April 2, 2016
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Table of Contents
  1. AMR discussed at UN High-Level Panel on Access to Medicines
  2. WHO holds multiple convenings on AMR
  3. WHO releases manual for developing national action plans on AMR
  4. UK Review on AMR report focuses on infection prevention, control, and surveillance
  5. Consumers International calls on large food chains to reduce antibiotic use for World Consumer Rights Day
  6. CDDEP study describes state of AMR in India, identifying drivers of resistance and opportunities for action
  7. American think tank CSIS recommends US adopt a national position on R&D business models
  8. Large US meat companies Cargill and Tyson to reduce antibiotic use
  9. Pew Charitable Trusts, IDSA, and food companies call on US Congress to increase funding for researching AMR in food system
  10. Climate change could increase the incidence of diarrheal disease

1. AMR discussed at UN High-Level Panel on Access to Medicines

In March, the UN High-Level Panel on Access to Medicines convened two global dialogues in London and Johannesburg to discuss ways that governments, civil society, pharmaceutical groups, human rights lawyers, and academia can promote innovation and access to vaccines, diagnostics, and medicines. The Johannesburg meeting also featured a panel discussing antimicrobial resistance. Speakers included Tamar Ghosh of Nesta who leads the Longitude Prize; Jon Pender who serves as Vice President of Intellectual Property & Access; Zakir Thomas who served as the Project Director of the Open Source Drug Discovery initiative for the Government of India, and Eva Ombaka, former coordinator of the Ecumenical Pharmaceutical Network in Africa. These global dialogues have recruited a broad range of stakeholder perspectives as the High-level Panel works towards a final report in June.Mandeep Dhaliwal, the Head of the Secretariat of the UN High-Level Panel on Access to Medicine and Director of Health and HIV at the UN Development Project, wrote an op-ed about antibiotic resistance published in the Guardian. Emphasizing the urgency of AMR, Dhaliwal cites the discovery of MCR-1 colistin resistance and the Review on AMR's estimate that 10 million people would die every year by 2050 in the absence of new antibiotics. Dhaliwal notes that President Obama, Prime Minister Cameron, and Prime Minister Narendra Modi have made statements on the need to act on AMR. The UK has committed $300 million to support microbiology surveillance capacity in developing countries. G7 and G20 leaders committed to take action at the World Economic Forum, and 80 companies made a joint declaration to create sustainable markets for antibiotics and stimulate research and development.

Dhaliwal also highlighted local-level actions, hand washing and immunization campaigns to control the spread of infections. Civil society can raise awareness on avoiding infections and educate patients about the proper use of antibiotics. This includes when to take antibiotics and the importance of taking the full course of treatment. She also states that public pressure has led the food industry to begin reducing misuse of antibiotics in agriculture. Dhaliwal stressed that "between the 20 richest countries and the major pharmaceutical companies there is no excuse for not finding the money needed" to tackle AMR. To develop 15 new drugs would cost $16 to $35 billion over the next ten years, a worthy investment to avoid the $100 trillion decrease in global economic output due to AMR without action now.
Johannesburg Global Dialogue: High-level Panel on Access to Medicines
Webcast of the Johannesburg Global Dialogue

2. WHO holds multiple convenings on AMR

A partnership between WHO and the Drugs for Neglected Diseases Initiative has led to the development of the Global Antibiotic Research & Development Facility (GARD). This collaboration, announced in November 2015, seeks to develop new antimicrobial treatments while ensuring conservation and equitable access. Charting the scientific agenda going forward, GARD held a consultation in Paris on February 29th. Through discussion of 10 project proposals, GARD has determined a set of priorities. In the short- and medium- term, GARD will support research on combining and improving usage of existing antibiotics, or combinations with non-antibiotic compounds, especially to treat gram-negative pathogens. This will involve systematic evaluation of antibiotic combinations, especially given that many older drugs were registered with incomplete pharmacokinetic/pharmacodynamic analysis. Research on combination treatments will also contribute to evidence-based stewardship and treatment guidelines.Several projects were dedicated to reformulation of existing drugs, in particular polymyxins (one of which is colistin), tebipenem, and co-amoxiclav. Reformulations to optimize efficacy, increase stability, and reduce toxicity is a priority for these drugs. Another short-to medium-term project theme is developing antibiotic strategies to target specific clinical infection syndromes. These strategies would be holistic, including rapid point-of-care diagnostics, antibiotic reformulations or combination treatments that are stable enough not to require a cold chain and formulations easy to administer regardless of age group. GARD named neonatal sepsis, melioidosis, gonorrhea, and typhoid fever as unmet needs to tackle. Lastly, GARD considered upstream research projects, such as a proposal to treat H. pylori by targeting bacterial cell wall development as an improvement over the current treatment standard of giving two antibiotics and a proton pump inhibitor. GARD plans to select projects in the coming months and launch two projects by the end of 2016.

