Dr. Larry M. Granger - How Might Scientific Advances And More Complete Data Help Achieve Our Shared Goals
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How Might Scientific Advances And More Complete Data Help Achieve Our Shared Goals - Dr. Larry M. Granger, Senior Leader of Antimicrobial Resistance, Animal and Plant Health Inspection Service, United States Department of Agriculture, from the 2018 NIAA Antibiotic Symposium: New Science & Technology Tools for Antibiotic Stewardship, November 13-15, 2018, Overland Park, KS, USA. More presentations at https://www.youtube.com/playlist?list=PL8ZKJKD9cmEffjOrjbBvQZeN2_SZB_Skc
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Dr. Larry M. Granger - How Might Scientific Advances And More Complete Data Help Achieve Our Shared Goals
- 1. REPORT TO NIAA SCIENCE AND DATA âHOW MIGHT SCIENTIFIC ADVANCES AND MORE COMPLETE DATA HELP ACHIEVE OUR SHARED GOALSâ NOVEMBER 14, 2018 KANSAS CITY LARRY M. GRANGER D.V.M. U.S. DEPARTMENT OF AGRICULTURE ANIMAL AND PLANT HEALTH INSPECTION SERVICE VETERINARY SERVICES
- 2. Better understanding of how antibiotic uses relate to resistance. Demonstrate agriculture participants are good stewards of antibiotics. Mitigate risks to human and animal health. Sustain and benefit the food chain, feed the world. Participate in global agenda, scoring well on âcore indicatorsâ. Good public policy. ⊠Policies based on complete and correct information ⊠Scientific analysis 2 Shared Goals Knowledge is a deadly friend When no one sets the rules. The fate of all mankind I see Is in the hands of fools. Epitah, King Crimson
- 3. Sometimes it is necessary to use antibiotics. When, Why, Which one and in What dose should I administer antibiotics? Veterinarians know stewardship is an ethical consideration guided by critical understanding of all aspects of the affected biome. Veterinarians need the data to make decisions. Use antibiotics when necessary, but not when resistance is augmented and goals are not achieved. ⊠Use cannot be justified as a convenience or conditioned behavior/cognitive bias. Data can determine if the desired result is achieved. Analysis of data can support judicious use decisions. 3 Antibiotic Use
- 4. AMR should convince us that more investment is needed in agriculture. Animal health and productivity are technical goals. There are associated marginal cost abatement concerns related to AMR. Measures of effective intervention should assure allocative efficiency of the economic system is considered. AMR affects marketability. AMR and global development goals are linked. (SGD) 4 Health of the Food Chain
- 5. We are in the midst of a revolution in medicine made possible by technology. ⊠Whole genome sequencing is a âmicroscopeâ that enables scientific observation, while computer analysis of data provides levels of understanding information never before realized. The character of the microbiota/pathogen can be revealed to us. 5 Applying Science
- 6. Provide the benefits of antibiotics without the risk of undesired resistance in pathogens or the biome. Probiotics CRISPR-Cas9 Phytochemicals Genetic variation Gut peptides Vaccination Hormesis Do some antibiotics have all the attributes that we desire of alternatives to antibiotics? 6 Alternatives to Antibiotics 1 Gay C.G., Seal B.S., Lillehoj H.S., Donovan D.M. (2014) Alternatives to Antibiotics: Recent Scientific Advancements. OIE Conference Booklet, Ed. 2014: Responsible and Prudent Use of Antimicrobial Agents for Animals; 74-75 âAlternatives to antibiotics are broadly defined as any substance that can be substituted for drugs that are increasingly becoming ineffective against pathogenic bacteria, viruses or parasites.â1 www.ars.usda.gov/alternativestoantibiotics
- 7. Confidentiality protections attempt to mitigate risk of attribution get in the way. Liability concerns prevent us from gathering information that would be useful to guide action. The threat of attribution drives whole genome sequencing out of the NAHMS biological sample collection planning. So long as we address confidentiality as the issue, we are losing opportunity. Can we avoid the risk? ⊠If risks are not avoidable, everyone should share responsibility. 7 Knowledge as a Friend
- 8. 8 National Animal Health Monitoring Systems is a National Reference Repository To access reports from previous NAHMS national studies or information on upcoming studies, visit the NAHMS Web site at http://nahms.aphis.usda.gov. Numerous citations in scientific literature each year, offers opportunity for hypothesis generation Benchmarks progress and practices in animal agriculture production sectors, allows examination of trends.
