August 31, 2016
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AMR on the International Agenda

1. Stakeholders weigh in on ongoing negotiations for outcome document of the upcoming UN High-Level Meeting on AMR
2. EPHA and Changing Markets release report on environmental pollution by the pharmaceutical industry contributing to AMR
3. World Bank-commissioned study finds lack of AMR surveillance readiness among network of East African laboratories

Updating Guidelines and Research on AMR
4. WHO releases updated treatment guidelines for gonorrhea, chlamydia, and syphilis 
5. McDonald’s USA announces early completion of goal to source poultry products raised without medically-important antibiotics  
6. U.S. FDA and CDC create isolate bank of resistant strains for developing diagnostic tests
7. EMA releases guidelines on determining minimum effective dosage of antimicrobials
8. Study suggests potential lack of effect of triclosan exposure on human microbiome

AMR on the International Agenda

1. Stakeholders weigh in on ongoing negotiations for outcome document of the upcoming UN High-Level Meeting on AMR

OIEOn September 2nd, negotiations will resume among Member States on the Outcome Document for the upcoming United Nations (UN) High-Level Meeting on AMR. This high-level meeting will occur on September 21 during the 71st United Nations General Assembly. The meeting will consist of two interactive, thematic panels-- one on the relevance of addressing AMR for the achievement of the SDGs-- in particular the health-related SDGs-- and the other on addressing the multisectoral implications and implementation challenges of AMR in a comprehensive manner. Each panel will include six discussants, including three Heads of State and representatives from civil society, industry, and academia. The resulting Outcome Document will outline the principles, commitments, and follow-on process for global coordination to address AMR across both human and animal health. 

A spate of journal articles, from various stakeholders from industry to academia to civil society, has rushed to weigh in on this ongoing process. In a commentary published in The Lancet by the Center for Disease Dynamics, Economics, and Policy (CDDEP), ReAct Europe, and others, the authors call for a UN High-Level Coordinating Mechanism (HCLM) on AMR that would engage in advocacy, monitoring and evaluation, resource mobilization, and multisectoral coordination to support implementation of the Global Action Plan on AMR across countries. A subsequent editorial from the CDDEP, University of Edinburg, Fudan University, and New York University published an editorial in Science magazine calls for more specific commitments on global targets, financing, and governance. Specifically, they recommend:
  • that global targets for antimicrobial consumption across all countries be set at the median global level of 8.54 defined daily doses per capita per year;
  • that a global fund of at least $5 billion per year be created to ensure sustainable financing of technologies and stewardship approaches; and
  • that a High-Level Coordinating Mechanism (HCLM) including the WHO, FAO, OIE, World Bank with other relevant UN agencies, other international organizations, major multisectoral stakeholders, and global experts under the Secretary-General be convened “to coordinate support for development, implementation, and monitoring of national action plans and relevant actions”; and
  • that financing be managed through a World Bank Trust Fund as a mechanism to solicit multi-year donor commitments for a global fund for AMR.In another editorial published in the WHO Bulletin, authors from the Wellcome Trust, University of London Pediatric Infectious Disease Unit, Astra Zeneca, Galen/Atlantica, and Jinja Publishing outline three key areas for global action on AMR:
    • that antimicrobial use in food animal production for growth promotion and disease prevention be phased out in favor of improved animal husbandry practices;
    • that surveillance and monitoring of drug resistance levels and antimicrobial use are ensured to provide a clear picture of local situations and to evaluate the impact of specific interventions; and 
    • that public health systems optimize the use of antimicrobials through improved sanitation and access to clean water, promotion of good hand-hygiene practices, and improved infection prevention and control in healthcare facilities.
    In another article published in the Transactions of the Royal Society of Tropical Medicine and Hygiene, authors across universities around the globe as well as the Food and Agricultural Organization of the United Nations describe AMR as both a One Health and One World issue, requiring coordinated action across sectors and countries. The authors caution that calls for global action will need to include both high-income as well as low- and middle-income countries. They call for the role of animal husbandry and aquaculture in low- and middle-income countries to be recognized in the development and negotiation of global policy recommendations. They also call for interdisciplinary research to bridge the gaps in understanding between the biomedical, environmental, animal health and social sciences. The authors conclude that integrated approaches applied on a global scale to reduce the selection pressure for antimicrobials and disrupt resistance transmission should not only be founded on One Health principles, but also be “based on economic evidence and on principles of social equity and global access to effective healthcare for people and their animals.”

