Breakthroughs Blog: Antimicrobial resistance

While overuse of antibiotics is often cited as a leading contributor to the development and spread of drug-resistant bacteria, recent studies reveal that pollution from antibiotic manufacturing plants in India and China is also playing a role. The wastewater released from these manufacturing facilities contains active antimicrobial ingredients, and in some cases, higher concentrations of these compounds are found downstream from these facilities than is found in patients currently taking antibiotics. One type of bacteria can acquire from another type of bacteria genes that confer resistance to a certain drug. Consequently, resistance is spreading rapidly in wastewater treatment plants in China—for every bacterium that goes into the plants, four to five drug-resistant bacteria come out. To combat this dangerous trend, advocates are calling on the US government, drugmakers, pharmaceutical retailers, and consumers to put pressure on these plants to stop polluting using diplomatic tactics and purchasing power. Meanwhile, new data from the European Medicines Agency indicate that while sales of antibiotics for use in livestock has declined modestly in the European Union, sales have increased for many of the world’s strongest antibiotics, including last-resort treatments and those deemed by the World Health Organization (WHO) to be “critically important in human medicine.” Between 2000 and 2015, insecticides prevented nearly 500 million deaths from malaria, however, this remarkable progress could be upended as mosquitoes develop resistance to pyrethroids, the most commonly used class of insecticides. Pyrethroids have been around for nearly 40 years, and while resistance to this class first appeared in 1993, it has been growing rapidly over the past decade, which has resulted in increased transmission of the parasite in some countries. The pipeline for new insecticides is limited, particularly those that are safe for use in bednets. IVCC, a public-private partnership and member of GHTC, is catalyzing research to both develop novel insecticides and products that combine pyrethroids with other agents to combat growing resistance. The organization has partnered with several pharmaceutical companies and is screening their libraries of more than 4 million chemical compounds to identify the three most promising, which they will then test to determine not only safety and efficacy, but also whether they are long lasting (i.e., effective for at least three years and able to withstand 20 rounds of washing). Other entities have created bednets that combine pyrethroids with pyriproxyfen—which sterilizes the mosquitoes—and piperonyl butoxide—which could make resistance mosquitoes vulnerable to pyrethroids again. For the former, results from an evaluation will be released shortly, and for the latter, results of small trials have been encouraging, but larger, more rigorous trials are needed. The WHO recently convened pharmaceutical companies and humanitarian organizations with the goal of establishing a mechanism to facilitate the sale of low-cost vaccines during emergencies. Under the program, pharmaceutical companies would pledge to provide predetermined vaccines at the lowest price possible during crises such as natural disasters or wars. Currently, many of the targeted drugmakers have agreements with Gavi, the Vaccine Alliance, through which vaccines are purchased in high volumes at these rock-bottom prices. However, the proposed mechanism would limit sales to nonprofits, rather than governmental bodies, to ensure that the vaccines procured would only be deployed as part of a crisis response. GlaxoSmithKline has already agreed to participate, providing its vaccine against pneumonia—the leading cause of death for children under five—at a reduced price during emergencies. The WHO is working to engage additional drugmakers as it seeks to expand the mechanism to cover vaccines against 23 different diseases, including cholera, measles, yellow fever, and hepatitis.

This weekend, Kenya became the first country to roll out the world’s first and only pediatric tuberculosis (TB) medicines. TB infects one million children each year, resulting in 140,000 deaths, and yet, children have historically been treated with crushed up pills in estimated doses. The new formulations, which were developed by TB Alliance, are not only appropriately dosed for kids, but they are fruit-flavored and dissolvable—making them much more kid-friendly than a handful of bitter pills that must be swallowed. Kids must remain on treatment for six months, and the improved dose, flavor, and delivery are expected to have a significant impact on adherence to the regimen, preventing the development of drug-resistant strains. An additional 17 countries have placed orders and plan to introduce the medicines in the coming months. Vaccines and drugs could soon be manufactured on-the-go with the use of a portable, handheld kit developed by researchers at Harvard University. The kit contains all the ingredients needed to produce biologics (medical products derived from biological, rather than chemical sources): both the DNA that triggers the production of proteins to fight disease and the proteins that synthesize the final product. The DNA and proteins are freeze-dried into pellets, making them easy to store and transport, and with just the addition of water, the vaccine or therapy is ready to use. The team put the kit to work, successfully producing four different biologics, however, the vaccine candidate had to be purified before use. More research and testing is needed, and it could be more than a decade before such a system would be safe and appropriate for use in low-resource settings. Diarrheal diseases are a leading cause of death among children under five, and a new study suggests that 89 percent of cases are caused by pathogens. Further, 78 percent of cases are caused by just six pathogens, including rotavirus, Shigella, enterotoxigenic Escherichia coli (ETEC), Cryptosporidium, Campylobacter, and adenovirus. The researchers analyzed stool samples from more than 10,000 children under five, half of whom had diarrhea, to determine the leading causes of childhood diarrhea. Of the six, there is currently only a vaccine against rotavirus, however, GHTC member PATH is currently developing vaccines against Shigella and ETEC. Scientists are exploring whether the powerful antimicrobials created by certain species of ants could be used to fight infection in humans. Over the past 15 million years, more than 200 ant species have evolved to farm fungi—a symbiotic relationship in which the ants collect plants, feed them to fungi, and in turn, the ants feed off of the fungi. However, some ant species are vulnerable to hostile fungi that attack the ants’ nests and farmed fungi and have consequently adapted to fight off pathogens. These species cultivate bacteria—which appear as white patches along the ants’ bodies—that produce antibacterial and antifungal compounds. So far, the results have been encouraging: 1 in every 15 of these antimicrobial agents have proved promising in the lab, compared to just one in a million of those discovered through soil sampling.

