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Adding trimethoprimsulfamethoxazole to cephalexin did not increase clinical cure in uncomplicated cellulitis

Question In patients with uncomplicated cellulitis, does adding trimethoprimsulfamethoxazole to cephalexin increase the likelihood of clinical cure? Methods Design Randomized placebo-controlled trial. ClinicalTrials.gov NCT00729937. Allocation Concealed.* Blinding Blinded* (patients, clinicians, {data collectors, outcome assessors, and statisticians}). Follow-up period 49 to 63 days. Setting 5 emergency departments in the USA. Patients 500 adults and adolescents >12 years of age (median age 40 y, 58% male) who had uncomplicated cellulitis (erythema without abscess [confirmed by ultrasonography], purulent drainage, or wound; and believed to be of infectious cause), with lesions 2.0 cm in diameter and present for <1 week. Exclusion criteria included current immunosuppression, infection at another site, underlying skin condition in the affected area, or history of IV drug use with fever. Intervention Cephalexin, 500 mg 4 times/d, plus TMP-SMX, 80 mg/400 mg twice daily (n =249), or cephalexin plus placebo (n =251) for 7 days. Outcomes Clinical cure (absence of failure: fever, increase in maximal erythema dimension by >25%, or worsening swelling or tenderness at day 3 or 4; fever, no reduction in maximal erythema dimension, or no reduction in swelling or tenderness at days 8 to 10; or fever or more than minimal erythema, swelling, and tenderness at days 14 to 21) at 14 to 21 days after randomization. Secondary outcomes included composite clinical cure (resolution of all signs and symptoms of infection, or improvement such that no additional antibiotic treatment and/or surgical procedures were needed), hospitalization, surgical procedure, or days missed from normal activities. 500 patients were needed to detect a 10% absolute difference in clinical cure, assuming a cure rate of 85% in the cephalexin plus placebo group and an 85% follow-up rate (90% power, 2-sided =0.05). Patient follow-up 82% in the primary per protocol analysis. Main results Groups did not differ for clinical cure, composite clinical cure, or hospitalization at 14 to 21 days (Table), surgical procedure at 14 to 21 days (11.9% vs 8.8%) or 49 to 63 days (15% vs 10%), or days missed from normal activities in the first 14 days (median 1 vs 1). Conclusion In patients with uncomplicated cellulitis, adding trimethoprimsulfamethoxazole to cephalexin did not increase the likelihood of clinical cure. Cephalexin plus trimethoprimsulfamethoxazole (TMP-SMX) vs cephalexin plus placebo in adolescents and adults with uncomplicated cellulitis Outcomes Event rates at 14 to 21 d RBR (95% CI) Cephalexin plus TMP-SMX Cephalexin plus placebo Clinical cure 84% 86% 2% (6 to 10) Composite clinical cure 73% 77% 5% (6 to 15) RRI (CI) Hospitalization 7.8% 5.2% 51% (28 to 216) RBR = relative benefit reduction. Other abbreviations defined in Glossary. RBR, RRI, and CI calculated from event rates in article. Absence of failure (see text for criteria). Resolution of all signs and symptoms of infection, or improvement such that no additional antibiotic treatment and/or surgical procedures were needed. Commentary The trial by Moran and colleagues supports the Infectious Diseases Society of America (IDSA) 2014 recommendations for the treatment of mild nonpurulent cellulitis (1) and supplies a basis for antibiotic stewardship in the ambulatory treatment of this common infection. The use of point-of-care ultrasonography (POCUS) ensured inclusion of only patients with nonpurulent cellulitis. Patients had mild nonpurulent cellulitis (defined as an absence of systemic signs), which was evidenced by only 1% of patients being febrile. The monotherapy group received an IDSA-recommended antibiotic, cephalexin, whereas the dual-therapy group also received TMP-SMX, an agent recommended by the IDSA for the treatment of mild purulent cellulitis. Most patients with mild nonpurulent cellulitis have Group A streptococcal infection; methicillin-resistant Staphylococcus aureus (MRSA) is rare (2). The lack of benefit from the addition of TMP-SMX reinforces the minimal causative role of MRSA in nonpurulent cellulitis and strengthens the IDSA guidelines, which recommend monotherapy for this clinical entity. Thus, when POCUS confirms nonpurulent cellulitis, routine use of dual therapy is not warranted. Further stewardship could be achieved by giving only a 5-day course (as recommended by the IDSA) compared with the 7-day course used in this trial (1). Extrapolating Moran and colleagues' results to clinical settings that lack POCUS should be done with caution: Determining the presence of purulence using routine physical examination has unacceptably high rates of disagreement between examiners (3), and POCUS has been shown to be more sensitive and specific than physician examination for detecting soft tissue abscesses (4).