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Recommendation 1: Develop common structure and process indicators for hospital antimicrobial stewardship programmes

Implementers: CDC, ECDC and other stakeholders

Antimicrobial stewardship is a coordinated programme that implements interventions promoting optimal antimicrobial prescribing to limit antimicrobial resistance and to prevent Clostridium difficile infections, an adverse event associated with antibiotic use. Antimicrobial stewardship contributes to high quality and effective health care by decreasing unnecessary antimicrobial-related diseases, deaths, and costs. To effectively promote antimicrobial stewardship, an understanding of the key elements of successful stewardship programmes and interventions is needed.

CDC and ECDC coordinated 20 antimicrobial stewardship experts (13 EU; 7 US) to participate in a modified Delphi process between March and May 2014 and an in-person meeting in June 2014. The outcome was a set of 33 indicators (17 core indicators and 16 indicators).

Report Synopsis:

https://www.cdc.gov/drugresistance/pdf/summary_of_tatfar_recommendation_1.pdf [PDF – 5 pages]

Full Report:

Report on the modified Delphi process for common structure and process indicators for hospital antimicrobial stewardship programs [PDF – 1.7 MB]

Manuscript:

A Concise Set of Structure and Process Indicators to Assess and Compare Antimicrobial Stewardship Programs Among EU and US Hospitals: Results From a Multinational Expert Panel

Recommendation 2: Convene a joint US/EU working group to propose standards for measuring antimicrobial use in hospital settings

Implementers: CDC, ECDC, and other stakeholders

Most human antimicrobial use occurs in healthcare settings. CDC and ECDC shared US and EU surveillance approaches and methods to measure antimicrobial use in these settings with the purpose of improving the comparability of the antimicrobial use data. This comparison requires synchronising data sources and methods (i.e. numerator) to generate common measures that can easily be compared (e.g., defined daily dose [DDD], days of therapy [DOT], etc.).

Implementers have enrolled one of the involved external experts, Professor Ron Polk, to begin writing, together with CDC and ECDC, a manuscript reviewing current standards for measuring antimicrobial use in hospital settings. This manuscript will be the final deliverable for this recommendation.

Recommendation 3: Collaborate on collection of data on sales and use of veterinary antimicrobial drugs in food producing animals

Implementers: FDA, EFSA and EMA

FDA and EMA continue to share information on monitoring of consumption of antimicrobial agents in food-producing animals.

The latest European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) report includes data on the sales of veterinary antimicrobial drugs in 2013 in 26 EU/European Economic Area (EEA) countries, and the reports are regularly shared with the FDA. ESVAC is developing the methodology for the collection of data on use by per species and on the establishment of defined units of measurement of antimicrobial consumption in animals (e.g. Defined Daily Dose Animal, Defined Course Dose Animal). An FDA representative attended the ESVAC annual network meeting presenting the advances made by the FDA in this area and participating on the discussions on the development of the ESVAC project.

FDA shared details of a major revision represented by the newly formatted FDA 2012 sales summary report on antimicrobials for use in food-producing animals, which was published in September 2014.

The FDA 2013 sales summary report, which subsequently was published in April 2015, was also shared with ESVAC.

FDA also shared its intention to extend the sales data requirements to include sponsor estimates of the percentage of product being used in each food-producing animal species.  While including species in data collection will only represent sales, it will allow for a better approximation of actual antimicrobial use by species. A proposal for the new requirement was published in May 2015, and FDA is analyzing public comments.

FDA, in collaboration with the U.S. Department of Agriculture (USDA) and the Centers for Disease Control and Prevention (CDC), held a jointly sponsored public meeting to obtain public input on possible approaches for collecting additional on-farm antimicrobial drug use and resistance data. Such data are important for assessing the impact of measures being implemented to foster the judicious use of medically important antimicrobial drugs in food-producing animals.  Presentations and the meeting transcript are available on FDA’s website.

Finally, FDA also informed the ESVAC of its recent involvement with the National Institute for Mathematical and Biological Synthesis (NIMBioS) in developing an analytic modeling framework for assessing the relationship between antibiotic use in livestock (measured at the population level) and the development of antibiotic resistance. This project was in response to the recognition that the connection between antimicrobial use and resistance is complex and that a suitable mathematical framework to analyze this relationship is currently unavailable. The NIMBioS project will identify strategic methods for data collection, analysis and synthesis to address research and regulatory questions and to allocate limited resources efficiently. These will further assist FDA in its ability to mitigate antimicrobial resistance in humans associated with the drug use in food-producing animals.

