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<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine HébertRenéeRita:Good morning. My name is Renée Barclay and I’m with NCCID. We’rea partner in <strong>Antibiotic</strong><strong>Awareness</strong>.ca. I’d like to thank you for joiningus and welcome to this webinar which is presented as part of<strong>Antibiotic</strong> <strong>Awareness</strong> Week. During this one hour session we willhear from three Canadian experts in <strong>the</strong> field of antimicrobialresistance.We suggest that you listen to <strong>the</strong> presentation on your computerspeakers however, if you need to, please feel free to listen bytelephone using <strong>the</strong> toll free number and code listed on <strong>the</strong> screen. Ifyou are not a presenter, we suggest that you put your phone on muteso that o<strong>the</strong>r participants don’t hear you. The upcoming threepresentations will be about twenty minutes in duration. During <strong>the</strong>presentation, we invite you to post questions by typing <strong>the</strong>m in <strong>the</strong>box on <strong>the</strong> left of your screen; it’s just in <strong>the</strong> lower left-hand corner.I would now like to introduce Rita Finley. She’s <strong>the</strong> SeniorEpidemiologist, Outbreak Management division at <strong>the</strong> Centre forFood-borne, Environmental and Zoonotic Infectious Diseases. Andshe’s with Public Health Agency of Canada. She will be speaking withus today about <strong>the</strong> Canadian Integrated Program for AntimicrobialResistance and Surveillance. Welcome, Rita.Hi. Good morning everyone, and thank you very much for joining ustoday. I am going to be giving you a brief introduction to issuesaround <strong>the</strong> use of antimicrobials in food animals and its contributionto <strong>the</strong> development and sp<strong>read</strong> of antimicrobial resistance in foodbornebacteria which, as most of you know, can <strong>the</strong>n cause a [incomp– seize? 1:42] in <strong>the</strong> Canadian population consumption ofcontaminated food products. I will also be giving a quick overview of<strong>the</strong> National Integrated Surveillance Program that monitorsantimicrobial resistance in [incomp 1:54] organisms andantimicrobial use in both <strong>the</strong> human and animal populations.And like Renee said, I’m a Senior Epidemiologist within <strong>the</strong> PublicHealth Agency of Canada. And I am also <strong>the</strong> Lead Coordinator of <strong>the</strong>human component of <strong>the</strong> Canadian Integrated Program forAntimicrobial Resistance Surveillance, or CIPARS.So, what are <strong>the</strong> main issues with regards to antimicrobial use inanimals? Both <strong>the</strong> use of antimicrobials in humans and animals isPUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 1
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine Hébertconsidered to be a major driver of antimicrobial resistance. Inanimals, <strong>the</strong>re is a widesp<strong>read</strong> use of antimicrobials for differentpurposes. This may be uses for <strong>the</strong>rapeutic purposes to treat disease,however, depending on <strong>the</strong> treatment and <strong>the</strong> animal, antimicrobialsmight be given to ei<strong>the</strong>r a single animal or to <strong>the</strong> entire herd throughfeed and water, <strong>the</strong>reby exposing healthy animal to <strong>the</strong>se products.Ano<strong>the</strong>r purpose of using antimicrobials may be used for growthpromotion to help growing animals digest <strong>the</strong>ir food more efficiently,get maximum benefit from it, and allow <strong>the</strong>m to develop into strongand healthy individuals. And be able to <strong>the</strong>n provide enough food for<strong>the</strong> current demand among our population.During <strong>the</strong> use of antimicrobials for growth promotion, <strong>the</strong>antimicrobials are provided at a very low sub-<strong>the</strong>rapeutic dose overa period of time, which <strong>the</strong>n may lead bacteria to develop resistance.And lastly, <strong>the</strong>y could be used also for prophylaxis to prevent disease.Of concern is <strong>the</strong> issue that some of <strong>the</strong> classes of antimicrobials, orsome of <strong>the</strong> antimicrobials used in animals belong to <strong>the</strong> same class,or are related to classes that are used in humans, which, in <strong>the</strong> eventof a human infection with a resistant strain, could limit treatmentoptions and increase <strong>the</strong> length of hospitalization or <strong>the</strong> need forhaving to use a more toxic substance.The transmission of resistant pathogens from animals to humanscould be through contaminated food, <strong>the</strong> consumption ofcontaminated food and/or water which could be, <strong>the</strong> water couldhave been contaminated through fecal organisms, or feces. And it canalso be through animals to workers and <strong>the</strong>ir owners, ei<strong>the</strong>r directlythrough contact with <strong>the</strong>m or through <strong>the</strong> environment in which <strong>the</strong>ylive in.So when we speak about increasing concerns of antimicrobialresistance related to antimicrobial use or presence of resistantorganisms in animals, we can classify <strong>the</strong> risk into two types ofhazards – <strong>the</strong> direct hazard and <strong>the</strong> indirect hazard.For <strong>the</strong> direct hazard, we include those resistant organisms thatinfect humans after food has been ingested or handled. Theseinclude, not only bacterias such as Shigella and [Gabriel 4:45], but weare also talking about Campylobacter and Salmonella. ThePUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 2
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine HébertEnterobacter comes through <strong>the</strong> organisms that carry resistancegenes, such as generic E.coli, that are part of <strong>the</strong> Commensal bacteriafamily. These are reservoirs of resistance genes for pathogenicbacteria and can transfer <strong>the</strong> resistance gene from a resistantbacterium through a pathogen bacterium, directly or via ano<strong>the</strong>rCommensal organism. There are, however, good indicators ofselective pressure of antibiotic usage reflecting <strong>the</strong> potential forresistance in future infections. And, <strong>the</strong>y act as a reservoir ofresistance. And as <strong>the</strong> reservoir increases, <strong>the</strong> plasmid reservoirbecomes larger and enables more frequent horizontal transfer ofresistance to pathogens in bacteria, such as Shigella and Salmonella.So, if you attended <strong>the</strong> webinar that we had on Monday, DoctorButler-Jones who is <strong>the</strong> Chief Public Health Officer of Healthintroduced this slide, and I believe some of you are familiar with itfrom o<strong>the</strong>r presentations. But this diagram is just a representation,pictorial representation of <strong>the</strong> epidemiology of antimicrobialresistance in food, and it just represents <strong>the</strong> complexity of this issue.This public health issue, as you can see, is not as straight-forward asresistance being present in our bacteria, and bacteria in a food item,but is <strong>the</strong>n consumed by a Canadian who <strong>the</strong>n becomes ill with aresistant strain. There are many o<strong>the</strong>r factors that can introduce andimpact <strong>the</strong> development of resistance.This diagram also showcases where in <strong>the</strong> food system ourantimicrobial is used. As you can see, <strong>the</strong>re are six different areasthat are encased in a circle, and <strong>the</strong>se are areas where antimicrobialsare used ei<strong>the</strong>r for treating disease, growth promotion, or preventionof disease through <strong>the</strong> use of prophylaxis, as I mentioned in <strong>the</strong>earlier slide.In order to have better information on antimicrobial resistance in <strong>the</strong>food chain and address this complex issue, <strong>the</strong> Canadian IntegratedProgram for Antimicrobial Resistance Surveillance, or CIPARS, wasestablished. I will be speaking more about this program in <strong>the</strong> nextcouple of slides.Since <strong>the</strong> 1990’s, or a little bit earlier, antimicrobial resistancebecame a priority and a public health concern for severalorganisations and governing bodies around <strong>the</strong> world. In 1998, <strong>the</strong>PUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 3
