Dear Stewardship People: Can't We All Just Get Along?

The following post is by Dr. Jasmine Marcelin from University of Nebraska Medical Center.

Teams should work together, not compete

I am an Antimicrobial Stewardship Leader. As the Associate Medical Director of Antimicrobial Stewardship at my institution, I work with another physician (Antimicrobial Stewardship Medical Director) and an ID-trained Antimicrobial Stewardship PharmD. We have a great setup, share audit and feedback responsibilities, and have different interests clinically and for research, which makes it great to divide tasks for initiatives. I focus on outpatient ASP and SSI prophylaxis, PharmD on AU initiatives and cost, and other MD on CDI. We cover for each other, review and co-author each other’s grants, papers and presentations, and present education to various hospital groups together. We work well as a TEAM.

Teams are great things. Nothing meaningful can be accomplished when working alone and in silos. Some ASP teams also include nurses, infection preventionists, advanced practice providers and laboratory personnel, and the specific ASP leadership model will depend on the resources at an individual hospital. Each of these groups bring a very specific and unique skillset to the ASP team. Why is it then, that we seem to find ourselves in the midst of an MD-PharmD power struggle?

In February 2018, the IDSA, SHEA and PIDS released a statement that ID physicians should be leading the way in Antimicrobial Stewardship. This statement shared the unique skillset that ID doctors bring to the ASP table, including years of clinical training in the diagnosis and management of infections. This position paper reads as a statement of support from our societies demonstrating our value to hospital leadership. “Hey C-suite, we have these requirements for ASP, and it says you need a leader that has ID expertise. We literally went to school for ID, and we already work for you, so here are these reasons why you should actually PAY us for what we know how to do well, instead of asking us to do it for free while we are on hospital consults?” The position paper did not say, “ID physicians are better than Pharmacists at ASP”. In fact, the document went on to state, “An ASP should also include at least 1 pharmacist, ideally with subspecialty training in ID. While ID physicians and pharmacists may often have the most central roles in an ASP, all members of the ASP team, including microbiologists and infection preventionists, provide distinct skills of great value.”

Notwithstanding the explicit acknowledgement of the value of the team model of ASP, perhaps the conclusion “ID physicians are well equipped to lead multidisciplinary ASPs given their training, expertise, and experience” offended some of our pharmacist colleagues. The publication was followed by a letter to the editor in May 2018 that stated, “In identifying ID physicians as uniquely qualified for these functions, the paper fails to acknowledge the essential leadership and skill set of ID pharmacists in stewardship”. The letter then concludes, “Best care for patients is achieved through multi-disciplinary stewardship where pharmacist leaders are key to success”. This letter led to a flurry of social media posts misguidedly comparing the “value” of ASP physicians vs pharmacists. A real world study of ID fellow experiences with ASP shared that fellows looked to “pharmacists, not ID physician leaders as primary resources for antibiotic teaching”, and there was a social media frenzy that pharmacists should lead ASP, not ID physicians.

Seriously?

People, this is not a competition! Pharmacists are uniquely equipped to lead ASP because of their special training in the PK/PD of antibiotics, adverse drug effects, drug-drug interactions, and costs. ID physicians are uniquely equipped to lead ASP because of their special training in direct patient care, being boots on the ground as well as eyes in the sky, and can always use the “peer” card when approaching rogue prescribers. The thing is, we are BOTH essential for a successful ASP, and organizations should strive to fund BOTH, because we complement each other. The thing is, we ID physicians have had a long struggle for institutional acknowledgement and respect of our invaluable contribution to patient care. In our fight for recognition, perhaps we have failed to let our pharmacist colleagues know that we appreciate what they do, and that our work is enriched by their contributions. Perhaps we should be intentional to thank our pharmacists for this contribution so that they do not feel we are trying to usurp them and dismiss their value.

Physicians acknowledge and applaud pharmacists’ tireless contribution and value added to the ASP team. We support you in leadership roles. When we say we as physicians are suited to be ASP leaders, it is because we are. It does not diminish your role as co-leaders in a multidisciplinary team; neither does your teaching of antibiotics to ID fellows diminish our role as clinical experts to trainees. Can’t we all just get along? Time to put this superfluous competition to rest and support each other’s value, for the patients’ sake!

Will Antimicrobial Stewardship be the Next Target for De-implementation?