In January 2015, ECDC, EFSA and EMA issued a first JIACRA report, the first Joint Inter-Agency analysis of the relationship between Consumption of and Resistance to Antimicrobials in humans, animals and food in the EU. This analysis addressed the available data obtained from the harmonised monitoring programmes of consumption and resistance of the three European agencies. The highlights of the report were shared with the FDA delegate attending the annual workshop of the ESVAC Network in March 2015. The main findings of the project were also presented at the 4th conference of antimicrobial resistance of the ASM. It has been recently decided to re-conduct the exercise in 2017.

Recommendation 4: Collaborate on implementation of the “Guidelines for Risk Analysis of Foodborne Antimicrobial Resistance” prepared by Codex Alimentarius

Implementers: FDA, EFSA, EMA, and DG SANTE

The FDA and EMA maintain regular bilateral meetings that include discussions on guidelines and recommendations for authorisation of antimicrobial drugs for use in veterinary medicine.  The guidelines are considered when performing risk assessments in EFSA.

Recommendation 5: Enhance information sharing on approaches to promoting appropriate use in veterinary communities

Implementers: EMA, DG SANTE, FDA, EFSA, and other stakeholders

Implementers for this recommendation work to enhance information sharing on approaches to promote appropriate use in veterinary communities.

Information on prudent use is available on the EMA and FDA web sites and is regularly discussed and shared during bilateral discussions. Both EMA and FDA also collaborate with the WHO Advisory Group on Integrated Surveillance of Antimicrobial Resistance (AGISAR) and World Organisation for Animal Health (OIE) on this topic; EMA has had additional engagement with WHO. Stakeholders including EMA, DG SANTE, FDA, EFSA, and others are working to enhance information sharing on approaches to promote appropriate use in veterinary communities.

Additional updates:

• Scientific advice on the impact of the use of antibiotics in animals on public health and animal health and measures to manage the possible risk to humans was prepared by the Antimicrobial Advice Ad Hoc Expert Group (AMEG) to the European Commission.
  • Request for scientific advice on the impact on public health and animal health of the use of antibiotics in animals [PDF – 5 pages]
  • Answers to the requests for scientific advice on the impact on public health and animal health of the use of antibiotics in animals [PDF – 83 pages]
• The EMA has recently published a reflection paper on the risk of antimicrobial resistance transfer from companion animals, which was shared with the colleagues from the FDA.
  • Reflection paper on the risk of antimicrobial resistance transfer from companion animals [PDF – 27 pages]
• In December 2013, the FDA took a significant step forward in addressing antimicrobial resistance by publishing Guidance #213, which calls on animal drug sponsors of approved medically important antimicrobials administered through medicated feed or water to remove from their product labels indications for use related to growth promotion, and bring the remaining therapeutic uses of these products under the oversight of a veterinarian by December 2016.
  • In March 2014, 283 applications were identified as being affected by Guidance #213. Since that time, 10 new generic and combination approvals were added to the list of affected applications. Some affected drug sponsors have already started implementing the recommended changes to their affected antimicrobial products: three applications have been converted from over-the-counter to prescription dispensing status; production indications have been withdrawn from one application; and 32 affected applications have been completely withdrawn. Sponsors of all of the affected applications remain committed to participating in the strategy.
  • In 2014, the FDA produced a web page to track progress (Animal and Veterinary List of Affected Applications)  in the implementation of its strategy to phase out production uses of antimicrobials and bring remaining feed and water drugs under veterinary oversight. In August 2015, the US Food and Drug Administration announced its third progress report on the judicious use of antimicrobials in food-producinganimals: Biannual Progress Report, Announces Public Meeting on Use of Antimicrobials in Food-producing Animals.
    http://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm459365.htm
  • The FDA, USDA, and CDC are working together to develop and implement a plan to collect additional data on antibiotic use in food-producing animals and conducted a jointly sponsored public meeting (Collecting On-Farm Antimicrobial Use and Resistance Data Public Meeting) on September 30, 2015, to obtain input on approaches for collecting on-farm antimicrobial drug use and resistance data.
• In early 2015, FDA provided ESVAC with an update on these efforts to promote the judicious use of antimicrobials in food-producing animals. FDA also provided the ESVAC an update on its plans to revise the veterinary feed directive (VFD) regulations, which are a key measure in ensuring the veterinary oversight of certain medicated feeds.  On On June 3, 2015 FDA published final revisions to the VFD regulation (Regulation to Help Ensure Judicious Use of Antibiotics in Food-Producing Animals); this new rule went into effect on October 1, 2015 and impacts the current VFD drugs (tilmicosin, florfenicol, and avilomycin).  FDA expects all other medicated feeds impacted by GFI #213 to transition to VFD by January 1, 2017.
• In September 2015 EC published guidelines on the prudent use of antimicrobials in animals, highlighting most important principles for prudent use and collating an inventory of experiences and measures taken by MSs (Guidelines for the Prudent Use of Antimicrobials in Veterinary Medicine) EC asked and EMA to produce a Joint Scientific Opinion on the measures to reduce the use of and the need to use antimicrobials in food-producing animals. The aim of the mandate is:
  1. to review the current measures and alternatives to both the use and the need to use antimicrobials,
  2. to assess the impact of those measures and alternatives on antimicrobial resistance in bacteria from food-producing animals and food, and
  3. to recommend options to reduce antimicrobial usage in animal husbandry in the EU. The deadline for delivering the Joint Scientific Opinion is December 2016.

