Krishan Yadav: High-Dose versus Standard Dose Cephalexin for Non-Purulent Cellulitis

  1. INTRODUCTION

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.

  1. OBJECTIVES

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. 

  1. METHODS

3.1 Study Design and Setting

A pilot double-blind RCT at The Ottawa Hospital Civic Campus.

3.2 Population

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

  1. Age <18
  2. Already taking antibiotics
  3. Abscess requiring drainage
  4. Prior SSTI secondary to methicillin-resistant Staphylococcus aureus
  5. SSTI from bite wound or post-surgical
  6. Immunocompromised (chemotherapy, febrile neutropenia, transplant)
  7. Known renal impairment (CrCl <60 mL/min)
  8. Pregnancy or breastfeeding
  9. 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.

3.3 Intervention

High-dose cephalexin: 1000mg PO QID ´ 7d

(Seven days was chosen based on a survey of Canadian emergency physicians.5)

3.4 Comparator

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.

3.6 Assessment

We will record at the index visit:

  • Demographics (age and sex)
  • Comorbidities
  • 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.

  1. IMPORTANCE

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.

REFERENCES

  1. 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.
  2. Murray H, Stiell I, Wells G. Treatment failure in emergency department patients with cellulitis. CJEM. 2005;7(4):228-234.
  3. 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.
  4. 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.
  5. 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.

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