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.

KPC, CRE, MDR-GNR: Call 'em what you will, but call for a national response!

There is an early release MMWR out today describing the recent trends in carbapenem-resistant Enterobacteriaceae (CRE) using data from the CDC's National Healthcare Safety Network (NHSN) and the Surveillance Network–USA (TSN). CRE infections, such as UTIs or intra-abdominal infections, cannot be treated with currently available antibiotics. The results of the MMWR study are not surprising - there are more CRE now - yet I find them rather chilling.

The proportion of Enterobacteriaceae that were CRE rose from 1.2% in 2001 to 4.2% in 2011 in NHSN hospitals and to 1.4% by 2010 in TSN facilities. In Klebsiella species, the situation is dire with 10.4% classified as CRE in 2011. By 2012, 4.6% of all facilities, 3.9% of short stay hospitals and 17.8% of long-term acute-care hospitals reported at least one CRE in their facility.

So things are pretty bad, at least 17.8% bad.

What can we do about this? This is what they say in the abstract: "Interventions exist that could slow the dissemination of CRE. Health departments are well positioned to play a leading role in prevention efforts by assisting with surveillance, situational awareness, and coordinating prevention efforts."

Which interventions? Certainly there are no evidence-based interventions, unless we call an uncontrolled quasi-experimental study evidence. The CDC authors made reference to VRE control efforts in the Siouxland, MRSA control efforts in The Netherlands and CRE control efforts in Israel. I think these are poor and overly optimistic comparisons for several reasons. For one, the first two efforts targeted Gram-positive bacteria and it's unclear if we can extrapolate these to control efforts targeting MDR-GNRs.  For example, we have effective antibiotics for VRE and MRSA (quinupristin/dalfopristin-approved in 1999; linezolid-approved in 2000, daptomycin-approved in 2003) but not for CRE.  Additionally, we can decolonize for MRSA but not CRE.

However, the most important aspect of the Netherlands and Israel examples were that they instituted NATIONAL RESPONSES aimed at MRSA and CRE. There are no such national efforts here in the US targeting CRE. This is what we have in the US per the MMWR report: "six states have made CRE reportable, and three additional states are actively pursuing this option." This is not a national response. This is a national tragedy. We can't expect CDC to say they can't handle the problem and we can't expect states to say they can't handle the problem. They are working their butts off with minimal support and no national will for a coordinated response. If we don't have a national response soon - it will be too late, but I'm not holding my breath.

I will leave you with an excerpt outlining the Israeli national CRE response from Mitch Schwaber's excellent report in CID. Do you think we have anything close to this going on here in the US? Me neither.

Update: Looks like NPR's "All Things Considered" will post an audio discussion of the CRE issue around 7pm ET here.

(Updated!) What you missed in Infection Prevention: December 6, 2012

1) Today's NEJM has lot's of interesting stuff.  First up, they have a review of the first cases of fungal infections associated with contaminated methylprednisolone injections in Tennessee. The report covers 66 case patients with 21 having confirmed Exserohilum rostratum infection and 1 having confirmed Aspergillus fumigatus infection.

2) Next up, NEJM has a perspective piece from the FDA that highlights infections secondary to contaminated antiseptic products including iodophors, alcohol products, CHG and quaternary-ammonium compounds.

3) And finally from the NEJM, Thomas Sandora and Donald Goldmann have a perspective piece outlining their suggestions for preventing hospital outbreaks of antibiotic-resistant bacteria. Most of what they offer is standard infection control dogma from the  - it's the healthcare worker's fault for not washing his/her hands diatribe - to the suggestion that a "parsimonious set of interventions aimed at reducing exposure to antibiotics may have the greatest effect on resistance." They even included a table of the suggested parsimonious stewardship interventions (below). I don't believe that any are backed by more than uncontrolled quasi-experimental studies or expert opinion. (Please correct me if I'm wrong!) Might they have recommended funding studies of these interventions instead?  It's hard enough to be a hospital epidemiologist in 2012 marketing the few evidence-based interventions at our disposal without laying the burden of making us defend interventions based on pure speculation on our backs.  Oh well.