- 9. 9 Veterinary Accreditation State and Federal Cooperation The âVCPRâ The VCPR is defined in different ways by States laws, Federal agencies, and by the American Veterinary Medical Association in AVMA policy, Principles of Veterinary Medical Ethics Accredited veterinarians act as agents of APHIS and under State authorities for health certification Module 23 â Use of Antibiotics in Animals Module 29 â Veterinary Feed Directive
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- 11. International Cooperation and Coordination World Organization for Animal Health (OIE) ⊠Chief Veterinary Officer (CVO) serves as USA delegate to the World Organization for Animal Health (OIE) ⊠The US has a Senior Leader in that role. ⊠Harmonization with the Terrestrial Code, AMR issues GHSA ⊠APHIS is USDAâs representative voice ⊠G7 Veterinary International Conference on Harmonization (VICH) Guidance Documents ⊠Center for Veterinary Biologics is active ⊠the VICH process works to establish harmonized, common technical requirements for veterinary medicinal products active 11
- 12. Larry M. Granger D.V.M. Senior Leader for Antimicrobial Resistance U.S. Department of Agriculture Animal and Plant Health Inspection Service Veterinary Services larry.m.granger@aphis.usda.gov https://www.aphis.usda.gov/aphis/ourfocus/animalhealth 12 âI guess everything does change, except what we choose to recallâŠâ My Favorite Memory, Merle Haggard
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- Thank you for inviting me to this conference. It is good to see the commodity groups in attendance, and good to see the wide array of representation from industry. When I attended the first one of these, we noted the absence of participants from the human health sector. It is good to see one health alive and well. Iâve been asked to talk about âHow might scientific advances and more complete data help achieve our shared goalsâ Letâs talk about shared goals.
- Notice I donât say anything about reducing antibiotic use. We have to know the outcome we expect. Already we have seen evidence that resistance patterns in animals are not different whether antibiotics are used or not. Do we need to drop below a critical mass? If we stopped using antibiotics in agriculture altogether, resistance would not go away. We donât know how resistance moves about the biome. We need more information about the effect of antibiotics on the biome. Weâve focused on how administration of antibiotics in doses high enough to meet therapeutic pharmacokinetic and pharmacodynamic thresholds, but for how long do we administer these? A perturbation to the biome occurs immediately upon administration dependent upon dose. Once that happens we can never put Humpty Dumpty together again. New population dynamics are created. There are 10X as many bacteria in and on our bodies as we are made of in the number of cells. They communicate with each other in ways that affect our bodily systems. How the biome is affected and how it recovers is as important in agriculture as it is in understanding human disease and therapeutics. Science is good. It is a way to find out things. Sometimes it is a reference to the body of knowledge that everyone agrees upon. It is based upon the premise that we state something as true, and then try to prove it to be wrong. Doing that is a good thing, because we can then restate what we believe is true, and test it again with the scientific method. Create the rule, and test the rule by proving the exception. If you can do that, the rule isnât true. A poorly designed experiment may determine that black horses eat more than white horses because we didnât count the total number of horses in each group. Science really doesnât tell us what should be done or what value it has. That is a different kind of question. Even the application of scientific principles is not really science. That is more properly termed technology. Iâm reminded of a lecture I listened to given by Richard Feynman, a physicist that worked at Los Alamos during the second world war and won the Nobel Prize in 1965, when he said that the difference in exposure to radiation with all the nuclear testing that had been done globally was less than the difference between sea level and living in Denver. Of course that doesnât matter if youâre standing next to the blast. We hear the mantra âantibiotic use everywhere causes resistance everywhereâ â not unlike the discussion in the 50âs and 60âs about nuclear testing. âReduce antibiotic useâ is that kind of goal. Darwinian selection does not play out the same way in the microbial world. Life has emerged as a result of symbiotic interaction with bacteria and a new family of arcahea. There is an opportunity to recover in anew way when antibiotics are withdrawn. The state that results may be worse, but it could be better. We donât always know.