As always at this time of year, the international diplomatic community is dealing with the adrenaline letdown following the conclusion of two weeks of mayhem in midtown for the United Nations General Assembly (UNGA). Attendees left with renewed inspiration, a few new political commitments, and for many, a nasty sinus infection that spread all too easily given the diplomatic necessity of copious hand-shaking. In our hyper-connected world where a single international event can spark a global outbreak of something far more deadly, it was apropos that two global health R&D topics received significant attention at this year’s assembly. Antimicrobial ResistanceAs GHTC has previously discussed, the assembly included a special High-Level Meeting on Antimicrobial Resistance (AMR), which was marked by an unusual level of agreement and commitment among member states and United Nations (UN) agencies on what actions are needed to address this challenge. The meeting concluded with the adoption of a political declaration, which among other priorities, acknowledges the importance of catalyzing R&D for the new diagnostics, vaccines, and antibiotics needed to combat AMR.The declaration specifically addresses R&D at three levels: National: Countries should include resources and policies to support R&D in their national AMR plans. Regional: Regional groups should develop regional AMR plans that leverage innovative partnership and incentive mechanisms to support R&D. Global: The UN system should include in its global AMR strategy sufficient policies to encourage global R&D efforts; the entire multilateral system (including development banks) should provide resources to support the above AMR plans, including for R&D; and the UN Secretary-General should establish an oversight group to ensure that all of these efforts are coordinated. We were pleased to see a dedicated call for all stakeholders in global health to ensure that R&D is a key part of addressing AMR and that sufficient resources are allocated to incentive mechanisms. Yet as one panelist rightly noted during the summit, “If I have three key points, they are implementation, implementation, implementation!” As the global community has seen far too frequently in the past, normative agreements reached at the UN require programming to translate them into progress on the ground. It will take civil society pressuring national governments to keep their commitments to this very progressive framework for it to have the impact it can and should. Access to Medicines TB medicines. Photo credit: PATH/Matthew DakinLess than one week before UNGA, the UN Secretary-General’s High-Level Panel on Access to Medicines (HLP) released its long-anticipated final report, which outlines dozens of recommendations from the panel in response to its mandate “to review and assess proposals and recommend solutions for remedying the policy incoherence between the justifiable rights of inventors, international human rights law, trade rules and public health in the context of health technologies.”Both the mandate and the process of developing the report was controversial, as evidenced by the dissenting commentaries contained in an annex to the report. As outlined in the HLP cochairs’ letter to the Secretary-General, the dozens of agreed recommendations fall into four broad categories: Governments must urgently increase their current levels of investment in health technology innovation to meet unmet needs and should enter into negotiations for a binding global R&D treaty that delinks the costs of innovation from the end prices of health technologies in order to address issues that existing innovation mechanisms have failed to adequately remedy. There must be much greater transparency to ensure that the costs of R&D, production, marketing, and distribution, as well as the end prices of health technologies are clear to consumers and governments. Governments and the private sector must refrain from explicit or implicit threats, tactics, or strategies that undermine the right of World Trade Organization (WTO) members to use flexibilities as reaffirmed in the Doha Declaration on TRIPS [WTO Agreement on Trade-Related Aspects of Intellectual Property] and Public Health. WTO members must register complaints against undue political and economic pressure, and take punitive measures against offending members. The Secretary-General should establish an independent review body tasked with assessing progress on health technology innovation and access, and a High-Level meeting on Health Technology Innovation and Access should be convened by 2018.  In this environment, given the timing of the release of the report, the UN Development Programme convened at the last minute an invite-only panel discussion on the final day of UNGA. The session featured forceful remarks from the panelists and advocates, in addition to a lone dissenting statement from a member state government reiterating their concerns over the mandate of the panel.Ultimately, however, the takeaway from the event was the same as from the AMR meeting earlier in the week: the panelists unanimously agreed that the HLP’s work is done and that the Secretary-General now holds responsibility for moving the agenda forward. As a group convened without a member state mandate, the HLP had no binding authority to enact or enforce its recommendations and can only advise on what possible solutions might be. Advocates in the room noted that civil society activism can help hold governments to account and drive forward the recommendations to implementation.Overall, UNGA 2016 showed both the strength and the weakness of our multilateral governance structures. The UN can dream big, convene the world’s most senior leaders, and get them to agree to normative statements. However, implementing those norms requires the full support of its member states. This is not to minimize the importance of such a convening role; we would not have made the progress we have against HIV and AIDS, for example, without the UN’s forceful leadership. What remains to be seen, however, is whether the is a similar confluence of civil society, member state government, and multilateral organization support to move forward the AMR and access agendas over the coming years.

