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. Nearly three-fourths of new and emerging human diseases are zoonoses, animal diseases that spillover into humans. Now, scientists are reporting “spillback” of human diseases into monkey populations in South America, as Zika virus becomes endemic and as Brazil faces its worst yellow fever outbreak in years. Human strains of Zika have been found in black-striped capuchin monkeys and marmosets, a concerning trend as these species could become a reservoir for the virus. Capuchins are often kept as pets, employed as street entertainers, or hunted as meat, and these routine interactions could lead to future human outbreaks. Meanwhile, Brazil’s yellow fever outbreak has killed nearly 70 people and more than 600 monkeys, threatening rare and endangered species in the Atlantic rainforest. Researchers at the University of Southampton have designed miniscule 3D spheres that can simulate conditions inside the human body, an exciting development that could help scientists better understand how pathogens interact with human cells. The researchers created one such sphere with a collagen matrix, similar to the makeup of human lungs, to study antibiotics that target and kill the tuberculosis bacterium. The 3D spheres can be used four times longer than existing 2D systems, enabling researchers to monitor the progression of infections over time. Colistin is often the last line of treatment for multidrug-resistant infections, however, its use as a growth promoter for livestock in China has led to the development of colistin-resistant bacteria on chicken farms. While colistin resistance was first reported in China in 2015, it has now spread to 25 countries across four continents. Scientists have discovered a specific gene (mrc-1) that confers resistance to colistin and that can be easily spread between bacteria. Now, a new study has revealed that mrc-1 is much more prevalent than previously believed. The gene was found in nearly all bacteria collected from chicken farms in China, even though only half of the samples proved resistance to colistin. The findings also suggest that flies may be accelerating the spread of colistin resistance by transporting resistant bacteria from farms to surrounding communities. A cocktail of three bacteria-killing viruses could provide rapid protection against cholera, filling a critical need during outbreaks, as vaccines do not provide protection until approximately two weeks after administration. The technique is known as phage therapy as it utilizes bacteriophages—viruses that target and kill specific bacteria. While phage therapy has been around for nearly a century, it was largely eclipsed by the advent of antibiotics, but has gained increasing attention in recent years in response to the growing threat of antimicrobial resistance. To develop the regimen, researchers at Tufts University School of Medicine first identified phages that target the cholera bacterium, and then narrowed their focus to those that can survive and function in the human small intestine, where cholera infection takes place. Animal studies suggest that the cocktail could prevent infection when taken just three hours prior to exposure. The research team has established an independent company, PhagePro, and plans to further test and develop the therapy.

The 140th session of the World Health Organization (WHO) Executive Board (EB) is officially done and dusted. Despite one of the lengthiest agendas in the history of the EB, the meeting actually finished a day early on January 31. As GHTC noted before the meeting, there were several agenda items relevant to global health research and development (R&D), in addition to broader decisions about WHO’s overall future direction. Some resulted in substantive decisions, while others served as an opportunity for delegates to provide input to shape resolutions for the World Health Assembly (WHA) in May. Here are the highlights from the week: Director-General Elections – Decision Point The biggest news out of the EB was the narrowing of the pool of Director-General (DG) candidates from six to three in preparation for a vote at WHA. Contrary to expectations heading into the EB vote, Dr. Sania Nishtar (Pakistan), Dr. Tedros Ghebreyesus (Ethiopia), and Dr. David Nabarro (UK) made the shortlist, while Drs. Flavia Bustreo (Italy) and Philippe Douste-Blazy (France), both of whom many considered to be strong contenders going into the meeting, failed to make the cut. The three have all positioned themselves as reform candidates, committed to continuing many of the reform processes started under outgoing DG Margaret Chan. The campaign now kicks into high gear, and it will be interesting to see if and how the candidates evolve their platforms to respond to priorities from the full membership of WHO now that they have made the shortlist. Global Strategy and Plan of Action on Public Health, Innovation and Intellectual Property – Decision Point The EB approved a new terms of reference for the Global Strategy and Plan of Action on Public Health, Innovation, and Intellectual Property (GSPOA), recognizing the need for WHO to consult