First, an honest confession, Mike's tweet had nothing to do with antimicrobial stewardship, but rather contact precautions. But his point is just as valid when discussing antimicrobial stewardship and there will come a time when forces will align to question the benefits and costs of stewardship programs since now and in the future they will lack the "necessary" cluster-randomized trial evidence supporting their existence.

There is a longer discussion to be had here sometime in the future, when I'm not writing a Center grant renewal, but the key question is what we consider "high-level" evidence. For most de-implementation supporters and indeed most infection control and stewardship guideline authors, high-level evidence is synonymous with individual or cluster-randomized trials. They simply cannot accept non-randomized, quasi-experimental designs as evidence. It is gotten to the point that the recent CDI Guidelines completely excluded quasi-expermintal designs from their level of evidence figure, despite the fact that one of the original Grade Criteria papers lists QE studies in its table and allows them to be ranked higher than RCTs, if certain criteria are met.

OK.  So why am I rambling on about level of evidence and misapplying a tweet from 2 weeks ago? There was a new systematic review just published in AJIC by Leandro Bertollo and colleagues that asked the question: "Are antimicrobial stewardship programs effective strategies for preventing antibiotic resistance?" To answer this question they reviewed all studies published between from January 2012 to January 2017 and followed the standard PRISMA statement recommendations for reporting their findings.

Results: They identified and extracted data from 26 studies, of which 22 were single-center and four were multicenter studies. Study designs are listed in Table 2, below, with the special note that none of the before/after studies included a contemporaneous, unexposed control group. A major concern that the authors identified was that in 7 of the 26 studies (30%), there was evidence that infection control interventions were implemented at the same time as the stewardship intervention and that the majority (57%) of the stewardship studies that reported positive results were confounded by simultaneous implementation of new infection control practices. High fives for hand hygiene.

Their conclusion: "There is no solid evidence that ASPs are effective in reducing antibiotic resistance in hospital settings. There are still few studies analyzing this matter, most of them with inappropriate study designs. We uphold the need for more studies with appropriate study designs and standardized ASP interventions targeting common microorganism-antibiotic pairs."

The need for more studies. Sounds like the siren call for de-implementation to me. Sure, we can wait around a decade or four for some magical $20 million cluster-randomized study that swabs all patients on admission/discharge, completes a full microbiome analysis and tracks patients for a year post discharge for resistant infections. Or, we can expand our ideas around what "high-level" evidence means and fund well-designed and controlled quasi-experimental studies and also consider strong epidemiological evidence, such as exposure to antibiotics leads to colonization with resistant pathogens. We can be logical. Yeah, not gonna happen. But at least you were warned.

Should surgeons be allowed to prescribe antibiotics without assistance?

It's the end of a long day on the ID consult service. You and the team have decided to recommend switching antibiotics on a post-op cardiac surgery patient since the S. aureus susceptibilities have returned and you'd prefer cefazolin over vancomycin for her MSSA bacteremia. The team text messages the primary surgical team and the intern meets the team in the ICU. You overhear the ID fellow's discussion with the surgical intern, who appears to not know the patient and who can't get approval from the senior resident, CT surgery fellow or the attending to make the antibiotic change since the whole team is scrubbed in the OR.

The above scenario is all too familiar to those who practice infectious diseases, and to be fair it could apply to other procedure-based subspecialties. But the question arrises, if only oncologists can prescribe chemotherapy, why is it that everyone is allowed to prescribe antibiotics? Is this really what is best for our patients? Yes, this is currently a controversial topic but these are the types of questions we need to ask if we're going to respond to the antimicrobial resistance crisis.

A group of researchers in the UK led by Esmita Charani and Alison Holmes began exploring the effects of culture and team dynamics on antimicrobial prescribing during surgical ward rounds and the results of their ethnographic study left me convinced that we must develop ways to improve antimicrobial prescribing on surgical services.