4) There is a report in today's Ottawa Citizen by Helen Branswell that nicely outlines two NDM-1 outbreaks that occurred (October 2011 and January 2012) in Toronto. The article covers an study published in ICHE and another in CID. The latter described the transmission of the NDM-1 between E. coli and Klebsiella species in the same patient.

5) Last-but-not-least, check out this story in NPR that highlighted an innovative research study out of Michigan State University. Researchers modeled the spread of murders in Newark, NJ as an infectious disease and discovered that murder appears to be transmissible like an infectious pathogen. They are now figuring out why some neighborhoods are more resistant to homicide and how they might "vaccinate" populations to reduce murder. Pretty cool and Go Sparty!

NDM-1's knocking at the door, Let 'Em In

This weeks MMWR has a report from Len Mermel's group of a patient initially hospitalized in Viet Nam. Upon readmission earlier this year to a hospital in Rhode Island she had a Klebsiella pneumoniae containing NDM-1 recovered from a urine specimen. The isolate was only susceptible to tigecycline, and the polymyxins.

Extensive surveillance testing was completed and one patient admitted to the same hematology-oncology unit grew an NDM-1 containing K. pneumoniae isolate from a rectal surveillance swab.  This isolate was indistinguishable from the index patient's isolates by PFGE, confirming patient-to-patient transmission.

Dawn of the age of untreatable infections? NDM-1 in India

"There is a tsunami that’s going to happen in the next year or two when antibiotic resistance explodes" - Abdul Ghafur, an infectious diseases physician in Chennai

Jason Gale and Adi Narayan have a feature article in this June's Bloomberg Markets discussing the rise of NDM-1 in India.  It's well researched and organized and does a nice job highlighting the human tragedy that's in our midst. There are quotes from Bob Moellering, Donald Low, Tim Walsh, Lindsay Grayson, David Livermore, Keith Klugman, and several clinicians and scientists in India that have been directly involved in NDM-1 discovery and treatment including Chennai microbiologist Karthikeyan Kumarasamy, who helped discover NDM-1.  Overall, this is a great resource for the intro to any NDM-1 or Gram-negative resistance talk.

I agree with CDC's Tom Frieden when he says that "we need to have good surveillance and ... we need to have good antibiotic stewardship," but I think we really need more than that. The article finishes with a quote by David Livermore who says "“Combine sophisticated medicine, poor sanitation and heavy antibiotic usage, and you have a rocket fuel to drive the accumulation of resistance...That surely is what India has created.”

Sure NDM-1 is in India but the problem of Gram-negative resistance is a much larger, non-border controlled, issue. Wasn't KPC first detected in North Carolina?  If we point (and then focus on) fingers, we miss the larger picture - Bruce Lee's Enter the Dragon? We need large investments in antibacterial discovery and infection prevention research and we need to build back up our public health infrastructure in the US. We're in this together.

h/t Jan Kluytmans

Addendum: I was concerned that Gale's well-written article would be used to point fingers and not pressure people to find solutions.  It seems that the first tweets from Bloomberg Markets are playing on fear and trying to scare people away from medical tourism in India.  It's too bad that articles like this can't be used to make a case for a coordinated response to the MDR-bacterial threat we face. I hope further discussion of this article takes a more long-term view.

Addendum #2: Now this editorial by the Bloomberg Editors is more like it. Although they still seem to miss that emergence is not limited to places like India with poor sanitation. KPC emerged in the US and MDR-Acinetobacter is alive and well on the East Coast.  If you haven't read it, Andrew Moore's 2003 story of the FDA's failure to approve magainin, is an amazing look into the barriers to antibacterial discovery.

Addendum #3: Listen to author Jason Gale discuss India's special place in the emergence of antibacterial resistance on PRI's The World. He says that "when you look at the drivers of drug resistance, India pretty much ticks every single box"

No NDM-1 in Healthy Mumbai Population! But ESBL in 24%

A Mumbai group screened 1000 consecutive fecal samples in healthy outpatients collected from January to June 2011 for carbapenem resistance using standard methods. In all samples, none were carbapenem resistant.  However, they found 227 E coli and 12 Klebsiella species that were ESBL producers. Compared to their 2004 study that found ESBL in 11% of healthy people, the increase to 24% is pretty alarming.  So good news and bad news in the same report. Just one comment: The same Mumbai group reported significant numbers (49 isolates) of NDM-1 containing Gram-negative bacilli in a study that included 310 carbapenem-resistant bacteria collected from Sept 2009 to May 2010.


