New CDC report on antibiotic resistance

Yesterday, the CDC released a new report on antibiotic resistant infections (full text here). It's a nicely done, mostly nontechnical report that seems primarily designed to raise awareness. There's not much new in the report except some updated estimates on the impact of these infections, which probably explains why the New York Times relegated its coverage to page 13. That piece, which quotes Eli, notes that the impact estimates are lowish, and CDC officials acknowledge that the estimates were intentionally conservative. As we've noted previously in this blog, we need more funding for prevention studies, new drugs, and better stewardship to protect the drugs we currently have.

Annual cost of HAIs in the US = $10 billion

A new paper in JAMA Internal Medicine aims to give us an update on the impact of healthcare associated infections in the US. Given all the focus on HAIs, particularly with the rollout of value based purchasing, this is an important study. The investigators performed a systematic review, which included papers that were published this year, to determine attributable cost estimates, used NHSN data for incidence estimates, then performed Monte Carlo simulation. Total cost of the 5 major infections (CLABSI, CAUTI, VAP, SSI and C. difficile) was estimated to be $9.8 billion per year. The table below shows the breakdown by infection type.

Eli may want to comment on the methodology of the study and the validity of the results, but I suspect these numbers will be cited frequently.

Manuscript Provenance: Why NEJM has a high retraction rate (and it's not a reason mentioned in the NYT)

A recent high-profile story in the NYT by Carl Zimmer discussed a surge in article retractions since 2000. Over the period 2000 to 2009, retractions have risen by 3300%. (see calcs below) The Time's article draws much of its data and discussion from a pair of editorials published by Ferric Fang and Arturo Casadevall covering "structural reforms" and "methodological and cultural reforms" and a recent news feature in Nature. I highly recommend the two calls for reform from Fang and Casadevall, which cover topics ranging from increased administrative burden to problems with grant review. However, it is hard to make a link from any of these problems and scientific error or misconduct without further research.

For example, much of the discussion falls into the category of "survival of the fittest" with scientists doing everything possible to publish in high-profile journals (e.g. NEJM), which then is supposed to lead to increased grant funding and wealth.  I'm not denying that this could be a factor in scientific fraud, but it's hard to imagine this would increase errors, directly. If you look at the NYT graphic (above), fraud is associated with a minority of all retractions. To provide evidence that a scientists desire for fame is driving the retraction epidemic, Fang and Casadevall, published another editorial that included an analysis linking impact factor of the journal to a retraction index. They found that the higher the impact factor, the higher rate of retraction with NEJM at the top.

Reasons given for the association include higher risk-taking by authors in papers submitted to high-ranking journals and that publications in high-impact journals may just be subject to greater scrutiny (e.g. via social media). These reasons are appealing, although I'm not sure there's a testable hypothesis among them. One testable "systemic aspect of the scientific publication process" that is likely to be associated with both journal rank and retraction (and more likely to be causal) is a manuscript's provenance.

Manuscript Provenance
In the art world, a painting's provenance refers to the chronology of ownership of a specific painting or work.  When I speak of a manuscript's provenance, I mean where it's been submitted and received peer review prior to publication.  As anyone who has submitted a manuscript knows, you almost always submit the paper to a higher-impact journal first and then if not reviewed or accepted, you aim a bit lower.  In fact, there is only one paper we've submitted out of >100, that's gone initially to a lower-ranked journal and then when rejected, was submitted and accepted by a higher-ranked journal.

Thus, manuscripts submitted and accepted at higher-ranked journals are more likely to have been reviewed only once, or received one round of peer review. Yes, I know that some papers go to JAMA then NEJM and some papers are submitted directly to a specialty journal and are reviewed once, but in general, papers published in higher-ranked journals have been through fewer rounds of peer review.  Unfortunately, these data are not easily available, but it's likely this hypothesis can be tested. Nevertheless, I think quantity of peer review is an important predictor of quality of the final product.  It is unlikely that more peer review could detect outright fraud, but most retractions aren't fraud related.

So before we blame the entire system for a few bad apples, there need to be more epidemiological studies as to why this is occurring.  My first suggestion is that we should consider manuscript provenance as a factor and my second suggestion is that journals should pay for peer review, so that it becomes a valued exercise.  Peer review service should also be considered for promotion. Sure the system could be improved in many ways, but it's a stretch from there to finding a causal pathway between a journal's impact factor and a higher retraction index. Oh, and this is all probably because of twitter anyway.


***Retraction Rate Calculation: Using rates of 3/year in 2000 to 180/year in 2009 from the NYT article and given that there's been a 64% increase in PubMed articles  (529,000 in 2000 to 866,000 articles in 2010), this represents an increase from 0.0006% to 0.02%, or a 3300% increase.

HAIs: An even bigger problem than we thought?

Our fellow blogger, Eli, has co-authored an interesting study in this month’s Archives of Internal Medicine. Using a national administrative database that contains 69 million hospital discharges, the investigators examined the attributable outcomes associated with two hospital-acquired infections—sepsis and pneumonia. The outcomes were stratified as to whether they occurred in association with a surgical procedure or not. When sepsis occurred post-operatively, it added on average 11 days to the hospital stay and $33,000 to the cost of care, and carried a nearly 20% attributable mortality. Post-operative pneumonia on average added 14 days to the stay and $46,000 to the cost of care, and had an attributable mortality of 11%. For cases not associated with surgical procedures, when adjusted for the preinfection length of stay, sepsis on average added 2 days to length of stay at an additional cost of $6,000, and was associated with an attributable mortality of 16%. Hospital acquired pneumonia in nonsurgical patients added 4 days to length of stay on average, added $11,000 to the cost of care, and had an attributable mortality of 10%. Extrapolating to the US population, the investigators estimated that these two conditions account for over 2 million hospital days, $8 billion in costs, and 48,000 deaths.

Diving into the murky sea of administrative data is a perilous business, but the authors of this paper took great pains to use diagnoses for which validation has been shown to be high level and were careful in their methods to minimize bias and confounding (the methods section of the paper is about twice as long as the results). The incidence of each of these complications is about 1% or less, which makes it difficult for the average clinician to assess impact in their patients. Importantly, what this study does not tell us is the fraction of these cases that are preventable. However, even if only a quarter are preventable, this paper tells us that healthcare associated infections are a big, big problem, and those of us who work in infection prevention have a very long journey ahead. 

Lastly, this study should remind us that our targets should be infections not organisms. This problem is too big to tackle one organism at a time. To the patient with life-threatening sepsis, it matters little whether the cause is MRSA, MSSA, or a multidrug-resistant gram negative rod. Multipotent interventions driven to high levels of compliance will be necessary to ultimately bring these infections to the irreducible minimum.