October 30, 2015
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Table of Contents
  1. G7 makes joint commitment on combating antimicrobial resistance
  2. Subway to phase out antibiotics from meat supply chain for US restaurants
  3. California passes first law in the US to limit antibiotics in animal agriculture
  4. Study suggests antibiotic consumption linked to weight gain throughout childhood
  5. UK AMR Review proposes global funding mechanism to stimulate rapid diagnostics innovation
  6. US officials propose framework for collecting data on animal use of antibiotics
  7. President's Advisory Council on Combating Antibiotic Resistant Bacteria holds first meeting
  8. Post-conference recommendations published from Uppsala Health Summit on antibiotic resistance
Other Recent Developments in AMR
1. G7 makes joint commitment on combating antimicrobial resistance
During the G7 Summit on October 8th and 9th in Berlin, Health Ministers from the G7 countries agreed on the "Berlin Declaration on AMR". The declaration emphasizes a three-fold approach involving improvement of infection prevention and control, conservation of existing and future antimicrobials, and enhancing research and development. It calls on the G7 nations to share best practices like those summarized in “Antimicrobial Resistance - Examples of Best-Practices of the G7 Countries.” The declaration also calls for greater coordination among the World Health Organization (WHO), Food and Agriculture Organization (FAO), and the World Organization for Animal Health (OIE). 
G7 Berlin DeclarationTo inform research and development prioritization, the declaration calls for stronger partnerships to identify pathogens of greatest concern. Further, the G7 will collaborate with the WHO to promote information-sharing and collaboration among a global network of experts from academia, industry, healthcare, veterinary care, regulatory agencies, food safety and agriculture, philanthropic organizations, and international organizations. The G7 will explore economic incentives to enhance research and development of new antimicrobials, vaccines, treatment alternatives, and rapid diagnostics. These incentives may include a global antibiotic research fund and a market entry reward for new antibiotics. The G7 encourages international harmonization on clinical trial requirements to help bring new antibiotics to market more quickly.

The declaration recommends strengthening antibiotic stewardship programs in medical and veterinary medicine, including the dissemination of timely information on pathogens and appropriate treatment guidelines. To ensure rational access to safe, effective, and quality-assured antimicrobials, the G7 will assess the feasibility of a global antibiotic product development partnership in collaboration with groups such as WHO and the Drugs for Neglected Disease Initiative (DNDi). Given the lack of comparable data on use of antibiotics and AMR prevalence, the G7 states will establish stronger surveillance at the national and regional level to support WHO, OIE, and FAO surveillance mechanisms. 

The G7 states will develop, or review and implement national AMR plans that incorporate the requirements of the WHO Global Action Plan. They will also support other nations in implementation of AMR plans and global capacity-building. To raise raise public awareness, the G7 will increase its education efforts including through participation in the WHO World Antibiotics Awareness Week. Looking ahead, the declaration calls for a High Level Meeting on AMR in 2016 at the United Nations General Assembly to promote increased political awareness and leadership on AMR. 

Dr. Margaret Chan, Director-General of the WHO, also addressed the G7 Ministers at this meeting on the need for a "one health" approach to most effectively reduce AMR. She described pressing issues associated with AMR, which include limited and unaffordable access to second-line antibiotics and the increasing prevalence of multiresistant bacteria in clinical settings. If current trends continue, the world will enter a "post-antibiotic era in which common infections will once again kill" and complex medical interventions will become too difficult to undertake without effective antibiotics. Dr. Chan emphasized how resistance is driven by overuse of antimicrobials in human and veterinary medicine, including through subtherapeutic use in food-producing animals. Acknowledging that acquiring definitive diagnoses can reduce unnecessary use of antimicrobials, Dr. Chan stated that rapid, low-cost, and available diagnostics can alleviate but not necessarily solve the problem. She stressed that AMR is a global risk whose management requires international cooperation. She described WHO collaboration with OIE to promote the prudent use of antibiotics, which included the creation of WHO and OIE lists of critically important antimicrobials for humans and animals, respectively. Dr. Chan closed her speech by underscoring the role of consumer groups and civil society in motivating industry change through informed decisions about the purchases of food produced from animals raised with antibiotics.
2. Subway to phase out antibiotics from meat supply chain for US restaurants
Subway, the fast-food sandwich chain, has announced a plan to eliminate antibiotics from meat served in its 27,000 US locations. In these locations, Subway will serve only chicken which has never received antibiotics by the end of 2016. A 2-3 year transition to turkey produced without antibiotics will begin in 2016. Subway will not complete its transition to antibiotic-free pork and beef until 2025. This move will take a longer time since the supply of beef raised without antibiotics in the US is "extremely limited" according to Subway. Nonetheless, Subway's new policy goes farther than McDonald's antibiotic commitment earlier this year by establishing a timeline for phasing out antibiotics in not only chicken, but also in the rest of its meat in the same way that Chipotle has done.

