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."

Update from ECCMID: Infectious disease and medical overuse

This is a guest post by Dan Morgan, MD MS. He's an Associate Professor of Epidemiology and Medicine at the University of Maryland, Baltimore.


At the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) meeting last week in Vienna, Austria, a session was dedicated to Medical Overuse and Infectious Disease. To me, it was great to hear smart people thinking about my job, infectious diseases, in the context/language of my hobby, medical overuse.  Medical overuse has been defined as the provision of care in which harms outweigh benefits or the benefits are so small that informed patients would not want care. Although it was the last session of the meeting, it was surprisingly well attended. A few high points follow:

Céire Costelloe from the UK presented work showing 80% of antibiotics are given as outpatients and promote risk of resistance greatest in the first week but antibiotics have a persistent effect six months after use. Targeting overuse of antibiotics in outpatient settings is likely key to address antibiotic resistance.

Alexander Friedrich from the Netherlands, presented a balanced view of how tests can drive overuse—such as blood cultures or rapid malaria testing, but also that testing may have a role in reducing overuse in the use of procalcitonin to stop antibiotics. If clinicians default to antibiotics, then testing may help them step back. However, if clinicians aren’t prone to empiric treatment, testing may increase treatment.

Stephan Harbarth from Switzerland then gave a great overview of how implanted devices like urinary, central-venous catheters and endotracheal tubes are risks for HAIs, MDRO colonization and are often overused. His message was that reducing use of devices is the primary way of reducing infections. (Although note, CDC and other agencies use rates per catheter day, which discourages removal of low risk catheters, so we may need a better metric—like “days of utilization”)

Finally I spoke, closing the session and the conference. My talk focused on what do we know about Overuse more generally and what can we do to prevent Overuse? To me, the basis of Overuse is a skewed view of testing and treatment. I reviewed the evidence of physician over-enthusiasm for benefits of testing and treatment and tendency to underestimate harms of both. I presented a general model for how to address overuse, the Choosing Wisely campaign and how CW could be used by those encouraging stewardship. On the theme of stewardship, there have been interesting studies showing the benefits of diagnostic stewardship, identifying what seems to be a growing trend to modify testing to improve antibiotic use.

There was, of course, much more from ECCMID that is publicly available. Take advantage of their site that has recordings of talks!

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

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

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.

something something antibiotics something something

It's been a crazy couple weeks out here on the edge of the prairie. Clinical service, grants, papers, holidays, Ebola?, the ESCMID-SHEA course in Phuket and SHEA2015 have swallowed up my fall. Get those SHEA abstracts ready folks - the deadline is fast approaching - January 16th.

In the middle of this chaos, the CDC's Get Smart About Antibiotics Week seemingly appeared out of nowhere and CDDEP investigators just published a very nice antibiotic use point prevalence study in 6 US hospitals in this month's Lancet ID to coincide with the 'Get Smart' Campaign. Nikolay Braykov and Dan Morgan led the study and Nikolay wrote up a nice post describing what they found, which I've excerpted below:

We undertook a chart review study at six institutions – two teaching centers, three community hospitals and one VA – looking at the indications for starting antimicrobials, the use of culture and radiology results and the patterns of modifying empiric therapy in the first five days of treatment. We found nearly two-thirds of inpatients were receiving antibiotics, with empiric starts dominated by combinations of vancomycin, piperacillin/tazobactam and fluoroquinolones. It is likely that a lot of those initial prescriptions were unnecessary, as 30% of patients lacked fever or abnormal white blood cell counts at the start.

Appropriate cultures (on or before start of therapy) were collected from 59% of patients, and although 60% came back negative, only 22% of all evaluated patients and had their antibiotics narrowed or stopped (Figure). More specifically, 22/59 (37%) of patients with negative urine culture and 11/22 (50%) of those with negative blood culture had antimicrobials stopped or narrowed. Of pneumonia patients with negative chest imaging that proportion was 12/50 (24%).

Narrowing or discontinuation (of antibiotic therapy) was more likely when cultures were collected at the start of therapy and no infection was noted on an initial radiological study. In turn, escalation was associated with multiple infection sites and a positive culture (see table below).

It seems like diagnostic uncertainty drives a lot of possibly unnecessary antibiotic use. These results underscore not only the need for rapid diagnostics, but also the importance of mechanisms to assure tests are ordered in time and their results are actually used to optimize therapy – goals attainable through better stewardship programs and physician education.

