High-dose Cephalexin for Cellulitis: A Pilot Randomized Controlled Trial
Phase: PHASE4
Conditions: Cellulitis
Sponsor: Ottawa Hospital Research Institute

 
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Study Protocol 
Title: High-dose Cephalexin for Cellulitis: A Pilot Randomized Controlled Trial 
 
Primary Investigator: 
Name: Krishan Yadav 
Title: Assistant Professor, Department of Emergency Medicine, University of Ottawa. Junior 
Clinical Investigator 
Name of Institution: The Ottawa Hospital 
Contact Email: kyadav@toh.ca 
 
Co-Primary Investigator: 
Name: Ian Stiell 
Title: Professor, Department of Emergency Medicine, University of Ottawa. Distinguished 
Professor and Clinical Research Chair, University of Ottawa 
Name of Institution: The Ottawa Hospital 
Contact Email: istiell@ohri.ca 
 
Trial Registration: clinicaltrials.gov NCT04471246 
 

 
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Roles and Responsibilities 
Our team members come from the Department of Emergency Medicine and the Division of 
Infectious Diseases with support from the Ottawa Methods Center. 
 
Dr. Krishan Yadav is Assistant Professor of Emergency Medicine, emergency physician and 
clinical epidemiologist. He is an early career investigator with a main focus on the management 
of cellulitis. He will oversee all aspects of the program. 
 
Dr. Ian Stiell is Professor of Emergency Medicine, Distinguished Professor and Clinical Research 
Chair, Senior Scientist, OHRI, and recipient of a CIHR Foundation Grant. He has extensive 
experience successfully leading randomized controlled trials and will help oversee study design 
and methodology. 
 
Dr. Debra Eagles is Assistant Professor of Emergency Medicine, emergency physician and 
clinical epidemiologist. She is an early career investigator and Associate Scientist, OHRI. She 
will provide input on study design and implementation, and assist with manuscript preparation. 
 
Dr. Kathryn N. Suh is Associate Professor of Infectious Diseases in the Department of Medicine 
and the Associate Director, Infection Prevention and Control Program at The Ottawa Hospital. 
She will provide clinical expertise with respect to study design and analysis. 
 
Dr. Jeff Perry is Professor of Emergency Medicine, Research Chair in Emergency Neurological 
Research, emergency physician and clinical epidemiologist. He will be an advisor for study 
design and implementation.  
 
Dr. Monica Taljaard is Associate Professor, Epidemiology and Public Health at the University of 
Ottawa, and Senior Scientist, OHRI. Dr. Taljaard has extensive experience with standard and 
cluster randomized controlled trials. She will oversee the data analysis. 
 

 
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1. INTRODUCTION 
Background  
Uncomplicated, non-purulent cellulitis is an infection describing the subcutaneous tissue of the 
skin.1 Group A streptococcus (Streptococcus pyogenes), β-hemolytic streptococci and 
methicillin-susceptible Staphylococcus aureus are the most common causative agents for non-
purulent cellulitis. Patients typically present to the emergency department (ED) with pain, 
redness, swelling and induration of the affected skin. The borders of the reddened affected skin 
are irregular and patchy in patients with cellulitis. A minority of patients may exhibit signs of 
systemic illness, such as fever or tachycardia. The diagnosis of non-purulent cellulitis is clinical. 
Once the diagnosis is made, emergency physicians are expected to select appropriate antibiotic 
therapy. The physician must select the appropriate route (oral versus intravenous), agent, dose 
frequency and duration.  
 