India Ministry of HealthOn February 23 to 25, the WHO South-East Asia Regional Office and Indian Ministry of Health and Family Welfare hosted a conference on AMR in New Delhi. A diverse group of 350 participants from 16 countries attended, including health ministers from the South-East Asia region, members of industry and civil society, and representatives of WHO. The main topics discussed were regulations to promote rational use, infection prevention and control, and surveillance in humans, animals, and the environment. Speeches from Minister Shri Nadda of the Indian Ministry of Health and Family Welfare and Dr. Poonam Singh, Regional Director of WHO South-East Asia, raised antibiotic use in animal agriculture as a reminder that AMR requires multisectoral solutions. Conference participants committed to strengthen collaborations to address the access gap for antibiotics, an issue that particularly affects rural areas. The WHO called for participation in the Global Antimicrobial Surveillance System and emphasized commitment to support India and the region through advocacy, capacity building and technical assistance, and supporting resource mobilization. The Indian Ministry of Health and Family Welfare launched a public awareness campaign for patients and pharmacists centered around labeling antibiotics with a red vertical line to indicate that they should only be taken with a prescription.

3. WHO releases manual for developing national action plans on AMR

A Manual for Developing National Action PlansThe WHO has released a manual for policymakers to develop national action plans on AMR. The manual proposes an incremental approach adaptable to specific country needs, circumstances, and resources. The WHO Global Action Plan on AMR (GAP), passed in 2015, sets forth a goal for all Member States to adopt national action plans by May 2017. The manual sets forth the following guiding principles for national action plans:
  1. A One Health approach that includes "actors and sectors human and veterinary medicine, agriculture, finance, environment, and consumers."
  2. Alignment with the five strategic objectives of the WHO GAP, which are to raise awareness of AMR, strengthen surveillance and research, reduce the incidence of infection through sanitation, hygiene, and infection prevention, optimize antibiotic use for human and animal health, and to build an economic case for sustainable investment that takes into account the needs of all countries, and increase investment in new medicines, diagnostics, vaccines, and other interventions.
  3. Prioritization and stepwise approach, with flexibility in planning and local priorities.
  4. A multisectoral systems approach that establishes joint ownership on the plan. The manual states that a plan should also take into account food security, food safety, and economic development. This includes support to farmers and producers in adopting good animal husbandry and biosecurity practices.
The manual lays out steps for implementation. First, the manual recommends creating a transparent and multi-department governance structure. Then, situational analyses should be conducted as the basis for priority-setting. The manual provides a list of indicators that would compose a robust situational analysis. Such an analysis includes rates of AMR burden, resistance to antiretrovirals, and multidrug-resistant tuberculosis. The manual recommends measuring various factors that drive resistance including perceptions and behaviors that lead to inappropriate use, quantity of antimicrobial use in human and animal health, and weak quality assurance or unregulated access. In addition, the manual recommends situational analyses that assess the capacity to enforce regulations on antimicrobial drugs, availability of alternatives to antimicrobials, capacity of country systems to regulate antimicrobial use, existence of policies and legal frameworks on AMR, and relevant stakeholders. The manual states that the core components of a national action plan are its strategic plan (goals and priorities), an operational plan (activities, timetable, responsible entities, budgeting), and a monitoring and evaluation plan.
 
The WHO promoted the ReAct Toolbox during a regional workshop on National Action Plans for AMR hosted by the WHO Regional Office for the Eastern and Mediterranean Region on March 14-17. The ReAct Toolbox, which includes a section on developing national action plans, is also listed as a resource in the WHO manual. The national action plans for sixteen countries are now accessible in the WHO library of national action plans.