A great point made recently is that the government’s resistance action plans should include steps to incentivize and expand the training of more ID physicians. Although the threat of drug resistance gets more public attention each year, “getting smart” about antibiotics, including their timely withdrawal and adjustment, ultimately requires the buy-in of current and future prescribers. 

Antibiotic Use is Common in Hospitalized Patients

Even with Ebola and Enterovirus D68 on their plate, CDC still finds the time to do one of their day jobs - antimicrobial stewardship. In today's JAMA Infectious Diseases issue, Shelley Magill and her CDC EIP colleagues published (open access) a point-prevelance survey of antimicrobial use in acute care hospitals. The one-day survey included 11,282 randomly-selected patients from 183 hospitals in the 10 EIP states. In addition to recording which antibiotics the patient received, they also determined the rationale for use: treatment of infection (including empiric therapy), surgical prophylaxis, medical prophylaxis, a noninfection-related reason, or unknown.

Approximately 52% of patients received antibiotics that day or the day before. 58% of patients in ICUs vs 49% in other locations received antibiotics. Of those on antibiotics, half received one antibiotic, while the remaining 50% received two or more antibiotics. This seems like an obvious target for stewardship efforts. Encouragingly, 97% of the patients had a documented reason for receiving the antimicrobial: 76% for treatment of infection, 19% for surgical prophylaxis, and 7% for medical prophylaxis. The majority of patients treated had either a lower respiratory tract infection (34%), UTI (17%), skin/soft-tissue infection (15%) or GI infection (11%). I've included Table 3 below that highlights frequently used antibiotics for community vs health care facility-onset infections.

Overall a nice study and one that adds to the growing body of literature quantifying the rate of antimicrobials used clinically. The take home messages are a bit harder to identify. It would have been nice to follow these patients longer and capture their microbiology results to determine the proportion treated appropriately. It is also harder to make sweeping generalizations about antibiotic use in acute-care settings because the patients are very sick and could benefit from antibiotic treatment. If this were the outpatient setting, calls for improved use would be easier to make. Although, it does seems like we use too much vancomycin and pip-tazo in hospitals.

Unintended Benefits of Antibiotics: Why antimicrobial stewardship is difficult

We frequently highlight the unintended consequences of antibiotic use, such as C. difficile or adverse drug events, as reasons to discourage inappropriate antibiotic prescribing and advance antibiotic stewardship. Avoidance of unintended consequences is also a major factor in physician selection of antimicrobials. Anecdotally, physicians prefer to avoid clindamycin because it's linked to CDI. In an old study, Jessina McGregor and I found that physicians were approximately twice as likely to prescribe an antibiotic if its use was associated with three days of diarrhea instead of five.

Unfortunately (for stewardship, not patients), antibiotics also have significant unintended benefits, which may drive their overuse. In the current issue of JID, Elizabeth Gilliams et al. report (free full text) a secondary analysis of a malarial therapy RCT (chloroquine +/- azithromycin) in Malawian children. 160 children with mean age 33 months were treated in each arm. Children in the CQ+AZ arm were 33% less likely to develop a subsequent lower respiratory tract infection and 26% less likely to develop a gastrointestinal tract infection than patients treated with CQ monotherapy. Time to development of a lower-RTI was 0.88 years when AZ was added vs 0.46 years with CQ alone, p=0.04. Time to first GI infection was also delayed with AZ therapy, 0.58 years vs 0.38 years, p=0.02.

Specifically, these finding are important because the CQ and CQ+AZ arms were considered equivalent for malarial therapy; however, physicians may now add azithromycin for these secondary benefits in addition to its potential to delay the reemergence of CQ resistance in the region. The number needed to treat was only 7 for both RTI and GI outcomes. Thus, for every 7 children given short courses of azithomycin during malarial therapy there will be one fewer case of GI infection AND one few RTI.

Lori Holtz and Phillip Tarr in an accompanying editorial (free full text) describe the difficult decisions now facing public health authorities in the developing world with regard to balancing the benefits vs harms of antibiotics. For example, earlier trials found that mass azithromycin for trachoma reduced infectious and all-cause mortality in children while the addition of amoxillin or cefdinir to malnutrition treatments reduced mortality by 40%. The editorial includes discussion of potential mechanisms behind the beneficial outcomes attributed to azithromycin. Importantly, they call for future studies to determine the etiologic agents causing the poor outcomes which azithromycin inhibits so they can be targeted and mass antibiotic exposure prevented. I hope they get what they ask for. However, these are likely bacteria, so I don't hold out much hope for research funding.