The research team observed the antimicrobial prescribing decision making of six surgical teams over a 3-month period. These included observation of 30 ward rounds and face-to-face, semi-structured interviews of 13 clinicians (5 consultant/attending surgeons, 3 registrars/residents, 2 nurses, 2 junior doctors/interns and the ward pharmacist). The qualitative analysis identified 4 key themes that influence antibiotic prescribing: (1) working in a constant state of flux; (2) communication jigsaw; (3) delegating antibiotic management; and (4) the need for an intervention. Here are a few quotes from the study:

Constant flux: There is a hierarchy as to who leads ward rounds (WR), but this is a shifting hierarchy whereby people are promoted or demoted from their position based on who is present on the WR...if the surgeon leading the WR is called away, for example to the OR, the line of authority shifts downwards and people must act up, for example the registrar takes on the role of the surgeon, the junior doctor ‘becomes’ the registrar and the medical student ‘becomes’ the junior doctor.

Communication jigsaw: WRs are often rushed, interrupted and dispersed and reconvened because of demands for the senior team to be in the OR. The constant disruption and people leaving and joining the WR means that members of staff will rarely be present for the entire WR. Because of being constantly split between the OR and the ward, communication within the surgical team occurs across different platforms. Key decisions are made, recorded and communicated not necessarily in medical health records but on handover sheets, text messaging, and applications on smartphones (e.g. WhatsApp). On many occasions a patient was thought to be on antibiotics by the team, and after further queries in notes and charts was found not to be on them, and vice versa.

Delegating antibiotic management: Surgeons tended to see the core elements of their role as relating to the surgical management of their patients, a role that is performed in the OR. The lack of priority given to antibiotic decision making is compounded by a lack of expertise, resulting in responsibility for antibiotic decisions being commonly delegated to others.

The need for intervention: The need and expectation to intervene means that often antibiotics are initiated for patients with no or little evidence of infection, but a high plausibility of infection in the minds of the surgeons. This process is rationalized by the surgeons as being an extension of their roles as ‘interventionists’. In the absence of evidence of infection what drives antibiotic decision making is a risk of failure, and a risk of blame. What is considered unique in surgery is that a patient has to be well enough to be able to undergo an operation, therefore any deterioration postoperatively is assumed to be a consequence of the surgery, and the decisions of the surgeon, and not the patient's underlying illness. These concerns drive a more conservative approach to antibiotic decision making leading to unnecessary and prolonged courses of antibiotics.

None of these points will appear very surprising to anyone who has cared for patients on a surgical service. However, the authors are to be commended for the care with which they completed this study and the wonderful structure they provided to the domains that influence antimicrobial prescribing. I agree with their assessment that "there is a need to explicitly assign the responsibility for antibiotic management of the surgical patient to a responsible, individual with necessary expertise... Diagnosis and treatment of infections is a specialty that requires expertise and training, therefore this is an opportunity to develop, with support from specialist microbiology laboratory and staff, a role for a clinician(s) responsible for perioperative antibiotic management. This will help to strengthen the antibiotic management for surgical patients and has the potential to facilitate continuity of care and to help overcome the substantial gaps in communication that have been identified in this study...The time is right to question whether we need to address the gap in antibiotic prescribing for surgical patients by developing this specific perioperative clinician role to manage infections. This is of critical importance considering the rising challenge of antibiotic resistance in postoperative patients."

John Oliver on Vaccines

Of course, how could we not share another great John Oliver video that covers an ID topic even if it's NSFW. One of the more insightful sections starts around 6:00, where he admits he understands why people are afraid of vaccines, since they are "getting injected by a needle filled with science juice." He also describes antibiotics as "poison used to murder things living in you." Now wouldn't antimicrobial stewardship be easier if patients and physicians thought of antibiotics as poisons and not just magical pills that have few side effects? What if we treated antibiotics like cancer chemotherapies?

Antibiotics: There's no free lunch

A new, important paper in JAMA Internal Medicine from Sara Cosgrove's group at Johns Hopkins demonstrates the collateral damage of antibiotics. In this retrospective cohort study of 5,579 internal medicine inpatients, 1,488 (27%) received a parenteral or oral antibiotic for at least 24 hours. The most common indication for antibiotics was UTI, Adverse events due to antibiotics were captured over the 30-day period after antibiotic initiation, with the exception of C. difficile infection and MDRO infections, which were captured over the ensuing 90 days. Median duration of therapy was 7 days. Of the patients treated with antibiotics, 19% had no clinical indication for antibiotic therapy, and 20% developed at least one associated adverse event. The breakdown of adverse events is shown in the visual abstract below (note: for this analysis, I combined the 30- and 90-day outcomes). We are becoming more cognizant that antibiotics are not benign therapies. Kudos to Sara and her colleagues for their work in raising our awareness.

