Adding Anti-MRSA to Cephalexin No Better for Simple Cellulitis

Diana Swift

May 24, 2017

Adding a methicillin-resistant Staphylococcus aureus (MSRA)-specific antibiotic to cephalexin monotherapy for uncomplicated cellulitis did not yield higher rates of clinical cure, a study published online May 23 in JAMA reports.

"In this randomized trial involving 500 mostly adult participants, a regimen with activity against MRSA, cephalexin plus trimethoprim-sulfamethoxazole, was not superior to a regimen lacking MRSA activity, cephalexin (plus placebo)," Gregory J. Moran, MD, an emergency medicine physician at Olive View-University of California, Los Angeles Medical Center, and colleagues write.

They note that emergency room visits for skin and soft tissue infections have increased with the rise of community-associated MRSA. The Infectious Diseases Society of America recommends that patients with cellulitis without systemic signs of infection, penetrating trauma, evidence of MRSA elsewhere, or injection drug use should receive an antimicrobial agent active only against streptococci. Despite these guidelines, however, US physicians frequently prescribe regimens that include MRSA activity for simple cellulitis. The researchers designed the study to explore whether this addition actually improves clinical outcomes in uncomplicated cellulitis, with a minimum 10% difference in cure rate considered significant.

Clinical cure rates were 83.5% for cephalexin alone vs 85.5% for combination therapy in a per protocol analysis (primary outcome population) compared with 69.0% vs 76.2%, respectively, in a modified intention-to-treat analysis. This suggests some potential superiority for combination therapy, the researchers write.

"However, because imprecision around the findings in the modified intention-to-treat analysis included a clinically important difference favoring cephalexin plus trimethoprim-sulfamethoxazole, further research may be needed," they add.

During 2009 to 2012, the study enrolled outpatients aged 12 years and older at five hospital emergency departments. Participants had uncomplicated cellulitis with no wound, abscess, or purulent drainage. The median patient age was approximately 40 years, 58.4% were male, and 10.9% had diabetes.

The researchers randomly assigned 248 patients to receive cephalexin, 500 mg 4 times daily, plus trimethoprim-sulfamethoxazole, 320 mg/1600 mg twice daily, for 7 days, and 248 patients to receive cephalexin monotherapy plus placebo for 7 days.

The study included 496 (99%) patients in the modified intention-to-treat analysis and 411 (82.2%) in the per protocol analysis.

In the per protocol analysis, clinical cure occurred in 182 participants in the combination therapy group compared with 193 in the cephalexin group, for a difference of −2.0% (95% confidence interval, −9.7% to 5.7%; P = .50).

But in the modified intention-to-treat population, clinical cure occurred in 189 participants in the combination therapy group compared with 171 in the monotherapy/placebo group, for a difference of 7.3%. The 95% confidence interval for this difference, however, was −1.0% to +15.5%, which included the minimum clinically important difference of 10% (P = .07).

Both groups exhibited comparable secondary outcomes such as drainage procedures, changes in erythema extent, presence of swelling/induration, tenderness, and invasive infections. Overall, adverse events were also similar in both groups, with about 90% classified as mild and the most frequent being gastrointestinal.

Interestingly, MRSA was cultured in 41 patients (10% of the per protocol population) who had treatment failure, suggesting MRSA plays a role in some cases of cellulitis that may involve small abscesses missed on screening or still developing.

Some researchers believe many cases of cellulitis may be misdiagnosed and are actually noninfectious conditions such as stasis dermatitis, the authors write. "It is possible that some participants [in our study] did not truly have an infection, but these participants likely reflect those treated for cellulitis in typical practice," they write.

These findings indicate that most cases of nonpurulent cellulitis can be safely treated without the addition of MRSA-targeting antimicrobials, Emily K. Shuman, MD, and Preeti N. Malani, MD, MSJ, from the Division of Infectious Diseases at the University of Michigan, Ann Arbor, write in an accompanying editorial. Dr Shuman and Dr Milani were not involved in the study.

Similar to the authors, they note that the modified intention-to-treat analysis raises the possibility that adding trimethoprim-sulfamethoxazole may prove somewhat superior to cephalexin alone, cautioning, however, that, "the results of this analysis were likely skewed by a relatively large number of patients who did not complete the recommended course of therapy and were thus excluded, although this likely reflects what occurs in everyday practice."

Dr Shuman and Dr Malani point out that skin infections increased in the United States from 4.6 million in 1997 to 9.6 million in 2006. "Although prescribing antimicrobials with activity against MRSA may be reasonable in some cases of skin and soft tissue infection, it is likely that the pendulum has swung too far in the direction of covering empirically for MRSA 'just in case,' " they write. They add that trimethoprim-sulfamethoxazole has weak activity against streptococci.

The commentators also point out that although adverse events were similar in both groups in the current study, previous research has found antibacterial combination therapy to be associated with more adverse effects such as diarrhea and a very common driver of emergency department use. "As these studies demonstrate, and as the study by Moran et al suggests, the addition of a second antimicrobial 'just in case' may often do more harm than good and may not be necessary for treatment of nonpurulent cellulitis without abscess."

This study was supported by a grant to Dr Moran and Dr Talan from the National Institute of Allergy and Infectious Diseases. Dr Moran reports receiving a grant and consulting fees from Allergan and a grant from Cempra. One author reports receiving a grant and consulting fees from Allergan. One author reports receiving speakers bureau/consultation fees from Merck, Allergan, the Medicines Company, Cempra, Summit Therapeutics, Tetraphase Pharmaceuticals, Paratek Pharmaceuticals, and Janssen Research and Development and research grants from the Centers for Disease Control and Prevention, Merck, and Cempra. Three authors report receiving a grant and consulting fees from Allergan. One author reports receiving consulting fees from Allergan, Cempra, GlaxoSmithKline, and Merck. The remaining authors and the editorialists have disclosed no relevant financial relationships.

JAMA. Published online May 23, 2017. Article abstract, Editorial extract

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