Riding the epidemic curve to glory, Gram-negative edition

Dan has discussed "riding the epidemic curve to glory" before. This is the phenomenom that occurs when a bundle of interventions is started just as an outbreak is entering the “downhill” part of the epidemic curve. Thus, the outbreak would have ended on its own, even without intervention, yet the hospital epidemiologist and their recommended interventions are incorrectly given credit for the success. This effect has only minor importance when looking at a single hospital outbreak. In that situation, it doesn't really matter why the outbreak ended, but it's sure nice that it did.  However, what if the hospital epidemiologist published a paper outlining the successful control of the outbreak? What if others published similar uncontrolled quasi-experimental studies describing how they controlled other outbreaks? Then it might be a problem, no? I think it could be a major problem since we really need to know that interventions work before we recommend them - we can't always rely on the luck of riding the epidemic curve.

This phenomenon is particularly concerning for me when it comes to control of MDR-gram negative infections. A little more background: Back in 2008 we published a paper in ICHE showing that Gram-negative infections were much more common in the summer (vs. winter). In fact, there were 28% more P. aeruginosa, 46% more E. cloacae, 12% more E. coli and 21% more A. baumannii clinical cultures in summer months. We validated these findings in 132 US hospitals and again found that Gram-negative organisms were more frequent in summer months ranging from 12.2% higher rates for E. coli to 51.8% higher for Acinetobacter spp.

Below I've pasted a figure plotting 8-years of monthly aggregate P. aeruginosa from our ICHE study. What if we waited to start interventions to control our peak in summertime pseudomonal infections until September (Intervention B)? I could then ride the epi curve to glory each fall as I reduced infections by 28%. I could then publish my findings and would be asked to write SHEA guidelines recommending what you should do. On the other hand, what if I tried to get ahead of things every spring and start intervening in May (Intervention A)? What if pseudomonal infections went up 5% over the next three months? In that case, I would be told my interventions didn't work, I wouldn't publish my findings and you'd certainly never let me write a SHEA guideline.

With that long background, I'm excited to report that our findings of summer season and higher temperature associated increases in Gram-negative pathogens have been validated in a recent PLoS One paper by Frank Schwab and colleagues.  In a cohort of patients from 73 ICUs in 41 German hospitals covering years 2001-2012, they examined the monthly incidence of 103,000 Gram-positive isolates (S. aureus, Coagulase negative staphylococci (CoNS), E. faecalis and faecium, S. pneumoniae) and 87,000 Gram-negative isolates (E. coli, P. aeruginosa, K. pneumoniae, E. cloacae, S. maltophilia, S. marcescens, Citrobacter spp., A. baumannii) and their relationship to the ambient temperature in the month isolated and also in the prior month.

They found that 11 of the 13 pathogens had a significant temperature association. Only E. faecalis and S. marcescens were not effected by temperature. All remaining Gram-negative pathogens (and CoNS) were positively associated with temperature, and the strongest correlation was with temperature in the prior month. Thus, higher temperatures = higher incidence of Gram-negative pathogens. The magnitude of the effect was similar to what we reported earlier. For example, we reported a 46% increase of E. cloacae in summer vs. winter while they reported a 43% increase. They also found that S. aureus, E. faecium and S. pneumoniae were more frequent when temperatures were colder.

So, as you are reading an outbreak investigation or listening to SHEA2014 talks this week in Denver, ask yourself "did the authors consider seasonal or temperature variation in their analysis?" And if the answer is no, tread carefully. The authors may have ridden the epidemic curve to glory, but you might not be so lucky if you follow their recommendations.

Climate change and hospital pathogens

Do hospital pathogens like living in a Greenhouse?

Nothing should dare threaten your coffee.  So when Starbucks announced today that global climate change is threatening coffee supplies, you knew it would get media attention. What's a journalist without their coffee and cigarettes? (aaaack) What about hospital pathogens? Could climate change impact hospital infection rates. We thought it might. (Note: by we, I mean my colleague from Maryland Judy Johnson - She's now in Gainesville).

Back in 2006, Judy and I were sitting on a park bench (it was a nice day) discussing the upcoming ICAAC abstract deadline and pondering what we should submit, when she suggested we look for seasonal variation in Gram-negative pathogens.  Judy mentioned some data suggesting Gram-negative infections were more common in tropical countries and we also discussed the high incidence of Acinetobacter infections in troops returning from Iraq. Sure, we also knew that others had noticed summer peaks in certain pathogens, but the prior research didn't control for meteorologic factors and also combined summer data from across the entire US (hint: Maine ≠ Texas). Thus, we felt there was room for further exploration.

In our initial analysis, published in ICHE (2008), we reported that summer season (vs. winter) was associated with 28% more P. aeruginosa, 46% more E. cloacae, 12% more E. coli and 21% more A. baumannii clinical cultures over 8 years. Importantly, we found that for each 10°F increase in temp, there was a 17% increase in the monthly rates of infection caused by P. aeruginosa and also A. baumanii. Of course, this was a single center study, so we needed more proof.

Mike Eber and our group have just published a follow-up study in PLoS One looking at BSI data from 132 hospitals over 8 years. Using 211,697 inpatient blood isolates, we again found that Gram-negative organisms were more frequent in summer months ranging from 12.2% higher rates for E. coli to 51.8% higher for Acinetobacter spp. And more interestingly, we reported that independent of season, monthly humidity, monthly precipitation, and long-term trends, each 10°F rise in mean monthly temperature was associated with higher Gram-negative bacterial BSI frequencies ranging between 3.5% for E. coli to 10.8% for Acinetobacter spp.  Thus, warm temps = more Gram-negative bacteremias; that is, even a warm winter is a bad thing.  Lots more work to do to figure out why this might be, but I think it's an interesting first (or second) step. Cheers.

Note: Special thanks to Ramanan Laxminarayan and Extending the Cure for supporting this project.

Things that make you go "hmmm"...

I’ve been in an undisclosed location for the past week or so. Hint—if I were to hop on the above watercraft and drive directly across the above body of water, I’d be in the city that in the Potawatomi language translates (roughly) as “fine land”.

In among my beach reading I ran across this article, about a recent biowarfare exercise:

“AVI BioPharma, Inc., and the Naval Research Center recently announced the successful completion of a rapid-response exercise conducted by the Joint Project Manager Transformational Medical Technologies…..In a total of 18 days, AVI conceived, designed and manufactured two novel RNA-based drug candidates, one against a Gram negative bacterial target and one against a viral target.”

Eighteen days to conceive, design and manufacture a drug active against a Gram negative pathogen! Meanwhile, the only option for treatment of many multiple-drug resistant Gram negative infections is a drug that’s over 50 years old.

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

Infections in the ICU: New data, new insights

This week's JAMA contains an important paper and editorial for all of us in infectious diseases and hospital epidemiology. The EPIC II study was a one-day point prevalence study of infections in 1,265 ICUs in 75 countries involving 13,796 adult patients.

Key findings include:

• 51% of the patients had infections (this includes both community-acquired and hospital-acquired)
• 71% of the patients were receiving antibiotics
• Gram-negative organisms accounted for 61% of the infections (up from 39% in the EPIC-I study done 15 years ago)
• MRSA accounted for 10% of infections
  

In my medical school psychiatry course, I learned that a delusion is a fixed false belief. And it's a delusion to continue to think that hospitals should fixate on MRSA and continue with a search and destroy strategy. The gram-negatives are a major threat not only because they are increasing in incidence but also because the therapeutic options are quite limited.