Exposing the myth of "UTI"

Last year, I posted on a commentary by Tom Finucane where he questioned the validity of the concept of "UTI." In a new paper in the Journal of the American Geriatrics Society, he expands on this, adding more evidence to question long-held dogma. I've read this paper three times, and have to admit it leaves you feeling a little like you did when you learned there is no Santa Claus. Most physicians have treated patients for "UTI," and we have long believed in the existence of what we thought is a common pathologic process. Tom Finucane shatters that thinking.

He lays out a number of important arguments:

• Bacterial colony counts in urine cultures do not predict the need for treatment.
• Urinary tract symptoms do not correlate with significant bacteriuria, pyelo-nephritis, or the risk for secondary bacteremia.
• The presence of pyuria does not predict the need for treatment.
• Acute uncomplicated cystitis is better managed with analgesia than antibiotics.
• Delirium in the elderly does not necessarily warrant urine culture, and treatment of bacteriuria in this setting is not necessarily indicated.

This paper is a must read for anyone interested in antimicrobial stewardship since "UTI" is one of the most common indications for initiating antibiotics in both the inpatient and outpatient settings. Dr. Finucane points out that the term "UTI" itself drives the antibiotic-prescribing reflex. And importantly, he notes that most people treated for "UTI" would probably be better off without treatment. "UTI" is deeply entrenched in our thinking, and although reducing antibiotic treatment of this flimsy construct will be difficult, this paper is a call to action. 

Negative study of the month, C. difficile edition

I like a good negative study, particularly when it’s a multicenter randomized trial about preventing our most problematic healthcare-associated infection. So let’s take a moment to appreciate this work from Amy Ray and colleagues.

These investigators randomized 16 hospitals to either standard cleaning or “enhanced cleaning”, which meant monitoring of environmental services personnel with feedback of performance (measured using fluorescent markers for cleaning and environmental cultures for disinfection). They measured the outcome of healthcare-onset, healthcare-facility associated C. difficile infection (HO-HFCA CDI). The study was powered to have >95% power to detect a 25% reduction in HO-HFCA CDI in intervention hospitals (and 70% power to detect a 15% reduction).

Bottom line: the intervention led to clear improvement in cleaning (better removal of fluorescent markers) and disinfection (reduction in % of C. difficile + environmental cultures in CDI rooms from 13% to 3%--which was the approximate rate of contamination in non-CDI rooms). Unfortunately, there was no reduction in HO-HCFA CDI during the intervention period, and no difference between control and intervention hospitals (see figure below and article for details).

Few people know more about CDI than Curtis Donskey (senior author of this study), so I encourage you to read their interpretation of these negative findings. They cover several potential explanations--the one I find most convincing is that the portion of HO-HCFA CDI attributable to organism acquisition during hospital admission may be smaller than we realize. Thus I agree that we need more studies to help us “identify effective strategies to reduce the incidence of healthcare-associated CDI.” 

I’ve already weighed in with my opinion on the most effective strategy.

Anyway, bravo to Ray and colleagues for an excellent addition to our knowledge about CDI prevention!

Wherein I reveal the top 3 approaches for preventing C. difficile disease!

1. Antibiotic stewardship

2. Antibiotic stewardship

3. Antibiotic stewardship

I’ve listed these in order of importance. Supporting evidence is accumulating, including three recent papers that I found very interesting:

Dingle, et al. Lancet Infect Dis 2017. This observational study from Oxfordshire, UK combined overall CDI rates, antibiotic use data, and whole genome sequencing to determine whether declining CDI rates were more likely driven by reduced antibiotic use or by transmission prevention efforts. The results are nicely summarized in Figure 2 from their manuscript (see below). It’s extremely cool to see how the big reduction in fluoroquinolone (FQ) use from 2005-2007 was followed by the near-extinction of FQ-resistant isolates. The disappearance of these FQ-R genotypes accounted for the entirety of the significant CDI reduction seen in Oxfordshire. If infection prevention approaches were a major driver of the CDI reduction, one would’ve expected to see at least some reduction in the non-FQ-R genotypes. Equally interesting: as FQ use crept up, rates of FQ-R CDI didn't follow, possibly due to eradication of these genotypes from asymptomatically colonized, or due to the still-lower usage (or usage in different populations). Anyway, there’s a lot of great detail in this report, so read it yourself, but the results support the centrality of stewardship to CDI prevention. LATE ADDENDUM: See this post by Marc Bonten and this Wellcome Open Research article for important caveats to the above "simple interpretation" of this study.

