Cellulitis
Conditions
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.
Interventions
DRUGCephalexin
1000 mg PO QID for 7 days
DRUGCephalexin + placebo
500 mg PO QID plus oral placebo for 7 days
Sponsors
The Ottawa Hospital Academic Medical Association
Canadian Association of Emergency Physicians
Ottawa Hospital Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Eligible patients will be randomized (1:1) to high-dose versus standard-dose arms. The randomization sequence will be computer-generated by a statistician
Intervention model description
The Investigators will conduct a parallel arm double-blind randomized controlled pilot trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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
1. Age \<18 years 2. Patient already taking oral antibiotics 3. Treating physician decides that intravenous therapy is required 4. Abscess requiring an incision and drainage or needle aspiration procedure 5. Known prior cellulitis secondary to methicillin-resistant Staphylococcus aureus 6. Cellulitis secondary to a human or animal bite wound 7. Surgical site infection 8. Malignancy and currently being treated with chemotherapy 9. Febrile neutropenia (temperature \>=38C plus absolute neutrophil count \<500 cells/uL) 10. Solid organ or bone marrow transplant recipient 11. Renal impairment with creatinine clearance \<30 mL/min 12. Pregnant or breastfeeding 13. Allergy to cephalosporins or history of anaphylaxis to penicillin 14. Inability to provide consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| Protocol Adherence | 7 days | % of patients that are adherent to allocated treatment for 7 days |
| 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 |
| 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 |
| 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) |
Countries
Canada
Participant flow
Recruitment details
Three randomized patients were excluded due to an alternat diagnosis, thus 66 moved forward for analysis (33 in each arm)
Participants by arm
| Arm | Count |
|---|---|
| High Dose Cephalexin The intervention is high-dose cephalexin (1000mg PO QID) for seven days
Cephalexin: 1000 mg PO QID for 7 days | 33 |
| Standard Dose Cephalexin The comparator is standard-dose cephalexin (500mg PO QID) plus oral placebo for seven days
Cephalexin: 500 mg PO QID plus oral placebo for 7 days | 33 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 2 |
Baseline characteristics
| Characteristic | High Dose Cephalexin | Standard Dose Cephalexin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical >=65 years | 13 Participants | 10 Participants | 23 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 22 Participants | 41 Participants |
| Age, Continuous | 56 years | 57 years | 56 years |
| BMI | 30.4 kg/m2 | 27.9 kg/m2 | 29.1 kg/m2 |
| Height | 1.72 metres | 1.67 metres | 1.7 metres |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Canada | 33 participants | 33 participants | 66 participants |
| Sex: Female, Male Female | 13 Participants | 13 Participants | 26 Participants |
| Sex: Female, Male Male | 20 Participants | 20 Participants | 40 Participants |
| Weight | 90 kg | 80 kg | 84.5 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 31 |
| other Total, other adverse events | 12 / 31 | 8 / 31 |
| serious Total, serious adverse events | 0 / 31 | 0 / 31 |
Outcome results
Primary
Oral Antibiotic Treatment Failure
% 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)
Time frame: Each patient was assessed for oral antibiotic treatment failure at the day 3 and day 7 follow-ups
Population: Of 66 patients enrolled and confirmed to have cellulitis by the Principal Investigator, 62 were assessed for treatment failure. Four were lost to follow-up and therefore could not be assessed for treatment failure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients Identified as Eligible for the Trial | Oral Antibiotic Treatment Failure | 3.2 percentage of enrolled in each arm |
| Standard Dose Cephalexin | Oral Antibiotic Treatment Failure | 12.9 percentage of enrolled in each arm |
Primary
Patient Recruitment Rate
% of patients recruited into the trial
Time frame: 6 months
Population: Number of patients within the 6 months of the trial that were determined to be eligible of the trial. Of 134, 69 were successfully approached and recruited in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients Identified as Eligible for the Trial | Patient Recruitment Rate | 51.5 percentage of eligible patients |
Secondary
Ability to Approach Eligible Patients
% of eligible patients that were identified as being eligible but missed (staff was unable to approach to recruit in trial)
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients Identified as Eligible for the Trial | Ability to Approach Eligible Patients | 14.2 percentage of eligible patients |
Secondary
Adverse Events
% of patients with adverse events (e.g. vomiting, diarrhea, rash) at 14-days measured via telephone follow-up
Time frame: 14 days
Population: Of the 66 enrolled and confirmed to have cellulitis, 4 were lost to follow-up. The remaining 62 were assessed for adverse events.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Patients Identified as Eligible for the Trial | Adverse Events | Nausea or vomiting | 9.7 percentage of enrolled in each arm |
| Patients Identified as Eligible for the Trial | Adverse Events | Diarrhea | 16.1 percentage of enrolled in each arm |
| Patients Identified as Eligible for the Trial | Adverse Events | Abdominal pain | 3.2 percentage of enrolled in each arm |
| Patients Identified as Eligible for the Trial | Adverse Events | Rash | 3.2 percentage of enrolled in each arm |
| Patients Identified as Eligible for the Trial | Adverse Events | Other | 6.5 percentage of enrolled in each arm |
| Patients Identified as Eligible for the Trial | Adverse Events | No adverse events to report | 61.3 percentage of enrolled in each arm |
| Standard Dose Cephalexin | Adverse Events | Other | 9.7 percentage of enrolled in each arm |
| Standard Dose Cephalexin | Adverse Events | Nausea or vomiting | 3.2 percentage of enrolled in each arm |
| Standard Dose Cephalexin | Adverse Events | Rash | 6.5 percentage of enrolled in each arm |
| Standard Dose Cephalexin | Adverse Events | Diarrhea | 6.5 percentage of enrolled in each arm |
| Standard Dose Cephalexin | Adverse Events | No adverse events to report | 74.2 percentage of enrolled in each arm |
| Standard Dose Cephalexin | Adverse Events | Abdominal pain | 0 percentage of enrolled in each arm |
Secondary
Assessment of Blinding
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.