Source: Deshpande et al. J Antimicrob. Chemother 2012.

100 to 200 Million with NDM-1 in India

Dr. Timothy Walsh, Cardiff

We've continued to follow the emergence of NDM-1 around the globe.  A recent interview in the Times of India that Tim Walsh gave was an interesting read and very concerning.  Walsh is the lead author of the recent Lancet ID paper that Dan commented on earlier this year which reported NDM-1 bacteria in 4% of drinking-water samples and 30% of waste-water samples in New Delhi.

Most concerning was his suggestion "that the carriage rate of NDM-1 in India is between 100 and 200 million" people.  Crazy.  The interview is a great read since he pulls no punches.


Source: Times of India, October 9, 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

NDM-1 in a US Military Hospital



source: wikipedia

Maryn McKenna has an interesting take on the MMWR report of NDM-1 in a US military hospital in Afghanistan. The patient had NDM-1 containing Providencia stuartii in a blood isolate collected early in 2011. This is the first case of NDM-1 in P. stuartii and in a US military hospital.  The parallels she draws to previous Acinetobacter infections in military hospitals are interesting. However, I'm not sure you can compare a specific species (Acinetobacter) to a plasmid-borne metallo-ß-lactamase (NDM-1), which can hop from species to species.

Either way, we will eventually need to beef up surveillance, infection prevention research and antibacterial drug discovery.  GNRs are not going away. I suspect the worldwide response to the many MDR-bacterial threats is going to require a significant reorganization and renewed focus (e.g. 1940s and 1950s) on how we fund these efforts. The days of nickel and diming these efforts, are coming to a close...

Staring into the abyss: MDR-GNR edition

We’ve been following the emergence and global spread of the New Dehli metallo-beta-lactamase (NDM-1). The latest chapter of that story came out today in Lancet Infectious Diseases, in a fine example of the newly named field of pharmacoecomicrobiology (say that three times fast!). Tim Walsh and colleagues sampled tap water and wastewater from the epicenter (New Dehli) and from Cardiff, UK. They found NDM-1 positive bacteria in 4% of drinking water samples and 30% of wastewater samples in New Delhi, but none in Cardiff. More alarmingly, they found this highly mobile resistance gene in a wide array of pathogenic bacteria. In addition to the Enterobacteriaceae (in which it has already been described), they found stable carriage of NDM-1 encoding plasmids in Aeromonas, Shigella and Vibrio cholera. Susceptibility testing confirmed phenotypic expression, revealing resistance to broad spectrum cephalosporins and carbapenems. On one hand, this is quite predictable (and furthermore, we know that even short-term visitors to an area of endemic resistance for gut bacteria will carry that resistant flora back home). On the other hand, it speaks to the inevitability of our new post-antibiotic era. This era has already begun, and will proceed incrementally as we see the steady loss of antibiotic classes we once referred to as “last-resort”.

David Livermore fights NDM-1, the 'super' superbug

David Livermore and NDM-1

There is a new story at MSNBC.com highlighting David Livermore, NDM-1, and the myriad of reasons for the expansion of MDR-bacteria and hospital infections: little investment in antibiotic discovery and infection prevention.  I like this quote from the article in regards to infection prevention: "If it is done properly, it can ease the demand for drugs in the first place."  Dr. Livermore is the Director of the Antibiotic Resistance Monitoring & Reference Laboratory (ARMRL) at the HPA Centre for Infections in London. The story is surprisingly well-written, includes the usual human-interest angle and quite long but worth a read.

h/t Mark Vander Weg

Weekend Links or WeekeLinks?

Jackie Robinson Rotunda - Citi Field

Pretty busy around here.  I just gave a talk on seasonal variation in hospital pathogens at the ID research conference this morning.  I saw Dan there.  He is alive, but on service. I think he had 12 consults one afternoon.

