**Transcript of Cyberseminar**

**Spotlight on Evidence-based Synthesis Program**

**Antimicrobial Stewardship Programs in Outpatient Settings, A Systematic Review**

**Presenter: Dimitri Drekonja, MD, MS; Gregory Filice; MD; Matthew Goetz, MD**

**May 12, 2014**

*This is an unedited transcript of this session. As such, it may contain omissions or errors due to sound quality or misinterpretation. For clarification or verification of any points in the transcript, please refer to the audio version posted at www.hsrd.research.va.gov/cyberseminars/catalog-archive.cfm or contact**Dimitri.drekonja@va.gov*

*Moderator:*Thank you everyone for joining us for today’s HSR&D Cyberseminar.  Today’s session is a part of our Spotlight on Evidence based Synthesis Program cyberseminar series.  Today’s session is antimicrobial stewardship programs in outpatient settings, a systematic review.  We will be discussing the systematic review during today’s call.  

Our presenter for today is Dimitri Drekonja.  He is a member of the Infectious Disease Section at the Minneapolis VA Healthcare System, and an assistant professor of medicine at the University of Minnesota Medical School.   He is joined by Doctor Matthew Goetz.  He is the chief of Infectious Disease Section at the VA Greater Los Angeles Healthcare System, program director at the UCLA affiliated program in infectious diseases and a professor of clinical medicine at the David Geffen School of Medicine at UCLA.

Also joining is Doctor Gregory Filice.  He is the chief of the Infectious Disease Program Disease Section at the Minneapolis VA Medical Center and a professor of medicine, adjunct professor of epidemiology and community health in the School of Public Health at the University of Minnesota Medical School.  With that, Doctor Drekonja, I’d like to turn things over to you.

*Dr. Drekonja*All right, well thank you everyone for joining us.  This is my first run through conducting one of these cyber seminars.  Hopefully the technology works and I follow along with it.  I look forward to the questions if they come up, and we’ll try to get to them as best I can.  

This was a cooperative effort as many of these things are, and just going to quick show you—these are the folks who helped out.  The collaborators and co-authors are Gregory Filice, Andrew Olson, Tim Wilt, who’s sort of the head of the evidence synthesis program here, Ron McDonald, Indulis Rutks, and Nancy Greer, who’s also on the call, was also instrumental in pulling all of this together.  There you see the expert panel and reviewers who helped out in terms of refining the topic and helping steer us and keeping us on task.  

A few quick words of disclosure that I think are mandated for these evidence based synthesis programs.  This is based on research conducted by the evidence synthesis program located here at the Minneapolis VA.  It’s funded through the VA QUERI program.  These conclusions are our own.  They don’t represent the VA, so don’t construe this as an official position of the VA.  None of us have any affiliations or financial involvement that would conflict with anything in here.

That being said, a few more words about what the evidence Synthesis Programs or ESP are.  These are sponsored by the VA Office of Research and Development and Quality Enhancement, the query.  They’re really the design to provide timely and accurate—we strive for accuracy, syntheses and reviews of topics that are identified, really, through a grounds up effort by VA clinicians, policy makers, managers, working to improve the health of Veterans.

It really builds on staff and expertise already in place at these sites that are designated by AHRQ.  Four of these evidence practice centers are also ESP centers.  You see them listed here, including the one here in Minneapolis.  Our—tried really to provide evidence syntheses on important clinical practice topics that are especially relevant to Veterans.  These reports are designed to develop policies, help implement effective services.  Also, very important is to guide the future research and identify gaps in clinical knowledge, and often that’s one of the more valuable things that can come out when we do one of these systematic reviews.

As mentioned, this is a pretty broad topic nominating process.  It can come from central office, from the VISNs.  Also, it’s from the field.  This is all facilitated through a coordinating center where there’s an online nominating process where anyone who feels that a topic is deserving of review can submit a form, and it’s gone through a venting process.  It goes up through the chain and eventually comes to one of the ESP Programs.  This is how these topics come into being.

Then a steering committee representing the research and operations provides some oversight and guides the program direction.  There is a TEP or Technical Expert Panel that is recruited specifically for each topic to help refine content and expertise.  The draft report goes out to external peer reviewers and policy partners.  This is a very open process where if you go into the intranet—just the intranet, not the internet, you’ll see the link there.  You can see the draft comments and the response to the reviewers.  This is a very transparent process to help bring the final publication out and make it available.

That being said, the current report, this is part of two. There was Antimicrobial Stewardship Program in inpatient settings.  This is its twin brother, that in outpatient settings.  We completed this back in September 2013.  It doesn’t seem like that long ago.  The full length report, and it is extensive, is on the VA intranet there at that link.  You do have to go into the—add the VA before the www.  I found it best by going to the VA intranet and then searching for ESP and it came up quite quickly.

From all that, I’m going to shift now to the background of how this started out.  I think most people listening in recognize that anti-microbial use is quite extensive.  We won’t even get into the agricultural use where it turns out that more antibiotics are used.  Over three million kilos of antimicrobial had been administer to human patients in the US in 2009, and don’t have any newer data than that, but very few would suggest that it has changed dramatically in the favorable direction.

Antibiotics are quite unique in that they influence not just the patient being treated, but also a surrounding ecosystem.  If you’re treating someone for hyperlipidemia with a statin, you can certainly injure that person’s liver.  You can have other adverse events.  The patient the next bed over or the family members will not be terribly affected by that.  Antibiotics are quite different in that use affects the environment.  If an ICU was using a lot of a certain antibiotic you will then eventually select out for resistance.  They are rather unique in their wide spread effects, not just to the unique patient.

We also know that with antibiotic use, especially with inappropriate and excessive use we see associations with increased microbial resistance and a higher incidence of antimicrobial associated *C.difficile* infection and many other drug related toxicities and increased healthcare costs.  That can range from trouble with anticoagulation with those on Warfarin.  It can range from adverse drug events like rashes, nausea, vomiting, diarrhea that is not *C.difficile*, but still associated with antibiotics.  This is associated with a lot of healthcare expenditure.