4. UK Review on AMR report focuses on infection prevention, control, and surveillance

UK Review on AMRThe UK Review on Antimicrobial Resistance has published a report on infection prevention, control, surveillance. The incidence of infectious diseases is associated with increases in antibiotic use, which in turn increases AMR. For this reason, the Review recommends increasing access to clean water and sanitation to prevent the spreading of infections, which will ultimately reduce AMR. The report puts forth a number of system-wide steps to prevent and control infections in healthcare settings. In addition, the Review calls for continued monitoring of the global burden of infectious disease, including surveillance of AMR.To establish the case for sanitation measures, the Review predicted the effect of universal access to improved water and sanitation in Brazil, Indonesia, India, and Nigeria. In these four countries, 494 million cases of diarrhea are treated with antibiotics each year. Universal access would lead to a 60% reduction in the volume of antibiotics used to treat diarrhea caused by inadequate water supplies and sanitation. The Review also analyzed public data from the World Bank and the World Health Organization on sanitation. They found that controlling for income, increasing access to sanitation in a country is associated with nine and a half years of additional life expectancy.

The Review calls for system-wide infection prevention and control (IPC) measures to address healthcare-associated infections (HAI). 7 out of 100 hospitalized patients in high-income countries, and 10 out of 100 in low and middle-income countries will acquire at least one HAI. A third of patients in intensive care units in high-income countries experience at least one HAI.  A quarter of healthcare-associated infections in long-term acute care settings are caused by drug-resistant bacteria. The report cites the example of England's 56% reduction of methicillin-resistant Staphylococcus aureus (MRSA) cases from 2004 to 2008 following the introduction of targets by the National Health Service (NHS). However, the report also acknowledges that targets may be arbitrary or too narrowly focused on specific pathogens (MRSA, C. difficile) or infection types (bloodstream infections). Nonetheless, the report stresses that improvements can be made through political, regulatory, and financial commitments to stewardship that encompasses a wider range of infections. Some of these improvements can be achieved through simple and inexpensive steps such as professionals washing hands more frequently and following checklists. The report suggests that there is a need for "modest funding" to conduct targeted studies on the efficacy and cost-effectiveness of individual IPC interventions, for example, on behavioral "nudges" to improve hand hygiene.

The Review argues that there remain significant gaps in the road towards reliable information on global AMR. In addition to aiding the decisionmaking of policymakers, such information could benefit healthcare professionals and patients. The report points out the challenge of enabling doctors and researchers to make informed clinical decisions using "big data" on AMR generated by new modernized diagnostics and cloud computing. The report notes that surveillance efforts are being carried out within the WHO, regional blocs, and philanthropic organizations. Countries have also put in funding to monitor the burden of AMR, such as through the US Global Health Security Agenda and the UK Fleming Fund. However, these surveillance efforts are not centrally coordinated and suffer from data gaps and delays. The Review calls for addressing how data are owned, used, and shared. In particular, there needs to be an alignment of incentives to incorporate private actors, such as private laboratories and hospitals in middle-income countries, into national and global surveillance systems. National and international regulation will be needed to enable or even enforce data sharing with public health agencies. The report also highlights the importance of surveillance in animals and the environment. Of the 180 member countries of the World Organization for Animal Health (OIE), 110 lack the systems or legislation to monitor antimicrobial use in animal agriculture. The only surveillance of AMR, such as through industrial pollution from antibiotic production, has occurred through small studies rather than routine surveillance systems.

This report is the last of a series of interim reports on AMR that precede the Review's final report to the UK Prime Minister in May 2016, which will outline the global costs of a coordinated global AMR surveillance system.

