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

3 thoughts on “Double Coverage, Cellulitis Edition”

  1. This is a tough study–while certainly I love to tout the IDSA guidelines regarding monotherapy, I will be the first to admit that I’m “loose” with adding the TMP/SMX in actual practice. I find myself actively looking for an excuse–diabetic? Have some Bactrim. Previous abscess or MDRO? Bactrim might be for you. Own a dog? Let me tell you about Bactrim. It’s definitely not the best medicine, but CA-MRSA is a tricky bug, I think, finding ways to force changes in our empiric therapies every few years, it seems.

    Ultimately, I think you hit the nail on the head–discussing with and educating patients about the failure rate of monotherapy (and it not meaning that someone messed up) is almost certainly the best practice here, and one that this study–and your post–will compel me to be more diligent about.

    1. I think you make the important point regarding the application of all medical evidence – how similar are the patients and practice setting to my own? How generalizable are their outcomes to my population? The failure rate is a significant consideration, and I think that’s where we get in trouble adjusting practice based on those.

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