$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.

...at least she didn't die of MRSA

For the past six months our group at Iowa has been collaborating with colleagues at the University of Utah on a project for CDC. We are tasked with measuring the burden of MDRO using systematic reviews to inform economic models that will project MDRO incidence and attributable cost over the next 20 years. We are studying pathogens like C. difficile, VRE, MRSA, ESBL-GNR and CRE. It's a tall order, but we expect that CDC and others will use these estimates to guide funding for research and prevention efforts. Since bacterial pathogen research is so widely underfunded compared to their burden of disease, these new estimates can only help.

But, it has occurred to me that the planned approach of estimating the burden of disease using pathogens typically categorized as MDRO, such as CRE and MRSA will result in serious underestimates of the bacterial pathogen burden and lead to perpetuating the chronic underfunding of our research and prevention efforts. A simple way of demonstrating the impact of neglecting susceptible bacteria is to focus on S. aureus. One widely cited estimate of yearly MRSA mortality burden is 18,650 in-hospital deaths. Ignoring secular trends and community deaths, while assuming 50% of S. aureus infections in the US are MRSA (and thus 50% are MSSA), we might estimate that S. aureus kills 37,300 people annual in the US. This would place S. aureus (one bacteria!) ahead of traffic deaths and rank it as the #11 cause of death in the US (see table below). Imagine if we included "susceptible" (and resistant) bacteria like E coli, Klebsiella and Streptococcus in a total bacterial burden estimate!

For those that will argue that we have effective antibiotics for MSSA, so that it's unimportant, I offer several counterpoints. First, people die of "susceptible" bacteria (18,650 MSSA!) and we don't fund HIV research based on mortality burden for only protease inhibitor resistant strains. Second, even strains we call susceptible are actually resistant to numerous classes of antibiotics - most MSSA is actually PRSA and try treating enterococcus with a cephalosporin. Third, by ignoring susceptible strain burden, we underinvest in strategies that could treat or prevent all infections, not just arbitrarily defined resistant ones. For example, S. aureus vaccines could prevent both MSSA and MRSA infections. If NIH (or CDC or ECDC) uses only MRSA burden to guide funding of S. aureus vaccine research, they would underfund by 50%.

You get my point, but I will leave you with my final reason for recommending inclusion of "susceptible" strains when measuring burden of disease for bacterial pathogens. Imagine if your aunt is very sick with an MSSA prosthetic hip infection in the ICU. And then imagine if the doctor comes to inform your family that she is very sad that your aunt has passed away, but adds... "at least it wasn't MRSA." Does that make you feel any better?

beer image: source

NIGHTMARE BACTERIA coming to your PBS station October 22nd!

It's not quite the Zombie Apocalypse, but these carbepenem-resistant nightmare bacteria are clearly the next scariest thing. PBS's Frontline seems to think so. Producer/Writer/Director Rick Young has pulled together a 1-hour investigation into antibacterial resistant infections including (it appears) NDM-1 and the NIH CRE outbreak. From the promotional material it also seems that the program will touch on the lack of investment in drug discovery in addition to excess use, as causes of the epidemic. Remember, check your local listings.

NIH KPC Outbreak - The Final Word?

We've covered CRE extensively over the past couple of years.  Never so extensively as we did when the 2011 NIH KPC outbreak was first publicized last August following the whole-genome sequencing report in Science Translational Medicine. Almost a year has past since that report and kerfuffle, so it is nice to see that Tara Palmore and David Henderson have found the time to share their experiences controlling the outbreak and the media storm that followed the publication of the original manuscript. They decided to label the section on the public reaction the "Unintended Consequences of Publication." This title is very disturbing, as it highlights why many outbreaks like these are never reported - publication bias. I'm glad they weren't afraid to publish again, so that we can all learn for this difficult outbreak. The report is freely available in PDF over at CID. I'll stop writing and let you get on with your required reading.

Nothing to see here, please move along

It's been a quiet week out here on the edge of the blogging prairie. Some of us are recertifying, some are in the middle of huge grant deadlines and some are chairing a giant meeting planning committee with the meeting imminent. But, we still think about you every second and we miss providing you with up-to-date infection prevention information...

In the interim, we have created a little poll off to the right, which you can use to let us know how you like to read or follow the blog.  Vote early and often.

From the nothing to see here column: We've heard new reports that the NIH KPC outbreak that was halted by whole-genome sequencing is back. On September 7th there was a new case of the KPC strain, the first since January and 19th overall. The blood stream infection resulted in the unfortunate death of boy from Minnesota, the seventh fatality attributable to the strain.

