By Richard R. Watkins, MD, MS, FACP, Division of Infectious Diseases, Akron General Medical Center, Akron, OH; Associate Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH. Dr. Watkins reports no financial relationships in this field of study.
Source: Pallin DJ, et al. Clinical Trial: Comparative Effectiveness of Cephalexin Plus Trimethoprim-Sulfamethoxazole Versus Cephalexin Alone for Treatment of Uncomplicated Cellulitis: A Randomized Controlled Trial. Clin Infect Dis 2013 Apr 1. [Epub ahead of print]
Uncomplicated cellulitis, defined as cellulitis without abscess, is most often caused by streptococci. The widespread dissemination of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has led to increased prescribing of antibiotics for cellulitis with activity against the organism (e.g. trimethoprim-sulfamethoxazole, doxycycline, clindamycin, and linezolid). This is despite the fact that CA-MRSA is associated with purulent cellulitis and abscesses, and optimal management is incision and drainage, not antibiotic therapy.1 Pallin and colleagues sought to determine if treating uncomplicated cellulitis with antibiotics targeting CA-MRSA and streptococci would lead to better outcomes compared to therapy against streptococci alone.
The study was a double-blind, randomized, multicenter, placebo-controlled trial conducted between June 2007 and December 2011. Participants were enrolled from one of three emergency departments in an area considered endemic for CA-MRSA. The diagnosis of cellulitis was made during routine clinical care by attending physicians. Most of the participants were generally healthy and were enrolled if they had uncomplicated cellulitis or if <1 cc of pus was observed or reported by the patient. A total of 146 subjects were included in the intent-to-treat analysis. All received cephalexin, while 73 also received trimethoprim-sulfamethoxazole (intervention group) and 73 were given placebo (control group). Participants were told to stop taking the antibiotics 3 days after they believed the infection to be cured, for a minimum of 7 days and a maximum of 14. Compliance was monitored by a log filled out by the participants. The primary outcome was the risk difference for cure, which was determined by an in-person exam at 2 weeks and a follow-up telephone interview and review of medical records at 1 month. Failure was defined as subsequent hospitalization, altering of antibiotics, drainage of an abscess, or recurrence of infection within 30 days. The secondary outcome was the association of nasal MRSA carriage at enrollment with clinical response.
The investigators found no significant benefit from the addition of trimethoprim-sulfamethoxazole, including those participants with purulence. Clinical cure was obtained in 62 of the 73 (85%) in the intervention group vs. 60 of 73 (82%) in the control group (P = 0.66). Five participants in each group had progression to abscess (P = 1.0). Seven of 142 (4.9%) for whom data were available were colonized with MRSA, and this was not associated with response to therapy (P = 0.67). There was a high rate of adverse events among the participants (51%) which was similar in intervention group (49%) vs. control group (53%) (P = 0.62). Most of the adverse events were minor (e.g. diarrhea, nausea, vomiting) but one participant in the control group developed C. difficile infection.
This study is timely and has important clinical implications. Given the current epidemic of CA-MRSA, it seems biologically plausible that targeting this organism when treating cellulitis would be advantageous. Indeed, the investigators noted they expected to find a benefit in the intervention group. That no benefit was found with the addition of trimethoprim-sulfamethoxazole seems to support the current MRSA treatment guidelines from the Infectious Disease Society of America (IDSA), which recommend not targeting CA-MRSA in nonpurulent cellulitis.2 The study included 19 subjects (13% of the total) with purulence, of whom 8 received anti-MRSA therapy and 11 did not. It was somewhat surprising that no difference was found between their outcomes. However, it is possible that the small number of patients prevented the detection of a significant difference.
The study had a few limitations. The researchers chose to exclude diabetics, and whether the findings can be extrapolated to these patients (most likely they can) requires further investigation. The diagnosis of cellulitis itself is subjective and open to interpretation. Also, since not all patients colonized with MRSA have positive nasal swabs, perhaps if axilla and groins had been collected a correlation between colonization and treatment response would have been observed. Should we abandon empiric coverage for CA-MRSA in uncomplicated cellulitis? The IDSA guidelines say yes and now there is evidence-based data to support this recommendation. However, I still recommend caution in patients with a previous history of MRSA or who are colonized, especially if purulence is present. A larger study that addresses these two scenarios would be beneficial.
1. Schmitz GR, et al. Randomized controlled trial of trimethoprim-sulfamethoxazole for uncomplicated skin abscesses in patients at risk for community-associated methicillin-resistant Staphylococcus aureus infection. Ann Emerg Med 2010;56:283-287.
2. Liu C, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52:e18-55.