The flipside of the coin is that when there are problems with inappropriate and excessive antimicrobial use, there is also a trouble when there is inadequate antimicrobial use.  Certainly that’s been well explored in pneumonia, in sepsis, in staph aureus infections.  We know that when the initial therapy is not active, and when antibiotic use is not done appropriately, that we see increased mortality and other adverse health outcomes.

This really brings up what antibiotic stewardship is.  This is not just an effort to limit use.  This is an effort to optimize antimicrobial use, to both help with the decision of should an antibiotic be administered, if so, which one and at what dose, what route, what duration.  The goals include improving patient outcomes.  That’s really the underlying goal of everything we do.  We hope to limit antimicrobial resistance, especially in this era where we see rising resistance and decreasing antibiotic development.  Reduce antimicrobial effects, whether they’re clinical or also at cost. 

That feeds into the next one, delivering cost effective therapy.  That is really the overall goal of stewardship and what we all strive to do as we implement various methods.  The various methods is key because there are a whole lot of things that qualify as antimicrobial stewardship.  This can include all sorts of things from multidisciplinary teams, which typically have involved infectious disease docs, clinical pharmacists, sometimes clinical microbiologists, infection control specialist and epidemiologist to help track the trends of what’s going on.  

It’s considered that it’s vital to have the support and collaboration of hospital, and in this case clinic leadership and administration to help bring about these changes, and help improve by and from all the effective practitioners.  One of the other key issues is having computer systems for decision making and tracking antimicrobial use, tracking which infections are waxing or waning, what you resistance trends are and also what adverse events are happening.

The intervention types that we included and that have been proposed in literature, you’ll notice the first one is really the mainstay of inpatient antimicrobial stewardship, and that’s prospective audit with feedback.  Really, I put a question mark there that that may be limited to inpatient only based on really prospective audits relies on an order being written.  The stewardship team looking at the clinical situation, looking at the order, giving feedback to the provider and changing it over the next several days as information comes in and as the initial clinical assessment is refined.

That works for the inpatient setting where there is this look and look back and sort of a constant assessment.  In the outpatient setting where often it’s a discreet visit and then there won’t be contact with the healthcare setting for several days or weeks, that may not feasible.  There’s also formulary restriction and preauthorization, so basically limiting the amount of drugs requiring preauthorization from certain providers to use certain medications.  Something we do everyday, education.  Then more structured things like guidelines and clinical pathways, so for certain diseases, ensuring the providers are aware of what the guidelines are or actually having a formalized pathway to put these patients into.

Antimicrobial cycling is something that is not something that I think is done terribly frequently anymore.  In the past this was done where a certain antibiotic would be used for some time period, often months, and then switched to a different one.  Then there’s other things such as order forms to sort of nudge people in the direction of okay, for this disease, you should consider using this diagnostic pathway, this treatment pathway and helping nudge people towards the correct or what is considered the correct treatment. 

Also, streamlining or de-escalation of therapy.  That is okay, a treatment was started and now we have more information.  There’s been time to reassess, moving the therapy down to something less broad.  Those optimization, trying to get—address the right dose for the infection being treated.  The purpose of this review was to really look at that myriad of different methods that’s out there and to synthesize the evidence about which of those methods are effective, and potentially which ones are most effective.  Also, to look at any harms in stewardship programs that are implemented, and looking again, particularly in the outpatient setting.

With the help of the Technical Expert Panel or TAP, we came up with these key questions, which is really where the review was structured around.  The first was, what is the effectiveness of antimicrobial stewardship programs in outpatient settings on the following.  A) The primary outcome was antimicrobial prescribing, really what happened with prescribing after stewardship.  This could be whether it was the decision to give an antibiotic, which antibiotic was selected, the duration of treatment.  Some of the studies looked at was the treatment guideline concordant.  They didn’t look at the decision to treat or not, but whether or not when they treated was it concordant with guidelines for the condition.

For secondary outcomes, these were the things that really we’re all interested in.  We hope that everything that we are doing leads to better outcomes for patients.  These are the patient centered outcomes, like return clinic visits, hospital admissions, adverse events, late antimicrobial prescriptions and patient satisfaction with care.  Also things like microbial outcomes, looking at do any of these programs alter the microbiota of the hospital.  Does the resistance panel change in the lab that’s monitoring these clinic areas?  Is there less resistance with stewardship?  Is there more resistance in areas without stewardship?

Then cost.  Cost is very difficult to get a complete understanding of because there’s both the cost of what this program and then the drug costs.  Also, the costs saved in terms of decreased hospital admissions, which may not be a cost of the clinic that the clinic would see from their stewardship effort, but really in terms of the healthcare system.  Total cost is what we are interested in, even though they may not be coming out of the same initial cost pool.

The other key questions were—the number two was what are the key intervention components associated with effective antimicrobial stewardship. That is of all these things, which ones seem to be the ones that are most effective and most crucial for success?  Dovetailing that into question three, does the effectiveness vary by the type of clinic or setting and suspected patient condition?  Perhaps a method works very well for upper respiratory tract infection, but has no effect on other conditions.

The last two key questions are number four, what are the harms of stewardship programs.  Then key question five, within the included studies what are the barriers to implementation, sustainability and scalability.  Really what limits these programs from being brought out on a large scale and what challenges were faced in terms of bringing these programs to fruition?  What can people who are trying to start up a stewardship program, what can they anticipate and plan for to try to come overcome some of these obstacles?

The way we do this—this is fairly typical for all of these evidence synthesis program reviews.  We first identified, has anyone done something similar?  Yes, there is an HRQ review published by Ranji in ’06 that had a search through 2004 to partially address these same key questions.  We basically summarized the literature that was presented in their review and then updated the search starting a little bit beforehand from 2000, up through November 2013.  Based on their same Cochrane search strategy and limiting it to the English language.

We then looked for additional studies in the various systematic reviews that we identified, reference lists of the retrieved articles and also suggestions from TEP expert panels and peer reviewers.  It turns out that some of these are—some searches are easier than others.  Stewardship does not have key terms that are readily found in Medline.  Some of these TEP panel members and peer reviewers were very helpful in identifying articles that manage to squeak through our net of electronic searches.

