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.

Global antibiotic resistance surveillance a.k.a. GLASS: one step closer to saving the world

New surveillance data released a week ago by the World Health Organization (WHO) illuminates a step towards a coordinated and standardized way to perceive the AR problem worldwide. Most of the report focuses on healthcare-related bacteria, but it is not limited to this. Probably a hidden gem includes a standardized characterization of each countries capacity and reporting infrastructure.

In the first report from the WHO's Global Antimicrobial Resistance Surveillance System (GLASS), 22 countries submitted data on 507,746 isolates with antibiotic susceptibility testing results (range 72-167,331 per country). To no surprise, Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Streptococcus pneumoniae, and Salmonella spp are the most commonly reported resistant bacteria; most of these reports do come from sentinel laboratories reported to their country designee. Although some countries report high values of “percent resistance”, often these reflect a single laboratory.

The direction GLASS is going is forward! Which is great. Its strength right now is to provide a one stop shop and platform to quickly read how a country representative describes their AR surveillance effort.

You can choose a country and view data here:Tableau feature of GLASS

This may be helpful for grant writing, collaborations, and consultations; however, for a variety of reasons, the actual results are a bit data-penic, and somewhat of a convenience sample. This is not to fault the GLASS effort at all - countries clearly with the capacity to have insight, visualization, and concrete values on the magnitude of their resistance problem didn’t submit data to this data call.  Although the reasons may vary and all be very valid, it does make the report less of a comprehensive source of global variations in the magnitude of the problem. The power of standardize reporting of “representative” laboratories can (and I believe will) help local health and government leaders prioritize efforts in country. Hopefully additional countries (including the U.S.) will contribute to future data calls. Full report is here:GLASS 2017

Regardless, WHO now provides all of us with an interactive feature (Tableau) to view country specific infrastructures (I counted 37 countries) and data (from 22 countries, although I have not checked all 22).

I don’t envy WHO staff trying to herd cats (cats as in those of us having [or having had] a say in AR surveillance reporting) to try to get all countries to report out data to them in a standard way, but I do applaud their efforts and hope the data submissions become more comprehensive – and thus the interface more usable.

GLASS, which was launched in 2015 to help achieve the goals of the WHOs Global Action Plan on 
Antimicrobial Resistance (AMR) includes establishing country-level surveillance of antibiotic use and resistance. There is a lot of momentum building globally on advancing in-country surveillance and innovation around tracking and transmission interruption. These include the Global AMR collaboration Hub in Germany (focusing on new drug development), SEDRIC (surveillance and epidemiology of drug resistant infections consortium), a new initiative funded by Wellcome Trust aimed to provide technical expertise and knowledge to address barriers with a focus on bringing new technology to bear on big data. In addition the Gates Foundation has contributed in numerous ways, including Grand Challenge Grants

When antibiotics don't work any more: Maryn McKenna's TED Talk

Maryn McKenna is a public health journalist whose stories, books and posts have been important for explaining antibiotic resistance to those not already immersed in its study. Her TED talk from last spring just became available - well worth the listen. If you want to read more, head over to her 'new' blog at National Geographic: Phenomena: Germination.

On penicillin

Today, we have a guest post by Philip Lederer, an Infectious Disease fellow at Massachusetts General Hospital and Brigham and Women’s Hospital, and a former Epidemic Intelligence Service Officer at the Centers for Disease Control and Prevention (CDC). His views do not represent any of those organizations.

Bright and alert, the elderly woman sat in a chair in the corner of her hospital room. Snow fell lightly outside. An IV ran into her arm, giving her antibiotics for a bloodstream infection. Meanwhile, she told me her story:

“I started nursing school in 1943 and soon after we first started giving penicillin. I don’t remember my first patient who got it, but we ended up giving it to many people. We didn’t realize at the time that penicillin would turn out to be so amazing. What I remember most clearly was the size of the 18-gauge needle we used. It was so big. We had to inject intramuscularly, into the patients’ buttocks, every four hours. It would turn their buttocks black. And the injections were so painful. 

When I would walk into a patient’s room, I would think, ‘Oh God, do I really have to do this again?’ 

But before penicillin, people died, and afterwards, they lived. The patients loved it and hated it at the same time. It was wonderful and horrible.”

Now, more than seventy years later, we are heading towards an era of untreatable bacterial infections. The penicillin miracle may someday be a memory. As an infectious disease physician-in-training, I see antibiotic resistant bacterial infections every day. I believe the writing is on the wall.

While the Centers for Disease Control and Prevention (CDC) and the White House have issued reports and launched initiatives, little is changing in the trenches, our hospitals and clinics. Antibiotics are prescribed widely and often carelessly. There are no easy solutions, other than a wholesale change in the practice of medicine and an emphasis on antibiotic stewardship.