5. Consumers International calls on large food chains to reduce antibiotic use for World Consumer Rights Day

Consumers InternationalConsumers International WCRD MapConsumers International (CI) organized a worldwide campaign calling on McDonald's, Subway, and KFC to make global commitments to stop the routine use of antibiotics in their meat supply chains. Over 75 consumer rights organizations in 60 countries carried out national campaigns to mark World Consumer Rights Day on March 15. In addition, several hundred people participated in the CI Thunderclap campaign, which automatically posted the message "McDonald’s, KFC & Subway: Help tackle #antibioticresistance health crisis- get #AntibioticsOfftheMenu!" on participants' Facebook and Twitter accounts. The Thunderclap's message reached 2.2 million people.On February 25th, CI published its Antibiotics Off the Menu report to describe the current state of antibiotic commitments from McDonald's, Subway, and KFC. The report criticizes KFC for its complete lack of an antibiotic policy, and McDonald's and Subway for their lack of policies that extend beyond the US and Canada. During World Antibiotics Awareness Week, CI wrote letters to the three companies calling for global commitments. In response, McDonald's did not inform of any new commitments on antibiotic use. Subway stated that it would roll out a similar antibiotic policy in New Zealand "as soon as possible," but without specifying a timeframe nor discussing whether they will make similar commitments globally.

KFC stated that it follows the local laws in the countries where it operates, without mentioning whether there might be commitments to end routine use of antibiotics used in human medicine. The CI report criticizes this argument as insufficient since many countries have not yet created adequate regulations on antibiotic use in agriculture. The Yum! Brands US website, the parent company of KFC, Pizza Hut, and Taco Bell, stated that the three chains are committed to sourcing chicken in the US raised without antibiotics critically important to human medicine by the end of 2016. However, there is no confirmation on whether this also applies to antibiotics defined as the WHO as "highly important" or "important." KFC Africa stated that its products are antibiotic-free at the point of consumption, which only ensures that foods are free of residues but does not indicate anything about whether antibiotics are used in the production process. CI's campaign and report have continued to emphasize the importance of consumer action to encourage large food companies to reduce their antibiotic use.

6. CDDEP study describes state of AMR in India, identifying drivers of resistance and opportunities for action

CDDEPA paper published in PLOS Medicine describes the factors contributing to high AMR burden in India and recommends prioritization of improved regulation of drug production and sales for human and animal use, management of physician compensation, and behavior change among doctors and patients. Poor public health indicators, rising incomes, and the availability of inexpensive over the counter antibiotics contribute to the high antibiotic use in India. India has seen increased prevalence of bacteria resistant to antibiotics including third-generation cephalosporins, fluoroquinolones, and carbapenems. New Delhi metallo-ß-lactamase (NDM) enzymes, which confer broad resistance to beta-lactam antibiotics (penicillins, cephalosporins, carbapenems), were first reported in India in 2008. Since then, NDM has been detected worldwide. The paper also emphasizes that restrictions on antibiotic use need to be balanced with ensuring access for those who need antibiotics and may not have access to doctors - especially in light of an estimate that lack of access to antibiotics kills more children in India than drug resistance does.In 2010, India was the world's largest consumer of antibiotics for human health, and 67% of the increase in global antibiotic consumption between 2000 and 2010 is attributable to Brazil, Russia, India, China, and South Africa. The paper suggests that population density is not to blame for the spread of resistant pathogens. Rather, India performs worse than countries like Brazil, China, and Indonesia on public health measures including immunization coverage and access to improved sanitation facilities. However, the government has committed to provide toilets and improved sewage through the Swacch Bharat Abhiyan (Clean India Program).

In discussing health system drivers of AMR, the paper points out how doctors routinely receive compensation from pharmaceutical companies and pharmacists in exchange for antibiotic prescriptions. Infection control is in need of improvement to address healthcare associated infections  - the national rate is 7%, and half of all patients in Indian hospitals receive antimicrobials. In 2014, the Central Drugs Standard Control Organization implemented Schedule H1, which requires a prescription for 24 antibiotics, though several antibiotics are not included and remain available over the counter. The paper also calls for antimicrobial stewardship and clinician education on appropriate use of fixed-dose combinations in parallel with improved quality control for substandard medicines. The paper also highlights the lack of regulations for antibiotic pollution from manufacturing facilities and wastewater treatment, which thereby allows resistant bacteria to spread through the environment. Similarly, India does not have regulations for the use of antibiotics in animal agriculture, with the exception of residue limits for seafood.

The paper praises the awareness building from efforts such as the Chennai Declaration. The Indian Council of Medical Research has established a surveillance program in 10 laboratories based at academic centers, and a surveillance platform is being created as a part of CDDEP's Resistance Map. Ramanan Laxminarayan, director of the Center for Disease Dynamics, Economics and Policy (CDDEP), co-authored the paper.