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine HébertWorld Health Assembly Resolution urged members, member statesto develop sustainable systems to detect resistant pathogens tomonitor volumes and patterns of use of antimicrobials, not only on<strong>the</strong> animal sector, but also on <strong>the</strong> human sector. And <strong>the</strong> impact ofany control measures that are implemented in ei<strong>the</strong>r population.Later, in 2001, <strong>the</strong> WHO released <strong>the</strong> Global Strategy for Containmentof Antimicrobial Resistance. And within this strategy, <strong>the</strong>yhighlighted <strong>the</strong> importance of having an inter-disciplinarycollaboration to address antimicrobial resistance appropriately andeffectively.As I mentioned previously, it’s a very [audio shuts down?] not only totake action but also have a representation of all <strong>the</strong> different sectors.In addition, in Canada in 2002, <strong>the</strong> report from <strong>the</strong> AdvisoryCommittee on Animal Uses of Antimicrobials and Impact onResistance in Human Health, provided recommendations on howbest to address AMR. And among <strong>the</strong> recommendations are <strong>the</strong>se twomain ones, which are to design and implement a national monitoringprogram of antimicrobial use in food animals and implementation ofongoing permanent national surveillance system of same, or arisingfrom food animal production.The national program was to provide <strong>the</strong> information collectedthrough surveillance on an annual basis through reports,publications, presentations, and be deciding a manner that wouldallow it to support and provide information for human health riskanalysis. integrate <strong>the</strong> animal health information with humansurveillance initiatives, and have methodologies that would allow itto be comparable to o<strong>the</strong>r international [audio] initiatives, such as inDenmat in Denmark and NARMS in <strong>the</strong> United States. The result of<strong>the</strong> World Health Assembly, WHO guidance and <strong>the</strong> committee reportand many o<strong>the</strong>r recommendations.The Canadian Integrated Program for Antimicrobial ResistanceSurveillance was established in 2002. This program is coordinated bythree centres within <strong>the</strong> Public Health Agency, in partnership withHealth Canada’s Veterinary Drug Directorate, <strong>the</strong> Canadian FoodInspection Agency, Provincial Agriculture and Public Health BuddiesAgricultural and Agri-Food Canada, academia and <strong>the</strong> privatePUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 4
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine Hébertindustry.So, <strong>the</strong> main objectives of this program, or CIPARS, is to provide aunified approach to monitor trends in antimicrobial resistance andantimicrobial use in humans and animals, and to be able todisseminate timely results so that we can have an impact and be ableto determine whe<strong>the</strong>r or not <strong>the</strong>re’s any measures that can beimplemented, or any programs that can be implemented to curtail orreduce, I guess, <strong>the</strong> resistance trends being observed.We also have as an objective to facilitate <strong>the</strong> assessment of <strong>the</strong> publichealth impact of antimicrobials used in both humans and animals,and to allow accurate comparisons with o<strong>the</strong>r countries that usesimilar surveillance systems, such as Denmark and <strong>the</strong> United States.So you can see that our objectives match <strong>the</strong> recommendations thatwere posed by different organizations and reports.And I hope you can see that this diagram on your computer, andbasically, this is, again, a pictorial representation of all <strong>the</strong> differentprograms that make up CIPARS. And we have two arms to it. Themonitoring of antimicrobial resistance, and data of antimicrobial use.As you can see in this picture, we have different surveillancecomponents to our program that are carried out ei<strong>the</strong>r by passive oractive surveillance which come toge<strong>the</strong>r systematically to give us agood overview of <strong>the</strong> status and trends of AMR and antimicrobial usein both populations. At <strong>the</strong> bottom of <strong>the</strong> diagram, and I hope you cansee it clearly, <strong>the</strong>re’s a legend where it shows that those arrows thatare in green are identifying where <strong>the</strong> methods of data representpassive surveillance. And <strong>the</strong> yellow arrows represent activesurveillance methodologies.So focussing on <strong>the</strong> antimicrobial resistance piece of CIPARS, on <strong>the</strong>human side, data is collected through passive surveillance in whichsome of <strong>the</strong> isolates are submitted by Provincial Public HealthLaboratories through to <strong>the</strong> National Microbiology Laboratories forsusceptibility testing.As of 2010, we have received a total of a little over 25 000 Salmonellastrains. And in 2010 we changed our testing scheme so that insteadof focussing on all different Salmonella [incomp 11:47] types, we’refocussing mainly on <strong>the</strong> top Salmonella strains that are related toPUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 5
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine Héberthuman infections in Canada.On <strong>the</strong> animal side, antimicrobial resistance information is obtained,again through passive surveillance of sick animals from isolatessubmitted by Veterinary Laboratories. These are animals that nevermake it into <strong>the</strong> abattoir or are introduced into <strong>the</strong> retail level. Theimportance of this piece of information is that it can give just aglimpse of potential issues that could be introduced by healthyanimals to consumers. And this piece collects information only onSalmonella.The farm surveillance piece is based on [sentinel incomp12:45..[music from someone’s phone] and we collect E. coli andSalmonella information from <strong>the</strong>se sentinels. The next up in <strong>the</strong> foodchain is abattoir, which provides information on what is coming infrom farms and entering <strong>the</strong> food chain. And this component takesplace across federally inspected abattoirs across <strong>the</strong> country [loudvoices from someone’s phone – Renee makes an announcement,apology to Rita]Okay, so going back to <strong>the</strong> abattoir...so, let me see, <strong>the</strong> Salmonellainformation is obtained from chicken and pork samples;Campylobacter from chicken and cattle; and E. coli from chicken,pork, and cattle. And <strong>the</strong> final component of <strong>the</strong> AMR surveillance is<strong>the</strong> retail piece, which gives us a picture of what consumers are beingdirectly exposed to by bringing it into <strong>the</strong>ir homes, and consumption.It consists of sampling from fresh raw meat samples from grocerystores, and sampling consists of chicken and ground beef which aretested for E. coli, Salmonella, and Campylobacter, contamination andresistance patterns – ground beef for E. coli, and pork for both E. coliand Salmonella.And as you can see at <strong>the</strong> bottom, we also have <strong>the</strong> antimicrobial usecomponent to our program. And on <strong>the</strong> human side, we collect <strong>the</strong>information on consumption of oral antimicrobial dispensed byCanadian pharmacies. And this is data that’s being provided by IMSBrogan. It is provided, it’s based on information provided by 5 000pharmacies and is extrapolated to an overall universe of 7 000pharmacies, so it gives us a full picture of what’s being prescribed bypharmacies across <strong>the</strong> country.PUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 6
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine HébertOnce we’ve obtained information, we classify it using <strong>the</strong> HealthCanada Veterinary Drug Directorate’s classification of antimicrobials.We analyse it and convert <strong>the</strong> data to define daily doses.And <strong>the</strong> farm surveillance component also provides us with aplatform to obtain information of antimicrobial use for swine herdsincluded in this program. And we also have ano<strong>the</strong>r piece ofinformation that comes through <strong>the</strong> Canadian Animal HealthInstitute; however it doesn’t provide information on which animalsectors are being prescribed which drugs.So, what have we observed through our surveillance program todate? We have found that chicken isolates demonstrate significantresistance to antimicrobials with certain Salmonella serovarsmirroring certain patterns in chicken and human isolates. As you cansee, between 2002 and 2008 we’ve seen a dramatic increase anddecrease, depending on <strong>the</strong> Salmonella sero type, across chickensamples obtained from clinical case, abattoir, and retail, and what weare seeing in humans as well. So as of 2004, Heidelberg strains havedecreased on <strong>the</strong> chicken and human sectors, while SalmonellaEnteritidis has been observed to increase across <strong>the</strong> chicken samplesand human strains as well.And as you can see here in blue, Salmonella Kentucky is a sero typethat is slowly emerging among <strong>the</strong> chicken samples that we’ve beencollecting and monitoring since 2003. However, on <strong>the</strong> human side, itdoesn’t seem to be causing a lot of human infections. However, whathas us concerned is <strong>the</strong> issue that antimicrobial resistance observedaround, across <strong>the</strong> Salmonella Kentucky isolates obtained fromhuman infections is mirroring what was being observed from <strong>the</strong>animal sector as well.So, as you could see, <strong>the</strong>re’s resistance to all least one antimicrobial.The increase has been observed in both human and chicken isolates,as well as resistance to Streptomycin and Tetracycline which is seento be increasing. And in 2008, having 50% of those Kentucky strainsfrom humans have resistance to this pattern.The o<strong>the</strong>r issue that we’ve been able to identify in, through ourprogram is <strong>the</strong> use of extra-label use of Ceftiofur and resistance tothis antimicrobial in Salmonella Heidelburg. Ceftiofur can be used inPUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 7