$1.2 billion Requested for Antibiotic Resistance!

You don't tug on superman's cape
You don't spit into the wind
You don't pull the mask off the old lone ranger
And you don't mess around with Jim

-Jim Croce

Most days, controlling the spread of antibiotic-resistant bacteria in hospitals feels like fighting with one hand tied behind our backs, or spitting into the wind or...  For example, we have very little control over whether patients are colonized or infected with antibiotic resistant bacteria on admission. It's not like we can move a hospital from the high-prevalence East Coast to the low prevalence Upper Midwest. And once resistant bacteria become endemic in our region/hospitals, we have few reliable evidence-based interventions to prevent patient-to-patient transmission.

So, it's with some trepidation that I began reading the President's proposal to provide extra funds to tackle antibacterial resistance. Would there be any funds for infection prevention? When discussing past initiatives, we've remarked on how little attention is given to infection control programs and research. This time, however, things are looking better.

Here's how the $1.2 billion will be distributed under the current plan:

• $650 million to the NIH and the Biomedical Advanced Research and Development Authority to expand development of antibacterial drugs and diagnostics
• $280 million for CDC-led efforts to curb overprescribing of antibiotics and track outbreaks of drug-resistant infections
• $47 million would go to FDA to evaluate new drugs and monitor livestock antibiotics use
• $77 million to USDA to help develop alternatives to the antibiotics used in farm animals
• $75 million to DoD and $85 million to VHA to focus on reducing antibiotic-resistent infections in health care settings 

This is a well thought-out list and is very close to how I would wish to distribute the resources. I would perhaps request a bit more for CDC to study HAI prevention interventions in addition to stewardship efforts; however, this extra-funding, while long overdue, is on target. I'm also encouraged that the President is asking for increased funds and not reducing other critical research in infectious diseases like HIV, TB and malaria. Let's just hope Congress can approve this request and it's renewed annually. It will be nice to get back to work preventing HAI - this time with two hands and a mask to keep the spit off our faces.

WHO: Antimicrobial Resistance

Last week the WHO released a report covering global surveillance for antimicrobial resistant bacterial pathogens. The report starts off by highlighting the major gaps in knowledge about the magnitude of the MDR-bacterial problem and suggests that the post-antibiotic era is a very real threat. While the levels of resistance in the report are very alarming, the authors also note that worldwide surveillance lacks coordination, so it's likely we're only seeing the very tip of the iceberg.  One interesting aspect of Dr. Fukuda's introduction was his acknowledgment that TB, malaria and HIV have much better surveillance systems and should serve as models for MDR-bacterial surveillance.

The report focuses on "nine" bacteria-drug combinations: E coli vs 3rd gen. cephalosporins and fluoroquinolones,  K. pneumoniae vs 3rd gen. cephalosporins and carbapenems, MRSA, S. pneumoniae vs. penicillin, nontyphoidal Salmonella and Shigella vs. fluoroquinolones and N. gonorrhoea vs. 3rd gen. cephalosporins.

I think the take home point is summed up in the reports Figure 1, which I've pasted below.  No new antibiotic classes since 1987. We can safely say that the bacteria didn't take a 30-year break while we rested on the laurels of the prior generation(s).

The report is 232 pages long, so you have two options if you want to learn more: (1) Head over to the WHO website and read the whole thing or (2) Listen to my 15-minute interview on Iowa Public Radio from last week. Just click on the audio player below or head over to IPR's page and listen there.



For additional reading on the US burden of antimicrobial resistant bacteria:

1) Sievert DM et al. ICHE January 2013 (2009-2010 NHSN Summary)

2) CDC 2013 Antibiotic Resistance Threats Report

State of Antibacterial Resistance in the Union

President Obama delivered his State of the Union address last night. The event is always an interesting spectacle. I enjoy seeing who stands, sits and claps during specific parts of the speech. Several sections really piqued my interest and I've pasted them below. I suspect this is the first time a President has used drug-resistant bacteria in such a high-profile speech. Perhaps this is an important milestone or tipping-point. One can hope.

"Listen, China and Europe aren't standing on the sidelines; and neither -- neither should we. We know that the nation that goes all-in on innovation today will own the global economy tomorrow. This is an edge America cannot surrender. Federally-funded research helped lead to the ideas and inventions behind Google and smartphones. And that's why Congress should undo the damage done by last year's cuts to basic research so we can unleash the next great American discovery. (Cheers, applause.)"

"There are entire industries to be built based on vaccines that stay ahead of drug-resistant bacteria or paper-thin material that's stronger than steel. And let's pass a patent reform bill that allows our businesses to stay focused on innovation, not costly and needless litigation."

