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.

Microbiome: passenger or vehicle?

Remember how you learned in BIO 101 that many fluids in the human body are normally sterile? And you know how you laugh with condescension when someone dares to question this dogma? After all, we know that the gut and the skin are full of microorganisms, but the lung? The bladder? This is inconceivable, heretical!

Well, actually, this, like many other dogmas that seemed like God's word at the time, has been broken open by some very interesting research emerging from multiple laboratories around the world. I was first stopped in my tracks about a year ago, while listening to an NPR story in my car and learning that the number of bugs we carried on and in us was about 10-times greater than the number of our own cells. Then, in a farm house in Cornwall a couple of weeks ago, while on vacation, I read an article in an October 2009 issue of Eureka, The Times monthly science magazine, which once again made me ponder our sojourns in life, the bacteria that cohabitate with us. And finally, today I saw this story in yesterday's NYT, which galvanized me into writing action. This grabbed me in particular:

Scientists are even discovering ecosystems in our bodies where they weren’t supposed to exist. Lungs have traditionally been considered to be sterile because microbiologists have never been able to rear microbes from them. A team of scientists at Imperial College London recently went hunting for DNA instead. Analyzing lung samples from healthy volunteers, they discovered 128 species of bacteria. Every square centimeter of our lungs is home to 2,000 microbes.

It grabbed me for two reasons:
1). I am a lung doctor, and a lot of the research that I do centers around lung infections. One type of this infection, ventilator-associated pneumonia or VAP, is the subject of much scrutiny by policy makers and payers, and is emerging as a quality indicator. There are many challenging issue in VAP, not the least of which is its treatment: because it is likely to be caused by an antibiotic resistant organism, and because at least one-half of all cases of suspected VAP never grows out a specific microbe, the recommended empiric treatment is with broad-spectrum drugs. The clinician treads a fine line between undertreating the patient at the expense of increased mortality or overtreating and promoting antibiotic resistance.
2). I have already written here about my thoughts on evidence and how we tend to approach our knowledge with the arrogance that blinds us to the possibility of being either under-informed or plain wrong. Well, here is the case where we were so convinced of what we knew, yet it was plain wrong! With the scientific skepticism and appropriate tools we are learning something completely opposite to what we thought we knew.

Taking this line of thinking one step further, can we now conceive of the possibility that what we expose our bodies to actually plays a role in our long-term health? To be specific, I mean something as simple as food and the way our food is produced. Monoculture and food engineering have become staples of our food production. Animals are raised in CAFOs in conditions requiring them to be on antibiotics to ward off infections and to help with growth. Additionally, to leverage the subsidized and abundant corn supply, food animals are forced into diets completely unnatural to them. Cows, for example, evolved over millennia to be ruminants meant to eat grass and hay, are fed a corn-based grain diet, which, by altering their gut environment, makes them much more likely to carry toxigenic E. coli. Although there is much nay-saying about whether antibiotics (and hormones, by the way), are passed on to humans through meat or milk, I have never seen any convincing scientific evidence to the contrary. So, if we eat meat that is microbiologically altered, and may also be exposed to antimicrobial residues that may in turn change our own native microbiome, is it possible that at least some of the emerging health issues are due to the travesty of monoculture production?

I am not saying that I have all the answers -- clearly, this research has a long way to go to establish causal pathways and potential points of intervention. But let's exercise our common sense and at least ask the questions. Do it early and often. And let's please agree that there is a certain burden of proof here that resides with the food production oligopoly. Oh, yeah, and let's not forget to continue limiting the use of antibiotics in human health too. And have a little bit of dirt... for lunch... every day...