High-dose vs. Standard-dose Cephalexin for Cellulitis

Background: Cellulitis is a common clinical condition that represents up to 3% of all emergency department (ED) visits. The current treatment failure rate is approximately 20%. This high treatment failure rate may be due to suboptimal dosing of cephalexin. The Investigators hypothesize that high-dose cephalexin may lead to lower rates of treatment failure and subsequently improved patient outcomes (less hospitalizations and avoidance of intravenous antibiotics)

Rationale: Before embarking on a large, multicenter trial, it is essential to conduct a smaller pilot to test and refine study procedures and to demonstrate feasibility.

Methods:

Design: The investigators will conduct a parallel arm double-blind randomized controlled pilot trial at the Civic and General campus ED of The Ottawa Hospital (TOH). The study will operate seven days a week from 0800 to 2000 over a 6-month timeframe. TOH Pharmacy will follow a randomization sequence and prepare study medication packages. Study medication packages will be dispensed to the patient by a registered nurse (RN).

Patients: Adult (age >=18 years) ED patient with non-purulent cellulitis determined by the treating emergency physician to be eligible for outpatient care with oral antibiotics.

Intervention: High-dose cephalexin (1000 mg PO QID) for seven days.

Comparator: Standard-dose cephalexin (500 mg PO QID) plus placebo for seven days.

Primary Feasibility Outcome: Patient recruitment rate (percentage of approached eligible patients who are successfully recruited). The goal is to recruit at least 29% of eligible patients.

Primary Effectiveness Outcome: 1. Oral antibiotic treatment failure, defined as a change in antibiotic (change in class of oral antibiotic or step up to intravenous therapy) within 7 days due to worsening infection, which is defined as:

• New fever (temperature ≥ 38.0C) or persistent fever at Day 3 follow up; or
• Increasing area of erythema ≥20% from baseline; or
• Increasing pain ≥2 points from baseline (numeric rating scale)

The secondary effectiveness outcomes are:

• Clinical cure (no erythema, pain and fever) at day 7
• Clinical response (≥20% reduction in area of erythema compared to baseline) at day 3
• Adverse events (e.g. vomiting, diarrhea, rash) at 14-day telephone follow-up
• Unplanned i) return ED visits; and ii) hospitalization at 14-day telephone follow-up

Importance: This pilot trial will be the first to compare high-dose cephalexin to standard-dose cephalexin for ED patients with cellulitis. The results of this pilot randomized trial will help inform the design and implementation of a larger, multicenter randomized controlled trial to answer this important clinical question.

Inclusion criteria

Adults (age >=18 years) with non-purulent cellulitis determined by the treating emergency physician to be eligible for outpatient care with oral antibiotics.

Exclusion criteria

• Age <18 years
• Patient already taking oral antibiotics
• Treating physician decides that intravenous therapy is required
• Abscess requiring an incision and drainage or needle aspiration procedure
• Known prior cellulitis secondary to methicillin-resistant Staphylococcus aureus
• Cellulitis secondary to a human or animal bite wound
• Surgical site infection
• Malignancy and currently being treated with chemotherapy
• Febrile neutropenia (temperature >=38C plus absolute neutrophil count <500 cells/uL)
• Solid organ or bone marrow transplant recipient
• Renal impairment with creatinine clearance <30 mL/min
• Pregnant or breastfeeding
• Allergy to cephalosporins or history of anaphylaxis to penicillin
• Inability to provide consent