There are a variety of exclusion methods of exclusion criteria.  I’ll just list them here.  Of note, the second bullet point, if there was no intervention or intervention of interest, if it was just education only or—and then further down, if it was a intervention focused on things like fungal or viral or tuberculosis infections, those were issues that we did not think were really germane to antimicrobial stewardship in the US.  We excluded those.

There are pretty standard methods for date abstraction.  We went through those.  Multiple investigators went through the various studies.  If there was an conflict we debated them internally.  The risk of bias is assessed using a method that the Cochrane review group uses.  We categorize all these studies by intervention types, which really was difficult for some studies because it turns out that many of them have multiple interventions or hybrid interventions.  They were actually included in both in education or as—sometimes there was a restrictive component along with an educational component.  They were difficult to completely categorize as one single type of study.

Along with that, once we retrieved all the information and sort of looked at the outcomes, we then decided, well can we pool the data and really sort of give a summary statement of here is how effective each individual method is.  That’s really a judgment call that you have to look at how heterogeneous are the outcomes that are reported.  In this case we felt that they really were—there was such a mixed bag that pooling them was not something that could be done, which makes it slightly unsatisfying in terms of reporting, a bottom line of antimicrobial stewardship is this effective.  Really in terms of accuracy and reporting we can’t include various things that just are not comparable, sort of an apples to oranges comparison.

This is the literature flow in terms of how this starts.  We start with a very large number of abstracts, 6 1⁄2 thousand.  On review of abstracts that goes down, we review the full text of about 600 articles.  The reasons for exclusion are over there on the right side of your screen.  Ten articles were found by answer to reviewer suggestions, which led us to a inclusion group of 50 articles, which is what the rest of the talk will be based on.

To briefly summarize the results of the existing HRQ review by Ranji, they focused on purely reducing unnecessary prescribing and improving antimicrobial selections.  They’re really two different aspects of stewardship.  What they found at that time in terms of reducing unnecessary prescribing, they had 30 trials that they included, and they did pool their analysis when they could.  They found interventions reduced the median absolute proportion of visits at which antimicrobials were prescribed.  Looking at the percentage of visits where an antibiotic was prescribed, the stewardship interventions reduced that percentage by nearly 10 percent, so 9.7 percent.

On average or the median follow-up was six months.  They also reported on additional 18 trials where the effect size was unknown, primarily because they reported only relative reductions.  The median relative risk reduction was 12 percent looking at the intervention group compared to the control group.  They noted that there were very few studies reporting patient centered outcomes, resistance outcomes or cost outcomes.  Their take home there was really a 10 percent reduction in the visits that ended up with anti-an antibiotic prescription and a 12 percent relative risk reduction in those where you couldn’t calculate an absolute reduction.

In terms of improving antimicrobial selection, so not just limiting use, but actually improving use.  They found 22 trials where they could pool their results.  They found that the interventions increased the recommended antibiotics by roughly 11 percent.  Then again, there were additional 11 trials that they could not include in a pooled model.  They showed that there was really an improvement in the recommended antimicrobials in general, and a decrease in the non recommended.  In all of these there’s some ambiguity in that the author’s definitions are variously well supported as to what was recommended and not recommended.

Again, they found no studies that reported patient centered outcomes, resistance.  Three did report cost decreases, but again, this is not the overall cost.  This is generally programmatic cost or cost to the individual clinic.

Shifting now to what we found.  That was the last two slides.  That was about the prior systematic review that went through 2004.  We updated this search, again, from 2000 to 2013.  You’ll note that if you add up all these things—I mentioned earlier that we included 50 studies.  If you add these up, the number of studies is greater than 50 because again, some had multiple interventions and so they’re included under each intervention.  

Abbreviations, I should specify up here, RCT is a randomized controlled trial.  CRCT is a cluster randomized controlled trial where clinics—if you have ten clinics and you randomize five clinics to an intervention and five clinics to a control, that is a cluster randomization.  Three were controlled clinical trials.  There was no randomization involved.  

Six were CBAs or controlled before after studies.  A before or after study is a relatively weak study where you assess something.  Something happens, some sort of intervention.  Then you assess it again.  The controlled portion means that there is some sort of control methodology in there where you have two clinics.  One serves as the control and then another one you implement an intervention and you look at the before and after results.  Adding a control arm, ideally takes care of some of the *[inaudible 00:21:55]*that you can see with just temporal trends.  That perhaps with time that same effect would have been seen and your control clinic helps take care of that.

ITS is an interrupted time series.  That is a methodology that’s considered to be slightly better than before or after where you look at multiple data points before your intervention, data points during your intervention and data points after your intervention.  Looking for both any levels of change and also the general trend of your change and what you’re assessing.  

You’ll note that looking through these the most numerous studies were in those of provider or patient education.  After that came various other things, including a fair amount on laboratory guide, it’s down at the bottom, which utilized Procalcitonin, polymerase chain reaction testing, generally for viral pathogens, trying to help with diagnosis of upper respiratory infections, C-reactive protein levels and others, including rapid strep testing.  Then there’s various other things such as communication skills, training, restricting policies, computerized support systems and one, actually a financial incentive from the Netherlands.  

The conditions that all these studies were based on, the vast—if we lump them together the main were in respiratory tract infections, 29 of the 50.  Then in that multiple or not specified, again, the large number of those were also respiratory tract infections.  After that came UTI with two studies, dental pain with one and one of sexually transmitted infections, which was in a unique clinic setting that was a sexually transmitted disease clinic.

I’m gonna quickly walk through this table just to show what we’re displaying here.  Then as you can see, the bottom there, that NR is not reported.  I’m using that blank space to put in a little key here.  What you’re looking at in the columns is first—the first column is the antimicrobial stewardship program intervention and the number of studies and what type of studies.  Next comes the prescribing rate use, which is the main outcomes of which, was an antibiotic prescribed.  Next comes drug selection, duration and was the use guideline concordant.

The symbols that we have there, a plus indicates that there was a significant difference and it favored the intervention.  The second column under provider and/or patient education looking at did it improve prescribing rate or use.  Nine studies had a significantly positive effect.  Six had the little approximate sign that indicates there was no significant difference between the intervention and a control group.  If there’s just a minus that means that there’s a significant difference that favored the control.  Plus/minus means that well, among the various outcomes there were positive effects in some and negative effects in others across the different studies.