with private-sector companies and establishing rules for this engagement as set out by the Framework for Engagement with non-State Actors (FENSA). Adopted in 2008, the GSPOA guides WHO’s work on fostering innovation and improving access to medical technologies for people in low- and middle-income countries. It was designed to promote innovation, build capacity, and mobilize resources by positioning WHO in a central and strategic role managing the relationship between public health, innovation, and intellectual property. As it nears its decade anniversary, WHO is undertaking a review of progress, as well as identifying areas for reform moving forward. In line with WHO’s move to put in place more stringent conflict of interest protections, initial drafts of the terms of reference for the review would have limited the agency’s ability to engage with private-sector companies involved in health R&D. The final draft as approved, however, recognizes the need to consult with these groups. Follow up to the Consultative Expert Working Group on R&D: Financing and Coordination and the UN Secretary-General’s High-Level Panel on Access to Medicines – Input/Information Point The EB’s session to review progress on the establishment of an R&D observatory and pooled fund at WHO to finance R&D as recommended by the Consultative Expert Working Group on R&D: Financing and Coordination (CEWG) was largely sidelined by member state debate on how or whether to carry forward recommendations of the United Nations (UN) Secretary-General’s High-Level Panel on Access to Medicines (HLP), which has proved highly controversial among member state delegations. In the run-up to the meeting, the officers of the EB decided not to include a separate item for discussion of the HLP’s findings in the EB agenda. As a compromise, the president of the EB permitted discussion of the HLP findings to occur under the existing CEWG agenda point. A number of countries, including Brazil, India, Iran, and others had strenuously objected to the exclusion of a HLP agenda item, arguing that WHO is relinquishing its global leadership role on a topic fundamental to health in not taking the lead on implementation of the HLP recommendations. Others, including the United States and some European delegations including Switzerland, Germany, and the UK argued that there was no consensus on the panel’s findings, that the report unfairly targeted specific countries, and that the HLP process had been overly narrow from the start in focusing on intellectual property, as opposed to a broader set of factors that impact access. The EB also did review progress on implementation of the CEWG recommendations. The final plan to establish an R&D observatory will be up for approval at this year’s WHA, while the proposal for a pooled fund to compliment the observatory is significantly less advanced, and work is still underway to determine exactly how a fundraising mechanism can be constructed to support it. GHTC delivered a statement at the meeting welcoming progress by WHO on the CEWG process and encouraging full funding of the observatory and ongoing consultation with stakeholders as the process moves forward. Antimicrobial Resistance – Input/Information Point Following on the heels of last year’s political declaration of the high-level meeting of the UN General Assembly on antimicrobial resistance (AMR), the EB reviewed progress made by WHO and other UN technical agencies to establish a plan to operationalize the declaration’s key recommendations, including spurring R&D for new antibiotics and other tools to combat AMR. As GHTC noted in our statement delivered at the EB, the effectiveness of follow up mechanisms to hold stakeholders accountable for their commitments on AMR will be critical to the overall success of the fight. Many delegates’ interventions focused on this need to deliver on commitments, and the tone of the session seemed to indicate that we will see a robust plan approved at WHA, which will be a great win for global health. R&D for Potentially Epidemic Diseases – Input/Information Point The EB reviewed progress by WHO on establishing an R&D blueprint for potentially epidemic diseases to reduce the delay between the identification of an outbreak and the deployment of effective medical interventions, calling for the agency to accelerate its work, given that the next outbreak can happen at any time. GHTC highlighted in its statement the importance of the blueprint addressing platform technologies, frameworks for collaborative R&D, and investing in regulatory/procurement systems strengthening. These efforts by WHO are part of its self-examination following lessons learned in the response to the Ebola outbreak. Heading into WHA in May, the agenda will be very full. In addition to the items above, the Assembly will also consider WHO’s response in crisis situations, polio elimination, immunization, WHO’s overall budget, implementation of the International Health Regulations to enhance global health security, global shortages of medicines and vaccines, and dozens of other items. GHTC will continue monitoring and will provide updates before, during, and after WHA.