NOW SEE THIS: Registration for ScienceOnline2013 is now officially open. It's the seventh annual un-conference exploring science on the Web and takes place Jan. 30-Feb. 2, 2013, in Raleigh, NC. Registration for the first round of 100 slots is closed for today, but there are two more opportunities to register: Thursday, Sept 20, 2012 at 2:00 PM (EDT) and Friday, Sept 21, 2012 at 11:00 PM (EDT). By rumor I heard that these sessions last only minutes, so log on near those start times and keep refreshing your browser. All seems pretty exciting.

The Rise of the MIC: Microbiological Industrial Complex

Mike "Alexander" Edmond

Note: This is the post I wanted to write regarding the NIH Clinical Center KPC outbreak last week until I noticed the posts and comments blaming the front line infection prevention staff.

"...we must guard against the acquisition of unwarranted influence, whether sought or unsought, by the military-industrial complex (MIC). The potential for the disastrous rise of misplaced power exists and will persist....As we peer into society's future, we-you and I, and our government-must avoid the impulse to live only for today, plundering, for our own ease and convenience, the precious resources of tomorrow. We cannot mortgage the material assets of our grandchildren without risking the loss also of their political and spiritual heritage." - President Eisenhower's Farewell Address January 17, 1961

In microbiology and clinical medicine, the MIC is the "lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation."  I think it's time to recognize a new definition for MIC: the Microbiological Industrial Complex. The MIC encompasses the industry, associated lobbying efforts and government agencies that most benefit from the adoption of expensive and unproven testing and treatment. The MIC has had a tremendous impact on infection prevention practice through economic forces pushing for MRSA active surveillance mandates and perhaps mandatory flu vaccinations of health care workers. This MIC leads to the utilization of expensive (and largely unproven) interventions at great cost both economically and to the well-being of patients.  The more we spend on expensive sequencing, the less we can spend on actual prevention. Hand hygiene might not be sexy, but it does more to prevent the spread of resistant infections than any PCR test.

The latest evidence of the insidious rise of the MIC is the initial discussion surrounding the NIH Clinical Center KPC outbreak. So far, the only paper describing the outbreak covered the miracle of whole-genome sequencing and how it helped halt the outbreak, which it most certainly did not. The outbreak was halted using a grab bag of unproven and expensive interventions including the hiring of 9 hand hygiene "police" that monitored infection control practice 24-7.  Even NIH's Henry Masur speaking today on the Diane Rehm show said that sequencing "didn't conclusively prove" (what caused the outbreak).  Both he and Jule Segre suggested they only stepped up their infection control efforts because of the whole genome sequencing evidence, which is almost certainly not true. They would have used infection control escalation even without expensive testing. (listen to the Diane Rehm show segment here)

To understand the power of the MIC, you don't have to look further than a recent MSNBC report, which noted that the NIH sequencing cost $40,000 and suggested that this technique could spawn a $1 billion industry in the US alone. In discussing the whole genome technique, Dr. Segre was noted to say "When you have patients in your ICU who just paid $100,000 for an organ transplant,"...spending a few thousand dollars to protect them from an outbreak of deadly bacterial infections "doesn't seem like too much to ask."

It seems to me that since there is no evidence that whole genome identified the source of transmission here or elsewhere and even if it did it wouldn't have altered the course of the outbreak, we might better spend our infection control research and clinical dollars elsewhere.  Unfortunately, the MIC has more money and more NIH backing. The NIH has a National Human Genome Research Institute but it doesn't have a "National Infection Prevention Institute", for example.

Almost a year ago, Mike peered through his crystal ball and accurately predicted the future of KPC prevention in the US.  The NIH outbreak and report starts the countdown, and much like MRSA before it, the prevention efforts will be focused on expensive DNA surveillance efforts backed by large industry lobbying efforts and not investments in the research and expansion of basic and simple infection control efforts. It is easy to blame the healthcare worker for not washing their hands and look for a quick scientific panacea (DNA). Sadly, given that there have been only four high-quality hand hygiene improvement studies since 1980, we haven't provided clinicians with the proven tools to improve hand hygiene. If we continue to bow to the pressure of the MIC and avoid the harder tasks of infection prevention, we will be squandering our precious resources of tomorrow (antibiotics), as Eisenhower warned 50 years ago.

Further Reading:
(1) Maryn McKenna: The ‘NIH Superbug’: This Is Happening Every Day
(2) Ed Yong:  Genome detectives unravel spread of stealthy bacteria in a hospital
(3) Dr. Judy Stone: The NIH Superbug Story-A Missing Piece
(4) Mike the Mad Biologist: Some thoughts on the CRE Superbugs

Image source: wikimedia commons

Not a failure, a lesson. The NIH KPC Outbreak

Mike posted about this yesterday and I'm sure we'll have more posts concerning the deadly KPC outbreak that occurred last year at the NIH Clinical Center. Since the whole report is behind a paywall (why is that??), I thought I'd describe the interventions taken to control the outbreak and also let you peruse the description of the 18 cases and 11 deaths (See table below).