Anderson, et al. Lancet 2017. I’m kind of embarrassed that we haven’t weighed in on this one yet, since the Benefits of Enhanced Terminal Room (BETR) Disinfection study is definitely “BETR” than most infection prevention studies. It’s a cluster-randomized, multicenter, crossover study that compares standard disinfection to bleach, UV-C, and bleach + UV-C for terminal room disinfection after occupancy by patients with MRSA, VRE, multiple-drug resistant Acinetobacter, or CDI. The outcome is acquisition of colonization or infection with the index organism by the subsequent room occupant. One reason I haven’t blogged about the study yet is that I really don’t know what to make of it. It’s a great study, but some of the results are confusing or counterintuitive, and don't make me want to rush out and buy more UV robots (full disclosure: we have a whole army of them at our hospital already, all of which were purchased prior to the results of this study). For rational takes on the entirety of the study I’ll outsource to our colleagues Jon Otter and Marc Bonten at Reflections IPC. As for the C. difficile results (see below for per-protocol results from Table 3 of the manuscript), UV-C didn’t reduce CDI risk beyond that of standard bleach disinfection. For the purposes of this blog post, I’m going to concur with the authors’ contention that “the environment might not play as large a role in C. difficile transmission as previously suspected” (or at least not as large a role when you’ve already cleaned said environment with bleach). It’s all about the antibiotic stewardship, baby!

Widmer, et al. Clin Infect Dis 2017. This is the laziest, least resource-intensive of these three studies, and also my favorite. What better way to determine whether an intervention to prevent transmission is effective than to just stop doing it and see what happens? [I’m now picturing Andreas Widmer leaning back on his office chair, feet on his desk, overseeing a decade of not placing CDI patients in contact isolation.]  I’m kidding, of course, in fact they did quite a lot of sampling of the contacts of these CDI patients (451 of them) to assess for transmission events. The upshot: only 2 (!) proven (and 4 probable) transmission events were documented using genome sequencing over the decade, and no outbreaks occurred. Of note, they did place those with “severe incontinence” in contact isolation (really, this is in the spirit of Standard Precautions), and all CDI patients were assigned a dedicated toilet. Oh, and they also had no active antibiotic stewardship during this time period, but report a >90% adherence to hand hygiene (paging Eli!). 

To sum up: three interesting studies, and the combined results lead me to conclude that, assuming I have a limited budget with which to reduce CDI, I’d be wise to invest most of it in active antibiotic stewardship.

Hand Hygiene and The Power of Labbit

Yesterday, Mike wrote about "The Power of Habit" and taught us that "40% of our daily activities occur without any active decision making" and suggested that "the trick...is for us to figure out how to get hand hygiene and stethoscope wipedown established as habits."  Of course, this all sounds reasonable. Besides hand hygiene, wouldn't it be great if we could get primary care doctors to stop prescribing antibiotics? Surely, poor stewardship is also a habit.

I used to believe, as Mike does, that infection prevention was a matter of education and re-education until good practice becomes habit. But after years of watching us fail to improve antibiotic prescribing and increase hand-hygiene compliance, I no longer believe in the magical thinking surrounding education and habits. First, there is minimal evidence that we can encourage folks to develop better habits - such as hand hygiene compliance. Take for example this recent systematic review on hand hygiene trials by Kingston et al. The authors reviewed studies published since 2009 and reported a baseline hand hygiene compliance of only 34.1% with a mean improvement to 57%. Some folks may look at this data and become excited about a 23% compliance improvement!!  But a realist would look at the data and realize that these trials couldn't have been the first time the healthcare workers in the intervention hospitals were exposed to hand hygiene interventions - their baseline compliance of 34% was after numerous rounds of "habit-forming" educational training.