- As antibiotic use is more under the direction of veterinarians, good stewardship as an ethical consideration is guided by critical understanding of all aspects of the affected biome. Veterinarians need the data to make decisions. They also have to read the label, and we need latitude to guide appropriate use beyond labeling. This can only come from regulatory action or from pseudo-regulatory infrastructure changes. An huge determinant is economics. We donât have third party payment, but we do have economic pressures. The clinician seeking a favorable outcome using antibiotics in treatment of large populations needs guidance on judicious use qualifications. The most important aspect of antibiotic use leading to resistance to eliminate is use of antibiotics when they do not achieve their desired result. Data can determine if the desired result is achieved. Advances in technology provide the opportunity for the best and first tenet of science to be exercised, that of scientific observation. Whole genome sequencing is a microscope while computer analysis of data provides levels of understanding information never before realized. We are in the midst of a technological revolution in medicine that we need to embrace without fear, especially fear of reprisal. We need to seek understanding to guide action, and be ready to evaluate actions we take based upon further data gathering and information analysis. This requires monitoring and sharing of data and information. Monitoring and surveillance are the keys to development of feedback loops that create conditions for a self-regulating dynamic system that is robust and resilient. Veterinarians, producers, and the consumer are all part of that system.
- There was a comment from UN WHO- re: beef at OIE two weeks ago. He said changes in the U.S. are being driven by fast food. He used NAE as evidence â results in a premium. What happens when antibiotic use results in a discount? He also said that beef is making no progress at all. That is based on what is being read in the media, not on any official government report. We need government to do its job for the health of our country. One health is multi-disciplinary. Or trans-disciplinary. I donât like the Venn diagram approach to demonstrating one health. It ignores the contributions of too many important perspectives from behavioralists, economists, social scientists, etc. Investment from the human health sector is important, and there are lessons to be learned about how use in populations affects the biome at every level. Pharma will not invest in new antibiotics for use in agriculture. We cannot ask them to pay for label changes that do not generate a return. AMR and global development goals are linked. NGOâs like the Gates Foundation and IGOâs like the IMF and World Bank are making significant infrastructure investments based upon AMR concerns. We may have to evaluate how we license and evaluate label indications. If we sought to find the person most educated to make these decisions, we would soon be describing the veterinarian.
- This is the Great Salt Lake. What happened here is the result of bridges in the causeway being filled in as the embutments began to sink. Water could no longer flow and salinity on one side increased. Halophilic bacteria live in the higher salt concentrations causing the pink color. Archaea and bacteria. Archaea possess genes and several metabolic pathways that are more closely related to those of eukaryotes, notably the enzymes involved in transcription and translation. Most have not been isolated in the laboratory. There are found with genomic techniques. Extremophiles. They are also part of the human microbiota, found in the colon, mouth, and skin.[One example is the methanogens that inhabit human and ruminant guts, where their vast numbers aid digestion. Only know this because we can detect unique DNA with higher levels of complexity than bacteria. Horizontal gene transfer occurs with unique mechanisms of transcription and translation. Rumen transplants Amy Pruden came to PACCARB. Her research into bacterial colonization of man constructed eco systems in water supplies and sewers is an example of profound changes humans are responsible for, beyond agriculture. There is nothing more scary than something we donât understand that could make us sick in our food or water.
- We donât know the background, safe or dangerous range. âPrecautionary principleâ vs ârisk analysisâ. CRISPR (/ËkrÉȘspÉr/) (clustered regularly interspaced short palindromic repeats) is a family of DNA sequences found within the genomes of prokaryotic organisms such as bacteria and archaea.[1] These sequences are derived from DNA fragments from viruses that have previously infected the prokaryote and are used to detect and destroy DNA from similar viruses during subsequent infections. Hence these sequences play a key role in the antiviral defense system of prokaryotes.[1] Cas9 (or "CRISPR-associated 9") is an enzyme that uses CRISPR sequences as a guide to recognize and cleave specific strands of DNA that are complementary to the CRISPR sequence. Cas9 enzymes together with CRISPR sequences form the basis of a technology known as CRISPR/Cas9 that can be used to edit genes within organisms. CRISPR associated proteins We have already learned something about how the immune system of prokaryotes work. We are using the technology to genetically engineer new organisms and to target those that are resistant to antibiotics with phages, sort of a virus of bacteria. We are finding ways to turn genes on and off. Does decreased use decrease risk of exposure to resistant bugs? Some diseases increase when use is abandoned. May overwhelm other effective mitigations (at processing for instance) Somehow, the legacy of feeding antibiotics for growth promotion has been linked to insanitary and overcrowded conditions of production. That may not be the whole story. Healthy animals is a good outcome. Antibiotics may be important to assure health when certain disease conditions exist regardless of husbandry or environment. No one wants to get sick from a bad bug, whether or not it is resistant. Letâs not do things that increase that risk. More information may lead to more flexible regulation. But, may need some regulation for other things â Is it snake oil or âessentialâ oils? Money should be spent to explore mass population differences in genetic responses to diseases and medicines. Human health should spend money in these areas. Monensin is toxic to cattle, but not in fed doses at the right stage of life. Ionophores are produced in the rumen. These are metabolites and may be involved in signaling. Check out the TED talk by Bonnie Basler and âquorum sensingâ on/off switches.