Recommendation 18: Establish a joint working group of international subject matter experts to identify key knowledge gaps in understanding the impact of antimicrobial use in animals on the risk to man from antimicrobial resistance

Implementers: FDA, CDC, USDA, EFSA, EMA, ECDC, DG SANTE, and DG RTD

The impact that the use of antibiotic drugs in animals has on the risk to man from antimicrobial resistance needs to be better understood. The use of antibiotic drugs in humans and animals selects for antimicrobial resistance; however, the mechanism by which resistance may be transferred from animals to man and the extent of the threat that this represents to human health is less clear. Likewise, different control strategies to limit to the risk to man from the use of antibiotic drugs in animals have been developed and a wide variety of alternatives to the use of antibiotic drugs are under development and evaluation. The working group has adopted a “One Health” approach, bringing in expertise from both human and veterinary domains to address this recommendation.

Collaborating by e-mail, three audio conferences, and three webinars, implementers have performed an inventory of identified knowledge gaps including existing work in the areas of research, surveillance and risk analysis. Based on this inventory table, the working group identified a sub-set of knowledge gaps that represent a high priority for collaboration and identified specific actions where added benefit would be gained from transatlantic cooperation or from participation by new TATFAR members. The actions identified are included in the new TATFAR implementation plan.

See the Report on Recommendation 18 [PDF -33 pages]

Recommendation 6: Establish an EU–US working group to assess the evidence for effectiveness of communications tools in promoting behaviour change to increase appropriate use and to develop joint priorities

Implementers: CDC and ECDC

In 2014, there was a high level of coordination between CDC’s antibiotic awareness week (November 17-23, 2014) and the European Antibiotic Awareness Day (November 18, 2014). Implementers worked also with PAHO, WHO/Europe, Canada, Australia, New Zealand, and South Korea to coordinate efforts. Collaborators coordinated a 24-hour Twitter conversation with a single hashtag (#AntibioticDay). All parties agreed on a plan to lead the conversation in a specific time-slot and on rules to allow a smooth transition of the conversation from partner to partner—thus enhancing the overall coordination. The evaluation of the joint social media activities generated a total of 41 million Twitter impressions (number of people that have a Twitter account that received the tweets with the hashtag #AntibioticDay).

Building on this success for 2015, implementers and other partners will again participate in a global Twitter chat on November 18 (European Antibiotic Awareness Day), as well as support the World Health Organization’s inaugural Antibiotic Awareness Week. (November 16-22). In the US, under the theme “Preserve the Power of Antibiotics”, CDC’s antibiotic awareness week (November 16-22, 2016) will engage professional societies, advocacy groups, for-profit companies, state and local health departments, the general public, the media, and others around antibiotic stewardship in the outpatient, inpatient, and animal health settings.

Recommendation 7: Consultation and collaboration on a point-prevalence survey for healthcare-associated infections (HAIs)

Implementers: CDC and ECDC

Since 2009, CDC and ECDC have attempted to harmonise key methods related to point prevalence surveys (PPSs) of HAIs and antimicrobial use. Although the ECDC and CDC protocols are not identical, additional variables were added to both protocols to enable comparison of results. CDC and ECDC completed their PPS of HAIs and antimicrobial use in acute care hospitals in 2011 and 2012, respectively, providing national estimates of HAI rates and of antimicrobial use, and information about the epidemiology of infections.

