Most emergency department (ED) patients with non-purulent skin and soft tissue infections (SSTIs; cellulitis or erysipelas) are treated with outpatient oral antibiotics. Guidelines recommend cephalexin 500mg QID for a minimum of five days.1 The oral antibiotic treatment failure rate in Canadian EDs is 20%.2-4 This unacceptably high failure rate may be due to suboptimal dosing. No studies have evaluated whether high-dose cephalexin (1000mg QID) is superior to standard-dose (500mg QID) cephalexin. We plan to conduct a pilot randomized controlled trial (RCT) to determine feasibility for a multicenter RCT to address this important question.
The primary outcome is oral antibiotic treatment failure, defined as any of the following after ³48 hours of therapy: (i) step-up to outpatient intravenous therapy; or (ii) hospitalization for intravenous therapy. Secondary outcomes include end-of-therapy (EOT) clinical cure (no erythema, pain or fever), proportion requiring additional antibiotics, and adverse events.
3.1 Study Design and Setting
A pilot double-blind RCT at The Ottawa Hospital Civic Campus.
3.2.1 Inclusion Criteria
Adults (age ³18) with non-purulent SSTIs that the treating physician intends to treat with oral antibiotics.
3.2.2 Exclusion Criteria
- Age <18
- Already taking antibiotics
- Abscess requiring drainage
- Prior SSTI secondary to methicillin-resistant Staphylococcus aureus
- SSTI from bite wound or post-surgical
- Immunocompromised (chemotherapy, febrile neutropenia, transplant)
- Known renal impairment (CrCl <60 mL/min)
- Pregnancy or breastfeeding
- Cephalosporin allergy
3.2.3 Patient Selection
A trained research assistant (RA) will identify and enroll eligible patients, and screen the ED log for missed cases.
High-dose cephalexin: 1000mg PO QID ´ 7d
(Seven days was chosen based on a survey of Canadian emergency physicians.5)
Standard-dose cephalexin: 500 mg PO QID plus placebo ´ 7d
3.5 Allocation Concealment and Blinding
The hospital pharmacy will independently prepare study medications with identical capsules. Patients, physicians and researchers will be blinded. Participants will be randomized (1:1) in computer-generated variable block sizes of four to six.
We will record at the index visit:
- Demographics (age and sex)
- Triage vital signs
- SSTI location and maximum dimensions of erythema
- Adverse events (medication events, unplanned ED visits, hospitalization)
The RA will assess patients in the ED for the primary outcome at: 1) mid-therapy (Day 3); and 2) EOT (Day 7). If a patient cannot return to the ED, the RA will contact the patient by telephone.
3.7 Data Analysis
For categorical variables, the chi-square test will be used to test for statistical differences between the groups. Differences between means of continuous variables will be assessed using Student’s t-test for independent samples. Analysis will be according to the intention-to-treat principle.
The oral antibiotic treatment failure rate is unacceptably high, which may be due to suboptimal dosing. This study will be the first to compare high-dose to standard-dose cephalexin for ED patients with non-purulent SSTIs. The results will help inform the design and implementation of a larger, multicenter RCT to answer this important clinical question.
- 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):e10-52. doi: 10.1093/cid/ciu1444.
- Murray H, Stiell I, Wells G. Treatment failure in emergency department patients with cellulitis. CJEM. 2005;7(4):228-234.
- Peterson D, McLeod S, Woolfrey K, McRae A. Predictors of failure of empiric outpatient antibiotic therapy in emergency department patients with uncomplicated cellulitis. Acad Emerg Med. 2014;21(5):526-531.
- Yadav K, Suh KN, Eagles D, et al. Predictors of Oral Antibiotic Treatment Failure for Non-Purulent Skin and Soft Tissue Infections in the Emergency Department. Acad Emerg Med. 2018:13492.
- Yadav K, Gatien M, Corrales-Medina V, Stiell I. Antimicrobial treatment decision for non-purulent skin and soft tissue infections in the emergency department. CJEM. 2017;19(3):175-180. doi: 110.1017/cem.2016.1347. Epub 2016 Aug 1017.