Reference: Washington Post's full-text of President Obama's SOTU address

Resistance versus Virulence

The conventional wisdom is that bacteria pay a “fitness cost” as they accumulate antibiotic resistances, a phenomenon I discussed in a short post last year. More resistant, but less fit, and (one hopes) less virulent. Thus some of the most problematic multi-drug resistant organisms (MDROs), such as Acinetobacter, cause disease almost exclusively in the most vulnerable patients—those bugs simply aren’t virulent enough to wreak their havoc in the healthy. When an MDRO does emerge as a major community scourge, as was the case with community-associated MRSA, it’s big news.

So I was surprised (not pleasantly) to read this report in PNAS about Pseudomonas aeruginosa strains that refused to adhere to convention. Using a mouse model and well-characterized P. aeruginosa mutants, the investigators found that strains with mutations in a gene encoding a particular outer membrane protein (one that provides an entry channel for carbapenem antibiotics) were more virulent—more likely to disseminate from the mouse GI tract, and more resistant to in vitro killing by acidic conditions or human serum. Now mice are not men, and a murine gut colonization model isn’t necessarily predictive of an organism’s ability to cause infection at various human body sites. Still, it is nerve-wracking to know that our carbapenem use might produce P. aeruginosa strains that are not only more resistant, but also more virulent! As the title of the accompanying editorial points out, it is indeed a “worst case scenario”.

Scanning EM of P. aeruginosa from the Public Health Image Library

Guest Post: IDWeek in Review

This is a special guest post by Dan Morgan, MD MS. He's an assistant professor at the University of Maryland, Baltimore.

After a hectic few days of conferencing at IDWeek I’m looking forward to my more hermit-like routine. Although fields of knowledge tend to advance relatively slowly, this IDWeek was inspiring for a number of interesting ideas emerging in hospital epidemiology. Although I'm sure I missed most of what happened while I was talking in the hallways or waiting in the lunch line, I'm still mulling over a few ideas on flights back to the East Coast that I would like to share.

Antimicrobial-resistance is increasing. This is a worldwide phenomenon in which what happens in one country affects other countries. This is an issue in the hospital with carbapenem-resistant enterobacteriaceae and Acinetobacter and although declining, MRSA is still a large problem. The community also is critical, holding a huge burden of resistance not only in MRSA but gonorrhea and other sexually transmitted infections, along with other pathogens like malaria and TB.

Manipulation of the microbiome is beginning to be seen as a therapeutic target. The remarkable experience with fecal transplants was frequently mentioned and a neater, cleaner method for taking a pill containing poop to populate the colonic microbiome is under evaluation in an ongoing trial in Canada from Thomas Louie at colleagues. Beyond C. difficile, nasal MRSA decolonization through microbiome manipulation was discussed by Mary-Claire Roghmann and the exploratory papers on obesity and other non-infectious diseases was reviewed by Bob Weinstein.

Public policies to promote HAI prevention were hailed as a success in a video presentation from Denise Cardo, and regardless of ones perspective, as stated by David Calfee and Brad Spellberg, public reporting of process measures and outcomes is here to stay.

Infection prevention outside the hospital was highlighted in multiple sessions. From debates on contact precautions in nursing homes, interventional studies by Lona Moody showing a benefit secondary to improved attention to standard infection control in long-term care facilities, and Mary Hayden's presentation on a bundle to prevent CRE in LTACHs.

Methodology of infection prevention studies is improving. Multiple cluster trials were discussed (those above by Mary and Lona and the BUGG study by Anthony Harris—full disclosure, I was a co-author with Anthony on this study) and methods to perform more rigorous quasi-experimental and pragmatic studies were well described by Jessina McGregor, Ebb Lautenbach and Marin Schweitzer in an advanced epidemiological session.

Technology is improving but several technologies (e.g interventions for room cleaning (Curtis Donskey) or hand hygiene (Kal Gupta)). However, when they are ready for prime time they will need to be integrated appropriately as one part of healthcare epidemiology.

Chlorhexidine patient bathing is the new black. After recent NEJM papers by Susan Huang, Mike Climo (and most other luminaries in healthcare epidemiology) there seems to be a move towards widespread adoption in the United States. At IDWeek, CHG was also presented as potentially beneficial for CRE prevention in LTACHs and despite nervousness around FDA warnings, is being used in NICUs. Some expressed concern for the possibility for future decreasing susceptibility to CHG.

Shutdowns have an effect! A power outage on Saturday ended some sessions early but the more remarkable shutdown was federal. Notable were the absences of organizer Scott Fridkin and many leaders who work for the CDC or VA. The rapture realized!