to prevent hypothermia among preemies in India. If the infant is healthy, the bracelet flashes a blue light every ten seconds; if the infant’s temperature drops, the light turns to red and an alarm goes off. The single-use device is safe and can be used for a month straight—even at home. Though a daily dose of pre-exposure prophylaxis (PrEP) can prevent HIV infection, stigma, cost, and frequent stockouts can impede adherence to the regimen. While only four doses per week is sufficient to protect men from infection, if women miss a single daily dose, they risk infection. To mitigate these barriers, researchers at Intarcia Therapeutics Inc. are developing an implant that would release PrEP over time, meaning just one visit to the doctor’s office would protect patients for an entire year. The device has already undergone advanced testing and is currently under review by the US Food and Drug Administration for the delivery of diabetes drugs. Researchers at the Center for Infectious Disease Research (CIDR) in Seattle are using mosquitoes, rather than syringes, to deliver an experimental malaria vaccine. The vaccine uses live, but weakened malaria parasites, which can only grow inside living mosquitoes. In an initial trial, ten volunteers were vaccinated, none of whom developed malaria and all of whom produced antibodies that could confer immunity against malaria. The antibodies were extracted from volunteers and successfully used to protect mice against malaria, however, additional trials are needed to determine their efficacy in humans. CIDR is partnering with the Maryland-based biotech company Sanaria to develop a more standard and sustainable vaccine delivery system, producing the weakened parasites and extracting them from the mosquitoes, and attempting to grow the parasites outside of the mosquitoes.

In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. Earlier this year, the World Health Organization released a list of the eight pathogens most likely to cause the next pandemic. All eight are caused by viruses, and all eight are zoonotic—originating in animals. To experts, this came as no surprise: viruses are able to rapidly evolve to infect different species or become more virulent, and nearly three-fourths of new and emerging diseases are zoonotic. Now, researchers are proposing the Global Virome Project, an initiative to characterize every virus in the world (well, 99 percent of them). Tracking down the estimated 1.3 million viruses in the world would cost nearly US$3.4 billion, however, proponents of the project argue that it would unearth insights into viruses en masse and ensure a basic scientific understanding of potential pandemic threats. New research suggests that nearly half of women infected with Zika during pregnancy will have adverse pregnancy outcomes, including miscarriages and birth defects. The study, which enrolled 125 women in Rio de Janeiro, Brazil, is the first to quantify the frequency of these complications among pregnant women who test positive for the virus. Overall, 46 percent of women experienced significant adverse outcomes, however, the true impact may be even higher. The study only followed infants for the first three months of life, but emerging research indicates that neurological and physical defects may develop throughout the first year of life. Further, the study reveals that risk is greatest for women who are infected during the first trimester (55 percent), though adverse outcomes remain common among women infected during the second (51 percent) and third (29 percent) trimester. Antibiotics and immune cells can only target bacteria when they are growing and dividing. Consequently, bacteria often become inactive to evade detection. Many bacteria rely on a toxin antitoxin system to achieve this. A pernicious environmental factor will prompt the bacteria to produce a toxin that puts themselves to sleep, and the abatement of that factor triggers the release of an antitoxin to wake the bacteria back up. Now, an international team of researchers has discovered that the toxin antitoxin system for E. coli, and potentially other bacteria, relies on oxygen to wake up the bacteria. When E. coli cells are dormant, both the antitoxin and oxygen must be present to destroy the original toxin. These findings suggest that oxygen could be the key to developing antibiotics that can wake up and consequently attack dormant bacteria.

The HIV virus is rapidly developing resistance to common antiretroviral drugs. In low- and middle-income countries (LMICs), 10 percent of patients starting antiretroviral therapy (ART) and 40 percent of patients restarting treatment are infected with drug-resistant strains. The leading contributor to drug resistance is failure to adhere to treatment—a problem that plagues nearly three-fourths of patients in LMICs. In low-resource settings, many patients only have access to older, more toxic drugs, and more than one third of clinics report stock outs of HIV medicines. If action is not taken to improve treatment for these patients, drug-resistant strains of HIV-1 could result in 300,000 new infections and 425,000 deaths over the next five years. Last week, the US Congress overwhelmingly approved the nearly 1000-page 21st Century Cures Act, a massive initiative that channels new funding into the US National Institutes of Health and alters the way the US Food and Drug Administration (FDA) regulates certain medicines and devices. While some advocates argue that it weakens the FDA’s regulatory review process, others have applauded the legislation for its potential impact on the development and approval of new antibiotics. One provision—the limited population approval pathway—would allow the FDA to approve antimicrobials and other drugs for serious or life-threatening infections based on smaller clinical trials, addressing the challenge of identifying an adequate number of clinical trial participants (i.e., patients who are infected with drug-resistant pathogens). Another component addresses the FDA’s approach to updating antimicrobial susceptibility interpretative criteria, which informs the development of diagnostics that help physicians prescribe the best antibiotics for a given infection. The provision enables the agency to rely on other organizations’ research and update its criteria accordingly, rather than reviewing the research in house—a time consuming and costly process. While the legislation will likely be signed into law by President Obama, it could take years to fully implement. Scientists have long known that the tuberculosis vaccine offers protection against a number of pathogens and even treats certain conditions (i.e., bladder cancer and asthma), and a recent study in Cell Reports may explain why. Studies in mice and humans revealed that the Bacillus Calmette-Guerin vaccine increased glycolysis—the process of breaking down glucose—in monocytes, a type of immune cell. The effect, which lasts long after vaccination, enhances monocytes’ immunological memory—their ability to remember pathogens they have previously encountered—improving their disease detection and response capabilities. These findings could help scientists devise new strategies for boosting the immune system or its response to certain diseases. The European Medicines Agency (EMA) released a statement last week indicating that patients treated with certain hepatitis C medicines may experience a resurgence of previously latent hepatitis B. The phenomenon applies to a new class of drugs known as direct-acting antivirals and includes Daklinza, Exviera, Harvoni, Olysio, Sovaldi, and Viekirax. While there have only been 30 reported cases, the EMA is recommending patients be tested for hepatitis B before starting treatment.