High-dose vs. Standard-dose Cephalexin for Cellulitis

Phase 4

Completed

Conditions: Cellulitis

Interventions: Drug: Cephalexin
Drug: Cephalexin + placebo

Registration Number: NCT04471246

Lead Sponsor: Ottawa Hospital Research Institute

Brief Summary: Cellulitis is a painful bacterial infection of the skin and underlying tissue that needs antibiotic treatment. There are approximately 193,000 visits to Canadian emergency departments (EDs) each year for cellulitis. Emergency doctors who treat patients with cellulitis must decide on the correct antibiotic agent, dose, duration and frequency. Cellulitis is most commonly treated with the oral antibiotic cephalexin. However, there has been little research to guide doctors with respect to cellulitis treatment, which has led to an overuse of intravenous antibiotics. In addition, the current treatment failure rate of 20% is unacceptably high. When compared to standard-dose oral cephalexin, high-dose oral cephalexin may reduce treatment failure, which would help decrease the need for intravenous antibiotics and subsequent hospitalization. A well-designed clinical trial is necessary to determine if high-dose oral cephalexin reduces treatment failure for cellulitis patients. This pilot trial will determine the feasibility and design of such a clinical trial.

Detailed Description: 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:

1. New fever (temperature ≥ 38.0C) or persistent fever at Day 3 follow up; or

2. Increasing area of erythema ≥20% from baseline; or

3. Increasing pain ≥2 points from baseline (numeric rating scale)

The secondary effectiveness outcomes are:

1. Clinical cure (no erythema, pain and fever) at day 7

2. Clinical response (≥20% reduction in area of erythema compared to baseline) at day 3

3. Adverse events (e.g. vomiting, diarrhea, rash) at 14-day telephone follow-up

4. 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 69

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
High Dose Cephalexin	Cephalexin	The intervention is high-dose cephalexin (1000mg PO QID) for seven days
Standard Dose Cephalexin	Cephalexin + placebo	The comparator is standard-dose cephalexin (500mg PO QID) plus oral placebo for seven days

Primary Outcome Measures

Name	Time	Method
Patient Recruitment Rate	6 months	% of patients recruited into the trial
Oral Antibiotic Treatment Failure	Each patient was assessed for oral antibiotic treatment failure at the day 3 and day 7 follow-ups	% of patients with oral antibiotic treatment failure 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: 1. New fever (temperature ≥ 38.0°C) or persistent fever at Day 3 follow up; or 2. Increasing area of erythema ≥20% from baseline; or 3. Increasing pain ≥2 points from baseline (numeric rating scale)

Secondary Outcome Measures

Name	Time	Method
Clinical Cure	Assessed for clinical cure at day 7and day 14 follow-up	% of patients with clinical cure (no erythema, pain and fever) at days 7 and 14
Adverse Events	14 days	% of patients with adverse events (e.g. vomiting, diarrhea, rash) at 14-days measured via telephone follow-up
Unplanned ED Visits or Hospitalization	14 days	% of patients with unplanned i) return ED visits; and ii) hospitalization, measured via 14-day telephone follow-up
Loss to Follow-up	Determined at final follow-up (day 14) if lost to follow-up	% of patients lost to follow-up at 14 days Patients were lost to follow-up if they did not attend any follow-up visit at days 3, 7 and 14
Ability to Approach Eligible Patients	6 months	% of eligible patients that were identified as being eligible but missed (staff was unable to approach to recruit in trial)
Assessment of Blinding	Patient were asked which dose of cephalexin they believe they received during the day 7 follow-up	The percentage of patients that correctly guessed their treatment allocation. To assess how well blinded the patients were to the medication they received, each was asked during the day 7 follow-up, after having finished their medication, to indicate which treatment they believe they received (500mg of 1000mg of cephalexin). Once unblinded to the allocation (after enrollment and follow-up complete), it was possible to determine which patients correctly guess the dose of medication they received.
Protocol Adherence	7 days	% of patients that are adherent to allocated treatment for 7 days