Burden of Disease 
Cellulitis is a common condition diagnosed and managed in the ED and carries significant 
financial burden on healthcare systems globally. Extrapolating from US data2, there are 
approximately 193,000 Canadian ED visits per year for cellulitis. Although Canadian data are 
lacking, a single Vancouver ED diagnosed 2234 patients with skin and soft tissue infections from 
2003 to 2004, representing 2% of all ED visits.3 A 2011 report by the Canadian Institute for 
Health Information found that cellulitis was the 5th most common reason for an ED visit in 
patients aged 45 to 64 years.4 Cellulitis is responsible for a significant healthcare system burden 
due to hospital admission and subsequent costs. We conducted a health records review at The 
Ottawa Hospital Civic and General campuses, and found that 29.6% of all ED patients with non-
purulent cellulitis are admitted to hospital.5 A study in the United States reported an average 
cost of $8023 USD for hospitalized patients with skin and soft tissue infections with a mean 
length of stay of 4.9 days.6 
 
Current Guidelines 
Owing to a lack of high-quality evidence, published empiric treatment guidelines are largely 
based on expert opinion.7-10 There are currently no Canadian guidelines for the management of 
skin and soft tissue infections. Despite the increasing burden of this common presentation, 
current evidence is lacking regarding the optimal management of cellulitis.  
 
Oral Antibiotic Therapy: Cephalexin 
The majority of ED patients with non-purulent cellulitis are treated with oral antibiotics and 
discharged home. Oral antibiotic therapy holds several advantages over the intravenous route, 
including lower risk of complications, decreased cost, and increased patient convenience and 
comfort.11,12 We conducted a national survey of 391 emergency physicians, which revealed that 
the majority (89%) prescribed cephalexin as first-line oral antibiotic therapy for a duration of 
seven days to treat patients with non-purulent cellulitis.13 The currently recommended dose 
range of cephalexin is 250mg to 1000mg QID (i.e. four times daily).14 Infectious Disease Society 
of America guidelines for treatment of skin and soft tissue infections recommend cephalexin 
500mg QID for a minimum of five days.7 However, high-dose cephalexin (1000mg) achieves a 
higher peak serum concentration than standard-dose cephalexin (500mg), and reaches serum 

 
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concentrations that are comparable to parenterally (i.e. intravenous or intramuscular) 
administered cephalosporins.15,16 Owing to its short serum elimination half-life (≤1 hour), 
cephalexin must be administered up to four times daily irrespective of the dose used.16  With 
higher peak serum concentrations, administering high-dose cephalexin may lead to a reduction 
in treatment failures for patients with non-purulent cellulitis. Locally, infectious disease 
specialists in Ottawa recommend the use of high-dose cephalexin, but this is not based on high-
quality evidence. There are no published studies evaluating whether high-dose cephalexin 
(1000mg QID) is superior to standard-dose (500mg QID) cephalexin. 
 
Oral Antibiotic Treatment Failure 
The oral antibiotic treatment failure rate in Canadian EDs is approximately 20%.5,17,18 If an oral 
antibiotic treatment failure occurs, patients are typically switched to intravenous therapy and 
may require hospitalization. Intravenous therapy has many disadvantages, including patient 
inconvenience, patient discomfort, the added risk of intravenous line complications and higher 
cost. The current high oral antibiotic treatment failure rate may be due to suboptimal dosing of 
first-line oral therapy. We hypothesize that high-dose cephalexin may lead to lower rates of 
treatment failure and subsequently improved patient outcomes (fewer hospitalizations and 
avoidance of intravenous antibiotic complications). 
 
 
2. RATIONALE 
Before embarking on a large, multicenter trial, it is essential to conduct a smaller pilot to test 
and refine study procedures and demonstrate that it is feasible to proceed with a multicentre 
trial.  
 
 
3. RESEARCH QUESTION & OBJECTIVES 
The ultimate goals of this research are to reduce antibiotic treatment failure, return ED visits 
and use of outpatient intravenous antibiotics. The specific goals of this double-blind pilot 
randomized controlled trial are to (1) establish feasibility and refine study procedures before 
embarking on a larger, fully powered multicenter trial; and (2) generate preliminary evidence of 
effectiveness comparing high-dose to standard-dose cephalexin for non-purulent cellulitis.  
Our specific objectives are to:  
1. Measure feasibility outcomes, including recruitment rate, success of blinding and adherence; 
and 
2. Measure patient outcomes, including oral antibiotic treatment failure rate and frequency of 
adverse events 
 
 
4. METHODS 
4.1 Design and Setting 
We will conduct a parallel arm double-blind randomized controlled pilot trial at the Civic and 
General campus emergency departments (EDs) of The Ottawa Hospital. The study will operate 
seven days a week from 0800 to 2000, and will be conducted over a 6-month timeframe.  

