In patients with cellulitis without abscess, empiric MRSA coverage does not significantly increase clinical cure rates as compared with empiric Streptococcus coverage alone.

In a randomized double blinded trial conducted at three EDs in a MRSA-endemic area, 153 immunocompetent patients diagnosed in the outpatient setting with cellulitis without abscess and <1 week of symptoms were randomized to either cephalexin and trimethoprim-sulfamethoxazole (TMP-SMX) or cephalexin and placebo.¹ Exclusion criteria included current use of antibiotics, renal insufficiency, need for inpatient admission, immunocompromised state, indwelling catheter, peripheral vascular
disease complicating the cellulitis, bites, marine or freshwater injury, and diabetes. Patients were treated for a minimum of 7 days and told to continue antibiotics until 3 days after they felt “cured,” to a maximum of 14 days. The primary outcome was clinical cure (defined as resolution of symptoms other than slight residual erythema or edema, and distinct from patient-assessed “cure” above) assessed at 12 and 30 days.

There was no difference in clinical cure across groups (85% in the cephalexin/TMP-SMX group vs. 82% in the cephalexin/placebo group, risk difference 2.7%, 95% CI, −9.3% to 15%; P = .66). There was no association between clinical cure and either nasal MRSA colonization status or purulence at enrollment (as defined by pustules <3 mm). Caveats include limited generalizability to the inpatient population and the exclusion of diabetics, who are at risk for polymicrobial infections.

These findings were supported by a subsequent double-blinded randomized trial of 496 patients at five US EDs that also compared cephalexin/TMP-SMX to cephalexin/placebo.² Inclusion and exclusion criteria were roughly similar to the study above, but this trial included diabetics (excluding diabetic foot infections). The primary outcome was clinical cure. The study used the absence of a series of failure criteria over 21 days including fever, erythema, swelling, and tenderness to define clinical cure.

Clinical cure occurred in a similar proportion of patients in each group (83.5% in the cephalexin/TMP-SMX group vs. 85.5% in the cephalexin/placebo group, risk difference −2.0%, 95% CI −9.7% to 5.7%; P = .50).

IDSA guidelines recommend against empiric antibiotics targeting MRSA for most cases of cellulitis in the absence of penetrating trauma, purulent drainage, active MRSA elsewhere on the body, known MRSA nasal colonization, injection drug use, or systemic inflammatory response syndrome (strong recommendation, moderate evidence).³

In patients with uncomplicated cellulitis, 5 days of antibiotics appears to be as effective as 10 days of therapy as long as there is initial and continued improvement.

This question was addressed in a single-center randomized controlled trial in which 121 patients aged ≥18 years with cellulitis of the face, trunk, or extremities were given 5 days of levofloxacin 500 mg PO daily and then randomized to receive either an additional 5 days of levofloxacin or placebo.⁴ Exclusion criteria included bacteremia, severe sepsis, deep soft tissue infection (e.g., abscess, osteomyelitis, fasciitis), need for debridement, diabetic foot infection with nonviable tissue, bite, or eGFR <10 mL/min. After 5 days of levofloxacin, 34/121 patients were not randomized, including 6 who developed abscess, 1 who developed bacteremia, 4 who were worse by 72 hours, and 5 who did not demonstrate any improvement by 5 days. The primary outcome was resolution of the infection at 14 days as defined by cessation of warmth and tenderness, improvement in erythema, and no recurrence at the same site by day 28.

There was no difference in the primary outcome (98% in both groups; P > .05). Caveats include the fact that patients worsening before 5 days were removed and not randomized, which likely led to lower than average treatment failure rates in either group, as well as the choice of levofloxacin—a somewhat atypical agent for cellulitis treatment.

Based on this article, IDSA guidelines recommend a 5-day course of antibiotics for uncomplicated cellulitis, noting this can be prolonged in the absence of improvement during the course (strong recommendation, high evidence).⁵