Pushing for New Treatment Regimens in Uncomplicated Cellulitis

Sahil Desai, Mercer University College of Pharmacy

Over half of the 14 million annual visits for skin and soft tissue infections (SSTIs) in the U.S. are caused by community-acquired methicillin-resistant Staphylococcus aureus (MRSA). These infections can be classified by severity and evidence of purulence. [1] Uncomplicated SSTIs are defined as localized infections without evidence of systemic response and do not meet the Systemic Inflammatory Response Syndrome (SIRS) criteria. These criterium include: white blood cell counts <4,000 μL or >12,000 μL; temperature <36°C or >38°C; respiratory rate >20 beats per minute (bpm); and heart rate >90 bpm. Guidelines recommend antibiotics effective against streptococci for uncomplicated cellulitis [2] but new treatment regimens are being explored to combat MRSA. [3]

Effect of Cephalexin Plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis [4]

Design Multicenter, double-blind, randomized; N= 411
Objective To compare cephalexin plus sulfamethoxazole-trimethoprim (SMZ-TMP) with cephalexin alone in treating uncomplicated cellulitis in the emergency department
Study Groups Cephalexin plus SMZ-TMP (n= 218); cephalexin plus placebo (n= 193)
Methods Patients older than 12 years of age with uncomplicated cellulitis, purulent drainage, and/or a wound caused by a possible infection were included.  Those with underlying skin conditions or any patient with a history of intravenous drug use and with concurrent fever, infection, or immunosuppression were excluded.

Patients received 7 days of cephalexin 500 mg four times daily plus four placebo pills twice daily or cephalexin 500 mg four times daily plus four pills of SMZ-TMP 400 mg/80 mg twice daily. Follow up evaluations occurred on days 3 to 4 (during therapy), days 8 to 10 (end of therapy), days 14 to 21 (test of clinical cure), and days 49 to 63 (extended follow-up) after enrollment.

Participants were classified with a clinical cure if they did not meet failure criteria at or before the the test of clinical cure visit. Some of this criteria included fever; increase in the maximal dimension of erythema by more than 25% from baseline; or worsening of swelling and tenderness by the visit during the treatment follow up visits.

“Per protocol” was participants who either took ≥ 75% of total dose of the study medication during the first five days and had an in-person test of cure visit or had clinical failure before the visit and received dose within the first 48 hours. “Modified intention to treat” (mITT-1) were those who had in person or telephone assessment at test of cure visit and who withdrew or were lost prior to evaluation. Those who had follow-up evaluation at any time of study were classified as mITT-2. Food and Drug Administration (FDA) early guidance endpoint were patients that completed the follow-up evaluation 48 to 72 hours after the start of treatment. The last three groups took ≥ 1 dose of study drug as well.

Duration 39 months – enrollment: April 2009 to June 2012; final follow up: August 2012
Primary Outcome Measure Clinical cure of cellulitis at the test-of-clinical-cure visit after enrollment
Baseline Characteristics  

  Cephalexin plus SMZ-TMP Cephalexin plus placebo
Median age, years (interquartile range) 39 (29-49) 41 (28-49)
Male, n (%) 137 (62.8) 103 (53.4)
Race, n (%)
White 123 (56.4) 111 (57.5)
Black 75 (34.4) 68 (35.2)
Asian 2 (0.9) 2 (1.0)
Other/Unknown 18 (8.2) 12 (6.2)
Median symptom duration, days (interquartile range) 3.0 (2.0-4.0) 3.0 (2.0-4.0)
Cellulitis location, n (%)
Head or neck 19 (8.7) 9 (4.7)
Trunk, abdomen, or back 17 (7.8) 19 (9.8)
Groin or buttocks 7 (3.2) 8 (4.1)
Upper extremity 52 (23.9) 50 (25.9)
Lower extremity 123 (56.4) 107 (55.4)
Temperature > 38ºC (>100.4ºF) at baseline 3 (1.4) 2 (1.0)
Results
  Cephalexin plus SMZ-TMP Cephalexin plus placebo Mean difference, % (95% CI) p-value
Clinical cure, n/total (%)
Per protocol 182/218 (83.5) 165/193 (85.5) -2.0 (-9.7 to 5.7) 0.50
mITT-1 189/248 (76.2) 171/248 (69.0) 7.3 (-1.0 to 15.5) 0.07
mITT-2 202/241 (83.8) 198/239 (82.8) 1.0 (-6.1 to 8.1) 0.85
FDA guidance early end point 63/237 (26.6) 62/233 (26.6) 0.0 (-8.4 to 8.4) 0.94

 

Adverse Events Common Adverse Events (cephalexin plus SMZ-TMP vs. cephalexin plus placebo): diarrhea (21.8% vs. 19%), nausea (19.8% vs. 16.5%), vomiting (7.7% vs. 7.7%)
Serious Adverse Events (cephalexin plus SMZ-TMP): acute-on-chronic kidney injury (n= 1)
Percentage that Discontinued due to Adverse Events (cephalexin plus SMZ-TMP vs. cephalexin plus placebo): 0.4% vs. 1.2% (specific reasons not mentioned)
Study Author Conclusions Cephalexin plus SMZ-TMP did not result in higher rates of clinical resolution of cellulitis in the per-protocol analysis.

 

In a clinical setting, compliance and drug tolerance play crucial roles. However, the per-protocol analysis may not have shown efficacy of the combined treatment as within-population compliance could have differed. Although statistical significance was not established, the parameters of the mITT-1 population represented an ideal setup for clinical significance to be demonstrated. The data from this study was collected 5 years ago; thus, the potential of different MRSA cellulitis strains to have acquired resistance cannot be ruled out.

 

References

[1] Eron LJ, et al. Managing skin and soft tissue infections. J Antimicrob Chemother. 2003;52(suppl 1):i3–i17.

[2] 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(2):147-59.

[3] Eckmann C, Dryden M. Treatment of complicated skin and soft-tissue infections caused by resistant bacteria: value of linezolid, tigecycline, daptomycin and vancomycin. Eur J Med Res. 2010;15(12):554-63.

[4]  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(20):2088-2096.

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