 
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4.2 Study Population 
4.2.1 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. 
 
4.2.2 Exclusion Criteria 
a) Age <18 years 
b) Patient already taking oral antibiotics 
c) Treating physician decides that intravenous therapy is required 
d) Abscess requiring an incision and drainage or needle aspiration procedure 
e) Known prior cellulitis secondary to methicillin-resistant Staphylococcus aureus 
f) Cellulitis secondary to a human or animal bite wound 
g) Surgical site infection 
h) Malignancy and currently being treated with chemotherapy 
i) Febrile neutropenia (temperature ≥38°C plus absolute neutrophil count <500 cells/µL) 
j) Solid organ or bone marrow transplant recipient 
k) Renal impairment with creatinine clearance <30 mL/min 
l) Pregnant or breastfeeding 
m) Allergy to cephalosporins or history of anaphylaxis to penicillin 
n) Inability to provide consent 
 
4.3 Orientation to Study 
The following will be used to orient and educate ED staff to the study: i) research team to 
individually orient all emergency physicians and residents; ii) oral presentation at grand rounds; 
iii) periodic email; and iv) posters in ED physician work areas.  
 
4.4 Patient Selection 
A trained research assistant (RA) will identify potentially eligible patients during weekday 
business hours, and will be available on-call for after hours. The RA will approach the treating 
physician to discuss enrolling eligible patients. After confirming patient eligibility, the RA will 
explain the study details to the patient and obtain verbal informed consent. In addition, the RA 
will screen the ED patient log to identify missed patients. 
 
4.5 Ethical Considerations 
Ethical approval for the proposed study will be sought from the Ottawa Health Science Network 
Research Ethics Board (OHSN-REB). As both high-dose and standard-dose cephalexin are 
currently used in practice, we do not perceive any risks to patients or any ethical challenges in 
conducting this study. 
 
4.6 Intervention and Comparator 
The intervention is high-dose cephalexin (1000mg PO QID) for seven days. The comparator is 
standard-dose cephalexin (500mg PO QID) plus oral placebo for seven days. The duration of 

 
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therapy was chosen based on a national survey of the Canadian Association of Emergency 
Physicians.13 
 
4.7 Allocation Concealment and Blinding 
Eligible patients will be randomized (1:1) to high-dose versus standard-dose arms. The 
randomization sequence will be computer-generated by a statistician from the Ottawa 
Methods Center (OMC) using a randomly permuted block design with randomly varying lengths 
of 4 or 6, Allocations will be stratified by cellulitis location (lower limb vs. other). The research 
assistant will log into a secure web-based system managed by the OMC to determine the 
allocation for each patient who has consented and been enrolled.  Cephalexin and placebo 
tablets will be encased in identical capsules, prepared and packaged independently by The 
Ottawa Hospital Pharmacy. The research assistant will verify the correct package for an enrolled 
patient with the ED nurse. The ED nurse will then dispense the study medications. The patients, 
treating physician and research team will be blinded. 
 
4.8 Outcomes 
Our pilot trial has both feasibility and (preliminary) effectiveness outcomes. 
 
4.8.1 Feasibility Outcomes 
The primary feasibility outcome is: 
1. Patient recruitment rate (percentage of approached eligible patients who are 
successfully recruited) over 6 months. Our goal is to recruit at least 29% of eligible 
patients (see Sample Size) 
The secondary feasibility outcomes are: 
2. Ability to approach eligible patients (goal <10% missed) 
3. Ability to blind patients using a questionnaire 
4. Protocol adherence (i.e. fully adherent to allocated treatment for 7 days) 
5. Loss to follow up at 14 days (goal <10% attrition) 
 