Stewardship Effective in C. difficile Prevention: A Meta-Analysis

As Dan mentioned last week, when 15% of asymptomatic hospitalized adults carry toxigenic strains of Clostridium difficile, it should alert us to focus on antimicrobial stewardship as a way to prevent CDI. But how effective are stewardship programs and does it matter what type of program you implement in your hospital? If only there was some sort of systematic review or meta-analysis to guide or decision making.

As if on queue, Leah Feazel and Marin Schweizer at University of Iowa published such a review and meta-analysis titled "Effect of antibiotic stewardship programmes on Clostridium difficile incidence" in JAC earlier this spring. Typical of projects completed by Marin and her group, they thoroughly combed the literature for papers. Here they identified 891 articles, reviewed 78 full articles and included 16 studies in their final analysis. Over all, stewardship programs were associated with a 52% reduction in CDI incidence. Importantly, programs appeared effective when implemented in whole hospital or geriatric settings and when utilizing a persuasive approach or a restrictive approach. I've provided the forest plot of studies below. An additional note is that the studies utilized various quasi-experimental study designs and based on the funnel plot, there appeared to be little publication bias.

Key points: (1) Stewardship works for CDI prevention, but it would have been nice if there was at least one funded RCT or cluster-RCT. (2) The meta-analytic approach, that Marin has pushed through her reviews of SSI bundles and hand hygiene interventions, is a fantastic way to guide medical decision making and should be considered for inclusion in future HAI guidelines. The reality is that infection prevention studies overwhelmingly utilize quasi-experimental designs. Why not identify the highest-quality QE studies and rigorously meta-analyze them as done here?

The In(patients) and Out(patients) of Antimicrobial Stewardship

I've been lucky enough to attend the 4th World HAI Forum on Antimicrobial Resistance this week in Annecy. This morning's excellent session on antimicrobial stewardship was chaired by Stephan Harbarth and Herman Goossens and brought to light many barriers to the wider adoption of stewardship by non-ID physicians. For one, the accuracy and economics of rapid diagnostics and algorithms were identified as a major barrier. In particular the negative predictive value, which would allow primary care physicians to stop (or not start) antibiotics, was suggested as a key target.

Another, brought forth by Kent Sepkowitz, was that the whole enterprise of "stewardship" lacks a main outcome measure or at least has transitioned from Decreasing Antimicrobial Resistance, to decreasing costs, shortening length of stay, educating the next generation of clinicians, and finally easing workload for ID specialists and trainees. He suggested that presenting stewardship as a patient safety issue with a primary target of drug resistance rates in key indicator organisms will bring greater rewards. Tom Gottlieb responded that the burden should be on the others to prove that stewardship doesn't work since antibiotics are such a limited resource. Bob Wachter implied that a key "bias" against stewardship in the US is that compared to the patient safety movement, which targets the individual patient as the beneficiary, stewardship benefits "others." Loreen Herwaldt said that a microbiome outcome could provide an individually-focused patient safety target.

Of course, I can't even begin to transcribe and communicate all of the excellent points made by the attendees. Fortunately, two interesting studies were published in the past 2 weeks that examined the impact of stewardship interventions in the outpatient and inpatient settings.

The first study by Jeffrey Gerber and colleagues in JAMA described an outpatient cluster-randomized trial in 18 pediatric practices. They examined prescriptions for acute respiratory infections 20 months before and 12 months after the intervention, which included one 1-hour on-site clinician education session followed by 1 year of personalized, quarterly audit and feedback of prescribing. Prescription of broad-spectrum antibiotics decreased by 6.7% more in the intervention practices compared to usual practice clinics, while off-guideline prescribing decreased by 10.7% more for pneumonia and 14% more for sinusitis. Evidence supporting the public health benefits (i.e. reduced resistance) of this intervention are not described in the paper.  In fact, the word "resistance" appears only once in the entire article.

