Here we go again: Active detection and isolation, C. difficile edition

An interesting study in JAMA Internal Medicine, likely to generate a lot of discussion, addresses the use of “active detection and isolation” (ADI) for control of C. difficile disease. This quasi-experimental, single-center study employed PCR screening (tcdB detection) of all patients admitted through the emergency department (patients admitted from other locations were excluded, as were “short stay” patients), and those that were found to carry toxigenic C. difficile were admitted into a kind of “quasi-isolation”—gloves were used, but not gowns or private rooms. So all-in-all, a very pragmatic (and somewhat idiosyncratic) intervention. Healthcare-associated C. difficile disease rates declined after the intervention, which students of prior quasi-experimental studies of ADI for MRSA and VRE will find unsurprising. 

At this point, I will outsource my blog post to Jon Otter and Martin Kiernan at the Reflections IPC blog. Go on, head over there for an excellent pro-con post about this study, and vote on the question posed at the end of the post. Then come back here to read my only additional observation…..I can wait (spoiler alert: I agreed with Jon).

OK, you’re back: the only thing I have to add to Jon and Martin’s excellent post is this: we’ve been here before. Recall the persuasive quasi-experimental studies (many single-center, some multicenter) of MRSA and/or VRE ADI published over the course of a couple decades. When better designed studies were eventually performed and published (e.g. STAR*ICU, REDUCE-MRSA, MOSAR, this one by Harbarth and colleagues that doesn't have a catchy acronym)—you know, studies that included concurrent control groups (control groups are for losers!), it became evident that ADI wasn’t the key to MRSA or VRE control. I think we’re headed down that road again, this time with C. difficile. Who’s going to step up and organize the multicenter, cluster-randomized trial we need to do now? Or perhaps better to ask: who is going to pay for it?

Why all the letters? STAR*ICU and VA studies agree!

Remember that April 2011 New England Journal of Medicine issue with results from two seemingly contradictory studies on MRSA control? Here was our take on both the VA and STAR*ICU studies, written the same week the studies were released. Apparently, some people chose to dust off their typewriters and comment the old-fashioned way. Those letters, and the authors’ responses, are now published. Aside from the last two letters, which make a good point about a flaw in the denominator of the VA study (the failure to remove patients not at risk for acquisition by virtue of already being colonized), all the letters start from the premise that these two studies have contradictory results.

As Charlie Huskins and his colleagues point out in their letter, this is a flawed premise. They point to Figure 3 of their paper to make this point—allow me to expand, since they were obviously working within some crazy word limit that bloggers are not bound by.

Below you’ll find Figure 3 from the STAR*ICU study, which graphs the number of MRSA and VRE “events” (new colonization or infection) during an extended baseline period and the intervention period, in both control and intervention units:

No differences between control and intervention units, and no significant difference from the baseline rates, right? Hold on a minute!! It really isn’t fair to compare these data to the VA data, since the VA study doesn’t include a concurrent control group and doesn’t include sufficient baseline data with which to perform a proper segmented regression analysis. So now let’s take all of that extraneous stuff out (you know, all that tedious extended baseline data and the control arm data—get rid of it!!!). Now the graph looks like this:

The trend line is mine, and demonstrates that MRSA and VRE events dropped by about a third in the intervention units. Since this measure incorporates both transmission and infection metrics, you’d predict it would land smack in the middle of the VA estimates for reduction in MRSA transmission (17-21% reduction) and infection (62% reduction). And it does!

So please stop claiming that the VA study and the STAR*ICU study don’t agree—they do agree, if you just ignore the baseline and control arm data. And as we’ve already learned, control groups are for losers.

Accentuate the negative

Dan has posted previously on how difficult it is for authors to get negative studies published.  Perhaps this is the real reason why the STAR*ICU study took 4+ years to make it to press.  I suspect that if the study was completed the exact same way that it was but found a benefit for barrier precautions, it would have appeared in press around 2009 or even earlier.  Just a guess.

Mike has posted at least twice on Ben Goldacre and his blog/book called Bad Science (part 1 and part 2).  Ben has a new post in the Guardian that discusses how medicine, academia and popular culture all favor positive, eye-catching and potentially spurious trial results and ignore important negative studies.  His discussion centers around a paper published last year that seemed to provide evidence of precognition - you know it before it actually happens.  That "positive" paper received tons of press, while a new negative study can't see the light of day.  I think this sort of bias plays a large role in infection prevention research - it is so much easier to publish a positive quasi-experimental study showing a benefit than a negative study.  This is why it was so great that after 4+ years of waiting the STAR*ICU study, which was a negative study, was published at the same time as the VA study, which showed a benefit.  This way, we could have a rational discussion with the positive/negative evidence receiving "almost" equal billing.

Ben Goldacre "Backwards step on looking into the future" Guardian 4/23/2011

STAR*ICU study published: Barrier precautions not effective

It's only one study. Everybody take a deep breath. OK, exhale.