This commitment comes as a response to the NRDC-led Subway campaign, which began in June with a public letter signed by over 40 advocacy groups. Specifically, the letter demanded that Subway define a time-bound plan to phase out routine use of antibiotics across Subway meat supply chains, acting immediately to end the routine use of antibiotics important for human medicine in the production of chicken sold in Subway restaurants, as well as adopting third-party auditing of its antibiotics use policy implementation. In August, NRDC launched a public petition at the time of Subway's 50th anniversary, which has since nearly 300,000 signatures. 

In September, NRDC and several partner organizations released a joint report rating top restaurant chains on their antibiotic use policies. The report was released in conjunction with a letter to the CEOs of top restaurant chains signed by 109 organizations representing public health, environment, and consumer interest. Subway was one of several chains to receive a failing grade due to their lack of a transparent antibiotic policy in the US. The letter signatories urged companies to publicly commit to an prohibiting the routine use of antibiotics in livestock growth other than in cases of treatment for sick animals, and communicate with their meat suppliers to establish these expectations.
3. California passes first law in the US to limit antibiotics in animal agriculture
Food Safety NewsThe California State Legislature passed Senate Bill 27 earlier this month banning routine use of non-therapeutic antibiotics in livestock. California is the first state in the US to take legislative action against the use of antibiotics for growth promotion in animals. The law, which will take effect in 2018, will prohibit the unnecessary use of antibiotics and require the development of antimicrobial stewardship guidelines for livestock. California farmers and ranchers will be forbidden from administration of all medically important antibiotics unless they first obtain a veterinary prescription or feed directive, proving that the drug is necessary for treatment of an existing medical condition or control of a disease outbreak. The bill also strictly prohibits administration of antibiotics for the purpose of growth promotion in livestock.  Noncompliant farmers will be fined 250 dollars per day, and subsequent violations would lead to a 500 dollar fine and mandatory education on judicious use of antibiotics. In terms of stewardship provisions, the California Department of Food and Agriculture will be required to develop proper antibiotic use and management practices in consultation with the Veterinary Medical Board, Department of Public Health, and state-based research institutions. This includes collecting data from representative samples on drug sales, usage, and antimicrobial resistance patterns to inform appropriate guidelines for dosage amounts and durations of veterinary-approved antibiotics.

Senator Jerry Hill introduced the original version of SB-27 in December of 2014, with the goal of curbing unnecessary use of antibiotics in livestock and poultry. Environmental groups including the Natural Resources Defense Council criticized the original bill on the grounds that it only replicated non-comprehensive FDA regulations on the use of growth-enhancing antibiotics, but still allowed for routine use of antibiotics in animals that are not sick. The NRDC called for closing the loophole for routine use and adding stewardship requirements, including monitoring and reporting of antibiotics used in livestock operations. With support from California Governor Jerry Brown, these amendments were incorporated during the summer of 2015 and the bill gained strong favorability with NRDC and related groups before being passed this month. Avinash Kar, Senior Attorney with the NRDC Health & Environment Program, called the bill a "landmark law" which “puts California at the forefront of U.S. efforts to end livestock misuse of antibiotics.”
4. Study suggests antibiotic consumption linked to weight gain throughout childhood
Researchers at Johns Hopkins University conducted an electronic health record analysis of over 160,000 children in the Geisinger Health System in Pennsylvania, showing that antibiotic may have a cumulative effect on childhood weight body mass index. Their study went beyond previous work on early childhood use of antibiotic by looking at antibiotic use throughout childhood. The study showed that at age 15, the 30,000 children in the sample who had taken antibiotics 7 or more times during childhood weighed an average of 3 pounds more than those who received no antibiotics. However, the study was limited to some extent by the lack of information on drug compliance and antibiotic use of children outside of the Geisinger Health System. Nonetheless, these results provide further evidence that antibiotic use can lead to long-term alteration of how the gut microbiota breaks down food through killing bacteria vital to gastrointestinal health. Furthermore, the weight gain in children makes sense in the context of the observation that penicillin byproducts caused weight gain in animals, leading to the modern use of antibiotic growth promoters to fatten up animals more quickly. The long-term weight gain implications of repeated antibiotic use reinforce the need for healthcare professionals to ensure judicious use of antibiotics.
5. UK AMR Review proposes global funding mechanism to stimulate rapid diagnostics innovation
The Review on Antimicrobial Resistance chaired by Lord Jim O'Neill has released a report on the key role of rapid diagnostics in addressing antimicrobial resistance. The report frames the use of diagnostics as a public good since they can guide appropriate antibiotic use, leading to long-term societal benefits of conserving antibiotics and preventing antibiotic resistance. However, the short-term reality is that it is more expensive and time-consuming for doctors and patients to use diagnostic tools compared to using an antibiotic precautionarily. At the same time, drug companies have little commercial incentive to develop rapid diagnostics, especially since they would limit the number of antibiotics prescribed and sold. The report proposes the creation of globally-coordinated Diagnostics Market Stimulus pots, which would guarantee revenue to developers of products that address unmet medical needs without judging in advance which diagnostics are best. These pots would be funded through a global payer as part of the $16 to $37 billion market intervention previously recommended by the Review