The second study by Greg Filice and colleagues at the Minneapolis VA examined the impact of an inpatient computer decision support system for antimicrobials on appropriateness of antimicrobial prescriptions in a retrospective cohort. The system was associated with a higher level of appropriate prescribing, 44% vs 33%. However, the most interesting finding was that the most important factor influencing prescribing was the accuracy of the initial diagnosis.  If the diagnosis was correct, prescribing was appropriate 62% of the time compared to only 11% when the diagnosis was incorrect or uncertain. Thus, unless we can help clinicians with their diagnostic accuracy, we will have a limited impact on antibiotic prescribing.

ok, back to the meeting for me...

The end of antibiotic stewardship, 2013 edition

Back in the 1990's when I was a wide-eyed ID fellow, I'd wonder out loud to my co-fellows Sara Cosgrove and Dan Levy why it was that we needed an oncologist's approval to prescribe chemotherapy but any clinician could prescribe antibiotics. My reasoning was that if you make a mistake with chemotherapy in a cancer patient, you only harm that one patient, but when untrained clinicians prescribe antibiotics all willy-nilly they harm the whole planet. Well, it's 2013 and I'm still wide-eyed and have the sinking feeling that antibiotic prescriptions are about to go way beyond willy-nilly. And I'm a bit scared.

The reason for my worry is this paper by Hanne Albert and colleagues in the European Spine Journal. In the study, patients with 6-months of low back pain and Modic 1 changes on MRI were randomized to 100 days of antibiotics (amoxicillin + clavulanic acid). The reasoning behind antibiotics for back pain is a study that found P acnes and C propinquum in surgical specimens from lumbar herniated disks. Anyway, the study reported improved primary and secondary outcomes with treatment and no change with placebo.

So why am I worried?  Just look at the headlines from my google search above. I would normally link to these articles, but I don't want to send traffic to posts that aren't appropriately skeptical of this single trial and the public health implications of giving everyone with back pain 100 days of antibiotics. One UK surgeon was even reported to have said this finding is worthy of the Nobel Prize. Yikes.

For an appropriately skeptical and balanced discussion of this study and the surrounding hype, please read this Observation in BMJ by GP Margaret McCartney. After I read the study and Dr. McCartney's excellent commentary, I forwarded them onto Sara Cosgrove. It was therapeutic for me to share my concerns with an old friend. But now I'm back to panicking.

Intrigued by the plot of Kent Sepkowitz’ perspective piece on antibiotic stewardship in the NEJM

This is a guest-authored piece by Dr. Tom Gottlieb (Senior Specialist in Microbiology and Infectious Diseases, Concord Hospital, New South Wales, Australia), wherein he discusses Kent Sepkowitz's latest commentary in the NEJM.

This is writ in the genre of a thriller in which a new generation of ID physician villains (the previous heroic ID generation’s illegitimate offspring, it seems ) abound as ‘fervent’ ‘chastisers of antibiotic overuse and abuse’. These ‘self-pitying’, ‘inept’, ‘feckless’ ‘prohibitionists’, ‘gnawed with regret’, indeed ‘deranged’, threaten to undermine and disenfranchise the orderly world of antibiotic prescribing, by seeking to banish miracle antibiotics forever from the world. Indeed their quest, (in cahoots with the loonies of the anti-vaccination lobby), is so dangerous, it is spelt out in the more sophisticated French; “an idée fixe”. These antibiotic nihilists cannot appreciate the true contribution antibiotic chemotherapy has made to individual patient care and also to the global well being of humanity.

Now I too enjoy debunking zealotry, and would not deny that there is plenty about antibiotic stewardship that is worth challenging in a balanced discourse. And stewardship, (or is it shepherd-ship?) can be clearly problematic. As ID physicians, we are frequently left in a schizoid situation where, as on one hand we attempt to control unnecessary use, on the other, in individual care we often contribute to broad-spectrum prescribing. Moreover some clever contrarianism never goes astray. But Sepkowitz’ pendulum swings beyond healthy scepticism, past contrarianism, to something akin to denialism.