Plans are in place for a second PPS in acute care hospitals for both the US (2015) and the EU (2016-2017). Ongoing communications and sharing of plans and modifications to US and EU survey methods have been very valuable as implementers seek to improve upon the previous survey experiences in the US and EU and enhance the utility of the HAI data. This collaboration will continue as Action 2.1 in the next TATFAR implementation phase 2016-2020.

Recommendation 8: Develop a process for transatlantic communication of critical events that may signify new resistance trends with global public health implications

Implementers: CDC and ECDC

Timely transatlantic communication and common actions are fundamental to respond to emerging threats and critical trends attributable to AMR. To allow for timely communication and for proper dissemination of information within the US, the EU, partner public health agencies, and ministries of health, CDC and ECDC drafted and approved terms of reference (ToR) on how international communication and actions about critical AMR surveillance results will occur and which type of information should be communicated. The ToR describes a procedure for notification when novel resistant phenotypes are identified, as well as quarterly conference calls in which CDC and ECDC subject matter experts discuss new AMR data and critical trends. These calls were initiated in 2012 and allow experts to exchange information on resistance but also on surveillance programs and protocols. CDC and ECDC continue to convene regular conference calls.  Recent topics include findings from ECDC’s EuSCAPE project (survey of carbapenemase-producing bacteria) and reports of CDC’s new national estimates of Clostridium difficile infections.

This successful collaboration will continue in the next TATFAR implementation phase 2016-2020. CDC, ECDC and other TATFAR partners will work together to develop a common US-EU system for sharing and analyzing bacterial resistance patterns for pathogens identified as urgent and serious threats (Action 2.2) and will develop a rapid alert system for this purpose (Action 2.3).  In addition, implementers will work with WHO to identify global strategies for global communication of important antimicrobial resistance results and trends.

Recommendation 9: Encourage efforts to harmonise, to the extent possible, interpretive criteria for susceptibility reporting of bacterial isolates across surveillance programmes in the US and EU

Implementers: CDC, ECDC, EFSA, FDA, EU Member States, EU reference laboratory for antimicrobial resistance, and other stakeholders

Government representatives are working with members of the Clinical and Laboratory Standards Institute (CLSI) Subcommittee for Antimicrobial Susceptibility and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) to harmonize surveillance interpretive criteria for the bacteria-drug combinations outlined in the WHO guidance for global antimicrobial resistance surveillance. This process has been facilitated by revisions of CLSI document M23 and the release of technical guidance for global surveillance by WHO. Surveillance interpretive criteria will be based upon data that is routinely generated in hospital laboratories. For pathogens that are not routinely tested in hospital laboratories, the surveillance interpretive criteria will be based upon epidemiological cutoff values agreed upon by implementers.

FDA and EFSA delegates attended meetings of the counterpart network on AMR monitoring in food producing-animals and food derived thereof to exchange views on further harmonization, in particular regarding AST methods, interpretive criteria and representative sampling.

This collaboration will continue as Action 2.4 in the next TATFAR implementation phase 2016-2020.

Recommendation 10: Workshop bringing together public health experts from the US and EU to develop consensus evaluation tools for hospital infection control programmes

Implementers: CDC and ECDC

This recommendation was ceased at the end of the last implementation period as both the CDC and ECDC agreed that a consensus could not be reached.  This is described further in the 2014 Progress Report [PDF – 1.1MB]. Due to lack of resources, there will be no peer-reviewed article for this recommendation.  Data on infection control practices (indicators) that will be collected through the ECDC Point Prevalence Survey of Healthcare-Associated Infections and Antimicrobial Use in European Acute Care Hospitals and the US National Healthcare Safety Network Patient Safety Component—Annual Hospital Survey will allow some comparisons between the EU and the U.S. when they are completed during 2016-2017.

Recommendation 11: Transatlantic strategy to facilitate vaccine development for HAIs

Implementers: CDC, DG RTD, and ECDC

This recommendation was ceased at the end of the last implementation period. CDC and ECDC use different models to interact with the vaccine industry and a common strategy could not be forged. This is described further in the 2014 Progress Report [PDF – 1.1MB]. Due to lack of resources, there will be no peer-reviewed article for this recommendation.