Review on Antimicrobial ResistanceThe report also recognized the need for greater funding for early-stage R&D activities, especially small and medium-sized companies who face difficulties securing private investments for an uncertain market. To achieve such funding, the report suggests that the previously proposed Global Innovation Fund for AMR could provide financial support to R&D for not only diagnostics, but also complementary technologies such as computer-learning or artificial intelligence systems to guide clinician diagnosis and treatment. The report also recommends further studies, especially large randomized control trials, to establish the long-term economic case for rapid diagnostics. Though these study costs are usually borne by the developers of a technology, the report calls on policymakers to support diagnostics trials given that diagnostics can serve as a public good.
6. US officials propose framework for collecting data on animal use of antibiotics
The US Food and Drug Administration (FDA), Department of Agriculture (USDA), and CDC hosted a meeting about collecting on-farm antibiotic data. At the meeting, representatives of these agencies proposed a new antibiotic data report for animal agriculture with integrated reporting of animal demographic and health, antibiotic sales and use, and antibiotic resistance. This proposed report would increase coordination among existing US antibiotic surveillance systems and address gaps in the data. The presenters from these three agencies argued for expanding collection of antibiotic data in animal agriculture to assess the efficacy of the FDA's Guidance #213 for Industry, which established a three-year timeline to phase out growth promoting antibiotics in animals. As William Flynn of the FDA points out in a presentation at the meeting, sales data currently collected by the FDA do not reflect actual use nor are they species-specific. Animal health and demographic indicators, which would provide context on whether antibiotic use is appropriate, are also limited. Resistance data for foodborne bacteria found in the National Antimicrobial Resistance Monitoring System (NARMS) is not linked to information on antimicrobial use in animals. The proposed report would draw upon expanded USDA on-farm data on animal health, demographics, and resistance; NARMS resistance indicators; FDA sales data, and FDA inspection data. During the public comment section of the meeting, consumer groups advocated for data collection at feed mills due to the common practice of adding antibiotics to pre-mixed animal feed, a data source which was not proposed by agency officials. Industry representatives were also present, including Kathy Simmons, the chief veterinarian of the National Cattlemen's Beef Association (NCBA). She commented at the meeting that the US government should refrain from implementing on-farm data collection before establishing a clear strategy for collection, analysis, and reporting. In addition, she stated that the NCBA believes reducing antibiotic consumption in animals should not be the only metric of success by which interventions are evaluated. The FDA is accepting public comments until November 30 and hopes to begin collecting data in 2016 for publishing in the new report in 2018.
7. President's Advisory Council on Combating Antibiotic Resistant Bacteria holds first meeting
Ellen WanThe President's Advisory Council on Combating Antibiotic Resistant Bacteria held its first public meeting on September 29 - the full meeting is viewable on the HHS Youtube channel. Dr. John Holdren, director of the White House Office of Science and Technology Policy, gave a keynote speech praising recent US progress on antibiotic resistance but calling for further action. For instance, Dr. Holdren mentioned how online laboratory integration has begun in preparation for the creation of an Antibiotic Resistance Communication Network that would disseminate early warnings, events, and trends for public health authorities. The panel discussion were structured around the 5 goals of the US National Action Plan for Combating Antibiotic-Resistant Bacteria, which are to: 1. increase antibiotic stewardship and infection control, 2. strengthen one-health surveillance, 3. advance the development and use of diagnostic tests, 4. stimulate research and development for new antibiotics, other therapeutics, and vaccines 5. improve international collaboration on AMR prevention, surveillance, and R&D. The council will form working groups for the 5 goals of the National Action Plan. These working groups will define key questions for the federal government and determine the outside expertise needed to move forward. Upon developing further policy recommendations, the council will hold another public meeting in early 2016.
8. Post-conference recommendations published from Uppsala Health Summit on antibiotic resistance
Uppsala Health SummitThe post-conference report on the Uppsala Health Summit has been published, containing recommendations from academic and governmental public health experts who gathered in June 2015 to discuss "A world without antibiotics." The Summit's workshops highlighted the need for increased commitment and leadership by national governments and international organizations. Further information and education was named a priority to increase awareness and understanding among target groups, including consumers, farmers, policymakers, and the food industry. Delinking incomes from sales of antibiotics could reduce the reliance on antibiotic sales for incomes among stakeholders such as healthcare workers, pharmacies, veterinarians, and the pharmaceutical industry. For instance, the report recommends that veterinarians should charge for advice and not only for prescriptions and medicines. 