Looking at this study you can see that in general for the—most of the data is in the prescribing rate and use column.  This is what most studies reported.  Not all of them reported other things like drug selection, duration or was guideline use guideline concordant.  You’ll note that in the first one, first column there, the prescribing rate and use, in general there is a favorable effect.  Nine studies favorable out of the 15 for provider and patient and education.  Three favorable for provider feedback with two showing no difference.

Under guidelines, again, three favorable, one no different.  Delayed prescribing, three favorable, one no different.  Then communication skills training, five favorable, one no different.  In the full report there is a large table, it’s actually table 13 if you want to access that, where it really lists the absolute magnitude of these effects.  There really was no good way to give these without burying you under an avalanche of numbers.  I can tell you that the impact of these effects varied quite a bit.

It went from say, one of them that I sort of highlighted was a provider of patient education.  There was a 4.2 percent decrease in the amount of antimicrobials used for the visits where there was an antibiotic prescribed.  That was for upper respiratory tract infection, sinusitis.  There was one that was no change.  Really the numbers vary quite a bit.  General, the reductions ranged anywhere from 4 percent up to 20, 30 percent, but quite a wide variety.  To look at those specific ones I’d refer you to the full report, because there really was no way to completely aggregate these numbers.

Looking at—this is a continuation, so communication skills, training was what we had ended up with up there.  Restriction, there was no clear benefit to restrictive policies.  Both of the studies really had a mixed message on those, improved in some ways, decreased in others.  Decision support showed some benefit.  Financial incentive improved prescribing rates for three of the seven drugs that were assessed, but not in all of them.  We gave that a favorable benefit.  

Down at the bottom, Procalcitonin rapid antigens, the testing test, PC or assays, they were fairly impressive in their effect.  In nine of the studies there was improvement in the intervention group that was statistically significant.  Then eight of the studies, one, there was no difference.  Here the effects were larger in that there was studies ranged from 30 percent reduction, some even up to 50 percent reductions in the percent of visits that resulted in an antibiotic use.  These had a larger effect than many of the other interventions.  I’ll get into that a bit later.

Looking at the patient centered outcome, so this is now looking at not just was an antibiotic given or was the right antibiotic given.  This is well, what happened in terms of clinically relevant things like return clinic visits, hospitalizations, adverse events, late antimicrobial prescribing.  I think the first thing you’ll notice is that there are a lot of NRs not reported.  This is just an area where we don’t have much data to report to you.

You’ll also notice that this is a dearth of plusses with a lot of numbers afterwards.  There were not a lot of studies that did show a benefit for these patient centered outcomes, and ultimately is what we’d like to think that we are affecting.  This is a continuation for all the various interventions.  Again, you’ll see a fair amount of not reported and a lot of equivalent signs and very few distinct improvements that were significantly favoring to intervention.

You’ll notice that in restriction there actually was the one study, there was a negative visit, that there were more return clinic visits in the restricted policy.  There was a significant increase in hospitalizations there as well.  

This one was actually quite easy to answer.  The key question one be, what is the effectiveness of stewardship on microbial and cost outcome?  Well, very simply microbial comes as a blank slate at this point.  No studies of outpatient stewardship looked at microbial outcomes.  This is an area where we really do need to know what is going on.  Cost, we have a little bit of data.  Seven studies reported dispensing cost.  Again, that is not the only cost involved in stewardship.  When you look at dispensing cost it’s not surprising that given that in general most stewardship efforts result in less prescribing.  Yes, there is less dispensing cost.

Three actually reported the program cost.  They broke down this down per patient for CRP testing.  They said this cost $6.00 per patient tested.  Others looked at their program cost for a provider education intervention.  They came up with a roughly $5,000.00 annual cost for this.  Again, there are many costs that aren’t factored in here, including the cost of repeat visits, of potentially preventing repeat visits.  A full cost in effectiveness analysis is not something that’s really presented in any of these studies.

Looking at what is the key in implementation components.  What things must be in the Stewardship Program to have a effective program?  There is limited evidence available.  Most of this came by speculation by authors.  A few had focus group interviews of their subjects after the intervention had been completed.  All of this with the caveat that this is highly speculative.  These are the key components that were suggested either by authors or by editorialists or by people responding to focus group questions.  

They include having a supportive leadership.  Having a team based approach.  Having patient education materials that can be used as an extension of the visit.  Having provider reminders and user friendly interfaces, which I think we all like to work in a system that actually is friendly in terms of utilizing these various things, and having evidence based materials that you feel that, yes, this reflects the state of the art and I can support this versus something that is just passed down as, “You should do this,” without much of an evidence base behind it.

Looking at the effectiveness in different settings.  If there is one type of clinic versus another or different suspected conditions, so this would be UTI versus URI, so respiratory versus urinary.  Hard to answer this in that the vast majority of all these included studies were in primary care clinics.  Again, the exceptions were in dental clinic for acute dental pain, a sexually transmitted infection clinic.  One study that was clustered random included urgent care sites and also an outpatient infectious disease clinic, which being an infectious disease person, perhaps that hardly representative.  

The mix of conditions, it ranged quite a bit.  Again, respiratory was the predominant one.  Twenty-nine of the studies were purely respiratory. Again, and those were they did not specify or they just said we assessed all antimicrobial use.  Respiration conditions did have quite a bit of those as well.  

Really, we came to the conclusion that for both setting and condition there really is not enough data to decide if effectiveness varies by either the setting that the Stewardship Program was implemented in or for what condition it is being implemented for.  There just isn’t data to let us know anything on either of those.  A similar theme here on key question four, the harms of programs.  Very limited reported, that includes limited reporting of return clinic visits, hospitalizations and adverse events.  

On the plus side, those that did report these things, they did not show any significant differences between the groups.  What we can say is that although we would like to have seen more reporting on these things, the studies that reported on harms did not detect any.  That should give us some confidence that what we’re doing, at the very least is not hurting people and probably given the favorable antimicrobial prescribing effects we’re seeing should be helping.