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine Hébertmany animal species, however it’s not labelled for use in chickens inCanada, and is currently being used in <strong>the</strong> extra-label manner for <strong>the</strong>control of E. coli in broilers, and it is done through <strong>the</strong> injection ofthis antimicrobial into <strong>the</strong> egg. Salmonella Heidelberg, it is notifiableat <strong>the</strong> national level on <strong>the</strong> human side. It is found among <strong>the</strong> topthree serovars in humans since1995, causing diarrhoea, vomitingand fever. And it can be quite invasive, causing septicaemia,myocarditis, extra-intestinal infections, and death. The treatmentconcern is that when <strong>the</strong>re’s resistance to ceftiofur, <strong>the</strong>re is gonna beresistance to Ceftriaxone, which is one of <strong>the</strong> drugs of choice fortreatment of pregnant women and children.So where else are we seeing resistance to Ceftiofur among our animalisolates? As you can see, among <strong>the</strong> different components of CIPARS,whe<strong>the</strong>r it’s <strong>the</strong> abattoir component, retail, or <strong>the</strong> clinical side, we’reseeing mainly <strong>the</strong> resistance present among chicken isolates. And indiagnostic clinical Salmonella, we’re seeing <strong>the</strong> majority fromturkeys, but however remember that <strong>the</strong> diagnostic clinicalSalmonella is seen in sick animals that never make it into <strong>the</strong> foodchain.And this is just a graph that shows what’s been happening withSalmonella Heidelberg and resistance to Ceftiofur since <strong>the</strong> beginningof <strong>the</strong> surveillance program. In 2003 we started noticing a high levelof resistance in Heidelberg infections in humans, and what’s beingpurchased from <strong>the</strong> retail level in Quebec. And <strong>the</strong> data was sharedwith industry in that province, and as of 2005 <strong>the</strong>re was a voluntarywithdrawal of this use in <strong>the</strong> poultry industry. In 2007, however,<strong>the</strong>re was a partial reinstitution of this antimicrobial in <strong>the</strong> poultryindustry, and as you can see from this graph, <strong>the</strong>re’s been a reemergenceof resistance to Ceftiofur in both Salmonella Heidelbergfrom human infections, and also from E. coli and Heidelberg isolatedfrom chicken retail samples.And as you can see, <strong>the</strong> incidence rate of persons sick with Ceftiofurassisted Heidelberg is also on <strong>the</strong> increase in provinces like Quebec,Ontario, and British Columbia.As I mentioned before, we also have information on antimicrobialsthat are dispensed in retail pharmacies in Canada. We have <strong>the</strong>PUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 8
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine Hébertinformation at <strong>the</strong> provincial levels but we can also summarize it at<strong>the</strong> national level. And here’s just a brief overview of what we’vefound for data for 2009. There seems to be quite a variation amongtotal number, total cost of antimicrobials and total consumption ofantimicrobials across <strong>the</strong> different provinces in <strong>the</strong> country, withNewfoundland and Labrador having <strong>the</strong> highest levels ofconsumption and total cost per 1000 inhabitant days, while Quebechas <strong>the</strong> lowest level of consumption, and B.C. has <strong>the</strong> lowest level,total cost of antimicrobials.If we compare what’s being dispensed for animals and compared to<strong>the</strong> human information that we have, and you can find thisinformation in our 2008 CIPARS annual report, we can see that totalactive ingredients in kilograms of antimicrobials dispensed bypharmacies for human consumption is a total of 197 000 kilograms,while in animals it is 1.6 million kilograms. However, this does notinclude antimicrobials imported for personal use under <strong>the</strong> personaluse provision of <strong>the</strong> Federal Food and Drugs acts and regulations,and doesn’t include active pharmaceutical ingredients which aredrugs imported in non-dosage form and compounded by licensedpharmacists or veterinarians, and used in veterinary medicine andused in food animal production.And finally, just ano<strong>the</strong>r piece or source of information ofantimicrobial use. This is information that’s collected through asentinel farm surveillance program from, through swine herds. Andin 2008, you can see that <strong>the</strong> only category one antimicrobial use ingrower finisher pig herds used was injectable Ceftiofur. The mostcommonly used antimicrobials, overall, were Penicillins, which we<strong>read</strong>ministered primarily via drinking water or injection. Macrolideswere <strong>the</strong> most common antimicrobial administered through feed.And <strong>the</strong>re were five herds that were part of this program in which noantimicrobials were used by any routes in <strong>the</strong> grower finisherproduction stage.So as I mentioned in <strong>the</strong> beginning, this program is based oncollaboration not only among <strong>the</strong> federal levels and also with <strong>the</strong>provincial/territorial levels. And in order to make it successful wereally need to have those collaborations in existence, and have aPUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 9
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine HébertRenéeRitawonderful collaborating relationship with o<strong>the</strong>r governmentagencies, and provincial, and academic, and industry levels.So this slide is just to acknowledge everyone that makes this programpossible and that provides information for us just to keep a goodsense of what is happening across <strong>the</strong> animal and human sectors, interms of Enteric disease and resistance.And if you need more information on CIPARS, we have our reportsavailable in both English and French at our phac website. And itincludes annual reports, short reports, and certain issue papers thatwe put out based on issues that we have identified as a public healthconcern among our surveillance system. And I don’t know if <strong>the</strong>re’sanyone with any questions, or if I’ve run out of time.We, we’re a bit pressed for time, Rita, but <strong>the</strong>re is one question about,how does Canada’s antimicrobial use compare to use in o<strong>the</strong>rcountries?That’s a really good question, and we are able to compare ourinformation with that of <strong>the</strong> European countries. I’m just gonna pullthat out for you in just a second. So, <strong>the</strong> European Surveillance andAntimicrobial Consumption puts out information, and I think <strong>the</strong>y’rea year behind so I can speak to 2008 data that we have for Canada to<strong>the</strong> European countries. So we’re very similar in levels ofconsumption with Finland and <strong>the</strong> Czech Republic. The ... I’m tryingto think. We have half <strong>the</strong> level of consumption that was estimated inGreece. Overall, in 2008 we ranked 14 th out of 31 European countriesthat were able to provide information. And this is in terms ofincreasing levels of consumption. We’re really low compared to <strong>the</strong>secountries in terms of consumption of Macrolides, Lincosamides , andStreptogramins; similar for Quinolones. And we were 18 th for ourlevel of Tetracycline consumption and Penicillin consumption. So Ithink we’re, if we compare ourselves to <strong>the</strong> data that’s available for<strong>the</strong> European countries, we’re kind of in <strong>the</strong> middle of <strong>the</strong> 31countries that provide information on an annual basis.And I just noticed today that <strong>the</strong>re is a group now that’s gonna beposting data for <strong>the</strong> United States on levels of prescriptionsdispensed by pharmacies, so we’ll be connecting with <strong>the</strong>m to try toget a sense of, how do we compare for <strong>the</strong> United States? LatinPUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 10