The kitchen sink: the problem
and the current solution

Infection control measures used:
1) Index patient placed on enhanced contact isolation on admission.
2) All ICU patients during the outbreak were placed on universal enhanced contact precautions during their entire stay
3) A wall was built in the ICU, so that all KPC+ patients could be placed in a new six-bed unit
4) Infection control compliance monitors were hired (peak use was 9 monitors) who ensured that all healthcare workers entering the rooms practiced enhanced contact precautions and hand hygiene. Suboptimal monitors were fired
5) A private firm was hired to decontaminate the ICU and all KPC+ patient rooms using hydrogen peroxide vapor
6) Staff were cohorted so that staff did not care for both KPC+ and KPC negative patients
7) When the KPC was found in a sink, they tore out the plumbing
8) Active surveillance culturing using rectal and throat swabs was utilized

What an amazing effort by Tara Palmore and others at NIH. Why did it take so long to control the outbreak? It's not their fault. I was in a similar situation with an acinetobacter outbreak in 2002. What I faced in 2002 and what Dr. Palmore faced last year is that there is almost no science behind infection prevention interventions. We literally don't know what works or where in works. What this outbreak demonstrates is what happens when you make little investment in infection control science in decades. We don't know how to prevent these outbreaks, so we throw the kitchen sink (literally in this case) at them hoping something works.

Not every hospital can afford to undertake all of the expensive construction and staffing interventions that the NIH did, especially since it isn't clear what works and what doesn't. Unless we make serious efforts in understanding the science behind hand hygiene compliance improvement, optimal use of contact isolation, environmental cleaning and other "unstudied" areas, this scene will continue to be repeated over and over again. These outbreaks are happening every day in the US and patients are dying (see below). We need science in infection prevention just as much as we need novel antibiotics.  The lesson needs to be that we fund CDC and other agencies to direct the infection prevention studies necessary to prevent and terminate these terrible outbreaks.

The wrong lesson is to blame frontline infection prevention staff for fighting an outbreak with one hand behind their back and not being successful. We need to stop blaming clinicians and start funding the science to assist our infection prevention efforts.  If we won't have novel antibiotics for 10-20 years, we better start getting serious about infection prevention.

NIH Embraces Hand Hygiene - VIDEO!!!

NIH Director Dr. Francis Collins sings "It's So Easy to Clean Your Hands"... and look out for David Henderson's back-up vocals - talent! All done to celebrate the NIH Clinical Center's first Hand-Hygiene Awareness Day.



h/t Monica Páez

Silver lining in rising MDR-N. gonorrhoeae?

We've written about poor funding for MDR-bacterial prevention studies and antimicrobial discovery. In fact, our NIH funding paper with Dan Kwon and Marin Schweizer looking at NIAID support for ESCKAPE-pathogen studies was just published in ARIC. It's a major problem, as there has been almost no governmental or private funding for antibacterial discovery in decades. Don't even get me started on funding for infection prevention studies. Only 4 good studies on hand-hygiene improvement since the 1950's, seriously?

With that background, I read with interest Gail Bolan's (CDC) editorial in this past week's NEJM.  In it she sounds the alarm for resistance in gonococcus based on a recent 17-fold rise in 3rd-generation cephalosporin resistance (cefixime) from 0.1% to 1.7% with higher rates in Western states. (See graph above) This rise in cephalosporin resistance follows sulfa resistance in the 1940s, PCN and TCN resistance in the 1980s, and fluoroquinolone resistance by 2007.

An interesting fact shared in the article is that when resistance to a particular drug class reaches 5%, the CDC's Gonococcal Isolate Surveillance Project(GISP) changes treatment recommendations to a new class of antibiotics. Sadly, only third-generation cephalosporins are left. I wonder if this class switch at 5% is contributing to the rise in resistance?  That question will remain unanswered - no funding. Also, imagine having a 5% threshold in hospitalized patients.  We would have run out of choices years ago!

So what is the silver lining in all of this?  I have a suspicion that politicians and others might be motivated by an STD with an annual incidence of 600,000 in the US. I'm not saying that politicians are at higher risk for STDs, no judging, but STDs put many people at risk, so there will be pressure to respond to this.  The silver lining is that antibacterials designed or discovered that are effective in treating GC will likely have efficacy for other MDR-bacteria, such as Acinetobacter. 

Thus, when Bolan and colleagues suggest that "the immediate priority is replenishing the drug pipeline to treat gonococcal infections," I have hope that people will listen.  There are few grassroots organizations fighting for antibiotic discovery, but there may be soon.  I hope so; our hospitalized patients are counting on it.