Thus, we need to be honest with ourselves and acknowledge that difficult system changes are needed to improve practice. For hand hygiene, for example, we need shelves outside rooms so nurses can rest things they're carrying while cleaning their hands. For clinicians we need rapid diagnostics and health information systems to inform antibiotic prescribing. Any talk of habits suggests that change can occur at an individual healthcare worker or prescriber level. And any suggestion that this is an individual healthcare worker problem will necessarily lead to learned helplessness and blame, neither of which will be productive.

In the end, we're going to need to move past our focus on "habit" and its flipside, blame. Let's work towards system change and innovation that directly address the barriers to hand hygiene compliance and proper antibiotic prescribing. You might have another name for it, but I'm gonna call it The Power of Labbit.

Labbit image source: Kidrobot Blog

Keeping Our Eyes on the Antimicrobial Stewardship Ball: Dr. Tom Price as the next secretary of HHS

This is a guest post from Judy Guzman-Cottrill. Dr. Guzman-Cottrill is a Professor of Pediatrics at Oregon Health & Science University and also an infection prevention and healthcare epidemiology consultant for the Oregon Health Authority’s HAI Program, where she serves as the Medical Director for Ebola and Emerging Pathogen Preparedness. 


Many healthcare providers ponder what the incoming 2017 administration will mean for their work, including myself. Dan and Eli have already written several blog posts about public health funding threats. As my description above says, I'm a hybrid of sorts: a part-time pediatric infectious disease clinical faculty member at Oregon Health and Science University, and a part-time consultant to the Oregon State Health Department’s HAI program.

First, we’ve all been thinking about our patients and their families. The next administration’s plan for the Affordable Care Act seems to change constantly. During President-Elect Trump’s campaign, he promised to completely repeal the ACA within his first hundred days in office. Post-election, he has suggested that the ACA will be repealed or amended. After meeting with President Obama, Mr. Trump has stated that he will maintain the continued coverage for preexisting conditions and young adult coverage on parents’ plans until 26 years of age. Most recently, however, Mr. Trump selected Dr. Tom Price to serve as secretary of Health and Human Services. What will his leadership mean for our patients, including those who rely on Medicaid and Medicare? Dr. Price has also supported changes which would not require insurers to cover pre-existing conditions. Almost more concerning to me is that Dr. Price is a member of the Association of American Physicians and Surgeons (AAPS), an organization that vehemently opposes antibiotic stewardship legislation, has publicly opposed the IDSA Lyme Disease guidelines on several occasions, and whose executive director has publicly supported a potential link between MMR vaccine and autism as recently as 2015. Important note: It is unclear to me which of these specific stances are also personally supported by Dr. Price. It would be good to know.

What about public health, MDRO prevention, and infection prevention? I already mentioned the AAPS opposition to antibiotic stewardship legislation. Will all of our hard work be left to the wayside? Over the past decade, I've been amazed by the accomplishments our field has made in improving judicious antibiotic use. Our surgical and critical care colleagues are finally starting to feel comfortable with shorter days of antibiotic therapy, and narrower spectrum. Hospitals are starting to fund physicians and pharmacists along with the informatics experts necessary to develop and maintain effective stewardship programs. During clinical rounds, even ID consultants are asking themselves, “Does this patient really need more antibiotics? Or am I prescribing them a personal anxiolytic?!” Stewardship progress is everywhere, including NICUs across the country, partnering with the CDC, to decrease antibiotic exposure in neonates. I worry that Dr. Price, an orthopedic surgeon, will tout stewardship as needless control over physicians who should prescribe antibiotics to whomever, whenever they please.

ID clinicians and public health colleagues, let’s all keep an eye on Dr. Price. We should be strong, vocal advocates for our at-risk patients and our public health programs, to ensure that our infection prevention and healthcare epidemiology work continues into the next decade.

At first he was only prescribed for me, now he's messing around with EVERYBODY !

Not just another guideline

Why is this man laughing? Because he co-authored an awesome antibiotic stewardship guideline!

The updated antibiotic stewardship guideline has been released, and is available at the Clinical Infectious Diseases website, and in pocket card and mobile versions. While the guideline will undoubtedly be essential for those tasked with establishing and running stewardship programs, it isn’t going to be frequently referenced by prescribers. 