In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. Scientists have identified a gene that stops tuberculosis (TB) from mutating and becoming resistant to antibiotics. Researchers at Centro Nacional de Biotecnología in Madrid and the University of Sussex in Brighton individually deactivated each of the 11,000 genes that make up the TB bacterium, and tested the modified strains against an antibiotic commonly used to treat the disease. The study revealed that the NucS gene, which produces an enzyme that repairs DNA, significantly reduces the frequency of genetic mutations, and consequently, the development of antibiotic resistance. As drug-resistant strains of TB have been reported in more than 100 countries, this discovery could pave the way for improved diagnosis and treatment, making it easier for clinicians and researchers to predict which cases of TB will develop resistance. The US Agency for International Development (USAID) is the largest donor of food aid worldwide, spending US$1.5 billion on wheat, sorghum, rice, and other edible commodities annually. As the food travels around the world, an estimated 1 percent is lost to spoilage, which amounts to 10,000 tons of food worth $15 million. Now, researchers at the Massachusetts Institute of Technology are exploring new ways to package the food to avert spoilage and are testing eight different bags of varying sizes and materials to determine their ability to protect against humidity, water damage, and pests. One model has a completely airtight liner that resists moisture, while another uses a biopesticide that stops insects from reproducing, rather than killing them. The research team is also investigating the use of an airtight liner for the shipping containers, rather than the bags themselves. The final results and recommendations will be available this summer. Gene drives, a promising technique for eliminating mosquitoes and eradicating mosquito-borne diseases, may be stymied by evolution. The novel method involves genetically modifying mosquitoes by introducing an unusually dominant genetic mutation that is passed on to the insects’ offspring, overtaking an entire population of mosquitoes within a few generations. To combat malaria, Zika, and other mosquito-borne diseases, scientists have engineered mosquitoes whose offspring are infertile, and initial trials suggest that gene drives could be a breakthrough in vector control. However, additional research indicates that as these manmade genetic mutations spread through a population, so too do natural mutations that counteract the effect. Furthermore, there is an immense amount of genetic variation among mosquitoes, which limits the potential targets for gene drives. To overcome this, some researchers are introducing multiple genetic mutations at once, however, it remains to be seen whether the manmade or natural mutations will be more powerful.

In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. The location of pig farms can influence human flu patterns, as farmworkers may be among the first exposed to new strains of swine flu. Researchers at Duke University compared a map of North Carolina’s concentrated animal feeding operation (CAFOs) to the location and timing of flu outbreaks in the state, concluding that counties with high numbers of CAFOs experience early peaks of flu cases during years in which a strain of swine flu is in circulation. However, the same effect was not seen in years when the most common strains of influenza did not originate in pigs. The trend is likely attributable to transmission of swine flu from pigs to farmworkers, and subsequently to their family and friends. While efforts targeting CAFOs, such as animal surveillance or vaccination, could decrease human risk for swine flu, a more affordable and immediate solution is for farmworkers and their families to get a flu shot as early as possible each year. Extensively drug-resistant tuberculosis (XDR TB) may be more infectious than previously believed, according to new research out of South Africa. Tuberculosis (TB) is difficult to treat as patients must take multiple pills a day over months or even years. When patients are unable to complete the regimen, the bacteria can grow resistant to the medicines, resulting in multidrug-resistant and XDR TB. However, a study of 404 XDR patients in South Africa suggests that only one-third of cases are due to treatment failures, whereas the remaining cases resulted from person-to-person transmission. These findings indicate that combatting XDR TB will require both improved treatment for TB patients and enhanced prevention and detection efforts. A common fungal infection, Candida auris, is growing increasingly drug resistant. Strains that are resistant to all three classes of antifungals have been reported in five continents. As with antibiotic resistance, antifungal resistance has emerged as a result of inappropriate and overuse of antifungals, and while it may not be as widespread, there are fewer classes of antifungals, providing few alternatives if a treatment fails. An investigation of 54 samples of C. auris found that nearly all were resistant to the first-line medicine (fluconazole), 22 were resistant to both the first and second-line treatments, and 2 were resistant to all three classes of antifungals. Further, standard approaches to disinfecting hospital rooms and equipment are insufficient to eliminate C. auris, increasing the risk of hospital-acquired infections. While cases remain limited, the fungus has an extremely high fatality rate, killing 60 to 70 percent of those infected. Nine recently approved and widely used hepatitis C medicines may have serious, unexpected side effects, including liver failure. The new antivirals cure nearly all patients, have fewer side effects than older medicines, and significantly shorten the duration of treatment. However, a new report published by the Institute for Safe Medication Practices details adverse effects, including potentially fatal liver failure and reactivation of the closely related hepatitis B. At this time, cases are rare and the findings are inconclusive, as the Institute did not have access to patients’ medical records that could shed light on whether the side effects preceded treatment. Now, the Food and Drug Administration is calling on physicians to screen and monitor for hepatitis B in patients taking the new medicines, and a similar approach might be needed to rule out the risk of liver failure.