- Message: âWe are still trying to look at bovine isolates and see if this strain of Salmonella is widely disseminated across US dairy cattle, or it its geographically limited and we think getting a data from all states would really help clarify this for us. Also, we have a state that is wondering if they submit more isolates from cattle than other states. We are trying to understand how isolate submissions from cattle vary by state or any other biases in reporting. Would you be available for a call to further discuss this issue? We would love to hear your thoughts on this.â We donât have an answer to an inquiry like this one. Human medicine has laws that protect the patients identity from disclosure. Some pathogens in people are commensals in animals. We are sharing our bacteria in this room. Cobalt 45 treatment. Maybe its time to revisit these discussions. There are other technologies available to us.
- The non-regulatory role of government needs support. Regulation takes many forms. Regulation that requires data submission, collection, analysis and reporting can become a âsunshineâ mechanism of self-regulation for participants. Weâve seen the success of this with the Pipestone approach. This could even be a pay-to-play marketing based initiative whereby participants âpayâ by providing data, and in return are rewarded by access to markets defined by their participation. The role of government could be to audit the system for fraud and make unbiased analysis of data available to the public.
- The initial phase of the NAHLN Pilot Project was launched in Q4 of FY 2017 with a call for participation to all laboratories being sent out through AAVLD. A total of 19 veterinary diagnostic laboratories were accepted into the project. In preparation of a 2018 launch date, two training webinars were held for the laboratories in November and December to confirm antibiotic sensitivity testing (AST) and data reporting requirements. Also since October, APHIS VS IT personnel have been working to develop electronic data messaging requirements for submitting data from this project to VS. We anticipate bringing 1-2 laboratories on line with electronic messing starting this spring, and adding 1-2 labs per month as resources allow. Â A monthly teleconference has also been established for laboratories to ensure testing methods are standardized and to share best practices across all laboratories. Laboratories are on track for initiating data submissions beginning in February of 2018. Â The non-regulatory role of government needs support. Regulation takes many forms. Regulation that requires data submission, collection, analysis and reporting can become a âsunshineâ mechanism of self-regulation for participants. This could even be a pay-to-play marketing based initiative whereby participants âpayâ by providing data, and in return are rewarded by access to markets defined by their participation. The role of government could be to audit the system for fraud and make unbiased analysis of data available to the public.
- FDA and USDA continue to collaborate with international organizations on the development of vaccines, antimicrobial drugs, and diagnostic tests for use in agriculture. USDA-FSIS, and CDC representatives continue to participate actively in international organizations whose goals are to optimize antibiotic use in animals, reduce antibiotic resistance, build consensus and harmonize methods. USDA-FSIS is collaborating with the Pan American Health Organization (PAHO) and the International Network of Food Analysis Laboratories (INFAL) to document regional capability for antimicrobial resistance work. USDA-NIFA's Agriculture and Food Research Initiative (AFRI) programs are funding projects targeting antimicrobial resistance ecology, an important knowledge gap. In August 2017, NIFA will co-sponsor a meeting on International Symposium on Environmental Dimensions of Antibiotic Resistance. Other ongoing projects address interventions to prevent emergence and dissemination of antimicrobial resistance at the population, animal and microbial levels, understanding antimicrobial resistance ecology through whole genome analysis of microbial communities, and understanding antimicrobial resistance mitigation strategies in cattle.
- We donât put people with a broken wrist in the hospital anymore. We donât use huge plaster casts, either. We certainly donât offer them cigarettes and candy to curb the appetite and relax the nerves. Sometimes I worry that discussion about resistance will result in action that takes away some of the most effective tools of technology we have. The veterinary profession is vested. The tobacco industry took one tack decades ago. The food industry should learn lessons from that. We need to all invest in agriculture. We can live without smoking, not without food.