4.8.2 Effectiveness Outcomes 
The primary effectiveness outcome is: 
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: 
a. New fever (temperature ≥ 38.0°C) or persistent fever at Day 3 follow up; or 
b. Increasing area of erythema ≥20% from baseline; or 
c. Increasing pain ≥2 points from baseline (numeric rating scale)  
The secondary effectiveness outcomes are: 
2. Clinical cure (no erythema, pain and fever) at day 7 
3. Clinical response (≥20% reduction in area of erythema compared to baseline) at day 3 
4. Adverse events (e.g. vomiting, diarrhea, rash) at 14-day telephone follow-up 
5. Unplanned i) return ED visits; and ii) hospitalization at 14-day telephone follow-up 
 

 
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Baseline clinical data will be recorded at the index ED visit. Patients will be assessed at a home 
visit by the research assistant on: 1) Day 3 (mid-therapy); and 2) Day 7 (end-of-therapy). If 
criteria are met for worsening infection, they will be sent to the ED for evaluation. If a home 
visit is not possible, the following alternate methods of follow up will be offered to patients: 
1. Video follow up via a mobile device (tablet or phone) using FaceTime, Zoom or Skype. 
The patient must own a mobile device with one of these applications in order to 
proceed with this option. If this option is chosen, the patient will be given a disposable 
tape measure and disposable temperature strip so that they can measure the 
dimensions of erythema and temperature, respectively during the video follow up. The 
patient will be asked to download a free mobile application (Preventicus Heartbeats; 
https://www.preventicus.com/en/) that will allow the patient to measure their heart 
rate at the time of follow up.  
2. Return to the ED for assessment. In this case, hospital parking fees will be reimbursed 
for the patient 
 
Study participants will complete a questionnaire on Day 7 regarding effectiveness of blinding, 
medication adherence and adverse events.  
 
4.9 Data Collection 
Data will be collected by the research assistant at the index ED visit, and on follow-up visits (day 
3, 7 and 14). Any paper files with identifying information will be kept separately and securely 
from all other study sites. These files will be kept in a locked filing cabinet in a locked office in 
an OHRI research office on F6 (Civic campus of The Ottawa Hospital). Data will be extracted 
from each record of treatment, which includes physician, nursing, consultant, triage, 
ambulance, and any consultation reports. This information will be obtained from hospital 
medical records (i.e. EPIC). Data will be entered into a secure web-based electronic data 
capture system. No identifying personal health information will be recorded into this system. 
Any potentially identifying information in the case record forms for each assessment plus the 
day 7 patient questionnaire are uploaded separately in the OHSN-REB application. 
 
4.10 Data Management 
The Ottawa Methods Centre will be responsible for creating and maintaining a secure web-
based database (i.e. the electronic data capture system). The case record forms will be available 
in electronic format via the secure web-based database. The research assistant will then enter 
the relevant data directly into the secure web-based database. Paper copies of de-identified 
case record forms will be stored in a secure and locked filing cabinet on F6 (Civic campus) of the 
research floor at OHRI. A list of participant names and MRN will be kept in order to contact 
patients at day 7 and 14. This list will be kept on the TOH/OHRI cloud that is password 
protected with only the Principal Investigator and Research Assistant having access to the file. 
These files are kept separately from any de-identified study documents.  All files will be 
destroyed after the required storage period according to TOH and OHRI policies.  
 
4.11 Sample Size   

 
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For the full-scale trial, a minimum of 52 participants must be recruited annually per site (see 
Appendix). The Civic and General ED treats approximately 200 cellulitis patients with oral 
antibiotics annually.5 If at least 180 patients can be approached per site per year, a minimum of 
29% (52 participants) must be recruited at each site to meet the feasibility target. Based on 
previous experience with similar trials, we anticipate being able to recruit up to 35% of eligible 
patients. With 180 patients approached at each site, a 90% two-sided confidence interval 
around the anticipated recruitment rate will have a total width of 0.12, i.e. a lower limit of 
0.291 and an upper limit of 0.413. Because the lower limit excludes the minimum feasibility 
target of 29%, we can be 90% confident that the future trial is feasible. Thus, our target sample 
size is 64 patients across both campuses over six months. 
 
