Uncomplicated Cellulitis? Consider Strep-only Coverage

Back in 2013, Dr. Pallin’s group in Boston published a study comparing clinical cure rates in uncomplicated cellulitis patients receiving cephalexin or cephalexin plus sulfamethoxazole-trimethoprim (SMX-TMP). I covered this study in a UMEM pearl, with the end result suggesting there was no difference in cure rate between the two treatment arms. Even in communities with high prevalence of MRSA, uncomplicated cellulitis cases without pus or abscess generally seem to be strep species. This was confirmed in the 2014 IDSA guidelines on SSTI in which they recommended streptococcal-only coverage for uncomplicated cases. A new study in JAMA reexamines this treatment strategy.

What They Did

  • Multicenter, double-blind, randomized superiority trial in 5 US EDs among outpatients older than 12 years with cellulitis and no wound, purulent drainage, or abscess (confirmed by bedside ultrasound)
  • 500 patients randomized to two treatment arms:
    • Cephalexin, 500 mg 4 times daily, plus SMX-TMP, 320 mg/1600 mg twice daily, for 7 days or
    • Cephalexin plus placebo for 7 days

What They Found

In the per-protocol population, clinical cure occurred in 83.5% participants in the cephalexin plus SMX-TMP group vs 85.5% in the cephalexin group (difference, −2.0%; 95% CI, −9.7% to 5.7%; P = .50).

Application to Clinical Practice

  1. It is important to note that cephalosporins, such as cephalexin, cover skin strep species pretty well but do not provide coverage against MRSA. Conversely, SMX-TMP or doxycycline provide strong MRSA coverage with questionable skin strep species coverage. So, the real question here is do we need to be covering for MRSA in uncomplicated cellulitis cases? The available data (and the IDSA guidelines) would suggest ‘NO.’ The 2013 Pallin study enrolled patients in Boston, while this new JAMA study enrolled patients from a diverse group of patients from 5 EDs. I think the conclusion is the same: even in communities with high prevalence of MRSA, uncomplicated cellulitis cases without pus or abscess generally seem to be strep species.
  2. Adherence to the study protocol favored the double-coverage group (oddly), with almost twice as many patients in the cephalexin monotherapy cohort taking <75% of antimicrobial therapy, missing follow-up visits, or other protocol deviations. There is some data supporting q12 hour dosing of cephalexin; perhaps that strategy would increase adherence if proven to be equivalent to q6 hour dosing. Or, perhaps choosing a twice-a-day cephalosporin (eg, cefuroxime) for strep coverage is another option.
  3. For a more detailed statistical analysis, Dr. Ryan Radecki provides a great summary on his EM Lit of Note blog, including a description of the intention-to-treat subgroup in which the authors speculated there may be a difference between the treatments.
  4. Linezolid is now available generically in the U.S., which has decreased its price somewhat. It covers both strep and MRSA if the patient does, in fact, need coverage for both.
  5. As a related aside, let’s at least avoid one-time vancomycin doses for SSTI, as explored in a blog post by Dr. Zlatan Coralic on Academic Life in EM.

* ‘Strep-only’ in the title refers to skin streptococcal species without the need for MRSA coverage. Cephalosporins, penicillins, and clindamycin are all options.


Moran GJ, et al. Effect of Cephalexin Plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis: A Randomized Clinical Trial. JAMA 2017;317(20):2088-96. PMID 28535235

Author: Bryan D. Hayes, PharmD

Attending Pharmacist, Emergency Medicine and Toxicology, Massachusetts General Hospital; Assistant Professor of EM, Harvard Medical School

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