Defining best practices for prudent use in combination with taxes and subsidies can foster an economic model for farming that does not depend on antibiotics. The report suggested that governments should use trade agreements, regulations, and public procurement policies to promote rational antibiotic use. Such tools could include provisions to ban antibiotic growth promoters in food and include environmental criteria for pharmaceuticals within good manufacturing practices (GMP). The report emphasized that rational use should encompass access to effective antibiotics and skilled healthcare professionals, diagnostic tools, and surveillance data in addition to avoiding non-prescription use and incentives for overuse. At the Summit, participants pointed out the need for long-term investments and collaboration, including sharing of data, among academia, small- and medium-sized enterprises, and large pharmaceuticals. These actions would intensify research and development of new treatments, vaccines, and diagnostics through long-term investments. In addition, the report called for further surveillance and studies on the burden of AMR to create reliable data and information to incentivize action. Access to finance was identified as a key prerequisite to implementing the WHO Global Action Plan and recommendations from the Summit.
Other Recent Developments in AMR
Antibiotic resistance could threaten the safety of complex medical procedures
New estimates published in the Lancet suggest that antibiotic resistance could create even more significant burdens for antibiotic prophylaxis in surgery and immunosuppressive cancer chemotherapy. This study provides important insights on how antibiotic resistance specifically impacts prophylactic use during complex medical procedures. Prophylactic use has been shown to reduce infections and mortality. The researchers estimated that between 38 and 51 percent of pathogens causing surgical site infections and 27 percent of pathogens causing infections after chemotherapy are resistant to standard antibiotics in the US. Through reviewing studies on antibiotic prophylaxis A 30 percent reduction in the efficacy of antibiotic prophylaxis for these procedures is estimated to result in 120,000 additional surgery- and chemotherapy-related infections per year in the US and 6300 infection-related deaths. The increasing prevalence of multidrug-resistant bacteria is a major concern given the risks of Gram-negative infections. Recognizing these concerns, the researchers drew attention to the need for more data to create treatment guidelines regarding the use of broader spectrum antibiotics for surgery or chemotherapy. This study was funded by DRIVE-AB (Driving Reinvestment in R&D and Responsible Antibiotic Use), a public-private consortium funded by the European Union Innovative Medicines Initiative.
UNICEF emphasizes importance of handwashing to reduce high child death rate
October 15th marked the 8th annual Global Handwashing Day, an international observance to “increase awareness of handwashing with soap as an effective and affordable way to prevent disease.” On the day, the United Nations Children’s Fund (UNICEF) warned that low rates of handwashing among children in low-income countries pose the danger of continued mortality from preventable diseases like diarrhea, despite improved access to clean drinking water.  UNICEF also noted that increased handwashing is a critical component for achieving the UN Sustainable Development Goal of “access to adequate and equitable sanitation and hygiene by 2030.”  Sanjay Wijesekera, head of UNICEF’s sanitation and hygiene programmes, stated that “along with drinking water and access to toilets, hygiene – particularly handwashing with soap – is the essential third leg of the stool holding up the Goal on water and sanitation.”