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine HébertRenéeAmerican countries, as far as I know, don’t put out any informationon antimicrobial use, as in <strong>the</strong> majority of <strong>the</strong> countries <strong>the</strong>y don’trequire prescriptions for getting access to antimicrobials, so it’sharder to compare ourselves to those countries at this time.Okay. Great! Thank you very much, Rita. We appreciate yourpresentation. And we will now be hearing from Doctor LynoraSaxinger, who is gonna be speaking about reducing antibioticoveruse in hospitals. She is <strong>the</strong> Associate Professor and Chair of<strong>Antibiotic</strong> Stewardship committee at <strong>the</strong> division of InfectiousDiseases at <strong>the</strong> University of Alberta. Thank you for joining us, Dr.Saxinger.Lynora My pleasure. Is this coming through okay.It sounds okay to me, yeah.Okay, great. And just to remind people, <strong>the</strong>re’s been a poll put up on<strong>the</strong> screen. In my screen it’s in <strong>the</strong> lower right-hand corner. I’m justcurious as to <strong>the</strong> audience that I’m addressing because my talk isfairly clinical, and so we’re going from agricultural and veterinary useall <strong>the</strong> way up to kind of very high-end hospital use. And so I wouldask everyone to go ahead and vote in that poll.And, as mentioned, I have this kind of provocative title ... Oh no. Now<strong>the</strong> poll is in <strong>the</strong> middle of my screen...and I can’t see my own slides.(laughs) So we’ll wait for a second for <strong>the</strong> poll to disappear, perhaps.So next slide. How am I advancing here? Okay, <strong>the</strong>re we go.So starting at <strong>the</strong> beginning, antibiotic use creates antibiotic resistantorganisms. I’ll point out that antibiotic resistance existed well beforepeople did, because microbes have had genetic arsenals to battleo<strong>the</strong>r in <strong>the</strong> field, so to speak. But certainly, using antibiotics is <strong>the</strong>biggest driver of antimicrobial resistance today. And <strong>the</strong> littlepictogram on <strong>the</strong> right just shows how <strong>the</strong> population will havesome, potentially have some resistant organisms within <strong>the</strong> pool,exposing <strong>the</strong> organisms to <strong>the</strong> antimicrobials, <strong>the</strong>n result in a finalpopulation that is highly resistant.And, again I can’t see my own slides. I don’t know how to make <strong>the</strong>poll go away. [RENEE: Um...I’ll try to get <strong>the</strong> poll off to <strong>the</strong> side foryou...<strong>the</strong>re.] That’s somewhat better.So, <strong>the</strong> collateral damage, of course, of use of antimicrobials isPUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 11
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine Hébertincreasing resistance in common pathogens, like Strep pneumo andTB, and selection for, and transmission of, ARO strains withinhospitals to vulnerable populations. So, a really great example isVancomycin resistant Enterococci in transplant patients, andClostridium difficile outbreaks in, basically patients throughouthospitals. But <strong>the</strong> landscape of resistance is really quite complexbecause things that work well to prevent resistance in some bacteriamay in fact exacerbate resistance in o<strong>the</strong>rs. So <strong>the</strong> use = resistance.Relationship is not entirely clear cut. And I’m just going to go througha way to classify <strong>the</strong> relationship, starting with what <strong>the</strong> bacteria aredoing with our antibiotics.So on <strong>the</strong> right of <strong>the</strong> antibacterial cell, and it just has cartoons ofvarious ways that bacteria can get around antibiotics. So <strong>the</strong>y canspit <strong>the</strong>m out using efflux mechanisms so <strong>the</strong> antibiotic molecule isactually pumped back out of <strong>the</strong> cell. It can chew <strong>the</strong>m up usingenzymatic degradation. It can also disarm <strong>the</strong>m using enzymaticalterations of <strong>the</strong> antibiotic structure so it no longer works. And <strong>the</strong>n,what I’ve termed ‘ducking’ is basically – cell wall changes and targetsite mutations of <strong>the</strong> bacteria, so that <strong>the</strong> target site of <strong>the</strong>antimicrobial no longer allows a fit. And, bacteria can also share andexchange <strong>the</strong>ir weaponry to defeat antibiotics with conjugation,transduction and transformation, wherein <strong>the</strong>y can exchange geneticmaterial that encodes for resistance genes.And you could break resistance down into: simple, moderatelycomplex, and complex resistance. Simple resistance is basically justdoing <strong>the</strong> math. Mycobacterium tuberculosis actually infects about athird of <strong>the</strong> world population, many of whom have latent infectionwhich does not have clinical consequence. But it also causessignificant morbidity, mortality. And it only develops resistance bychromosomal gene mutations at a predictable rate. So, Isoniazid, youget 1 x 10 -6 resistant mutants per cfu. Rifampin, it’s 1 x 10 of a 9 th . Sofor both, it’s about 10 -15 per cloning forming units.And when you look at someone with active TB, <strong>the</strong>y usually havefewer than that M. tb organisms in <strong>the</strong>ir infection, and so developinga resistance to both antibiotics will be rare because you need to havea larger population to select for dual resistance. Unless <strong>the</strong> meds arePUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 12
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine Hébertimproperly taken, in which case you can have multiplication of <strong>the</strong>bacteria and expansion of <strong>the</strong> numbers with sub <strong>the</strong>rapeuticconcentrations.The moderately complex resistance would be things likeStaphylococcus aureus and Enterococci. I have a picture of a baby<strong>the</strong>re because <strong>the</strong>se strains are born, not made. They don’t developresistance during <strong>the</strong>rapy, with <strong>the</strong> exception of VancomycinIntermediate Staph aureus, which is fortunately rare. But both of<strong>the</strong>se types of organisms can exchange DNA with a variety of o<strong>the</strong>rspecies, so multi-drug resistant strains can circulate, even in <strong>the</strong>absence of prior exposure. And that can sp<strong>read</strong> between hospital andcommunity.Going back to Rita’s complicated ecosystem diagram, <strong>the</strong> flowbetween hospital and community in <strong>the</strong>se particular organisms isdefinitely <strong>the</strong>re. And <strong>the</strong>se actually are often best controlled usinginfection control as well as antimicrobial stewardship. But complexresistance is where our patients will have <strong>the</strong> most problems, andthis is where <strong>the</strong>re’s a very direct and complicated relationshipbetween use and resistance. So if you use non-fermentative gramnegativebacteria as exemplars of this type of resistance, such asPseudomonas aeruginosa and an emerging pathogen calledAcinetobacter baumanii, intrinsic resistance mechanisms thatactivate on exposure are very common. So Pseudomonas can actuallydo almost everything I showed you in that first cartoon, can reduceexpression of <strong>the</strong> outer-membrane proteins that will allow entry, soit can block entry. It can activate one or more of several multidrugresistantpumps that efflux a variety of antibiotics so can <strong>the</strong>n...it canei<strong>the</strong>r block entry or spit <strong>the</strong>m out. And it can also increaseproduction of b-lactamases and o<strong>the</strong>r native enzymes in response toexposure to an antimicrobial. And <strong>the</strong>se porin and pump mechanismsmake it possible that when you expose <strong>the</strong> bug to one class ofantibiotics, you can see emergence to o<strong>the</strong>r classes as well.And <strong>the</strong>n in addition to <strong>the</strong> intrinsic mechanisms, gene swapping isvery common in <strong>the</strong>se organisms, and both Pseudomonas andAcinetobacter can <strong>read</strong>ily exchange DNA with multiple o<strong>the</strong>r species.And <strong>the</strong>re was a report in, I think in 2007, of an Acinetobacter thatPUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 13
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine Héberthad basically panned resistant strain in a human infection thatcontained an 86-kb region that encoded 140 determinants that gaveresistance to at least 7 classes of antibacterial agents. And when <strong>the</strong>yanalysed that segment, it suggested that <strong>the</strong>re had been genesacquired from Pseudomonas, Salmonella, and E. coli, among o<strong>the</strong>rs.So that’s a bit of a frightening story.So, as doctors looking at <strong>the</strong>se isolates, what are we, what are ouroptions? One thing that’s been tried is combination antibiotic<strong>the</strong>rapy. This works in simple resistance like TB because we justcan’t develop resistance to two agents at once in simple resistance.But in complex resistance, it can co-select resistance. Examples ofthat would be Fluoroquinolone selection for resistance to imipenemin Pseudomonas isolates, and Cephalosporin selection of resistanceto Vancomycin and E. Faecium. So using <strong>the</strong> drug that might select fora resistance to o<strong>the</strong>r agents that might be of potential importance.And combination <strong>the</strong>rapy, as a net approach, has not been shown toreduce resistance of emergence overall. There is a role in someinfections, though.Antimicrobial cycling also seemed like a good idea, but has beenshown to not be useful, at least in <strong>the</strong> ways that it’s been tried. This iswhere you use a broad spectrum empiric antibiotic for a period oftime, so when you’re starting someone on a very powerful agent, youchoose one agent for maybe three months, and <strong>the</strong>n <strong>the</strong> next threemonths you suggest that everyone choose a different agent. And thistries to change selective pressure being applied to <strong>the</strong> residentbacteria, but it doesn’t work. It’s difficult to enforce, <strong>the</strong>re’s variedmicrobiology, resistance patterns, and patient intolerance of drugs,so you can’t use <strong>the</strong> drug du jour. And <strong>the</strong> <strong>the</strong>oretical underpinningsof cycling strategies might be flawed in that we al<strong>read</strong>y havemultidrug resistance in our hospitals. Some antibiotic classes canselect for resistance to o<strong>the</strong>r classes. And designing a regimen toreduce selection pressure is virtually impossible.So <strong>the</strong> o<strong>the</strong>r option is to stop irritating <strong>the</strong>m. Use antibiotics asneeded to prevent sequelae of serious infections. And <strong>the</strong>re’s threepossible ways that we can reduce antibiotic use, and this is justlogical. Ei<strong>the</strong>r before <strong>the</strong>rapy, we choose only to treat patients whoPUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 14