2. EPHA and Changing Markets release report on environmental pollution by the pharmaceutical industry contributing to AMR

OIEA recently released briefing by the European Public Health Alliance (EPHA) and Changing Markets describes how the pharmaceutical industry has contributed to the spread of AMR through environmental pollution from manufacturing facilities. This report includes findings from on-the-ground investigations and reports from 2015 and 2016 on the conditions by which the most commonly prescribed drugs in the United Kingdom are manufactured. 

The report findings detail the lack of transparency along the pharmaceutical supply chain and the mismanagement of antibiotic waste from production facilities. Most of the global supply of drugs are manufactured by contracted facilities in China and India. A significant share of this production is outsourced by major multinational pharmaceutical companies headquartered in Europe and the United States. The report shares eleven case studies of contracted facilities throughout China and India. The various case studies describe instances of withdrawal of products from markets following failed inspections, local reports of antibiotic effluent being emptied into major waterways from specific facilities, and notices of local government citations against production sites due to poor production practices.
 The report concludes with a call to the National Health Service and other major purchasers to leverage their purchasing power to compel change in production practices by:
  1. blacklisting companies found to be contributing to the spread of resistance through poor manufacturing practices;
  2. demand that pharmaceutical companies make their supply chain of antibiotics more transparent and improve upon it;
  3. review and modify procurement policies including supplier codes of conduct to ensure environmental and AMR criteria in contractual agreements; and 
  4. promote legislation to incorporate environmental criteria into Good Manufacturing Practices (GMP).

3. World Bank-commissioned study finds lack of AMR surveillance readiness among network of East African laboratories

The Center for Disease Dynamics, Economics, and Policy (CDDEP) published a report of a World Bank-commissioned case study of East Africa Public Health Laboratory Networking (EAPHLN) Project and their ability to conduct national and regional AMR surveillance. The 32 laboratories in this network, located across five neighboring countries, include a central reference facility in each country as well as satellite laboratories. The study found that despite substantial funding being allocated towards facility upgrades, the laboratories continued to lack bacteriology capacity. Many of these facilities are also used infrequently, performing few microbiology cultures or drug susceptibility tests. This underutilization significantly reduces their readiness for national AMR surveillance efforts. The report also details the benefits, costs, feasibility, and importance of AMR as follows:
  • The cost of AMR surveillance is relatively low if the laboratories are already well-functioning and are able to produce reliable results. 
  • Other costs of AMR surveillance go towards information technology, capacity for data analyses, personnel time and training, and software. 
  • At the facility level, AMR surveillance offers value in providing information including the early detection of resistant strains to help guide clinical staff in their decision-making for antimicrobial treatment.
  • At the national level, AMR surveillance offers value in providing information so that standard treatment guidelines can be updated and AMR trends can be tracked.
  • At the global level, AMR surveillance can help promote further understanding of AMR across countries, providing a more global picture.The report concludes by offering a number recommendations for EAPHLN and other low-resource surveillance laboratories including, but not limited to:
    • that countries should enroll into the WHO Global Antimicrobial Surveillance System for technical assistance towards capacity building, training, and implementation;
    • that countries should contribute available susceptibility data to CDDEP’s ResistanceMap;
    • that capacity for these laboratories be built with national government ministries, consultant physicians, and investments towards technology; and 
    • that countries should source animal blood products from local farm or prepare blood agar plates centrally. 