Recommendation 12: Policymakers should strongly consider the establishment of significant incentives to stimulate antibacterial drug development

Implementers: FDA and EMA

Discussion among stakeholders is continuing around possible new incentives to stimulate R&D for innovation in this area. Important is the discussion on new business models and on European side the IMI project DRIVE-AB that is starting in 2015. Comparing the various options emerging in US and EU will help in the definition of incentives options.

Recommendation 13: Increase communication between US and EU research agencies to identify common scientific challenges that may represent opportunities for collaboration.

Implementers: NIH and DG RTD

Representatives from DG Research and NIAID hold regular conference calls to share information about planned activities, including calls for proposals, workshops and research-oriented activities resulting from high-level activities (e.g. CARB and JPIAMR).

• Representatives from DG Research and NIH held a conference call and exchanged information on the development of prizes to incentivize the development of novel diagnostics.
• NIAID has participated in meetings with several EU members states on the topic of antimicrobial resistance.
• This collaborative work continues as Action 3.3  in the implementation phase beginning in January, 2016.  The following symposium and workshop have already been held:
  • NIAID and JPIAMR, along with the Swedish Research Council and DG RTD, held a Symposium entitled “New Frontiers in Antibacterial Resistance Research,” 20 and 21 January 2016. The objectives of the symposium were:
    • To discuss cutting-edge approaches to address antibacterial resistance.
    • To foster communication and research collaborations among scientists in the EU and US
    • To share information on funding opportunities to advance antibacterial resistance research.
      A summary of this workshop can be found in the New Frontiers in Antibacterial Resistance Research [PDF – 5 pages].
  • NIAID and IMI ND4BB, along with DG RTD and JPIAMR, held a workshop entitled “Transatlantic collaboration of clinical trials related with antimicrobial resistance” on January 22, 2016. The objectives of the symposium were:
    • To share information on current existing initiatives for clinical trial networks for antimicrobial resistance, in order to learn from each other and avoid duplication of efforts;
    • To discuss challenges and opportunities to overcome barriers for the efficient conduct of high-quality global clinical trials;
    • To foster opportunities for collaboration between the different networks and initiatives in the EU, US and CA to facilitate clinical research in our fight against AMR;
    • To produce concrete deliverables and action points towards solutions and recommendations to overcome the barriers identified through better alignment of existing networks and resources.
      A summary of this workshop can be found in the Report of the Workshop on Transatlantic Collaboration on Clinical Trials Related to Antimicrobial Resistance [PDF – 8 pages].

Other TATFAR members, including FDA, EMA, BARDA and CIHR were also represented and played an active role in the meeting.

Recommendation 14: Publicise funding opportunities to the EU and US research communities

Implementers: NIH/NIAID and DG RTD

The TATFAR website has been updated to include current information on funding opportunities from TATFAR partners (See the TATFAR Links and Resources page). Additionally, representatives of NIAID and IMI ND4BB presented on funding opportunities at the Keystone Symposium on Gram-negative drug resistance.  Representatives of DG Research and NIAID gave a joint presentation on global cooperation in AMR research funding at the meeting on “Overcoming gaps in research & development on antimicrobial drug development” that was organized by the WHO and Brazil. Under Action 3.3 in the new implementation phase (2016-2020), representatives from NIAID and DG RTD will give a joint presentation at ECCMID in April 2016.

Recommendation 15: FDA and EMA will discuss ways to facilitate the use of the same clinical development programme to satisfy regulatory submissions to both Agencies

Implementers: FDA and EMA

Following the release in 2012-2014 of guidance documents covering the possible pathways for development of new antibacterial agents in various indications, the agencies have reached a high level of convergence and put in place approaches that ensure that the same clinical trials can satisfy requirements from both agencies.

Recommendation 16: Establish regular meetings between FDA and EMA to discuss common issues in the area of antibacterial drug development and regulation

Implementers: FDA and EMA

Regular teleconferences are taking place on a monthly basis to inform and discuss on any emerging issue related to development of new products or related to those already approved.

Recommendation 17: Exchange information on possible approaches to drug development for bacterial diseases where limited drugs are available

Implementers: FDA and EMA

Regular teleconferences described under Recommendation 16 also include discussion related to new antibacterial agents that can address unmet needs related to AMR.