7. American think tank CSIS recommends US adopt a national position on R&D business models

CSISThe Center for Strategic & International Studies (an American think tank) has published a paper arguing that the US needs to formulate an overarching policy on business models to stimulate research and development of new antibiotics while encouraging conservation and appropriate access globally. Reporting the results of a private CSIS roundtable on proposals to stimulate antibiotic development, the paper notes how conversations have begun on delinkage mechanisms, and push and pull economic incentives. For instance, the UK is working with pharmaceutical companies on assessing the feasibility of a licensing fee reimbursement model. Under such a model, payers enter a contract with a pharmaceutical company to pay upfront fees for access to a drug that are not based on sales volumes. In partnership with the European Federation of Pharmaceutical Industries and Associations, the EU has funded DRIVE-AB, a project to investigate alternative business models. CSIS suggests that the US develop a position lest it get left behind while other countries continue with collaborative implementation of new business models. In particular, CSIS recommends that the White House consider and implement the recommendations of the Combating Antibiotic Resistant Bacteria (CARB) Economic Incentives Working Group. These recommendations were submitted in September 2015 to the White House Office of Science and Technology Policy. However, the White House has not made public the recommendations nor an implementation plan. This led 30 stakeholder organizations to send a letter to President Obama in December 2015 asking for the release of the CARB Economic Incentives Working Group report.The paper discusses the history of AMR policy responses and attributes a lack of political and scientific attention to AMR to the 2001 terrorist attacks and anthrax mailings in the US. However, as the paper describes, attention to AMR has increased significantly in the form on the US National Action Plan, the WHO Global Action Plan, resolutions from FAO and OIE, and prioritization by the G7 and UN General Assembly. The paper calls suggests that information sharing and coordinated decision-making are needed, with the possibility of a binding international agreement. The paper notes that the US-EU Transatlantic Task Force on Antimicrobial Resistance (TATFAR) has provided a space for exchanging best practices and joint activities such as awareness campaigns. In addition, the Global Health Security Agenda contains AMR as one of its 11 action packages for improving infection prevention and control. The US has committed to assisting at least 30 countries in implementing these action packages over the next 5 years, with investments of over $1 billion. CSIS wrote the paper with the "generous support" of the pharmaceutical firm Merck.

8. Large US meat companies Cargill and Tyson to reduce antibiotic use

Tyson Sustainability ReportCargill, one of the largest meat processors in the US, has stated that it will cut antibiotic use in cattle by 20 percent in 4 feed yards in in the US. Cargill will also make the same 20% reduction for 4 cattle feed yards operated by Friona Industries, which supplies Cargill with cattle. These changes will affect 1.2 million cattle. Cargill's press release claims that the cattle affected by this announcement were not previously receiving antibiotics important for human medicine for growth promotion. In 2014, Cargill eliminated growth promoting antibiotics from turkey; however, a Food Animal Concerns Trust report found that Cargill and numerous other turkey producers continue to allow the routine use of antibiotics. Cargill has also created a website dedicated to transparency in its beef production, where it has published its antibiotic position. In that position, Cargill has stated that it is encouraging other cattle feeders to "evaluate" their antibiotic usage, training producers in "optimal antibiotic usage", researching alternatives to antibiotics, and engaging with stakeholders to understand consumer expectations on antibiotic use. Cargill was previously linked to multistate outbreaks of Salmonella Enteritidis from ground beef and multidrug resistant Salmonella Heidelberg from ground turkey.Tyson Foods has launched a line of pork produced without the use of antibiotics, added hormones, gestation crates, and artificial ingredients. This change will account for approximately 5% of the company’s total pork sales or 1 million hogs per year. Gary Mickelson, a Tyson spokesperson, framed the decision motivated by increasing consumer choice rather than improving public health. He also noted that sick animals treated with antibiotics under veterinary supervision will not be included in the antibiotic-free line. Tyson's announcement coincides with the release of their annual sustainability report, which contains a progress update on their commitment to eliminate antibiotics used in human medicine from US broiler chickens by September 2017. In 2015, Tyson established working groups with its farmers to consider antibiotic stewardship programs in their cattle, hogs, and turkey supply chains. Their report states that in 2015, 86.2% of chickens were treated without, while 6.3% were treated with human antibiotics under veterinary supervision.

