Thursday, January 20, 2011

To guideline or not to guideline, that is the question in... pneumonia?

Addendum 1/20/11, 1:27 PM
I want to add something to this, since I have been reflecting on the data more. It turns out that about 3/4 of all patients had an organism isolated felt to be causative of their pneumonia. Among these patients, over 80% in each group received empiric treatment that covered the pathogen. This means that 4 out of 5 patients in both groups received appropriate antibiotic coverage. What the authors skimmed over briefly is to talk about de-escalation. De-escalation is the guideline recommended strategy which entails reducing the spectrum of treatment after culture results become available to only those antibiotics that cover what has grown out. So, if, say, a patient is being empirically treated for Pseudomonas aeruginosa with double coverage, and the culture grows our MRSA and no Pseudomonas, the two anti-pseudomonal drugs should be stopped immediately. The investigators state that they did apply a de-escalation protocol, and that by day 3 50% and by day 5 75% were essentially de-escalated. The fact that they state this in the Discussion section makes me think that this was inserted in response to a reviewer. It is a pity that they did not include de-escalation in their stratified analysis, as it may be at least somewhat explanatory for the findings. 

I always felt that there was something intangible and intuitive about my assessments of the critically ill for whom I cared. I could not always explain why I thought one particular patient was more ill than the next, but there was that little something that I must have noticed out of the corner of my eye, and if I tried too hard to focus on it, it would disappear like a puff of smoke. Yet, docs make these pre-conscious assessments all the time. And though these hints drive treatment choices, they are distinctly difficult to quantify scientifically.

A new paper that was just published in The Lancet Infectious Diseases online is a great illustration of what happens when our analyses fail to account for these intuitions. The phenomenon is referred to as "confounding by indication", and it is the perennial plague of observational clinical research. Just to summarize, the study was an observational study of guideline implementation for the treatment of healthcare-associated pneumonia among ICU patients. The central guideline was that for the choice of empiric antibiotics selection. The initial choice of antibiotics, even before the definitive results of cultures are available, is based on the clinician's best guess at what organism(s) may be causing the pneumonia. Among these severely ill patients, the risk of having a bug that is resistant to many antibiotics is higher than for patients who come from the community with pneumonia, and this propensity drives the recommendation for a broader antibiotic coverage for these cases. It has been shown by us and many others that missing this initial opportunity to cover the bug(s) adequately subjects patients to a doubling or even trebling of the risk of death, regardless of whether the coverage is broadened later to include the culprit organism(s).

Back to the study. The four academic medical center that participated in it enrolled 303 eligible patients, of whom 129 were treated with antibiotic combinations that comported with the guideline recommendations (guideline compliant treatment) and 174 received other combinations that did not fit the guideline recommendations (guideline non-compliant). To their surprise, the investigators discovered that 28-day survival was actually higher in the non-compliant group than in the compliant one. And even after doing a great job of adjusting for many potential factors that made the groups different, this paradoxical disparity persisted, with an overall near-doubling in the hazard of death at 28 days in the compliant as opposed to the noncompliant group. Now, this is a fine how-do-you-do! So, does this mean that the guideline is actually killing people by advocating broader coverage? Well, not so fast.

First, I have to acknowledge that I may be engaging in rescue bias right now. Having said this, taking biological plausibility into account, the findings are very likely explained by confounding by indication. Namely, the docs who choose, say, dual rather than single therapy against gram-negative bacteria may be pre-consciously incorporating some intangible patient data into their choices, data that are not well represented by either laboratory values or disease severity scoring systems. I know this is a bit "soft" and maybe even "touchy-feely", but ask any doc, and s/he will confirm this phenomenon.

On the other hand, to be fair and balanced, I do have to agree that there may be other explanations. These include the possibility that our guideline recommendations, never really prospectively validated, may be wrong. Perhaps there is something about the untoward effects of these broad spectrum regimens that is at play. Maybe it is as simple as the "no free lunch" principle, and that even in the situation of covering appropriately broadly, introducing additional drugs increases not only their benefits, but also the risks associated with them. Finally, I have to acknowledge the possibility that we just have no clue what any of this means because our understanding of how antibiotics work in the setting of these types of pneumonia is flawed.

Now, let's put all of this in the context of our multiple discussions about data and knowledge on this web site. Several factors suggest that my initial explanation is correct. The bulk of the evidence points to the fact that skimpy early coverage increases the risk of death. Also, over a century of understanding and the durability of the germ theory imply that antibiotics are important in treating serious bacterial infections. So, the pre-test probability of the validity of the finding in the paper is pretty low. This is not to say that the study should not inject caution and self-examination into how we treat severe pneumonia; it absolutely should! This is also a place where we definitely need well designed interventional studies to confirm (or debunk) what we think we know to be true. In the meantime, as we often intone on this blog, let us not throw the baby out with the bath water.

Disclosure: I have done a lot of work in this area, so I have a potential intellectual COI with the study. Also, at least some of my research has been funded by the manufacturers of some of the antibiotics included in the guidelines.


  1. Great post, your stuff is just great, and keep it up.

    On your addendum, when you state that by omitting deescalation in analysis, we might miss explanation for findings, meaning:

    1) There is no difference, Type I error regardless

    2) there is something more to continuing 2 vs 1 abx and we are harming patients.


    Also, love the little comment on placing the post submission sentence into discussion from reviewer re: deescalation. It is that kind of nuance that I would never detect, and it is hugely helpful for someone who likes appraisal, but is not an active researcher or reviewer. Please add more of this insight in future posts.


  2. Hi, Brad, thanks fro your kind comment. What I mean by my de-escalation comment is that perhaps there is something harmful about not de-escalating in the absence of a bug to treat. Alternatively there may be something harmful about complying with de-escalation even in the absence of an identifiable bug in some patients. After all, culture is a pretty blunt instrument -- only about 50-75% of all patients with HCAP ever grow anything out.