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine Héberthave a true bacterial infection; during <strong>the</strong>rapy, avoid <strong>the</strong> use ofunnecessary combinations, and unnecessary excess spectrum; andtowards <strong>the</strong> end of <strong>the</strong>rapy, treat only for as long as is required tocure <strong>the</strong> infection. That seems very simple but actually it’s morecomplicated in practice. Reducing prescriptions for viral infections in<strong>the</strong> community is probably <strong>the</strong> most important thing overall in termsof volume of use, as shown in Rita’s graph.But what do we do in hospital? Because in hospital is kind of where<strong>the</strong> most ill patients are, <strong>the</strong> most vulnerable patients are, allconcentrated in a place where we use a tremendous amount ofantimicrobials. So, we know that broad spectrum antibiotics savelives, and delaying appropriate treatment of patients with a range ofserious infections can be fatal. So, withholding antibiotics whileyou’re trying to figure out what’s going on is often inappropriate. Andthis points out <strong>the</strong> challenges in intervening at <strong>the</strong> time of acuteillness, because you don’t want to withhold potentially life-saving<strong>the</strong>rapy.So <strong>the</strong> point, I think, where we can do some work is rationalizingantibiotic use by shortening duration of <strong>the</strong>rapy when clinicalimprovement is secured. And streamlining to <strong>the</strong> most targeted,safest choice of antibiotics when culture results are available. Butfrankly, and this is almost embarrassing, <strong>the</strong>re really is a lack of dataon <strong>the</strong> most appropriate duration of <strong>the</strong>rapy for common infections.Physicians often extend courses beyond clinical improvement just tobe sure, and certainly, most patients don’t experience full resolutionof <strong>the</strong> signs and symptoms, and inflammatory manifestations of aninfection very early. So although you might have killed all of <strong>the</strong>bacteria involved in a Cellulitis infection or in a Pneumonia, you stillwill have redness and swelling of <strong>the</strong> limb, or you still will have chestx-ray chances. And people just are not comfortable leaving patientsoff antimicrobials, because antimicrobials create <strong>the</strong> feeling of safetyfor everybody.So shortening <strong>the</strong>rapy, what patients truly need, and clinical acumenbecomes an interesting thing to discuss. There’s an underlying beliefthat antibiotics are at worst a neutral <strong>the</strong>rapeutic choice. People feelsafer with <strong>the</strong>m. They don’t think <strong>the</strong>y can do any harm. But, on anPUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 15
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine Hébertindividual level, <strong>the</strong>y can have side effects, hypersensitivity, rashes,become colonized and <strong>the</strong>n experience <strong>the</strong> effects of C. diff infection.And, as a society – <strong>the</strong>se are societal drugs because <strong>the</strong> drug use inone patient affects everybody who might be exposed to that patient’seventual resistance flora – you see emergence and sp<strong>read</strong> ofantimicrobial resistant pathogens. So this belief about <strong>the</strong> safety ofhaving people on antimicrobials for prolonged courses is ill-advisedand actually potentially dangerous.Now, I’m just gonna remind people that in <strong>the</strong> past, occasionallypeople would get severe bacterial infections. Actually, I would argue,very commonly because <strong>the</strong>y were more common <strong>the</strong>n. And beforeantibiotics were introduced, people often survived severe bacterialinfections. There’s very eloquent and detailed descriptions in medicaltextbooks from <strong>the</strong> 1800’s of classic courses of diseases in <strong>the</strong>absence of antibiotics. And trying to predict whe<strong>the</strong>r patients wouldlive or die, because that was <strong>the</strong> only role of <strong>the</strong> physician at <strong>the</strong> time.This is just a picture from when a newly-minted physicianadministered oxygen to a 16 year old with bacterial pneumonia, andhe recovered, living to <strong>the</strong> ripe age of 91. And he actually got apublication out of that. He wrote it up and explained <strong>the</strong> physiology.And people lived without antibiotics in <strong>the</strong> past.So, how much do we need? When Penicillin was introduced in 1944,<strong>the</strong>re was a whole series of case reports showing things that treatinga hundred patients with Penicillin who had pneumococcalpneumonia. And <strong>the</strong>y said, in general <strong>the</strong> results were satisfactorywith doses of 10 000 units every 4 hours for one and a half to twodays. And <strong>the</strong>n later, most of <strong>the</strong> patients, 31, were treated for threeto four days. And as long as <strong>the</strong>re’s no complicating factors, <strong>the</strong> initialimprovement persisted as a permanent cure.Now, I will admit that, in general, we’ve probably shifted bacterialtolerance of antibiotics up and our bacteria are not as sensitive as<strong>the</strong>y were back in <strong>the</strong> 1940’s, but that idea that <strong>the</strong> initialimprovement persists as permanent cure in <strong>the</strong> absence ofcomplicating factors, I think, is one that we might ...it might be worthtalking about a little bit more.And <strong>the</strong>n a few brave people have done studies in a very, very illPUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 16
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine Hébertgroup of patients. So, patients who were in <strong>the</strong> ICU with ventilatorassociated Pneumonia. So <strong>the</strong>y’re intubated, on a ventilator, ill. And<strong>the</strong>y compared 8 vs. 15 days of antibiotics in 401 patients withventilator associated pneumonia that was diagnosed fairlyrigorously, and <strong>the</strong>re was no difference in pulmonary infection,mortality, ventilator-free days, organ-failure free days, and <strong>the</strong> lengthof ICU stay between <strong>the</strong> groups.The one comment I would make on some of <strong>the</strong>se papers is that <strong>the</strong>reis some dependence on which pathogen is present. And so, I don’tthink that you can just have a blanket approach to things. Butcertainly, if a ventilator associated Pneumonia patient can improveafter 8 instead of 15 days of antibiotics, it makes me wonder why somany patients basically remain on antibiotics until <strong>the</strong>y leavehospital.Sorry, I’m just gonna turn that off. ..So basically, I think we usually over-treat. There’s been a few studieson community acquired pneumonia 3 vs. 8 days of Amoxil, and <strong>the</strong> 3day regimen was equivalent in efficacy to <strong>the</strong> 8 day regimen, if <strong>the</strong>patient substantially improved in <strong>the</strong> first 3 days. Again, this is notone size fits all, and it requires some follow-up and clinical acumen.This would be considered non-definitive. If you look at <strong>the</strong>ir graphs,<strong>the</strong>re was a trend towards better outcomes in <strong>the</strong> 8 day group, butagain, it depended, I think, on <strong>the</strong> underlying condition of <strong>the</strong> patient.And so it supports more studies. But here’s an open question: whofunds studies of using established antimicrobials in a different way ina hospital setting?So <strong>the</strong>re are some consequences of inducing complicated resistance.This is gonna be accelerated cause we’re running short on time. Afew cases from last week; I was on call. So <strong>the</strong>re’s a 33 year old manwith head trauma in a collision, in severe neurologic compromise. Hehad recurrent isolation of Pseudomonas in bronchial secretions, andhe developed a clinical Pneumonia. Before he developed <strong>the</strong>Pneumonia, he’d had a little bit of flirtations with various antibiotics.He’d been put on Ceftazium for a few days. And <strong>the</strong>n when we sawhim, prior to my involvement, he actually had a Pneumonia with aPseudomonas, and he was given Colistin plus Aztreonam, whichPUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 17
