Double Coverage, Cellulitis Edition

The Infectious Disease Society Guidelines are fairly reasonable when it comes to cellulitis. Non-suppurative cellulitis – that is to say, without associated abscess or purulent drainage – is much less likely to be methicillin-resistant s. aureus. The guidelines, therefore, recommend monotherapy with a ß-lactam, typically cephalexin. Conversely, with a suppurative focus, trimethoprim-sulfamethoxazole monotherapy is an appropriate option. However, it’s reasonable to estimate current practice involves prescribing both agents somewhere between one fifth and a quarter of cases – presumably both wasteful and potentially harmful. This trial, therefore, examines this practice by randomizing patients to either double coverage or cephalexin plus placebo.

The short answer: no difference. The rate of clinical cure was a little over 80% of both cohorts in the per-protocol population. Of those with follow-up and treatment failure, over half progressed to abscess or purulent drainage on re-evaluation – and about two-thirds were cultured out as s. aureus. There was no reliable evidence, however, co-administration of TMP-SMX prevented this progression.

The really fun part of this article, however ties into the second line of their abstract conclusion:

“However, because imprecision around the findings in the modified intention-to-treat analysis included a clinically important difference favoring cephalexin plus trimethoprim-sulfamethoxazole, further research may be needed.”

This hedging stems from the fact 17.8% were excluded from the enrolled cohort for inclusion in the per-protocol analysis – and, depending on the modified intention-to-treat analysis definition, there was actually up to a 7.3% difference in failure rate favoring double coverage (76.2% vs 69.0%). This resulted from almost twice as many patients in the cephalexin monotherapy cohort taking <75% of antimicrobial therapy, missing follow-up visits, or other protocol deviations.

The best Bayesian interpretation of this finding is probably – and this is where frequentism falls apart – simply to ignore it. The pre-study odds of dramatic superiority of double coverage are low enough, and the outcome definition for the modified intention to treat cohort in question is broad enough, this finding should not influence the knowledge translation of this evidence. Stick with the IDSA soft-tissue guidelines – and one antibiotic at a time, please.  It is important to recognize – and educate patients – that about 1 in 6 may fail initial therapy, and these failures to not necessarily reflect inappropriately narrow antibiotic coverage nor therapeutic mismanagement.

“Effect of Cephalexin Plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis”
http://jamanetwork.com/journals/jama/article-abstract/2627970

Blood Cultures Save Lives and Other Pearls of Wisdom

It’s been sixteen years since the introduction of Early Goal-Directed Therapy in the Emergency Department. For the past decade and a half, our lives have been turned upside-down by quality measures tied to the elements of this bundle. Remember when every patient with sepsis was mandated to receive a central line? How great were the costs – in real, in time, and in actual harms from these well-intentioned yet erroneous directives based off a single trial?

Regardless, thanks to the various follow-ups testing strict protocolization against the spectrum of timely recognition and aggressive intervention, we’ve come a long way. However, there are still mandates incorporating the vestiges of such elements of care –such as those introduced by the New York State Department of Health. Patients diagnosed with severe sepsis or septic shock are required to complete protocols consisting of 3-hour and 6-hour bundles including blood cultures, antibiotics, and intravenous fluids, among others.

This article, from the New England Journal, looks retrospectively at the mortality rates associated with completion of these various elements. Stratified by time-to-completion following initiation of the 3-hour bundle within 6 hours of arrival to the Emergency Department, these authors looked at the mortality associations of the bundle elements.

Winners: obtaining blood cultures, administering antibiotics, and measuring serum lactate
Losers: time to completion of a bolus of intravenous fluids

Of course, since blood cultures are obtained prior to antibiotic administration, these outcomes are co-linear – and they don’t actually save lives, as facetiously suggested in the post heading. But, antibiotic administration was associated with a fraction of a percent of increased mortality per hour delay over the first 12 hours after initiation of the bundle. Intravenous fluid administration, however, showed no apparent association with mortality.

These data are fraught with issues, of course, relating to their retrospective nature and the limitations of the underlying data collection. Their adjusted model accounts for a handful of features, but there are still potential confounders influencing mortality of those who received their bundle completion within 3 hours as compared to those who did not. The authors are appropriately reserved with their conclusions, however, only stating these observational data support associations between mortality and antibiotic administration, and do not extend to any causal inferences.

The lack of an association between intravenous fluids and mortality, however, raises significant questions requiring further prospective investigation. Could it be, after these years wandering in the wilderness with such aggressive protocols, the only universally key feature is the initiation of appropriate antibiotics? Do our intravenous fluids, given without regard to individual patient factors, simply harm as many as they help, resulting in no net benefit?

These questions will need to be addressed in randomized controlled trials before the next level of evolution in our approach to sepsis, but the equipoise for such trials may now exist – to complete our journey from Early Goal-Directed to Source Control and Patient-Centered.

“Time to Treatment and Mortality during Mandated Emergency Care for Sepsis”

http://www.nejm.org/doi/full/10.1056/NEJMoa1703058

You’ve Got (Troponin) Mail

It’s tragic, of course, no one in this generation will understand the epiphany of logging on to America Online and being greeted by its almost synonymous greeting “You’ve got mail!” But, we and future generations may bear witness to the advent of something almost as profoundly uplifting: text-message troponin results.

These authors conceived and describe a fairly simple intervention in which test results – in this case, troponin – were pushed to clinicians’ phones as text messages. In a pilot and cluster-randomized trial with 1,105 patients for final analysis, these authors find the median interval from troponin result to disposition decision was 94 minutes in a control group, as compared with 68 minutes in the intervention cohort. However, a smaller difference in median overall length of stay did not reach statistical significance.

Now, I like this idea – even though this is clearly not the study showing generalizable definitive benefit. For many patient encounters, there is some readily identifiable bottleneck result of greatest importance for disposition. If a reasonable, curated list of these results are pushed to a mobile device, there is an obvious time savings with regard to manually pulling these results from the electronic health record.

In this study, however, the median LOS for these patients was over five hours – and their median LOS for all patients receiving at least one troponin was nearly 7.5 hours. The relative effect size, then, is really quite small. Next, there are always concerns relating to interruptions and unintended consequences on cognitive burden. Finally, it logically follows if this text message derives some of its beneficial effect by altering task priorities, then some other process in the Emergency Department is having its completion time increased.

I expect, if implemented in a typically efficient ED, the net result of any improvement might only be a few minutes saved across all encounter types – but multiplied across thousands of patient visits for chest pain, it’s still worth considering.

“Push-Alert Notification of Troponin Results to Physician Smartphones Reduces the Time to Discharge Emergency Department Patients: A Randomized Controlled Trial”
http://www.annemergmed.com/article/S0196-0644(17)30317-7/abstract