For only the fourth time, the United Nations General Assembly (UNGA) convened a high-level meeting focused on health, which was held during the recent 71st UNGA. Following on the footsteps of the recently released “Review on Antimicrobial Resistance” report (commonly referred to as the O’Neill report), member states gathered to discuss antimicrobial resistance (AMR) and global and national commitments to address this threat. The report estimates that by 2050, 10 million people will die every year because of AMR and the rise of “superbugs.”  At the heart of the high-level meeting was an acknowledgement that the threat of AMR is very real, with multidrug-resistant tuberculosis accounting for one-third of AMR deaths every year and some infections, such as gonorrhea, now only treatable using the last class of antibiotics available. Member states want to address today the overuse of antibiotics, both in human and animal health, improvements in infection prevention and control, and supporting R&D that brings new medicines to market, in order to prevent a return to the days when a scraped knee could kill a child. Before diving into the outcomes of the high-level meeting, it is worth noting a few things that characterized the conversation. First, it is clear that there was a conscious effort on the part of the meeting organizers to use the platform of the General Assembly to reframe AMR as a “One Health” issue where agriculture, animal health, and human health are all aspects to be addressed in an AMR response. And while the World Health Organization (WHO) does not have the authority to direct policy for the Food and Agriculture Organization (FAO) or the World Organization for Animal Health (OIE), the General Assembly does, and it was clear (both from the framing of the summit and the text of the political declaration) that expectations are that the three United Nations (UN) agencies will work together for a coordinated response. Second, the sense of unanimous agreement in the room is something rarely seen at the UN. While there may have been some discussions around the edges of specific technical language, the impression was that member states and UN agencies are on the same page and committed to addressing AMR (unlike HIV and AIDS, for example, where even countries who endorsed the declaration had concerns around some of the action points). The political declaration on AMR, universally endorsed and formally adopted by member states, specifically calls for: Countries to commit to: Developing appropriate action plans and policies to address AMR. Mobilizing additional resources, including for innovative approaches and R&D. Ensuring that surveillance is part of these plans. Undertaking public awareness and education activities on AMR and the dynamics that drive it (including a focus on patient-driven demand for antibiotics). Utilizing a multisectoral model incorporating innovative partnerships and incentive mechanisms to pursue the “One Health” approach. WHO, FAO, and OIE should finalize a global development and stewardship framework to both protect the effectiveness of current technologies as well as to support the development of new technologies. WHO, FAO, OIE, the UN, multilateral development banks, and all other stakeholders should support the national, regional, and global action plans described above. The Secretary-General should establish a cross-UN coordinating group cochaired by WHO and the Secretary-General’s office to guide efforts on AMR, as well as to prepare a report for the 73rd General Assembly outlining progress and recommendations to accelerate it. In the context of the recent release of the report of the High-Level Panel on Access to Medicines (HLP), it is also worth noting that concerns around access to medicines are also evident in the AMR declaration. Unlike the broader access to medicines debate, however, there is a clear acknowledgment of the need to discourage overuse of antibiotics to preserve their effectiveness while ensuring that those who need them have access. Overall, the future implications of the high-level meeting and declaration will depend on what happens next. AMR is squarely on the international agenda and the meeting brought the global community together in an expression of shared desire to fix the problem, which is entirely positive. Unfortunately, shared desire is by no means sufficient to address a problem as complex as AMR. As one panelist said, “If I have three key points, they are implementation, implementation, implementation!” The determinant of the meeting’s success lies in whether the action plans are developed and then acted upon. As for the role of civil society and nongovernmental organizations, holding governments accountable over this is precisely where the global health community can step up through advocacy and mobilizing public pressure to create political will.