You might have already heard about this study and you might even know the results.  Someday, someone might discuss how this study was designed, and why the investigators decided to ship all of the microbiology specimens to NIH for processing resulting in a 5-day test turn-around time.  Someday, someone might explain why this study took 4 years to publish and the saga behind its eventual publication in the NEJM.  Someday, someone might even discuss how the difficulties completing this study might be hindering NIAID from funding other infection prevention clinical studies.  Someday, someone.

What can I say about the study?  Barrier precautions (ie. gloves or gowns/gloves) are ineffective in halting the transmission of MRSA and VRE in ICU settings.

Methods: The cluster-randomized trial (ie a largish quasi-experimental study but with a cool fancy name - see my "Random note" below) was completed in 2006 with the intervention lasting 6 months from March to August 2006. There were 10 intervention ICUs and 8 control ICUs.

Random note: There were 18 ICUs in this study, so it's somewhat like an 18-person RCT.  With such small numbers you can't expect that all measured and unmeasured confounders to be randomly distributed between the intervention and control ICUs. Thus, this is more like a large QE study than a standard RCT and needs to be analyzed as a QE study using multivariable regression controlling for known sources of confounding. Don't believe me? Check out Table 2 to see how different the intervention and control arms were in regards to topical and systemic antimicrobial exposure. You would not typically expect these "significant" differences in a large RCT (or large cluster-RCT).

Microbiology: Nasal swabs for MRSA surveillance cultures and stool or perianal swabs for VRE surveillance cultures were obtained from all patients within 2 days after their admission to the ICU, weekly thereafter, and within 2 days before or after their discharge from the ICU. Swabs were shipped overnight, 6 days a week, to the NIH. The mean number of days from obtaining surveillance cultures to reporting of results was 5.2 days.  I would have liked to see this reported in median days and I would also have liked this number to be reported from time of admission and not time from obtaining the culture since 2 days could pass between admission and obtaining the culture.

Planned Intervention: Known colonized or infected patients were placed on contact precautions. All other patients were placed on universal gloving from the time of admission until their discharge or until the results of surveillance cultures results returned. If surveillance cultures were positive, patients were upgraded to contact precautions (gowns/gloves) and if they were negative, they were downgraded to standard precautions.

Actual intervention as implemented: In the intervention ICUs, 92% of the ICU-days were spent under barrier precautions (51% contact precautions and 43% universal gloving) while in the control ICUs, 38% of ICU-days were spent under contact precautions.  Thus, indepedent of what anyone says, this study is about whether increasing barrier precautions from 38% to 92% reduces transmission. Also, 4 times as many patients in the intervention group were exposed to a topical antimicrobial (e.g. mupirocin), 12% vs 3.2%. Now, some will say that there wasn't 100% compliance with these interventions. I agree, this is not an efficacy trial.  As Ebb and I said in our JAMA commentary yesterday, cluster-randomized trials are real-world effectiveness trials in the domain of infection prevention.

Compliance: Overall, 47% of contacts in the intervention arm occurred with clean gloves and exit hand hygiene compliance vs 25% in the control ICUs. Compliance with contact precautions was relatively good in the intervention ICUs: gloves 82% and gowns 77%. Hand-hygiene compliance was also higher in the intervention vs. control ICUs (69% vs 59%)

MRSA or VRE colonization or infection: The mean incidence of MRSA or VRE per 1000 patient days at risk was actually higher in the intervention arm than the control arm (40.4 vs 35.6, p=0.35) but this was not statistically significant.

My thoughts:  How can this study not find a benefit when so many others have? Since most of the previous studies were uncontrolled quasi-experimental studies and we know that uncontrolled QE studies can over-estimate the measure of effect, it is possible that barrier precautions don't work.  It is also possible that other factors need to be included in any MDRO prevention program including attention to environmental cleaning and far higher compliance with the hand hygiene and contact precautions. However, the compliance rates reported in this study are not abnormally low (at least at the mean/median). Finally, perhaps decolonization is needed to achieve the results (at least for MRSA) that we've seen in other studies.

Another criticism that we've heard and will hear again is that the turn-around time for the microbiology was too-long.  This is mostly a red herring.  Since we have little evidence that gowns add much to gloves, and 92% of contacts in the intervention arm occurred with gloves, this study had FAR better glove compliance than we would expect with any typical ADI program in the real world.  The use of universal gloves in the pre-result period in the intervention arm really saved this study and, thus, it provides VERY useful information and should not be discounted. A quicker test turn-around would not have magically led to reduced transmission. Sorry.

Again, this is one study and it shouldn't be the last.  AHRQ is funding some very important MRSA (and VRE) prevention trials that many of us are involved with and I hope the publication of this paper won't discourage AHRQ (or NIH or CDC or VA) from funding these large and important studies.

What this study really tells us is that we can't fall back on legislative mandates in MDRO prevention and we must continue to search for the right combination of interventions along with developing better implementation strategies. Don't stop with the STAR*ICU study. Let this be the beginning.


Huskins W.C. et al. NEJM April 14, 2011