Damn it, I too need to reach for the French dictionary. Un agent provocateur? Peut-être, saboteur? Because there is significant damage caused when worthwhile attempts, not as suggested by Sepkowitz to deny antibiotics for patients, but to preserve antibiotics into an uncertain future, are derided by ID doyens. But without him providing us with any cogent examples of groups or policies that would support the existence of these villanous ‘antibiotic prohibitionists’. And the very simplistic, polemical, good versus evil like vision he paints, creates a disservice to the antibiotic debate. (Or is it that for the sake of a good argument, as Oscar Wilde wrote, Sepkowitz feels that “in matters of great importance, style, not sincerity is the vital thing”)

I agree with Sepkowitz that “just in case” prescribing, often saves the day in settings of uncertainty. But one of the banes of our clinical existence is ‘just in case’ prolonged orthopedic prophylaxis, ‘just in case’ ceftriaxone in heart failure, ‘just in case’ stat gentamicin dose pre catheter removal, just in case treatment in case confusion is caused by a urine infection, or a few more days of treatment ‘just in case’, etc..; situations in which antibiotics are used to treat the prescribers’ anxieties rather than the patient’s condition.

I find Sepkowitz’s piece in the NEJM more a diatribe than a commentary. But it is a very useful piece too. It is a wake-up call that if we fail to convince other ID physicians regarding the merits of prudent antibiotic use, we have a long way to go to change attitudes amongst medical peers or in the community.

Image: Nicolas Poussin's Adoration of the Golden Calf. "The Golden calf of Stewardship" paraded in front of idolatrous ID physicians?

More antibiotics NOT more better in sepsis

There is a meme in antibiotic therapy for all infectious disease clinical syndromes that earlier and more antibiotics lead to lower mortality. I'm not sure that this meme is supported by data from good studies, but it has been so effectively spread through the establishment that its very existence goes unnoticed (check this abstract's first sentence). I think this unproven belief threatens effective antimicrobial stewardship and is partially responsible for the emergence of antimicrobial resistant organisms, but I digress...

Published online in JAMA this week is a randomized trial of dual antibiotic vs monotherapy in sepsis funded through the German Sepsis Research Network (SepNet). The 2.5 year study in 44 German ICUs compared meropenem monotherapy (n=298) with meropenem+moxifloxacin (n=278) in patients with sepsis or septic shock. Patients were treated for 7 to 14 days or until discharge or death and duration was informed by a procalcitonin-guided treatment protocol on study days 7 and 10. The primary outcome was mean of daily total Sequential Organ Failure Assessment (SOFA) scores over 14-days with similar scores in both monotherapy (7.9 points) and dual therapy (8.3 points) patients, p=0.36. 28-day mortality was 22% in the mero and 24% in mero+moxi patients (p=0.58) and 90-day mortality was 32% in the mero and 35% in the mero+moxi patients (p=0.43).

Groups were similar and infections were predominately pneumonia, intra-abdominal and GU. Blood cultures were positive in 33% of patients with Escherichia coli and MSSA being the most commonly isolated, while 18 had MRSA from any source. 100% of cultures tested were susceptible to the mero+moxi combination while 94% of specimens were susceptible to meropenem monotherapy.

This is an important study and one that should make us question current empiric therapy dogma. However, it doesn't answer the question whether antibiotics overall made a difference and whether other therapeutic options including source control might be more important.  It's nice to see clinical ID slowly emerge into the modern evidence-based medicine era even if so few studies are completed in the US.

image source: http://abacaxihortela.blogspot.com/2011/09/only-1.html

NPR's Science Friday on Antibiotic Resistance!!

On today's Science Friday Ira Flatow welcomed Dr. Stuart Levy from Tufts, Maryn McKenna the author of Superbug, Brad Spellberg from Harbor-UCLA and Elizabeth 'Betsy' McCaughey (Former Lt. Governor, New York and Death Panels - page 432). Stuart Levy is well known for his many years of work studying resistant organisms and developing new antimicrobials and Brad Spellberg is very well spoken. Brad's description of the debate around MRSA screening was fantastic and his explanation of the difficult issues surrounding new drug discovery (economic and FDA) was great. His call for actual research funding to figure out how to do terminal cleaning and figure out optimal prevention strategies was spot on.

Maryn McKenna, unfortunately, didn't get many words in but her comments around antibiotic stewardship in humans AND animals are very important. There is one point in the middle where Ira questions Ms. McCaughey's conflicts of interest around cleaning agents, listen for that. Near the end Ira brings up triclosan use in household products and Stuart Levy, having done much of the research on the harms associated with triclosan's use, offers a great description of why we should avoid it. Ira summarizing the discussion said that "we are going to devolve into the 18th century" where we won't have any effective antibiotics and "to me it sounds like you're just rearranging the chairs on the Titanic." Enjoy!

Direct audio link (here)
Website (here) with speaker info and audio link on the upper left side of the page