Finally, a key question five, this is what are the barriers to implementation, how sustainable is the practice?  Is this something that can be scaled up beyond the single or multiple clinics that were being studied?  As far as implementation there was limited data.  Largely there was the convenience of interventions, the access to training materials and the efforts to include patients were raised as potential facilitators.  

Really, if you have the ability to introduce one of these interventions versus the other, that is something that is likely going to help with implementation.  If you have access to training materials for a certain intervention such as a local hospital, implemented a program that is willing to come and help share their material, that would be something that may help with implementation.  

These are all speculative things that came up in discussions, nothing that was purely assessed in a more rigorous manner.  Similar result was sustainability.  There were seven studies that provided follow-up that was of longer term duration.  Anywhere from one to four years with mixed results.  A general these was that several showed an initial improvement, but by the time they got to one year out they were—the intervention and control groups were equal.  

There were notable exceptions to this.  There was one, an education outcome that had a sustained benefit three years out.  They noted this was despite the fact that there was decreasing intensity of the intervention, so less training, less provider feedback, but yet there was a sustained benefit that maintained quite a ways out.  Another one with a computer decision support model showed a sustained benefit four years out.  

There is some data to suggest that yes, stewardship efforts are not sort of a one time push where everybody gets excited then things go back to the status quo.  Yes, you can maintain these, but it would be great if we had more data other than these promising examples.

Lastly on the scalability of the—the barriers to scalability, not much data, but three studies did report information looking at issues regarding how to bring these out.  In one there was a favorable effect of a pilot study.  Then when they increased the size by roughly three fold the effect it was promising in the pilot study disappeared.  The thought was that this might have been less rigorous intervention when the effort had to be diluted over a larger pool of providers.  

The second, some authors speculated the need to train multiple providers resulted in differences and effectiveness that really—it depended on who you got as your, what they called an academic detailer.  Someone to provide in person feedback really resulted in a positive or negative effect as to how good that individual provider was.  

Lastly there was one, the European study that was across countries.  They used a web based training module.  There was concern expressed, but again, this was sort of concern that was expressed in focus groups afterwards, not based on a lot of hard data that web based training wouldn’t translate across borders and into some cultures of the different countries included.

What I think I take out of reviewing this literature is that Stewardship Programs in the outpatient setting can decrease antimicrobial prescribing.  The strength of evidence is greatest and that gets to medium strength for communication skills, training and laboratory testing.  That laboratory testing was the Procalcitonins, CRP, rapid strep detection and PCR, things like that.  The strength of evidence is low for other interventions, but it is a consistent body of evidence in that the vast majority of interventions do show that yes, you can decrease antimicrobial prescribing.  

The next step to show that this affects patient outcomes, really the data is limited there.  The data is also limited on cost, especially a true global assessment of cost, not just the cost of the individual program.  There is no data on resistance and little data outside of primary care clinics.  For sustainability, scalability and implementation got dropped off the list there, but there is limited evidence.

We felt that this—I mean this really does largely agree with the prior Arch report.  New to this review is information about the laboratory testing.  Procalcitonin is a relatively novel technique.  CRP has been around for quite some time.  The use of it as a decision support tool has been increasing.  All of these methods seem to have a fairly impressive effect in terms of the size and reducing antimicrobial prescribing.  

My speculative assessment of this is that these objective results are rather welcome to providers who are really looking at a clinical scenario, judgment decision, does this patient have a condition that merits antibiotic prescribing.  Here is an objective hard data point in a number that you can refer to the literature and tell people that you know what, “Studies have shown that in patients with a lab result like this, they do very well without antibiotics.”  It can be a very nice tool to help in the discussions with patients that no antimicrobials are needed.

It may also be that all the public awareness that we’re getting for antimicrobial resistance is having a bit of an effect here as well in that if you’re implementing a stewardship program, and the public is aware that antibiotics are losing their effect on—there’s the CDC threat report that was released recently.  That of course was too recent to have any sort of effect.  Their Get Smart Program to improve antibiotic use has been ongoing for several years.  All of this may enhance stewardships and efforts in the future and my have helped out with some of the stewardship efforts that came out since the last report.

My overall conclusions, and then I’ll turn this over to Doctor Goetz, is that outpatient stewardship is effective in reducing antimicrobial prescribing.  We don’t know what the optimal interventions are, and rather than let that paralyze us, I would say that whatever intervention, you have the resources to implement with confidence and without too large an effect on your clinic’s overall structure is probably a good thing to do. 

We don’t have any evidence that there are adverse affects on patient outcomes, at least wide spread effects or beyond a single study showing a increase in patient visits after a restrictive policy.  We really don’t know what the sustainability, the scalability and the implementation barriers are.  Further information on that would be very welcome as everybody struggles to implement a Stewardship Program.

I believe I am done with that.  No, sorry, I am not done with that.  The future research needs, large scale studies, if possible to evaluate patient outcomes would be really welcome.  Some of those maybe impractical to do as a denoble study, but as large healthcare systems such as the VA implements stewardship efforts, documenting what happens to our patient outcomes and comparing sites that are implementing stewardship versus sites that are yet to implement them maybe one way to get around this.

Again, these are challenging to conduct and large systems may be able to utilize as their data that they gather as they implement things and use them to do deFacto studies that may not be purely randomized trials, but still will provide useful data.  Then comparative effectiveness studies to really define the effective strategies of each component.  This sort of gets into the infection control realm where we know that many things have worked when done as bundles, but we don’t know which actual intervention is the most effective thing. Trying to tease that out is a challenge or do we just simply go with a bundle approach and do things as helped and not know exactly which component is the true driver of the beneficial effect that’s yet to be explored.

Now I am done.  That’s my contact information here.  Certainly will answer typed in questions.  Doctor Goetz, I think I will leave it to you.

*Dr. Goetz:*Thank you.  I think I have control now.  I’m Matt Goetz, previously introduce.  Amongst other things I am here with the VA Antimicrobial Stewardship Task Force Implementation Subcommittee.  I’m here to provide our comments on the value of this report, which we’re very pleased to receive.  While it doesn’t—Dimitri very clearly indicated, doesn’t provide the answers to all questions as to how outpatient stewardship programs should be conducted.  Provides a broad and important overview about what works, how well it works and provides us with further information about the effectiveness of program and the lack of harm.