4.12 Data Analysis 
Baseline demographic and clinical characteristics of participants will be described using 
descriptive statistics. Primary and secondary feasibility outcomes will be described using 
frequency and proportion with two-side 90% confidence intervals. Primary and secondary 
effectiveness outcomes will be described using frequency and proportion in each arm, together 
with 95% confidence intervals for the difference between the two arms. Analysis will proceed 
according to an intention-to-treat protocol. 
 
While every effort will be made to avoid attrition, the prevalence of any missing data will be 
described in each arm and multivariable regression analysis will be used to identify baseline 
characteristics associated with attrition. Any identified characteristics will need to be adjusted 
for in the primary and secondary outcome analyses to avoid bias due to attrition.  Single or 
multiple imputation will be used as sensitivity analysis to explore the implications of non-
randomly missing data under extreme assumptions about attrition. 
 
4.13 Data Monitoring 
As this is a pilot study, we will not be utilizing a data monitoring committee or preplanned 
interim analyses. A research coordinator will conduct trial auditing monthly independent from 
the study investigators.  
 
 
5. IMPORTANCE 
Approximately 193,000 patients visit Canadian EDs each year for cellulitis.2 If a pilot randomized 
controlled trial is successful in demonstrating feasibility, a larger multicentre trial has the 
potential to show that high-dose cephalexin is a cheaper, less-invasive option compared to 
intravenous antibiotics. This work has the potential to demonstrate a meaningful reduction in 
treatment failures for this common clinical problem. This pilot study will be the first to compare 
high-dose cephalexin to standard-dose cephalexin for ED patients with non-purulent 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.  
 
 
6. STUDY ORGANIZATION, ETHICS AND DISSEMINATION 

 
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The first five months will be dedicated towards obtaining OHSN-REB approval, study orientation 
and education for ED staff, and working with the TOH pharmacy for study medication 
preparation. Over six months, we will enroll patients for this randomized controlled trial. Data 
analysis will then be conducted followed by manuscript preparation. 
 
Milestone 
 
 
 
 
 
Timeline 
Target start date: 
 
 
 
 
04/2020 
Hire research staff 
 
 
 
 
05/2020 
 
OHSN-REB approval  
 
 
 
03/2020 – 05/2020 
 
Study detail education for ED members 
 
05/2020 
TOH Pharmacy study medication preparation 
05/2020 
 
Database creation 
 
 
 
 
04/2020 – 05/2020 
Patient enrolment 
 
 
 
 
06/2020 – 12/2020 
Data analysis  
 
 
 
 
12/2020 – 03/2021 
Target end date: 
 
 
 
 
04/2021 
 
6.1 Protocol Amendments 
The findings from this pilot study to determine feasibility may reveal certain protocol 
modifications are necessary for an optimally conducted future multicentre trial. Any 
modifications for a future larger scale trial will be communicated by the primary investigator to 
all other investigators and such changes will be reflected in any research ethics board 
submissions.  
 
6.2 Informed Consent 
The emergency physician will inform the patient about the study (i.e. we are assessing two 
different approved doses of the most commonly used antibiotic for cellulitis) and will ask for 
permission to allow a research assistant to speak with the patient about the study. If permission 
is granted, the emergency physician will delegate the task of obtaining oral consent (i.e. 
structured script read to the patient and ability to answer any questions the patient may have) 
using the integrated consent model to the research assistant. The integrated consent model has 
been chosen as the two treatment doses being evaluated are currently used in practice by 
doctors when treating cellulitis. The approved dosing range for cephalexin is 1g to 4g daily. 
Therefore, we anticipate minimal risk to patients who decide to participate in the trial, and the 
integrated verbal consent approach allows for a robust and practical approach to the consent 
process in the Emergency Department setting. 
 
