By Richard R. Watkins, MD, MS, FACP, FIDSA
Associate Professor of Internal Medicine, Northeast Ohio Medical University; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH
Dr. Watkins reports that he has received research support from Allergan.
SYNOPSIS: A randomized, multicenter, placebo-controlled clinical trial that enrolled patients presenting to emergency departments with uncomplicated cellulitis found the addition of trimethoprim-sulfamethoxazole to cephalexin did not lead to better outcomes.
SOURCE: Moran GJ, Krishnadasan A, Mower WR, et al. Effect of cephalexin plus trimethoprim-sulfamethoxazole vs. cephalexin alone on clinical cure of uncomplicated cellulitis: A randomized clinical trial. JAMA 2017;317:2088-2096.
The increase in skin infections caused by community-associated methicillin-resistant Staphylococcus aureus (MRSA) over the last 10-15 years has led many clinicians to prescribe antibiotics with anti-MRSA activity to treat cellulitis. However, guidelines from the Infectious Diseases Society of America recommend that in cases without systemic illness, penetrating trauma, intravenous drug use, or evidence of MRSA elsewhere, therapy should be directed only against streptococci.1 Therefore, Moran et al sought to determine whether covering for MRSA improves outcomes in cellulitis. This was a randomized, double-blind, placebo-controlled clinical trial that enrolled patients ≥ 12 years of age who presented to five U.S. emergency departments with uncomplicated cellulitis, defined as erythema without an abscess, purulent drainage, or wound. All patients underwent an ultrasound to rule out an underlying abscess at enrollment. They were assigned a 1:1 ratio to receive either a seven-day course of cephalexin plus placebo or cephalexin plus trimethoprim-sulfamethoxazole (TMP-SMX). The primary outcome was clinical cure of cellulitis at the test-of-cure visit 14-21 days after enrollment in the study. Failure was defined at day three or four as fever, an increase in erythema by 25% from baseline, or worsening of swelling and tenderness by the visit. Failure at days eight to 10 was defined by fever, no decrease in erythema, or no decrease in swelling or tenderness. Failure at days 14-21 was defined as fever or more than minimal erythema, swelling, or tenderness. For patients who met failure criteria, investigators ended assigned antibiotics and administered another non-study antibiotic, along with assessment for possible surgical drainage.
The study was designed as a superiority trial. The modified intention-to-treat population was defined as patients who took at least one dose of study medication and were subjected to an interview through the test-of-cure visit or withdrew from the study and/or were lost to follow-up. The per-protocol population was defined as those patients who took at least 75% of the total doses of study medicines during the first five days and completed an in-person test-of-clinical-cure visit.
In the per-protocol population, clinical cure was achieved at 14-21 days in 182 of 218 patients enrolled in the cephalexin/TMP-SMX group and in 165 of 193 in the cephalexin/placebo group (P = 0.50). However, in the modified intention-to-treat analysis, the cephalexin/TMP-SMX group showed a numerically (but not statistically significant) higher clinical cure rate (189/248) compared to those who received cephalexin/placebo (171/248) (P = 0.09).
Of the 36 who experienced treatment failure with cephalexin/TMP-SMX, 10 exhibited an abscess at the time of clinical failure and nine developed purulent drainage. Of the 28 patients with clinical failure in the cephalexin/placebo group, 10 exhibited an abscess at the time of clinical failure and 10 also developed purulent drainage.
Among the 60 patients with clinical failure who had culture data available, MRSA was isolated from 41, methicillin-susceptible S. aureus (MSSA) from eight, and streptococci from two (3.3%).
Regarding adverse events, there were no significant differences between the groups, and 90% of the reactions were considered mild. The most common adverse event was gastrointestinal upset, which occurred in 46% of the cephalexin/TMP-SMX group and in 38.7% of the cephalexin/placebo group. One case of Clostridium difficile infection occurred, which was attributed to clindamycin administered after a treatment failure with cephalexin/TMP-SMX. One patient who received cephalexin/TMP-SMX developed acute-on-chronic kidney injury that subsequently resolved.
This study supports the notion that routine antibiotic coverage for MRSA is not necessary when treating uncomplicated cellulitis. As an accompanying editorial noted, the different findings between the modified intention-to-treat analysis and the per-protocol population likely can be explained by the large number of patients in the analysis who did not complete the recommended course of therapy and, thus, were excluded.2
Indeed, adherence actually was lower in the cephalexin/placebo group, making it unlikely that drug intolerance led to post-randomization bias. The most common reason for clinical failure was the development of an abscess, for which the primary management is incision and drainage. Thus, it should not come as a surprise that many cases of treatment failure occurred when only antibiotics (including those that treat MRSA) were prescribed and an abscess was present.
There were some limitations in this study worth mentioning. First, despite enrolling nearly 500 patients, the power was limited such that it is possible the effect of TMP-SMX therapy could have improved outcomes in some of the subgroups. Second, bedside ultrasound may not be available in some settings, and using physical examination alone is not reliable to detect abscesses. Third, there are many cases of uncomplicated cellulitis that resolve without antibiotics, which could have biased the results toward the null hypothesis. Despite some uncertainty in the different findings between the per-protocol group and the modified intention-to-treat analysis, this study suggests the addition of a second antibiotic to cover for MRSA in cases of uncomplicated cellulitis is unnecessary. One caveat is that patients with clinically undetectable abscesses or with abscesses in evolution likely will experience treatment failure, although it can be argued that in these cases incision and drainage is more important than the antibiotic chosen. Finally, the dangers of unnecessary and excessive antibiotics are well-described, and Moran et al should be commended for helping advance antibiotic stewardship in the ambulatory setting.
- 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:e10-52.
- Shuman EK, Malani PN. Empirical MRSA coverage for nonpurulent cellulitis: Swinging the pendulum away from routine use. JAMA 2017;317:2070-2071.