Orphan-drug funding crowding out antibiotic discovery?

There's an interesting story today by AP Health writer Matthew Perrone that delves into reasons why little is spent on antimicrobial drug discovery in the US.  His hypothesis is that funding for orphan drugs is crowding out antibiotic drug discovery in the private sector, forcing the US Government into action.  The evidence offered is compelling, including the fact that 11 of the 30 new drugs approved last year were for rare medical conditions, the highest level since FDA incentives began about 30 years ago. These incentives include extra patent protections, higher pricing and a streamlined FDA review. The results speak for themselves: the first new SLE therapy in 50 years and first new Hodgkin's therapy in 30 years.

However, the evidence that this is actually spurring US-government funded antimicrobial drug discovery is weak.  We're offered the somewhat misleading fact that "since 2006, government spending on research for familiar diseases like staph infections, smallpox** and botulism** has increased more than 660 percent, from $54 million to $415 million last year." OK...so what does this have to do with antimicrobial discovery?

To further highlight the dearth of investment in antibiotic discovery, we have this quote from Dr. Anthony Fauci: "We have pushed the envelope more toward diminishing the risk for companies so that they'll be more interested in getting involved with us and developing things like vaccines and antivirals." To be fair, he cold be talking about the mythical Staph vaccine. But seriously, whatever happened to "eschew obfuscation, espouse elucidation"?

The rest of the article highlights new investment in therapies for tularemia and agents of bioterror and new flu-vaccine manufacturing techniques. I had my hopes up for a minute.

**Note: There are on average 110 cases of botulism in the US every year and zero cases of smallpox.  This compares to 19,000 DEATHS from MRSA per year, which would be at least twice that high if we included MSSA. Familar does not equal common.

Source: Matthew Perrone, SFGate (AP) 1/25/2012

Death of the Mid-Career Investigator

Now that we Iowans have failed to select a candidate in the GOP caucuses, we can turn our attention to other political pursuits.  There is an important article just released in PLoS ONE by Kristin Matthews and colleagues at Rice University that describes the aging of the biomedical-research community in the US and its potential impact. 

The authors report that the average age of an NIH investigator rose from 39 to 51 between 1980 and 2008, while the average age of a new (first time) investigator rose from 36 to 42 during the same period. They also make some interesting comparisons to the average age of Nobel Laureates to determine if the rising age barriers at NIH could impact future innovative ideas and research. They found that during the same period, 96 scientists won a Nobel Prize in medicine or chemistry for biomedical research at an average age during the awarded research of 41 and 78% completed their research before age 51. They suggest that scientists do great work early in their careers but now those early careers won't be funded.

They conclude that "if nothing is done to reverse the rising age of PIs and first-time grantees, the scientific community could lose a generation of researchers, leading to an unsustainable biomedical research infrastructure and a dearth of talent participating in NIH-funded projects in the near future." I think a similar problem exists in infectious diseases and infection prevention research.

A world filled with only postdocs  (source Matthews et al PloS ONE)

Thus, there appears to be little funding or opportunity in the early and particularly mid-career period. This results in many fine and well-trained investigators leaving biomedical research in their 40's and never returning. Sure, a few lucky people will survive this pyramid scheme, but there won't be enough senior investigators in 10-20 years to mentor the next generation.

I'm not sure what the solution is or even the exact problem.  Is it ageism in scientific review committees or the lack of tenure-track faculty positions at the University level?  I suspect both of those issues are intertwined.

Source: Matthews et al. PLoS ONE 12/28/2011

Funding for antibacterial resistance research. Not so much.

At least no funding for ESCKAPE pathogen research

I just got back from attending the World HAI Forum in Annecy and the 1st ICPIC meeting in Geneva.  Both great meetings.  I will share my thoughts on the implications of ICPIC in a later post.

Last year at IDSA, Roy (Trip) Gulick stated that there are now 10,000 possible ART combinations for HIV treatment.  When he said that, I instantly got a sinking feeling in my gut.  Right now, there are many people colonized and infected with resistant bacteria for which we have NO EFFECTIVE THERAPY.  Sorry for shouting.  Think about the MDR-Acinetobacter or NDM-1 strains that are circulating.  Pretty soon we won't even have effective therapy for community UTIs.

As I thought about why this might be, I looked for the federal funding picture for antibacterial resistance research, but there were no published data.  So, we found the numbers ourselves.  I presented the data last week and Marin McKenna kindly described our findings at the World HAI Forum on her Wired Superbug blog.  She did a much better job describing our research findings than I could have.  If you're interested in reading about how much NIH/NIAID spends on antibacterial resistance research, head on over to her blog...

UPDATE:  We published these findings in the first batch of articles in the ARIC journal, see: Kwon et al. 2012 ARIC