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Commentary on: Moran GJ, Krishnadasan A, Mower WR, et al. Effect of cephalexin plus trimethoprim-sulfamethoxazole vs cephalexin alone on clinical cure of uncomplicated cellulitis: a randomised clinical trial. JAMA 2017;317:2088–96.
Skin infections are one of the most common infections in ambulatory medicine. Yet, despite the high incidence of these infections, there remain questions about optimal treatment of cellulitis without abscess. Cellulitis without abscess is particularly challenging, as the aetiology of this infection remains relatively elusive. Studies employing molecular diagnostic techniques for bacteria from needle biopsies of cellulitis have failed to determine the aetiology of cellulitis without abscess. Current thinking is that cellulitis is usually caused by Group A Streptococcus and occasionally Staphylococcus aureus, possibly including methicillin-resistant S. aureus (MRSA). However, the relative contribution of these pathogens is unclear and the need to include anti-MRSA therapy as part of treatment for cellulitis without abscess is unclear. A small clinical trial found no advantage to adding anti-MRSA therapy for cellulitis, but was underpowered.1 To this end, investigators sought to compare two regimens for cellulitis, one that treats Group A Streptococcus and methicillin-susceptible S. aureus alone compared with another regimen that includes additional coverage for MRSA.
The investigators randomised subjects with cellulitis to either 7 days of cephalexin 500 mg orally four times a day with placebo or the same dose of cephalexin combined with trimethoprim-sulfamethoxazole (TMP-SMX) four single strength pills twice daily. The primary study outcome was clinical cure at the test of cure visit, which occurred 14–21 days after enrolment. Subjects were all outpatients who underwent ultrasounds to exclude abscess. Key exclusion criteria included severe immunosuppression.
In the per-protocol analysis, clinical cure in the cephalexin-only group was 83.5% (182/218) vs 85.5% (165/193) in the cephalexin plus TMP-SMX group, a non-significant difference. Similarly, in a modified intention-to-treat analysis, clinical cure in the cephalexin-only group was 69.0% (171/248) vs 76.2% (189/248) in the cephalexin plus TMP-SMX group, which was also a non-significant difference (P=0.07). Another analysis using more recent US Food and Drug Administration criteria, which examines clinical response 48–72 hours after treatment initiation, failed to show differences between groups. Tolerability and adverse events in the two groups were similar. Slightly over 10% of subjects failed with an abscess or purulent infection, with a non-significant trend towards greater proportion of abscess or purulent infection in the cephalexin-only arm. Of the 60 patients with clinical failure and cultures available, MRSA was isolated in 41 (10% of the study population).
The aetiology of cellulitis remains unclear.2 This clinical trial sought to determine if MRSA coverage was needed to improve cure rate compared with treatment that did not cover MRSA, specifically cephalexin. Although there was no significant difference between the groups, there were modest non-significant trends favouring the dual therapy treatment that included anti-MRSA compared with cephalexin-only treatment. Surprisingly, 10% of the per-protocol study population, despite having negative soft tissue ultrasounds, had MRSA at treatment failure. This suggests that in MRSA-endemic areas like the USA, a sizeable minority of patients with cellulitis have MRSA as their aetiology, lack an organised abscess at the time of presentation, but will have an infection that will evolve into a purulent type given enough time and/or exposure to antibiotics.
One could take a ‘glass half empty’ approach to cellulitis that highlights the small chance of MRSA, and thus choose dual therapy or an equivalent combination that covers MRSA, worrying about the small chance that cephalexin alone will be insufficient to treat outpatient cellulitis. Alternately, one could take the ‘glass half full’ optimistic approach and rationalise that MRSA is uncommon and the benefit of additional MRSA coverage to cephalexin is small to nil. Probably, the latter approach is the most prudent. No subjects in the trial progressed to invasive disease when they failed, suggesting that even if clinical failure occurs, severe and life-threatening consequences would be very unlikely.
Implications for practice
Given the high incidence of skin infections, which has an incidence of approximately 4 per 100 persons per year,3 it would wise to practice good antibiotic stewardship. Avoiding overly broad treatment for outpatient cellulitis will minimise the selective antibiotic pressure that further drives the emergence of drug-resistant bacteria.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.