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine Hébertshould be raising red flags with people who are familiar with thistype of <strong>the</strong>rapy. He required a decortication because of an Empyema,he had to have a surgical clean-out of his chest, and he remainedcolonized with this bug. And when it was first isolated, it wassensitive to Aztreonam, and intermediate to Ceftazidime, andsensitive to Colistin, but resistant to all Aminoglycocides,Carbopanems, and Pip Tazo. And <strong>the</strong>n after he was exposed toCeftazidime for four days, just towards <strong>the</strong> end ofSeptember/beginning of October, we actually induced Aztreonam ofCeftazidime resistance, leaving it susceptible only to a single agent,Colistin, which we are unfortunately having to use more of <strong>the</strong>se daysfor multi-resistant bugs.Ano<strong>the</strong>r case is a 38 year old man with leukemia who is recentlydischarged from <strong>the</strong> ward after induction chemo<strong>the</strong>rapy. He wasdoing very well. He was afebrile but he was still neutropenic and sohe was put on oral Cipro and Clavulin as an outpatient. He returnedto <strong>the</strong> hospital with very severe sepsis requiring massive support,and <strong>the</strong>y started him on Vanco, Pip Tazo, and Tobramycin. We wereasked to see him when his blood cultures became gram negativebacilli, and we actually changed him to Imepenam because we wereconcerned that this arose while he was on Clavulin and Cipro. And<strong>the</strong> susceptibility results, which came back after he died, showed thathis isolate was really susceptible only to Colistin. He had septic shockin spite of maximal support, and after an intra-cerebral bleed relatedto his abscess, care was withdrawn. And so this 38 year old man diedof a multi-resistant Pseudomonas.And a third case from <strong>the</strong> same week – a 90 year old man who camein with vomiting with tube feeds. Quite unwell, but systematicallystable. And his daughter is his main caregiver and very devoted. Hisurine analysis showed more than 50 White Cells. He was sent homeon oral Cefixime from <strong>the</strong> Emergency Room. The blood culturesbecame positive for gram negative bacilli. The patient’s family wascalled, <strong>the</strong>y came in and <strong>the</strong>y started outpatient Ceftriaxone becauseapparently, he looked quite well. The patient was actually receiving<strong>the</strong> Ceftriaxione when <strong>the</strong> following result was received. He had an E.coli isolate that was susceptible only to Carbopenems, Colistin, andPUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 18
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine HébertAmikacin – so he had an E.S.B.L. E. coli. He’d had no recent infectionsor antimicrobial <strong>the</strong>rapy. He’s been in a healthcare setting for a hipfracture several months before, but that was <strong>the</strong> only evidentpotential risk for E.S.B.L. acquisition unless he acquired it in <strong>the</strong>community.So this is not really a brave new world, this world of very resistantmicrobes affecting people in hospital. There’s been a lag in newantibiotic development for resistant gram negatives. So we haveColistin, Aminoglycosides, Tigecycline if it’s not a Pseudomonas. And<strong>the</strong>n what? Not so much. And so I put up that picture to remind usthat what we’re looking at is what our children will inherit in termsof resistance.And so after going through all this and thinking about materials forthis talk, I decided that <strong>the</strong> most practical tactic to reduce antibioticoveruse right now is looking and focussing on duration of <strong>the</strong>rapy.We have to get back in <strong>the</strong> motive, looking at <strong>the</strong> patient’s progress todetermine shorter vs. longer courses. We should be getting somestudies going on duration for common infections. If people areunsure about how patients will do if antibiotics are stopped, <strong>the</strong>yshould see <strong>the</strong> patient and follow-up to make sure <strong>the</strong>y’re okay. Itmakes really no sense to give 10 to 14 days of antibiotics for skininfections when we know you only need 7 or 8 days to treat mostventilator-associated Pneumonias. We really should be trying topreserve Quinolones because <strong>the</strong>re are no oral options for gramnegatives in <strong>the</strong> pipeline. And this is kind of a side issue, which I thinkis none<strong>the</strong>less important. We need rapid diagnostics to allow earlierstreamlining of <strong>the</strong>rapies, so that we can reduce <strong>the</strong> brut of <strong>the</strong>rapygiven at <strong>the</strong> onset.And so, I’m finishing with this slide, which is how I was trying toconceptualize <strong>the</strong> risk and benefit in antimicrobial use. When westart off with broad, empiric life-saving <strong>the</strong>rapies in hospital, we’redoing a very good thing. But quite quickly <strong>the</strong>re’s increasing risk ofside effects – adverse events in toxicity that take place – and selectionof resistance and creation of resistance begins to accelerate. At <strong>the</strong>end, you pretty much have inevitable super-infection with organismsthat are not covered by <strong>the</strong> broad <strong>the</strong>rapy, and resistant pathogens.PUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 19
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine HébertRenéeAnd so, what we should really be looking at doing is having peoplestop treatment before <strong>the</strong> risk-benefit crosses and follow <strong>the</strong> patientfor outcomes. And with that I’m going to close.Thank you very much, doctor Saxinger. It’s really interesting. And,because we’re a bit tight on time, I’m going to hold off on <strong>the</strong>questions for now, but I will just mention that <strong>the</strong> presentations willbe available on our website. They will be translated and available onour website, at <strong>Antibiotic</strong><strong>Awareness</strong>.ca for those who want to see<strong>the</strong>m afterwards. And with that, I will introduce our next speaker,which is doctor Daniel Thirion. And he is Clinical Associate Professorand Pharmacist at <strong>the</strong> Faculty of Pharmacy, Université de Montréal,and McGill University Health Centre. Hello Daniel. Are you <strong>the</strong>re?Yes I am. Hello everyone. Thank you for inviting me again for thisopportunity, a presentation on Antimicrobial Resistance. First, I wantto thank also <strong>the</strong> first two speakers, who have done an excellent jobon presenting two important issues in regards to antimicrobialresistance.What I’m going to try to do is present different aspects that wereinitially discussed, and hopefully, this will give a complete view of <strong>the</strong>issues surrounding antimicrobial resistance. So, actually, I’m justgonna skip <strong>the</strong> objectives. Initially, what I was going to present wasperspective of <strong>the</strong> global problem on antimicrobial resistance, <strong>the</strong>pathways to resistance, and just identify some of <strong>the</strong> concerns ofresistance in Canada and try to identify <strong>the</strong> strategies that we’reimplementing to avoid emergence of resistance and how we have toadapt <strong>the</strong>rapy and practice.So usually, when I present antimicrobial resistance to clinicians, thisis a slide I use; it takes about half an hour to explain. And I’ll go overit much quicker. The important concepts that are needed tounderstand, first is <strong>the</strong> genetic development of antimicrobialresistance, and selection of resistance in a single patient. This isactually very well explained on <strong>the</strong> FDA video that’s available if youjust look on, through Google, it’s actually pretty easy to find. And so,genetic development of resistance, I think, was well explained on <strong>the</strong>first two presentations, and I won’t go over that. And selection ofresistance actually was also well explained by Dr. Saxinger, so I won’tPUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 20