Time frame: Patient were asked which dose of cephalexin they believe they received during the day 7 follow-up
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients Identified as Eligible for the Trial | Assessment of Blinding | 33.3 percentage of enrolled per arm |
| Standard Dose Cephalexin | Assessment of Blinding | 60.1 percentage of enrolled per arm |
Secondary
Clinical Cure
% of patients with clinical cure (no erythema, pain and fever) at days 7 and 14
Time frame: Assessed for clinical cure at day 7and day 14 follow-up
Population: Of the 66 enrolled and confirmed to have cellulitis, 4 were lost to follow-up. The remaining 62 were analyzed for clinical cure at days 7 and 14.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Patients Identified as Eligible for the Trial | Clinical Cure | Clinical cure at day 14 | 45.2 percentage of enrolled in each arm |
| Patients Identified as Eligible for the Trial | Clinical Cure | Clinical cure at day 7 | 16.1 percentage of enrolled in each arm |
| Standard Dose Cephalexin | Clinical Cure | Clinical cure at day 14 | 38.7 percentage of enrolled in each arm |
| Standard Dose Cephalexin | Clinical Cure | Clinical cure at day 7 | 6.5 percentage of enrolled in each arm |
Secondary
Loss 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
Time frame: Determined at final follow-up (day 14) if lost to follow-up
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients Identified as Eligible for the Trial | Loss to Follow-up | 6.1 percentage of enrolled per arm |
| Standard Dose Cephalexin | Loss to Follow-up | 6.1 percentage of enrolled per arm |
Secondary
Protocol Adherence
% of patients that are adherent to allocated treatment for 7 days
Time frame: 7 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients Identified as Eligible for the Trial | Protocol Adherence | 75.8 percentage of enrolled and analyzed |
| Standard Dose Cephalexin | Protocol Adherence | 75.8 percentage of enrolled and analyzed |
Secondary
Unplanned ED Visits or Hospitalization
% of patients with unplanned i) return ED visits; and ii) hospitalization, measured via 14-day telephone follow-up
Time frame: 14 days
Population: Of the 66 enrolled and confirmed to have cellulitis, 4 were lost to follow-up. The remaining 62 were assessed for unplanned ED visit or hospitalizations at the day 14 telephone follow-up
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Patients Identified as Eligible for the Trial | Unplanned ED Visits or Hospitalization | Unplanned visit to family doctor within 14 days | 6.5 percentage of enrolled in each arm |
| Patients Identified as Eligible for the Trial | Unplanned ED Visits or Hospitalization | Unplanned return to ED within 14 days | 22.6 percentage of enrolled in each arm |
| Patients Identified as Eligible for the Trial | Unplanned ED Visits or Hospitalization | Unplanned hospitalization within 14 days | 0 percentage of enrolled in each arm |
| Standard Dose Cephalexin | Unplanned ED Visits or Hospitalization | Unplanned visit to family doctor within 14 days | 6.5 percentage of enrolled in each arm |
| Standard Dose Cephalexin | Unplanned ED Visits or Hospitalization | Unplanned return to ED within 14 days | 16.1 percentage of enrolled in each arm |
| Standard Dose Cephalexin | Unplanned ED Visits or Hospitalization | Unplanned hospitalization within 14 days | 0 percentage of enrolled in each arm |