Updating Guidelines and Research on AMR

4. WHO releases updated treatment guidelines for gonorrhea, chlamydia, and syphilis

On August 30, the World Health Organization (WHO) released new guidelines for the treatment of gonorrhea, chlamydia, and syphilis. Treatment for these bacterial sexually transmitted infections (STIs) is becoming more difficult due to increasing resistance to antibiotic therapies. According to the WHO, overuse and misuse of antibiotics has contributed to this resistance limiting treatment options for patients in recent years. Gonorrhea has developed the strongest resistance to antibiotics with some multidrug-resistant strains unresponsive to any available drugs. When left untreated, these STIs can result in long-lasting medical conditions including infertility, pelvic inflammatory disease, miscarriage, and a higher risk of HIV infection. The updated WHO guidelines for these three STIs are based on the latest available evidence on the most effective treatments:
  • Gonorrhea. To address growing resistance to this STI, the WHO has recommended that countries update national treatment guidelines and that they monitor the prevalence of gonorrhea resistance to various antibiotics within the population. The updated guidelines recommend that physicians and healthcare professionals take into account local resistance patterns when prescribing an appropriately effective antibiotic. The WHO also recommends against prescribing quinolones for the treatment of gonorrhea due to high levels of resistance.
  • Syphilis. The WHO now recommends a single dose of benzathine penicillin injected intramuscularly as this is the most effective treatment and comparatively cheaper than oral antibiotics. At the most recent World Health Assembly, it was recognized that this medicine has been in limited supply for many years. The WHO has received reports from health care providers in countries with high burdens of this STI across three WHO regions. In response, the WHO is working with other stakeholders to identify specific countries with shortages and to provide assistance in monitoring global availability of this medicine. 
  • Chlamydia. The WHO now recommends that countries update their treatment guidelines immediately as outlined in the Global Health Sector Strategy for STIs (2016-2021) endorsed by Member States at the World Health Assembly in May 2016. These guidelines are also in line with Global Action Plan on AMR, adopted in Mary 2015 by the World Health Assembly. 

5. McDonald’s USA announces early completion of goal to source poultry products raised without medically-important antibiotics

On August 1st, McDonald’s announced that it had completed a major goal of serving chicken products raised without antibiotics important to human medicine almost a year ahead of schedule. Originally, the food retailer sought to complete this goal by March 2017. The company cited its collaboration with suppliers and farmers “on a large scale” as being instrumental in achieving this goal early. McDonald’s manages all of its chicken supply chain with suppliers, Tyson and Keystone Foods, which contributed to the rapid implementation of this commitment. McDonald’s sourcing of beef products, on the other hand, may be much more difficult to change as their purchases are through various cattle ranchers.

Steven Roach, Food Safety Program Director of Food Animal Concerns Trust, a member organization of the Antibiotic Resistance Coalition, noted that McDonald’s implementation of this policy demonstrates that this goal of reducing antibiotic use in food supply is indeed attainable, “[moving] the chicken industry as a whole towards less use of medically important antibiotics.” He also expressed hope that McDonald’s would expand this policy globally and make such commitments for other meat products on its menu. Mr. Roach also noted that other food retailers like Subway, Taco Bell, and Wendy’s have made similar commitments, but that other large chicken procurers like KFC have yet to do so. On August 11th, Mr. Roach joined consumer advocates from the Natural Resources Defense Council (NRDC) and U.S. Public Interest Research Group (PIRG) to deliver 350,000 petition signatures to KFC headquarters in Louisville, Kentucky. The petition urges the company to join other food retailers in committing to source poultry products without the routine use of antimicrobials. In addition to the petition, a billboard was parked outside a local KFC that read, “Superbugs killed 23,000 Americans last year, KFC. Get your chickens off drugs.” Representatives from Yum! Brand Foods, an umbrella organization that includes KFC, declined to meet with consumer advocates despite advance warning of the petition delivery and billboard. They released a statement a few days prior to the petition delivery stating that the company was in the process of reviewing its policy.