Proceeding through my prepared slides, I’m sure that 90 percent of the audience is aware of the VA Antimicrobial Stewardship Task Force, which was established three to four years ago with a charge to optimize care for Veterans by developing, deploying, and as you can read, monitoring a national level of strategic plan for improvement in antimicrobial therapy management.  The specified objectives for the task force were to summarize current performance and improve impriorities for stewardship, to catalogue ongoing antimicrobial therapy improvement activities.  

I think many of you are well aware of the share point that the Stewardship Task Force has established, which is, I think, a quite well curated share point wherein we’ve collected a sample of policies and procedures and other information document that have been developed by the many excellent stewardship programs around the country.  The objectives have been to develop a plan to leverage clinical information tools, which is an ongoing, a rather difficult, but project, which is progressing.  To define key leadership actions at the national level and facility level in response to specific needs.

Many of you will be aware of the fact, probably everybody is aware of the fact that there’s now a stewardship directive that was issued about three months ago specifying that all VA facilities need to have plans and construct a stewardship program.  Not so much—and as you know, probably the Stewardship Task Force has been very active itself in developing a business plan for the justification of stewardship programs, for presentation to facility administration in order to build the case to develop the appropriate resources for robust programs. 

There have been a large number of sample policies and procedures that have been developed by the Antimicrobial Stewardship Task Force, which are available on the share point.  Which include conversion from IV to oral antibiotic therapy, policies and procedures for addressing unnecessary double anti-anaerobic therapy, the policies and procedures for outpatient parenteral  antimicrobial therapy programs, de-escalation of drugs used to treat MRSA when MRSA becomes less of a concern in the presence of negative cultures, de-escalation of the use of broad spectrum [inaud.] agents and policies and procedures addressing the minimization of antimicrobial therapy in people who have failed to have *C-difficile* infections.

I’m gonna re-summarize many of the things that Doctor Drekonja said regarding the ESP review.  Again, it’s important to emphasize that there are benefits that are demonstrated.  They may be modest, but they are benefits in terms of prescribing rates and the improvements in the selection of therapy.  While there are few data and patients that are outcomes, the majority of the data beneficial, with the one caveat as pointed out, the restricted policies may have—at least were shown in one study to have negative impact in terms of return visit and hospitalization.

The fact that there are no microbial outcomes dated is—well on the one hand disappointing.  On the other hand not especially surprising, particularly when we look at resistances in outcome as was emphasized in the background material to the presentation, really a long term ecological impact that will likely take a longer scope and duration of study that is available in most of the studies that have been performed.

Not surprisingly, as is pointed with improved or decreased prescribing rate, not surprising that the decreased expensing cost, recognizing that really should be the least important of our outcomes.  Because we really want to focus on patient care related issues.  The intermediary outcome of decreasing inappropriate or unnecessary antibiotic use is highly likely to have a strong beneficial impact on the population as a whole.  

That goes to the next point of course, there is no evidence upon that’s been demonstrated.  We’re going to always raise the caveat that more rigorous long term studies can be done, but given the importance of antimicrobial resistance and overuse, this is reassuring data.

Summarizing then, while more research is needed, which is almost always the case, the evidence is more than sufficient to continue to promote prudent prescribing practices.  It not quite was well formatted here as I hoped it would be.  I tried here to summarize in a single slide a tremendously robust analysis done by the ESP as to what works and what doesn’t work.  I focused here on prescribing rates and use where we have the most robust data.

As Doctor Drekonja very nicely indicated, we have a wealth of recent data showing the value of rampant laboratory results in decreasing prescribing rates.  Whether that’s through Procalcitonin, rapid antigen detection, particularly for group A strep or C reactive protein.  Eight of the nine studies that looked at this summarizing the data in the ESP show positive affect and indicated in Doctor Drekonja’s presentation, really the largest effect on prescribing practices.

That’s really followed by communication skills training, which comes out in five of six studies to be a benefit.  Looking at the details of the ESP report, perhaps some of the strongest benefits came from studies that combined communication skill training with rapid laboratory detection.  Then we see that there is benefits and decision support systems in four of the six studies that were done.  

Then I’ll let you—people on the presentation read the rest of the bullet points where we have a number of other strategies that have shown some benefits.  In addressing the issue of a single approach versus a bundled approach, I think it’s fair to conclude that just as with infection control that we’re much more likely to see  benefits from bundled approaches and then simply relying on one strategy in isolation.

Okay.  As Doctor Drekonja indicated, there are a number of other topics that are addressed.  One point that we were looking at is implementation as to whether there was a single best way that’s been well documented to put these programs in place.  There’s little specific guidance, I really couldn’t say that there’s a magic bullet for implementing programs.  I think the things that come forth are clearly things that fit well into provider workflow, so convenient interventions.  The need for leadership support and team approach with clinical champions, importance of including stakeholders with patient education. 

At the same time the large scale interventions are challenging if one looks across the whole VA.  Then again, the emphasis that laboratory results that provide objective data appear to be very useful, and doing a little bit of editorializing myself and expanding upon what Doctor Drekonja said, I think that some of the value of laboratory testing is that it can reaffirm the clinician, the perspective as to what needs to be done for the patient and provide objective data that decreases uncertainty.

Thinking about the stewardship across the entire VA, scalability is always an issue.  What comes forth in the review is the need to ensure a consistency of the approach to implementation.  In that regard the simpler the interventions are, probably the more scalable they are.  Again, thinking about sustainability where the goals are to have long term interventions that are successful, that’s shown to be a challenge.  In the limited data that are available, I guess reading through the report, one of the things that occurs to me is that there’s the evidence, the benefit of computer decision support.  Perhaps because the computer itself is sustainable.

Okay.  Going to future research needs.  We certainly, from the Stewardship Task Force agree that broad scale studies to evaluate outcome to be welcome.  Comparative effectiveness studies are certainly valuable too, and as this Stewardship Task Force is moving forward, I just want to mention that several of the interventions for the outpatient realm that we’re looking at for the next year, looking at antibiotic specific interventions, addressing fluoroquinolones and disease specific interventions.  Addressing urinary tract infections and acute respiratory infections, with the advantage of course being that the far more data and studies looking at interventions for respiratory tract infections.

