Date: February 27th, 2018

Reference: Moran et al. Effect of Cephalexin plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis – A Randomized Clinical Trial. JAMA May 2017.

Guest Skeptic: Chip Lange is an Emergency Medicine Physician Assistant (PA) working primarily in rural Missouri in community hospitals. He also hosts a great #FOAMed blog and podcast called TOTAL EM.

Case: A 22-year-old male with no significant past medical history arrives to your department for an area of tender erythema to the right forearm for two days that has grown in size without purulence or drainage.  With point of care ultrasound, you diagnose cellulitis without the presence of an abscess affecting a 6cm diameter area.  When deciding how to treat for this condition, you have read recently that cephalexin could be used alone and that trimethoprim-sulfamethoxazole (TMP-SMX) may not be needed to cover for methicillin-resistant staphylococcus aureus (MRSA).

Background: There have been multiple SGEM episodes on abscesses but only one on cellulitis. It was with Meghan Groth (@EMPharmGirl). The SGEM bottom line was for patients with uncomplicated cellulitis, TMP-SMX may represent an alternative to clindamycin in patients with no major co-morbidities (SGEM#131).

Typically, with cellulitis we lack a specimen to obtain a culture and blood cultures are frequently not helpful.  With the difficulty to definitively determine the source, Beta-hemolytic streptococci are presumed to be the dominant pathogens.  In the case of purulent skin infections though, MRSA is the most common cause.

Currently, the Infectious Diseases Society of America (IDSA) guidelines for patients with cellulitis without systemic signs of infection, penetrating trauma, injection drug use, or other evidence of MRSA recommend only prescribing antibiotics against streptococci (1).

Clinical Question: Does cephalexin plus TMP-SMX result in higher clinical cure rates in uncomplicated cellulitis versus cephalexin alone?

Reference: Moran et al. Effect of Cephalexin plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis – A Randomized Clinical Trial. JAMA May 2017.

  • Population – Patients over twelve years of age with uncomplicated cellulitis (erythema without an abscess, purulent drainage, or wound believed to be of infectious etiology present for less than one week with at least 2cm diameter area of involvement).
    • Exclusions: There were 26 exclusions in their supplemental documentation. Some of the exclusions were patients with allergy to study drug, pregnancy/nursing or expected pregnancy, underlying skin conditions in the affected area, history of IV drug use with fever, concurrent infection at another site, or immunosuppression.
  • Intervention – Cephalexin 500mg four times daily plus TMP-SMX 160/800 two tables twice daily for seven days
  • Comparison – Cephalexin plus placebo for seven days
  • Outcome:
    • Primary Outcome: Clinical cure at 14-21 days after enrollment. This was defined as not meeting failure criteria that was decided by consensus prior to the study (fever, increase in size >25%, worsening of swelling and tenderness during treatment, no decrease in maximal dimension of erythema, no decrease in swelling or tenderness by the end of treatment and fever or more than minimal erythema, swelling or tenderness by the test-of-clinical-cure visit).
    • Secondary Outcomes: Composite clinical cure, surgical drainage procedures, changes in erythema size, presence of swelling/induration and tenderness, invasive infections, skin infections at the same or different site, hospitalizations, similar infections in household contacts, days missed from normal activities and work/school, and days of analgesic use.

Authors’ Conclusions:Among patients with uncomplicated cellulitis, the use of cephalexin plus TMP-SMX compared to cephalexin alone did not result in higher rates of clinical resolution of cellulitis in the per-protocol analysis.  However, because imprecision around the findings in the modified intention-to-treat analysis included a clinically important difference favoring cephalexin plus TMP-SMX, further research may be needed.”

checklistQuality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. YES
  2. The patients were adequately randomized. YES
  3. The randomization process was concealed. YES
  4. The patients were analyzed in the groups to which they were randomized. YES/NO. They did two modified intention-to-treat (ITT) analyses and at per-protocol (PP) analysis.
  5. The study patients were recruited consecutively (i.e. no selection bias). UNSURE. Not explicitly stated.
  6. The patients in both groups were similar with respect to prognostic factors. YES
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. YES. However, blinding could be broken if a patient had treatment failure or an adverse event.
  8. All groups were treated equally except for the intervention. YES
  9. Follow-up was complete (i.e. at least 80% for both groups). YES/NO. Yes, for the mITT but no for the PP. Only 77.8% of the cephalexin alone group was included in the primary outcome of the per-protocol analysis
  10. All patient-important outcomes were considered. UNSURE
  11. The treatment effect was large enough and precise enough to be clinical significant. NO. There was no statistical difference in the primary outcome and there was lack of precision around the point estimate in the mITT-1 analysis.