Instead, treatment guidelines for specific clinical syndromes are more likely to guide prescribing decisions, either by direct application or via their incorporation into facility specific practice guidelines or CMS measures. Thus the impact of the stewardship guideline will be limited unless stewardship principles are also incorporated into treatment guidelines, pathways, and quality measures. This point was made in a recent editorial by Brad Spellberg, Arjun Srinivasan and Chip Chambers, and I know that HICPAC plans to summarize the stewardship principles that should be incorporated into all ID-related treatment guidelines. 

Ensuring that antibiotic stewardship principles are considered carefully when infection-related quality measures are established is a continuing challenge—once a measure is tied to payment and/or public reporting, the law of unintended consequences takes over, including consequences for antibiotic use. We learned this with the ill-fated “4-hour rule” for treatment of community acquired pneumonia, which likely led to an untold number of inappropriate antibiotic doses and C. difficile cases, and we’re struggling with it again around the new sepsis measure. 

Finally, truly informed stewardship awaits a lot of research and development progress: to better establish dose and duration of therapy for common conditions, to improve diagnostics to allow more rapid directed therapy, as well as improved capacity to distinguish bacterial, fungal and viral etiologies, to more precisely determine the relative impact of different antibiotics on host microbiota (and the implications thereof), etc., etc., etc. Someday, I hope, we’ll be able to look back at the 2016 guideline and marvel at how rudimentary it is—for now, though, it’s excellent, so go read it!

Photo credit: US News and World Report

Antimicrobial Stewardship and C. difficile Therapy: It's Complicated

The CDC's Get Smart About Antibiotics Week (November 16-22, 2015) is upon us. To do our part, we bloggers are using this (and hopefully other) posts to "Highlight Get Smart Week on your website" as CDC suggested as an Activity Idea. Of course, the problem with getting smart about antibiotics is that it's really complicated. Sure, reducing unnecessary antibiotic use (e.g. don't treat viruses) seems simple, but the toolkits necessary to assist primary care physicians aren't yet fully developed (e.g. improved rapid diagnostics). And don't even think about inpatient stewardship. I've yet to see antibiotic selection guided by the existence of bacterial multidrug efflux pumps, for example, but hopefully that's coming too. This is not meant to be discouraging, it's just to say that we have a long road ahead and we must keep pushing forward with stewardship-focused basic science studies and clinical trials including implementation science.

With all that in mind, I came across what appears to be an important paper in the November 15 issue of JID by Brittany Lewis and colleagues at Memorial Sloan-Kettering. The authors asked a fairly simple question - what happens to gut flora when it's treated with C. difficile specific therapies and how does antibiotic selection alter colonization resistance to C. difficile, VRE, CRE and E. coli challenges. The authors designed their study around a typical antimicrobial stewardship question: should we treat C. difficile infection (CDI) with metronidazole, vancomycin or both?

Using a mouse model (9 mice per treatment-time point), each was treated for 3 days with metronidazole, vancomycin or both. Fecal samples were then tested for bacterial population diversity (16s sequencing) and susceptibility to C. difficile spore inoculation at 1, 3, 7, 14 and 21 days. As you can see in the figure below, most metronidazole-treated mice could not support C. difficile growth (red circles) after seven days, while many who received vanco or vanco+metro remained susceptible to infection out to 3 weeks. At 7 days and 14 days, 11% and 0% of metronidazole-treated mice were susceptible, respectively. In those treated with vanco, 89% were susceptible at day 3 and 100% were susceptible at day 7. This suggests that vancomycin might increase risk for recurrent infection compared to metronidazole.

Given those findings, it is not surprising that mice treated with metronidazole alone maintained a relatively stable microbiota (See figure below - click to enlarge), which could explain their reduced susceptibility to C. difficile. Among those treated with vanco or vanco+metro, mice with higher levels of disrupted microbial communities were less able to suppress C. difficile growth.

Perhaps more importantly in our fight against antibacterial resistance, a second aim of their study (see figure below) found that mice treated with vancomycin (pink circles) were far more susceptible to VRE, carbapenem-resistant K. pneumoniae and E. coli than metronidazole treated (black circles) or untreated mice (open circles) for at least two weeks post therapy.

In summary, in this sophisticated mouse model, exposure to oral vancomycin was associated with higher risk of C. difficile, a prolonged highly disrupted microbiota and an elevated risk of VRE, CRKP and E. coli colonization compared to those treated with metronidazole alone. There seems to be an increased push to treat CDI patients with oral vancomycin, but given these findings, one wonders if increased utilization of PO vancomycin might be right for an individual patient (although there might be higher recurrence), but wrong for society with increased emergence of VRE, CRKP and other pathogens. After reviewing this study, I'm surely a bit smarter about antibiotics, but unsure of how to treat patients with CDI...and so it goes.