# I think that the VA patient population maybe a little bit different than the overall population and urinary tract infections and the over treatment of asymptomatic bacteria, is something that we will likely be addressing.  Especially given the interaction between fluoroquinolone use and emergence of Carbapenem-resistant Enterobacteriaceae

Overall I would say that the VA is very well positioned to conduct future research as a large integrated healthcare system with the advantages of our electronic medical records and corporate data warehouse.  

With that I’ll just end with my final slide, which sort of summarizes the subcommittees of the Antimicrobial Stewardship Task Force, along with Doctor Drekonja, I’ll be happy to entertain any questions that the people in the audience might have.

*Moderator:*Great, thank you.  Doctor Filice, did you have anything you wanted to comment on before we open up for questions?

*Dr. Filice:*Doctors Goetz and Drekonja did a fabulous job of synthesizing a huge amount of information.  A couple of concerns and a couple of things that I think may give us more confidence of what we’re doing may work.  First, publication bias is a real concern.  For many fields this included—it maybe more likely that positive results get in the literature than negative results.

Dimitri talked a little bit about the few studies that looked with a longer period of time and saw a decrease effect.  That maybe because the programs themselves are less effective.  With many of these—nearly all of the interventions there’s tremendous potential for contamination, which may give the appearance that effects are diminished.  If the knowledge about antimicrobial use and the attitudes about eliminating them appropriately spread into the control groups, you’re going to see a diminished effect over time.  It still may be working on the overall antimicrobial culture.

One thing that I think people who are charged with setting up a program will be asking themselves, if not immediately over time, many of them may address one particular area, one particular group of prescribers, one particular disease.  Then after they make an impact they may say, “Well now, should we change what we do?  Should we add a new area?  Should we shift to a different area where there may be a need for some improvement?”  I don’t think any literature really helps us with that.

Many of the studies were done by champions, people who believe in stewardship.  They have tremendous energy, enthusiasm, fervor.  One of the things that many of us will be thinking about is how is stewardship done in places where you don’t have those champions?  I don’t have an answer for that, but I think it certainly would be a good area for future research.

Then finally, many of these come from academic centers.  There are a lot of non-academic hospitals, clinics, healthcare systems.  We don’t have a lot of information about how to do this in non-academic settings.  I’m thinking particularly about education, the time, the resources to do education and teach things like communication skills, which maybe less easy to come by in non-academic settings.  Otherwise there’s little to add.

*Moderator:*Okay, great.  Thank you.  We actually have not received any questions then at this point.  For the audience, if you do have any questions for our presenter or either of our discussants, please take this opportunity.  You can type your questions into the Q and A box in the lower right hand corner of your screen.  We are happy to take any questions on anything that was discussed during today’s presentation.  

Either the three of you presented things spectacularly or we’re getting questions, long questions that are being typed in here.  One or the other.  If any of the three of you have anything additional you’d like to say while we are filling a little time here waiting for questions?

*Dr. Drekonja*Well, I might ask Doctor Goetz if he would elaborate a little on the clinical tools.  He tantalized us with a little bit of information about thing—resources like the corporate data warehouse can be used.  I think it’s—what little I know about it is it’s a very exciting area for future research and perhaps more importantly, implementation?

*Dr. Goetz:*Correct.  It’s a large topic certainly.  Yes, the VA—one of the examples of how the VA informatic resources are being used is a project being read by Matt Samore and Makoto Jones from the Salt Lake City VA.  Wherein the collaboration which the CDCs NHSN Program, they are rolling VA medical facilities to participate in the antimycotic use component recording system.  

There are approximately 15 VAs I believe that are now participating in phase one of this, with another approximately 25 going to be joined in phase two.  Where they are facilitating the pathway to report antimicrobial use on inpatients, though, this does not address outpatients.  For the VA facilities then to be able to do cross comparisons of antibiotic use and compare them to those to facilities nationally.  A very good initial approach to starting the objective data on our patterns of antibiotic use.

I know that the group with Salt Lake City has also had a wide number of other research projects where they have in particularly looked at, for example, how, through our surveillance logs that have been used for MRC detection in the VA, correlate with the presence or absence of negative cultures for methicillin resistance staph aureus and how that might be a useful tool for antimicrobial de-escalation.  Or if not even de-escalation, for guiding empiric choices of therapy in selective patient populations.  

I think those are the two examples of how the corporate data warehouse has been very valuable.  I will say that it does take a considerable amount of expertise though, to work directly with the corporate data warehouse.  There are challenges in terms of data cleaning.  It is a spectacular resource, which is I think unparallel to the United States.

*Dr. Drekonja*Might someone, Doctor Goetz, who is thinking about how a stewardship program might look, be able to look forward someday to a time when we could get information about our own hospitals antimicrobial use from the corporate data warehouse in a fairly user friendly way?

*Dr. Goetz:*Antibiotic use cubes are being developed by the group in Salt Lake City and are being rolled out.  I know in region one we have access to those data now.  The group in Salt Lake City has been working hard to make that more readily available.  I don’t want to—I’m wary of giving a date about access.  There are tremendous strides, which are being made.  Always wary about promising things that I’m not doing directly myself.

*Moderator:*Great, thank you.  We have received a couple of questions in here, so we will go through those here.  Would you have any suggestions regarding where to try to start in outpatient?

*Dr. Drekonja*I think that’s a great first question.  That really partially depends on what problems you have identified.  I think that if you just know that I have a clinic, and I think we use more antibiotics than we should, you’re starting at ground zero.  You don’t really have much to go from there.  I think the first step would be to do some sort of internal audit and see what are the patients that you see.  If you are in a VA clinic, I assume most here are.  

Certainly we have a lot of respiratory infections, a lot of urinary tract infections.  Given that the data is most robust for respiratory tract infections, that’s probably the easiest place to start and to be able to read the literature and get a sense of okay, here are stewardship programs that have worked.  I think the first step would be to figure out whatever audit type mechanism you could do.  What are our issues?  If you find that the vast majority of your respiratory infections are handled appropriately, then that’s probably not the most high yield place to go.

I think an assessment of what’s going on.  Then looking to the literature to guide you.  I think here the biggest wealth of studies there to help guide you will be in respiratory infections.  I think that would be my first step.