Key Results: They recruited 500 people to be in the study. The median age was 40 years and there were a few more males than females included in the trial. Patients had symptoms for an average of three days, more than 50% were on the lower extremity, about 10% had diabetes and 4% reported a history of MRSA.

No difference in clinical cure rate

  •  Primary Outcomes: Clinical cure at 14-21 days after enrolment

209 table

    • Per Protocol: Patients who took at least 75% of the study medication and had an in-person follow-up visit or had clinical failure before the test-of-cure visit and received at least 75% of the study medication during the first 48h of treatment.
    • Modified ITT-1: Patients who took at least one dose of the study medication and had an in-person or telephone assessment at the test-of-cure visit, as well as those who withdrew from the trial, were lost to follow-up, or had missing or unassigned outcomes
    • Modified ITT-2: Patients who took at least one dose of study medication and had an in-person follow-up evaluation at any time during the study.
  • Secondary Outcomes: No significant difference between treatment groups
  • Treatment Failures:
    • Cephalexin + TMP-SMX: 36 patients with 10 (28%) had an abscess at and 9 (25%) had purulent drainage
    • Cephalexin + Placebo: 28 patients failed treatment with 10 (36%) had an abscess and 10 (36) had purulent drainage
    • MRSA: 60 patients failed treatment AND had material to culture. Of those, 41 (68%) grew MRSA
  • Adverse Events: No significant differences between treatment groups. Most adverse events were mild (90%) and the most common was gastrointestinal.

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  1. Inclusion/Exclusion Criteria: The criteria were stringent, and many patients will probably not fall into this category of uncomplicated cellulitis.  Purulent cellulitis or cellulitis with abscess seems to be a growing problem.  These are the patients that most likely benefit from TMP-SMX.  Truly uncomplicated cellulitis would be low risk for MRSA and ideally would make sense to use cephalexin alone, but this seems to be a diminishing group of patients.
  1. Alternative Antibiotics: This trial only addresses TMP-SMX but other antibiotics could be used such as clindamycin which has good strep and staph coverage.  Additionally, other antibiotics that have MRSA coverage would include doxycycline.  However, TMP-SMX, with its low cost and easy use, is probably the most popular for many clinicians.
  1. Ultrasound: Point of care ultrasound (POCUS) was used to evaluate for abscess. Although more and more clinicians are learning POPCUS skills some rural providers may not have the skills or access to the technology. This makes it harder to interpret the results for those settings.
  1. MRSA: An equal portion of MRSA was isolated among clinical treatment failure in each group. However, the study was not powered to find a difference in this subgroup. It is still possible with a larger sample size that a statistical and clinical significance could be found. In addition, only 4% of patients had a history of MRSA. Clinicians working in communities with higher MRSA rates will need to consider this factor when deciding how to clinically apply this study.
  1. Dosing Regimen: The dosing and regimen with TMP-SMX may be different than what most people are currently doing based on previous research using the double dose instead of the “quadruple dose” of this trial.  Furthermore, since TMP-SMX does have activity against streptococcus, it may be worth doing a study comparing cephalexin and TMP-SMX both as a single drug regimen.

Compare the Authors’ Conclusion to the SGEM Conclusion: We generally agree with the authors’ conclusions.

SGEM Bottom Line: In patients with uncomplicated cellulitis the routine addition of TMP-SMX is not required to improve the clinical cure rate.

Case Resolution: You discuss the situation with the patient further and he seems to be at low risk for MRSA and do not believe that coverage with TMP-SMX is needed.  After a careful and detailed discussion, you and the patient decided to use cephalexin alone to treat his cellulitis.

Clinical Application: Cephalexin can be used in patients’ who are low-risk for MRSA on its own but other antibiotics that will cover for strep and staph as well should be considered.  This could still be TMP-SMX but other options include clindamycin for single antibiotic coverage.  This paper will not change my clinical practice at this time.

Chip Lange (PA)

Chip Lange (PA)

What Do I Tell My Patient? We are going to prescribe you an oral antibiotic called cephalexin for your cellulitis.  Sometimes we have to use two oral antibiotics for patients with MRSA. This is a certain type of infection that the regular oral antibiotics do not work. However, you are al low risk for a MRSA infection. If you do not improve or get worse, it could be MRSA and we can another oral antibiotic called TMP-SMX. Another option if that happens is to switch to another single oral antibiotic called clindamycin that treats MRSA but can give you more diarrhea. Sometimes we even have to use intravenous antibiotics to treat these skin infections. Let’s just see how the cephalexin works and please come back if you are getting worse, not getting better or are worried.

Keener Kontest: Last weeks’ winner was Dr. Ted Macher from Chatham. Ted knew Jokichi Takemine (1854-1922) was the Japanese American chemist who isolated epinephrine in 1901.

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  1. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014;59(2):147-159.