However, Tyson continues to use antibiotics used in human medicine. Their report states that 3.5% of chickens were given feed containing human antibiotics, and 4% of chickens were preventively injected with antibiotics as embryos. The report also states that Tyson does not add antibiotics or ractopamine (a growth-promoting drug) to turkey feed, and that antibiotics are administered through drinking water. While Tyson has reported progress in reducing human antibiotics, their report does not disclose data on the specific types or quantities of antibiotics used. In addition, the report claims that, "At the farm, veterinarians will sometimes prescribe antibiotics that are added to drinking water to treat sick chickens or control disease. This is the only way we administer human antibiotics to our broiler chickens because it’s not feasible to treat individual chicken."

9. Pew Charitable Trusts, IDSA, and food companies call on US Congress to increase funding for researching AMR in food system

Pew Charitable TrustsThe Pew Charitable Trusts, Infectious Diseases Society of America, and several large food companies sent a letter to the US Congress Subcommittee on Agriculture calling for US Congress to support the funding increases for USDA and FDA to address AMR in the food system requested by the 2017 Presidential Budget. The food company signatories were Wal-Mart, Cargill, Costco, Hormel Foods, McDonald's, Applegate, Bon Appetit Management Company, and Tyson Food. These additional funds for FDA and USDA for AMR could help the continued issues summarized by Dr. David Wallinga of the Natural Resources Defense Council. The voluntary phaseout of antibiotic growth promoters has been slow - among 293 products affected by the voluntary phaseout, only one antibiotic is no longer being used for "production indications" (growth promotion), and three are no longer given over-the-counter. The US also continues to allow routine preventive use of antibiotics, and the US lacks numerical targets for agricultural antibiotic use reduction.President Obama's 2017 budget request includes $42 million for the US Food and Drug Administration (FDA) to work on the Combating Antibiotic-Resistant Bacteria initiative, which includes supporting the rational use of antibiotics in animals. This includes funding to support additional data collection under the Animal Drug User Fee Act, which currently only facilitates for aggregate antibiotic use data in animals. In particular, the FDA aims to understand how the Veterinary Feed Directive and the voluntary phase-out of antibiotic growth promoters will affect antibiotic use and resistance trends. The letter also notes that the USDA has "decades of experience" at gathering and protecting farm data that is then used to improve animal management practices, despite privacy concerns raised by the meat industry.

The President's Budget also requested $61 million for the US Department of Agriculture (USDA). This funding would allow the USDA and its Animal and Plant Health Inspection Service (APHIS) to research the development of AMR and spread of resistance in animals and humans, and alternatives to antibiotics in animal agriculture. The funding would also go towards educating veterinarians and producers as well as conducting voluntary surveys on antibiotic use.

Congress did not ultimately approve the $77 million funding increases proposed by President Obama for the 2016 budget. However, the 2016 Congressional Budget did add $375 million in new funds, mainly for AMR surveillance and research in humans. This letter is a follow up to a letter sent in November 2015, also calling for increased funding to address AMR in the food system.

10. Climate change could increase the incidence of diarrheal disease

Researchers at Emory University have found that a 1°C temperature increase in mean temperature is associated with an 8% increase in E. coli-caused diarrhea, a finding that reinforces the urgency of strengthening disease prevention and control measures in the face of climate change. The study, published in the Journal of Infectious Diseases, looks at the temperature and diarrhea trends in 15 countries reported across eighteen studies. Fifteen of the eighteen studies found a positive association. This positive association may reflect a number of factors identified in previous research, including increased replication and survival rates of bacteria, higher transmission rates, larger animal reservoirs of pathogens in summer months, and seasonal changes in human susceptibility to disease. Since the researchers had sufficient data from Bangladesh for a subanalysis, they found that the country could see an additional 794,000 cases of E. coli-driven diarrhea by 2035. According to the WHO, 1.7 billion cases of diarrheal disease occur annually, leading to the deaths of around 760,000 children under the age of 5. This study points to the need to improve sanitation, water distribution, and food safety in light of the evidence that temperature increases is associated with diarrheal disease risk.

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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/Strategic Policy Program at Johns Hopkins Bloomberg School of Public Health. 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
rramach9@jhu.edu.