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine Hébertgo into that.What’s important also to recognize, is <strong>the</strong> emergence of resistanceei<strong>the</strong>r through <strong>the</strong>rapy or through a population. And this also was...Ithink I’m putting an emphasis again on this, <strong>the</strong>re are some infectionsand specific species of bacteria who are more susceptible to produceresistance when <strong>the</strong>y are exposed to antibiotics. And we see this incommunity, associated with Streptococcus pneumoniae. Or we cansee this maybe more in <strong>the</strong> hospital, associated with gram negativeinfections.And as we look toward <strong>the</strong> o<strong>the</strong>r end of <strong>the</strong> spectrum, we know thatsome bacteria are actually more susceptible to transmission ofresistance than <strong>the</strong> strains of resistance, and this we see more withMRSAs. So, as al<strong>read</strong>y mentioned, for Staph aureus, <strong>the</strong> mostimportant interventions are infection control. And with o<strong>the</strong>rresistance such as Strep pneumo, <strong>the</strong> most important interventions isantimicrobial stewardship. And I think, overall, if we want to curbthis, we want to be able to maintain both of <strong>the</strong>se programs, infectioncontrol and stewardship as a collaborative practice, to be able toaddress <strong>the</strong> whole issue of antimicrobial resistance in ourpopulations.Next point is laboratory testing for resistance, so if you want tounderstand resistance and <strong>the</strong> problems, you have to be able tounderstand <strong>the</strong> laboratory aspects of testing for resistance and howyou detect it and interpret those results.And after that, you go on to empiric drug selection according to thoseresults, and adjust <strong>the</strong>rapy according to sensitivity results. We alsoadjust empiric drug <strong>the</strong>rapy according to surveillance studies thatshow us some patterns of resistance in certain areas that are ei<strong>the</strong>rin <strong>the</strong> hospital or in <strong>the</strong> community setting.Okay, so that goes over that slide in about...record time.Just so that we understand what’s going on, and again, this waspresented a little bit earlier, I’m gonna go to <strong>the</strong> next slide. I know<strong>the</strong>re’s some lag so I hope this pops up at <strong>the</strong> same time I see it. If youlook at this graphic that was published about ten years ago, it shows<strong>the</strong> mortality rate per 100 000 patient years in <strong>the</strong> 20 th century. Andwe see that mortality rate associated to infectious diseases was closePUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 21
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine Hébertto 50% of all mortality causes. And most of <strong>the</strong> patients usually diedei<strong>the</strong>r from Influenza followed by complications of Pneumonia, orfrom Tuberculosis.And <strong>the</strong> decrease in mortality that we saw over <strong>the</strong> 20 th century ismostly due to three factors. These three factors are: one, personalhygiene (people washing <strong>the</strong>ir hands, washing <strong>the</strong>ir food before <strong>the</strong>yeat it); and second is cleaning up our cities (having a good system forevacuation of trash and sewer systems); and our third impact wasthrough development of antimicrobials, mostly for treatment ofTuberculosis and o<strong>the</strong>r severe infections.And as we know, <strong>the</strong> problem is that we do have constant emergenceresistance associated with <strong>the</strong> use of antibiotics. But we have stoppeddevelopment of new antimicrobials, especially for <strong>the</strong> gram negativeswhich continues to be an issue.So I’m just gonna show you <strong>the</strong> next slide over here. So, through <strong>the</strong>FDA, <strong>the</strong>re was 500 new registrations for new drugs, but only 6 of<strong>the</strong>m were for antibiotics. And this is not a guarantee that <strong>the</strong> Stateswill reach clinical setting use.Okay, so you do have an idea of what <strong>the</strong> impact is for antimicrobialresistance. We do know that when resistance pops up, it causes adelay in <strong>the</strong>rapy. We delay <strong>the</strong>rapy, <strong>the</strong>n <strong>the</strong> patients are at higherrisk of complications. They ei<strong>the</strong>r need more surgical procedures orit leads to more diagnostic procedures to make sure that <strong>the</strong>re’s aresistance or something else is going on. And, at <strong>the</strong> end of <strong>the</strong> wholething, patients are at risk of complications, are also at higher risk ofmortality and increased length of stay in hospitals.If you want to convince someone about <strong>the</strong> impact of antibiotics, thisis actually a pretty good study that was done by our Intensivist inWestern Canada, where you see that if you’re using <strong>the</strong> rightantibiotic up-front on <strong>the</strong> first day, for patients who are at high riskfor complications, you will have a much better survival than patientswho are exposed to <strong>the</strong> wrong antibiotic, so an antibiotic that doesnot cover <strong>the</strong> pathogen question.This is actually – and I want to make sure that everybodyunderstands this – this is actually very important for patients whoare at high risk of complications or at risk of mortality, and thisPUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 22
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine Héberthappens mostly in <strong>the</strong> intensive care unit. We’re not talking aboutpatients who are in <strong>the</strong> community setting as if <strong>the</strong>ir risk ofcomplications and is much slower. So if you don’t get <strong>the</strong> rightantibiotic you still have a chance of catching <strong>the</strong> patient two to threedays later, waiting for lab results and adjusting <strong>the</strong>rapy. And this isactually quite important when we’re trying to choose whichantibiotics we’re putting on our <strong>the</strong>rapeutic guidelines.When we’re doing this for Quebec, we’ve decided that foroutpatients, we can use a certain antibiotic and we can expect ahigher level of resistance in <strong>the</strong> community and still use thatantibiotic because <strong>the</strong> patients are at lower risk of complications.However, if it’s in <strong>the</strong> hospital setting, for patients who are very sick,<strong>the</strong>n we will use broader spectrum antibiotics and hopefullystreamline <strong>the</strong>m very quickly once <strong>the</strong>rapeutic results are available.Again, if you want to look over where are <strong>the</strong> consequences ofantibiotic resistance we can check on, <strong>the</strong>re’s a review here fromMaragakis which shows <strong>the</strong> risk of death, length of stay, andattributable costs associated with different types of infections. I don’twanna go into too, too many details with this, but you do see a higherrate of mortality associated with resistance. Okay, I mentioned thatdevelopment resistance can be well explained through <strong>the</strong> video on<strong>the</strong> FDA website, so you do have <strong>the</strong> website here that’s mentioned ifyou want to go and find it.Very briefly, on this next slide, we’re seeing antimicrobial resistancepathways. So again, I think Doctor Saxinger had one of <strong>the</strong>se slides up<strong>the</strong>re showing a similar pattern of mechanisms of action andresistance. And actually, I come up with <strong>the</strong> same explanation from afrancophone perspective, I guess. So we have <strong>the</strong>se little Pac Mansthat chew up <strong>the</strong> antibiotics, we have some that try to pump out <strong>the</strong>antibiotics, we have o<strong>the</strong>r mechanisms that just try to duck bymutating and changing <strong>the</strong> target site for <strong>the</strong> antibiotics.Okay. So as I mentioned, for emergence of sp<strong>read</strong> of antimicrobialresistance, some are most importantly sp<strong>read</strong> through contact, andthis is actually important for MRSA. And we just keep on sending out<strong>the</strong> same message of washing your hands and respecting infectioncontrol procedures. While in o<strong>the</strong>r cases it’s selective pressure onPUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 23
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine Hébertexposure to antibiotics, and we can see this with Strep pneumo. Andactually, I would like to relate this issue to our, one of <strong>the</strong> firstspeakers who was showing <strong>the</strong> amount of antibiotics used in <strong>the</strong>province. And, as you didn’t notice, in Quebec, <strong>the</strong>re was <strong>the</strong> lowestuse of antibiotics per capita sold in <strong>the</strong> community. And this, I couldsay, is probably <strong>the</strong> result of Clostridium difficile, as a lot ofphysicians became aware of <strong>the</strong> problem with C. diff and <strong>the</strong> cause ofdeath that was associated with it, and stopped prescribing antibioticsfor indications where it was not really necessary. And <strong>the</strong> populationwas also aware of this and stopped requesting for antibiotics. And Ithink that shows how much potential we can go and get in <strong>the</strong> o<strong>the</strong>rprovinces to decrease antibiotic use.Now, that’s one of <strong>the</strong> aspects, is trying to address <strong>the</strong> indication ofantibiotics and decrease that aspect. The o<strong>the</strong>r impact that we didn’thave was publishing provincial guidelines on how to diagnose, andwhich infections require what kind of antibiotic, for what type ofduration. And that pertains to <strong>the</strong> second aspect of it, is <strong>the</strong> durationof <strong>the</strong>rapy.Okay, so, interventions to overcome antimicrobial resistance...this isfor specific patients who get a resistant infection, and we do adjust<strong>the</strong>rapy for different aspects. For example, in certain situations, inempiric situations, if we suspect resistance, we’ll ei<strong>the</strong>r add on anantibiotic or choose an antibiotic that has broader spectrum. Thismostly occurs for severe infections for patients admitted into <strong>the</strong> ER,or going into <strong>the</strong> ICU. What we might also want to do is increase doseof certain agents, and we have seen this with Amoxicillin where we’reusing higher doses in <strong>the</strong> community empiric <strong>the</strong>rapy to treat for aStreptococcus pneumoniae.Now, all <strong>the</strong>se adjustments cannot be done vaguely. You do needgood data to make appropriate decisions. And it really depends onwhat kind of resistance we’re seeing, and what is <strong>the</strong> bug, and whatkind of antibiotic you’re using. So if we’re looking at <strong>the</strong> Amoxicillin,we have data that supports increased dosing does have some efficacyfor increasing resistance for Streptococcus pneumoniae. However,with MRSA, it’s an alteration of <strong>the</strong> target site with Penicillins. Evenincreasing doses will have no efficacy, and in those cases, you have toPUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 24