Children and infants are especially vulnerable to pathogens and parasites transmitted by unwashed hands. In sub-Saharan Africa where child mortality rates are highest, UNICEF and WHO report that handwashing levels are below 50 percent in the 38 countries with available data. Over 800 of about 1,400 child deaths each day are due to inadequate sanitation or hygiene, according to UN estimates. In an effort to promote handwashing education and practice, governments and international organizations partnered with schools around the world on Global Handwashing Day, including in Haiti, Sri Lanka, Vietnam, and the Democratic Republic of the Congo.
New diagnostic technology tracks body immune response to distinguish bacterial infections
A research team at the Duke University Center for Applied Genomics and Precision Medicine have been working on a diagnostic tool that tracks the body's immune response to infection rather than the presence of specific pathogens. The tool could aid clinicians in more efficiently distinguishing bacterial infections from other sources of infection, helping to avoid unnecessary or excessive prescription of antibiotics. In addition, existing rapid diagnostics for detection of streptococcus and other common bacteria miss more than 50% of infections and often have false positives. The Duke team focused on gene expression patterns in the immune cells of patients who were symptomatic for viral or bacterial infections. By tracking the genetic signatures of these cells, the researchers identified significant differences between the gene expression patterns involved in responses to viral versus bacterial infections.  

The team, led by clinician-researchers Ephraim Tsalik, Geoffrey Ginsburg, and Chris Woods, published their findings in Expert Review of Molecular Diagnostics and also presented at the U.S. Food and Drug Administration’s Public Workshop on Non-Microbial Biomarkers of Infection for In Vitro Diagnostic Device Use on October 16th. The FDA workshop identified next steps toward advancing this novel diagnostic tool, including the need for development of performance standards and rigorous clinical trials to evaluate safety, validity, and accuracy of the technology.
High doses of antibiotics associated with changes in gut microbiome and development of mice
In a study published in Nature Communications, researchers from New York University showed that short-term exposure to high doses of antibiotics led to developmental changes in growth and body composition as well as changes to the gut microbiome in mouse models. The study aimed to evaluate the long-term consequences of early-life antibiotic use, which typically involves short high-dosage pulses in order to treat infections. Researchers administered this “pulse antibiotic treatment” (PAT) to young mice through three short but potent doses of amoxicillin or tylosin, the two most frequently prescribed pediatric antibiotics. Both of these antibiotic dosages led to increased body mass and bone density in the mouse pups, with amoxicillin yielding greater lean mass and tylosin yielding more fat mass. Both PAT treatments also led to disruption of the gut microbiome of young mice, including diminished microbiota diversity and delayed recovery of species following antibiotic treatment. Taken together, the study’s findings on body composition and gut microbiota suggest that early-life PAT treatment can influence the metabolic and developmental patterns of children, and these results are supported by human epidemiological studies of early-life antibiotic use.

This study also has important implications for antibiotic resistance brought on by changes to gut microbiota. Genomic data collected by the researchers suggested that PAT administration led to selection for gut microbes containing resistance genes. Future research can expand upon this evidence by typifying the exact changes in microbiota composition that arise from early-life PAT dosages.
Genetically engineering "innate" antimicrobial properties in food
Researchers from the German companies Nomad Bioscience and Icon Genetics have discovered the possibility of using genetically engineered plants to produce antimicrobial proteins that could prevent foodborne illness. In a study published in the Proceedings of the National Academy of Sciences, the researchers demonstrated that plants including tobacco, spinach, and lettuce are capable of producing high levels of colicins: proteins with extremely potent antimicrobial properties. Colicins naturally occur in E. coli as a means to kill competing bacterial strains. The study tested the potential for colicins to be extracted from GMO plants and applied to contaminated food products to serve as “non-antibiotic” antibacterial agents. Researchers found that a mixture of two classes of colicins could successfully control all major foodborne pathogenic strains of E. coli. Additional benefits of colicins include their relatively low cost compared to mainstream heat processing and acid washes used to treat meat products, and the fact that these proteins have less of an effect on taste and quality. The German team hopes to market their discovery using the U.S. FDA’s regulatory approval process known as “generally recognized as safe,” or GRAS. They claim that getting colicins approved as food additives in small quantities should not be challenging, since these proteins naturally occur in human intestines. However, E. coli bacteria have been shown in lab experiments to development resistance to colicins.

Note: The ARC Newsletter will periodically capture key meetings and developments, as well as news and resources, on antibiotic resistance for Coalition members and partners. This newsletter is prepared and published through ReAct North America and the Program on Global Health and Technology Access at the Sanford School of Public Policy at Duke University. The ARC Declaration on Antibiotic Resistance can be found here. Please share items for consideration for inclusion in future newsletters by writing to Reshma Ramachandran at reshma.ramachandran@duke.edu.