We're moving to a new research building next week here at the Iowa City VA, so I'm busy packing up the stuff that I unpacked only 5 months ago when I arrived.  The building is called "Building 42."   42 is Jackie Robinson's uniform number.  Those of you that have seen my old office will remember the Jackie Robinson poster that I had hanging next to the Jim Henson-Kermit poster.  I think I will call the building the 'Robinson Building' or maybe just 'Jackie'.

Here are some interesting posts for your weekend reading pleasure:

1) Pig-Borne ST-398 S. aureus infection (France) - Clin Infect Dis

2) FDA and the 29-million pounds of livestock antibiotics - Maryn McKenna Superbug blog

3) First 2 cases of NDM-1 in S. Korea

4) Clinical outcomes in HAIs and antibiotic resistance in European ICUs (Lancet ID)

NDM-1 in the US (Boston, California and Illinois)

MGH - where one NDM-1 patient was treated

Out of ICAAC there is a report of three carbapenem-resistant (NDM-1) cases in the US, all of whom had medical care in India prior to travelling to the US. Per a Tribune article, "the three U.S. cases involved three different bacteria that remain susceptible to at least one of three antibiotics: colistin, polymixin and tigecycline, said Karen Bush, an Indiana University professor..."  If you'll notice, the reports all call NDM-1 a 'superbug.'  I find this funny since NDM-1 isn't even a bacteria but a gene that can be found in several pathogens, as described in this ICAAC report.  Anyway, gotta feel bad for MRSA.  Just when it let its guard down, this new guy just takes over.  Kinda like what Nadal has done to Federer.

Boston Globe Article
Chicago Tribune Article

Update:
NDM-1 MMWR report from June 25 (thanks to Maryn McKenna for the tip)

More on NDM-1s

A few weeks ago, Eli blogged on the emergence of NDM-1 producing Enterobacteriaceae in Asia. Now, 3 patients with the organisms have been detected in Canada. You can read about it here.

NDM-1 containing Enterobacteriaceae

With yesterday's report suggesting a decline in MRSA, it is now time to switch gears and panic about other organisms. As Dan said so well yesterday, "MRSA isn't the only bug out there, it's just the most famous." Today's report is from Lancet ID by researchers in UK, Pakistan and India on a novel resistance mechanism in Gram-negative bacteria called the NDM-1. NDM-1 stands for New Dehli metallo-B-lactamase 1. I guess when you name it "1" you are expecting a "2" and maybe a "3". Even the Great War wasn't called WWI until World War II started or at least ended.

The report is very nice and includes background information discussing the rise of various resistance mechanisms in GNR including ESBLs (CTX-M-15) and KPCs. The group initially discovered the NDM-1 containing resistance gene in a patient in Sweden after the patient returned from a hospital admission in New Dehli. This new report includes descriptions of isolates collected in Chennai (south India), Haryana (north India), UK and other areas in India, Bangladesh and Pakistan. Little information is given as to how the samples were obtained. After initial screening, all isolates were tested for presence of the bla(ndm-1) by PCR.

As an example of the results, from Chennai there were 3521 isolates of Enterobacteriaceae screened with 141 (4%) resistant to carbapenems. 44 of the 141 were NDM-1 positive, which is about 1% of all of the isolates. Most were E coli (19), K pneumoniae (14) and E cloacae (7). By 2009, NDM-1 strains were the dominant carbapenemase-producers in the UK. In most isolates NDM-1 was carried on plasmids although 3 UK isolates carries the NDM-1 on their chromosome.

All of this is quite concerning. It is not this specific gene/mechanism that's troubling, it's the constant introduction and spread of many different types of resistant GNRs in our inter-connected world. Look at the figure. The chickenpox spread of NDM-1 that now covers India and the UK will soon spread to Germany, the US and beyond. While we have new classes of antibiotics recently introduced that are active against MDR-Gram positive bacteria, we have very few new classes in the pipeline that are active against GNR. When the US Surgeon General, Dr. William H Stewart said in the 1960's that it was "time to close the book on infectious disease" and/or "the war against infectious diseases has been won", he probably wasn't thinking about Gram negative bacteria.

Lancet ID article

link to newer NDM-1 post