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine Hébertchange antibiotic classes.There’s o<strong>the</strong>r aspects we also use, and this was also brieflymentioned, to prevent emergence of resistance during <strong>the</strong>rapy. Thereis some limited evidence that combination <strong>the</strong>rapy can be effective.We’ve seen this a little bit with Pseudomonas, and we’ve seen thisalso in T.B. or, again, in certain fungal infections such asStreptococcus Meningitis. We will also use some type of interventionwith pharmacological agents when we’re talking about transmissionof resistance between patients or within <strong>the</strong> institution. So you’veprobably heard of using Puracyn or o<strong>the</strong>r agents such as Rifampin or[tmpsmx 58:55] to decolonize patients who are positive with MRSA.unfortunately, <strong>the</strong>se measures are only short-lived; <strong>the</strong>y are effectivein <strong>the</strong> short term. However, resistance does emerge during <strong>the</strong>setypes of interventions in your institutions.Just to get an idea of what’s going on, CCAR was an organization thatwas sort of a central link to all of our organizations who had aperspective on how to address antimicrobial use. Unfortunately <strong>the</strong>iractivities have stopped recently.But just to show all <strong>the</strong> aspects of stewardship, it’s actually quitebroad, and it’s not just one type of professional or just one type ofgroup or organization that can address antimicrobial resistance onits own. And that’s why it’s important to have certain champions ineach of <strong>the</strong> fields to be able to promote appropriate use of antibioticsor infection control, or modify practices to be able to curbantimicrobial resistance. And, I’m not showing a slide on this, but<strong>the</strong>se interventions do have an impact, and we can definitely see itwith MRSA.If we’re looking down south of <strong>the</strong> border, in <strong>the</strong> U.S. <strong>the</strong> MRSA ratesin <strong>the</strong>ir community is increasing and has passed <strong>the</strong> 50% mark. Soempirically, <strong>the</strong>y do have to cover for MRSA. And we’re still not doingthat in Canada because our MRSA rates vary between areas, but cango between 5% and 30%, depending on <strong>the</strong> situation.Surveillance methods has al<strong>read</strong>y been presented, but in <strong>the</strong> humanpopulation we’d have two groups that are surveying resistance inCanada: one is called <strong>the</strong> CAN-R which is mostly a research initiativethat was initiated in Winnipeg; <strong>the</strong> o<strong>the</strong>r one is of course, from ourPUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 25
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine Hébertfederal governments, which is The Canadian Nosocomial InfectionSurveillance Program where you can find most of <strong>the</strong> data.In Québec we have our own groups. One of <strong>the</strong>m is called L’Institutnational de santé publique du Québec, where we do have anantimicrobial resistance committee who is overlooking surveillanceand interventions that have to be performed to curb certain aspectsof resistance that are, that can be a threat to public health.And this is an example of interventions that can be performed to tryto curb antimicrobial use. This is <strong>the</strong> one that we’re using for ourcommunity practice. In Québec, we have a group that’s called LeConseil du médicament, or now called INESSS, Institut nationald’excellence en santé ... okay, it’s a really complicated thing in French!But what I’m just saying is that we do have guidelines that wedistribute to all health care practitioners who have an issue withantibiotics. So ei<strong>the</strong>r prescribing it, surveying it, or administrating it,so it’s mostly our nurses, pharmacists, and physicians that arereceiving <strong>the</strong>se guidelines and that are constantly being updated.And I do know that <strong>the</strong>re are o<strong>the</strong>r guidelines that exist acrossCanada, including <strong>the</strong> Bugs n’ Drugs that’s in Western Canada, and forCanada, we do publish ano<strong>the</strong>r book that’s called The Snippets forSnappy Antimicrobial Therapy. And <strong>the</strong> reason we do this is because<strong>the</strong> resistance patterns in Canada are different than <strong>the</strong> resistancepatterns that are in <strong>the</strong> U.S. or around <strong>the</strong> world, so that’s why we doneed our local guidelines to be able to chose our antibioticsappropriately, according to <strong>the</strong> indications.And last but not least, as mentioned from <strong>the</strong> second talk, isAntimicrobial Stewardship. Here is one of <strong>the</strong> definitions. But Iwanna point out, and this is actually critical, <strong>the</strong>re is one aspect that’smissing in this and its indications. So it’s making <strong>the</strong> right diagnosisfor antibiotics. Using antibiotics for viral infections, as you do know,is not necessary. You can use antivirals for viral infections, butantibiotics is not required. And that’s where we’re seeing most of ourimpact in our Stewardship Program in our institutions.The o<strong>the</strong>r aspects, of course, are choosing <strong>the</strong> right antibiotic, at <strong>the</strong>right dose, given through <strong>the</strong> right route of administration for <strong>the</strong>appropriate amount of time. And this is actually to improve outcomesPUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 26
<strong>Antibiotic</strong> <strong>Awareness</strong> Week, November 2011Rita Finley, Lynora Saxinger, Daniel ThirionTranscription: Marjolaine HébertRenéeand avoid emerging resistance within our institutions and within ourpopulations.So, just a brief review, but I don’t wanna go over this because I knowyou’ve al<strong>read</strong>y seen this aspect of what are <strong>the</strong> goals of AntimicrobialStewardship and its benefits. In Québec, again – I’m sorry to poundyou with Québec stuff, but, and <strong>the</strong>re are excellent examples acrossCanada, especially in Ontario for stewardship, that <strong>the</strong>y’re taking alead on this, but we do have a framework for optimal antimicrobialuse in our institutions, and trying to push forward appropriatesurveillance and intervention methods across <strong>the</strong> whole province.So just in summary, <strong>the</strong> messages that I want you to go home withare actually pretty simple. First, wash your hands – don’t get <strong>the</strong> bugand don’t give <strong>the</strong> bug. And use antibiotics appropriately. So, whenneeded, for <strong>the</strong> right one, with <strong>the</strong> right one, <strong>the</strong> right dose, and for<strong>the</strong> determined amount of time. And I’ll conclude on saying, youshould sp<strong>read</strong> <strong>the</strong> word – not <strong>the</strong> disease.So, thank you very much everyone for participating. You do have myslides and I will remain available if you have any questions, ei<strong>the</strong>rnow or through <strong>the</strong> internet, through email.Thank you very much, Daniel. We really appreciate that, and we are abit over so I won’t put it out for any more questions. But as youmentioned, we will have all <strong>the</strong> slides up on <strong>the</strong><strong>Antibiotic</strong><strong>Awareness</strong>.ca website. They will be translated andavailable in both official languages, so we invite you to go <strong>the</strong>re. Andalso, to check out <strong>the</strong> resources that we have for healthcareproviders.And finally, we have a survey about today’s webinar. We’d appreciateyour feedback, if you wouldn’t mind just spending just a few minutes.It’s not long, just to tell us what you thought about today’s webinar.Thank you very much. This concludes <strong>the</strong> <strong>Antibiotic</strong> <strong>Awareness</strong>week. Thank you for joining us, and have a good afternoon. Bye-bye.END OF RECORDINGPUBLIC HEALTH AGENCY of CANADA//AGENCE DE LA SANTÉ PUBLIQUE du CANADA 27