Stewardship, Stewardship, Stewardship

There has been a plethora of antimicrobial stewardship scholarship published these past few weeks. I'm currently on the inpatient medicine service and have even been harassed by the antimicrobial stewardship team (humor), so I only have a moment to briefly highlight three can't miss articles:

(1) Manisha Juthani-Mehta and co-authors just published an excellent JAMA Viewpoint discussing Antimicrobials at the End of Life.  It is open-access (free), so I hope you have a chance to read it thoroughly, but the main points include:

1. "Evidence-based and goal-directed counseling about infection management at the end of life must be a routine part of advance care planning and treatment discussions between clinicians and patients with advanced illness."
2. "Clinical algorithms aimed at improving antimicrobial stewardship from an infectious disease standpoint must also integrate treatment preferences when applied to patients near the end of life." 
3. "To the extent that inadequate outcome data hinder decision making, researchers should consider whether there is adequate clinical equipoise and need to justify a carefully designed randomized trial comparing symptom control and survival among patients with advanced illness who receive antimicrobials vs high-quality palliative care for suspected infections."

(2) Dan Livorsi and colleagues at the Sidney and Lois Eskenazi Hospital and the Richard Roudebush Veterans Affairs Medical Center in Indianapolis just published an important qualitative study in September's ICHE of factors that influence antibiotic prescribing among inpatient physicians (10 resident and 20 staff physicians). I'm happy to add that Dan Livorsi has just joined our group in Iowa City, where he is helping to jump-start our stewardship programs. Key findings of his study include:

1. "Antibiotic overuse is recognized but generally accepted; 
2. the potential adverse effects of antibiotics have a limited influence on physician decision making;
3. physicians-in-training are strongly influenced by the antibiotic prescribing behavior of their supervising staff physicians; and
4. other physicians’ prescribing decisions are sometimes questioned, but there is limited peer-to-peer feedback or critique."

(3) Nick Daneman and colleagues in Ontario examined antibiotic use and secondary harms in 607 nursing homes housing 110,656 residents in a recent JAMA Internal Medicine. Their findings are quite striking (if not surprising) in that antibiotic use varied from a low of 20.4 antibiotic days to a high of 192.9 antibiotic days per 1000 resident days. Antibiotic-related adverse events were higher in "high-use" nursing homes even among patients who did not receive antibiotics. An interesting finding (for someone in Iowa) was that rural facilities were overrepresented in the highest tertile of antibiotic use (see figure below), but after accounting for other nursing home– and patient-level characteristics, rurality was found to be protective against antibiotic-related harms." Would be interesting to figure out why rurality is associated with higher antibiotic use but fewer harms but my guess is that rural folks are just awesome. Of note, Lona Mody and Chris Crnich published an accompanying editorial that is worth reading.

The Times They Are A-Changin’, and we need better data to keep up….

I recently pointed to the need for more studies comparing different durations of therapy for common infections. In an editorial in the September 2015 issue of Antimicrobial Agents and Chemotherapy, Jesus Rodriguez-Bano points to an equally important priority for comparative effectiveness studies: assessment of existing antimicrobials for organisms that are currently not considered good targets for those drugs. The problem he discusses is the rising rate of carbapenem use that has followed the global spread of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. 

Carbapenems are the drugs of choice for serious infections due to ESBL-producers, but several narrower spectrum agents (e.g. piperacillin-tazobactam, cephamycins (e.g. cefoxitin, cefotetan)) have in vitro activity against many of these organisms. What’s lacking are well-designed comparative trials examining whether these older agents might be similarly effective for selected serious infections (e.g. bacteremia, sepsis) due to ESBL-producers. The study by Matsumura and colleagues that the editorial accompanies provides some support for the effectiveness of cephamycins in the setting of ESBL-E. coli bacteremia, but is limited by its retrospective cohort design and its power.

Given the urgent threat of carbapenemase-producing Enterobacteriaceae (CRE), it would be nice to have more non-carbapenem options to turn to when confronted with these “garden-variety” ESBL-producers.