6. U.S. FDA and CDC create isolate bank of resistant strains for developing diagnostic tests

Nature Medicine recently published a news article describing a collaborative effort between the U.S. Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC)  to develop an antimicrobial resistance isolate bank for researchers and diagnostic manufacturers to test their products. This repository of drug-resistant bacterial isolates comes in response to complaints from diagnostic companies of having poor access to newly resistant strains needed to further validate their tests. This effort was formally launched over a year ago in July 2015 and was instrumental in the diagnostic manufacturer Cepheid's launch of its newest test for Carbapenem-resistant Enterobacteriaceae (CRE). According to Fred Turnover, Cepheid's Vice President of Scientific Affairs, such a repository was necessary as the number of resistant strains isolated from patients needed for a trial is limited. The CDC has oversight of the management of isolates within the repository, while the FDA is responsible for managing access to these specimens. Companies are able to request access to these samples through a website managed by the FDA. The almost 400 strains are available free of charge and include both bacterial and fungal species. The agencies hope to increase the number of samples to 1,000 isolates including additional fungal species. Besides validating diagnostics tests for resistant strains, companies are also using this repository to bring more quickly their technologies to market. For instance, Roche is using the sample bank early in the development process of its GeneWeave Smarticles Technology - a diagnostic test that aims to detect antibiotic susceptibility in patient isolates. The agencies have also shared samples upon request with researchers and companies developing antimicrobial compounds and performing other academic research. 

The FDA has also created FDA-ARGOS, a database with approved microbial sequences in parallel with the FDA-CDC isolate bank. The database contains reference sequencing data for different microbial pathogens, which diagnostic manufacturers can also use to create tests to detect resistant genes. In June 2016, the CDC also developed the Antibiotic Resistance Lab Network of eight labs across the United States that will monitor emerging drug resistance in hospitals nationwide. This network will also contribute new samples of resistant microbial samples to the FDA-CDC isolate bank.

7. EMA releases guidelines on determining minimum effective dosage of antimicrobials

The European Medicines Agency (EMA) has released guidelines for pharmaceutical manufacturers for determining the minimum effective dosage for antimicrobial drugs. The agency recommends that manufacturers rely on metabolic and mechanism of action analyses for determining proper dosage. They also outline how manufacturers can use microbiological data to minimize or eliminate any need for clinical trial studies to ascertain the proper dosage of medicines. According to the EMA, such data can help to accelerate antimicrobial drug development as manufacturers would be able to undertake efficacy studies more rapidly. The agency did caution that manufacturers would need the appropriate microbiological data before conducting efficacy analyses. For instance, the EMA has suggested conducting time-course studies to determine the relationship between antimicrobial activities and drug concentration.

8. Study suggests potential lack of effect of triclosan exposure on human microbiome

A recent study published in mSphere found no changes due to the use of triclosan--an antibacterial found in almost 75% antibacterial soaps--in the human microbiome of volunteer subjects. For four months, volunteers were given triclosan-containing personal products (i.e. toothpaste, hard and liquid soap, and dish soap) to use at will and then were transitioned to using personal products without triclosan for an additional four months. Another group of volunteers began with non-triclosan containing personal products and then switched to products without triclosan. Although urinary concentrations of triclosan were found to be higher in volunteers during the time they were using triclosan-containing products, the stool, molar, and incisor microbiomes did not change. Researchers also did not find a change in serum endocrine markers. 

These surprising results come after other suggestive evidence in rat and fish species that triclosan exposure is associated with disruptions in the microbiome. In these studies, however, the animals were exposed to much greater concentrations triclosan for significantly longer durations. For instance, unlike in humans who are exposed to triclosan through toothpaste and soap products that are rinsed off, animals were immersed in triclosan or consumed the antibacterial in food. Another reason that these results might have differed, according to a piece in Science magazine, may be because triclosan exposure for humans begins as early in the prenatal stage allowing for the human microbiota to adapt. In the study with human volunteers, for instance, triclosan was still found in urine even during periods of not using triclosan-containing products. 

Future studies might analyze the impact of the dose, timing, and route of administration of triclosan on human microbiota. As evidenced by its continued presence in water sources, triclosan tends to accumulate persistently in the environment. Moreover, some studies have also suggested that there might be specific developmental periods where microbiota changes due to triclosan exposure may have differential effects as well as potential lasting impacts on neurological and immune development. 

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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.