The research assistant will be trained to obtain oral consent using an OHSN-REB approved 
script. Once the discussion is complete, the research assistant will document the discussion and 
patient decision on the study page under the research section of the Epic electronic health 
record. The patient will be provided with an information sheet that includes study information. 
The informed consent script and patient information sheet are uploaded separately within the 
OHSN-REB application. 
 
6.3 Confidentiality 

 
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Participant confidentiality and privacy is strictly held by the principal investigator and the staff. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. All research activities will be conducted in as confidential a manner as 
possible. Authorized representatives of the OHSN-REB, or OHRI may inspect all documents and 
records for audit purposes.  
 
6.4 Declaration of Interests 
All study investigators have no financial or competing interests for this study. 
 
6.5 Access to Data 
Dr. Yadav and his study team will have access to information collected about the identity of 
participants, The OHSN-REB and OHRI will be granted direct access to the participant’s study 
files for verification of clinical trial procedures and data should it be requested for audit 
purposes.  
 
6.6 Ancillary and post-trial care 
Not applicable. 
 
6.7 Dissemination policy 
The investigators plan to present the study results at an annual Emergency Medicine scientific 
meeting and aim to publish the results in peer-reviewed journals. Study participants will be 
given contact information for the principal investigator and will be encouraged to contact the 
research team should they wish to be informed of the study results. All study results will also be 
made available on clinicaltrials.gov. All results will keep the identity of all participants 
confidential and no identifying data will be published.  

 
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Appendix A. Preparatory Work 
A. Preliminary Sample Size for Future Full-Scale Trial 
The estimated treatment failure rate with standard-dose cephalexin is 20%. For a multicenter 
trial, a total of 2552 participants are required to achieve 90% power to detect a minimum 
important difference of 5% in treatment failures in the high-dose cephalexin versus standard-
dose cephalexin arm. We plan to conduct the full-scale trial at 20 centres over 2.5 years, which 
would require a minimum recruitment of 52 participants annually per site. Our research group 
has established relationships with >20 Canadian EDs where we have previously conducted 
successful studies.     
 
B. National Survey of ED Physicians 
We surveyed 391 Canadian emergency physicians to identify how cellulitis is treated in the 
ED.13 The most commonly prescribed oral antibiotic is cephalexin and the most common 
duration is 7 days. 
 
C. Local Survey of ED Physicians 
We surveyed 57 emergency physicians at The Ottawa Hospital (67% response rate).  Physicians 
were asked two questions: 
1. “If a randomized trial was conducted comparing high-dose (1000mg) to standard-dose 
(500mg) cephalexin for adults with cellulitis, would you be willing to enrol patients into this 
study?” 98.2% stated YES 
 
2. “If high-dose cephalexin is shown to be superior to standard-dose cephalexin for treating 
cellulitis, would you use high-dose cephalexin?” 100% stated YES 
 
The results of this survey confirm that the physicians in our ED are willing to enrol patients for 
this planned randomized controlled trial.  
 
D. Defining Oral Antibiotic Treatment Failure 
There is no validated uniform definition of antibiotic treatment failure. We conducted a 
systematic review to examine treatment failure definitions for patients with non-purulent skin 
and soft tissue infections in the literature.19 The findings of this review were used to develop a 
robust, clinically meaningful definition of oral antibiotic treatment failure. 

 
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Stenstrom R, Grafstein E, Romney M, et al. Prevalence of and risk factors for methicillin-
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Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and 
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Consensus Document on the Management of Cellulitis in Lymphoedema. British 
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Chow M, Quintiliani R, Cunha BA, Thompson M, Finkelstein E, Nightingale CH. 
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Wise R. The pharmacokinetics of the oral cephalosporins--a review. J Antimicrob 
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Murray H, Stiell I, Wells G. Treatment failure in emergency department patients with 
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Peterson D, McLeod S, Woolfrey K, McRae A. Predictors of failure of empiric outpatient 
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Emerg Med. 2014;21(5):526-531. 
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Yadav K, Nath A, Suh KN, Sikora L, Eagles D. Treatment failure definitions for non-
purulent skin and soft tissue infections: a systematic review. Infection. 2019.