*Dr. Filice:*I second those comments completely.  In most settings the antibiotic use for acute respiratory tract infections is substantially greater than for urinary tract infections.  There is ample data about the overuse of antibiotics, respiratory tract infections.  Perhaps the first step would be do a retrospective review of treatment patterns in the outpatient setting, because some sense of the issue is in your own facility.  I would be very surprised if there’s any facility that doesn’t have at least a 50 percent overuse.

*Moderator:*Okay, great, thank you.  The next question that we have here.  Any indication as to what outpatient settings prescribe the most antibiotics.  Hold on.  No studies on ED prescribing and stewardship effort?

*Dr. Drekonja*That is a difficult thing to completely answer, because the clinics that prescribe the most in one facility may not be the same as the facilities that prescribe the most in others.  Actually, I know Doctor Goetz has looked at data within the VA in terms of variation antibiotic use among VISNs, and just as they vary among VISNs they vary among different sites.  I know within our institution, I’ve looked both in our emergency department, which is sort of lumped together with our urgent care.

Here we certainly have a fair amount of inappropriate antimicrobial use in both settings, both in the emergency department and standard outpatient clinic.  I’m not sure that that’s universally applicable.  It partially depends on local dynamics, what’s going on in that emergency department.  It’s tough to give a blanket answer that yes, emergency departments are always better or worse than clinics, which are always better or worse than urgent cares.  There’s a lot of local and regional variability.  Some of it just depends on who your personnel are and what their passions are.

*Dr. Filice:*Yeah, I think a lot of it also depends upon the clinic structure and how one—whether their urgent care visits are fully worked into the pact model or whether there are still a substantial number of use of urgent care or triage clinics as to what the patient flow is.  I would wager that overall the total amount of outpatient antibiotic use is greater in primary care clinics.  If you will, the density per patient visit is likely greater in the emergency department or urgent care clinics.  On a per patient visit aspect there’s greater opportunity in urgent care or emergency department.  It may not cover the greatest number of patients in total.

*Moderator:*Okay, great, thank you.  The next question we have here, among the 50 studies included in the review, did you see differences in key outcomes by year of publication?

*Dr. Drekonja*That’s an interesting question, and I’m not gonna be able to answer terribly well.  Other than say that given among the key question one where we looked at antimicrobial prescribing, that’s where the most data was.  That did not vary tremendously overall.  I mean all of the included studies showed a benefit, some were larger than others.  I do not recall in all—I know that we did not formally asses it, but I do not recall an obvious trend that jumped to me.  

I can tell you that among the lab testing, again, the CRP Procalcitonin, rapid antigen detecting, those are newer studies for the most part.  If one did do such an analysis that might suggest that oh, the later studies are showing more of an effect.  I’m not sure that that’s later or if that’s because this methodology was being reported later in the included studies.  Again, this is not a huge time period.  We’re talking 13 years.  I would be surprised if there was a massive or even a significant change in publication by year.

*Moderator:*Great, thank you.  The next question that we have here, does every UTI require an FQ?  For example, how can you guide providers to less aggressive treatment?

*Dr. Drekonja*For those who are wondering what a fluoroquinolone—does every UTI require fluoroquinolone?  No, that is the short answer.  How can we guide providers to less aggressive treatment?  That is part of—that really is stewardship in a nutshell, just phrased differently.  Local susceptibilities, local champion, if we’re referring people to guidelines on urinary tract infections, they will note that floroquinolones are not recommended.  Although, there is some question in men because male UTI maybe considered a unique or at least very different disease than female.

The first step I would go to is look at your local susceptibility profile.  Here in Minneapolis, actually trimethoprim-sulfa has a more favorable profile for R gram negatives, which are the typical bugs of UTI than the Ciprofloxacin.  Encouraging people to utilize prior cultures.  I think this is part of stewardship is to educate people that UTI is a—for the most part a non-urgent or a non-life threatening disease, and going to a drug, which is highly valued like a fluoroquinolone, immediately versus getting a culture and starting with something like trimethoprim-sulfa, nitrofurantonin, if the renal function allows or even phosphomycin, which there is more and more data emerging on would be beneficial.

Knowing your susceptibility profile locally and encouraging people to get cultures, which again for a male UTI is recommended, but is often not done, would help in terms of getting people on the correct treatment.

*Dr. Filice:*I would add to that one of the other really critical strategies is making sure that only symptomatic bacteria is being treating.  Patients who are asymptomatic, unless they’re undergoing urological procedures or pregnant, not very common in the VA, there is no indication for routine antibiotic utilization for asymptomatic bacteria.

*Dr. Drekonja*Yes, thank you.  I should have put that in.  That is an ongoing interest of mine, that you add something we see on a daily basis.  I would also add that a symptom that has to be at least conceivably tied to the urinary tract.  Fatigue or worsening chronic low back pain, those are pretty tenuous connections to the bladder.

*Moderator:*Okay, great, thank you.  We are out of questions, but I do have one final comment here.  No questions, but a comment.  I enjoyed your presentation.  If you are planning studies of stewardship to address UTI in the outpatient setting, I would be interested in discussing possible collaboration.

*Dr. Drekonja*Thanks for the comment, and I see who made it.  Yes, I would gladly like to collaborate on things like this.  Nothing immediately in the works for me, but I am also similarly interested.

*Dr. Filice:*Well speaking on behalf of the Stewardship Task Force, Doctor Troutner, who I see wrote that comment and to my colleague Greg Filice, yes, I do think there will be opportunities.

*Moderator:*Fantastic.  With that I actually just put up a feedback form to the audience.  If you all could take just a few moments to fill this out while we wrap things up.  We definitely read through all of your feedback and use it for our current and upcoming sessions.  I do want to thank all of our presenters today, Doctor Drekonja, Doctor Goetz, Doctor Filice.  We really appreciate the time that you put into present—into preparing and to present for today’s session.

These sessions are well attended.  Our audience really appreciates everything that is presented here.  To our audience, thank you everyone for joining us for today’s session, and we do hope to see you at a future HSR and D Cyber Seminar.  Thank you everyone.

*[End of Audio]*

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