High-dose vs. Standard-dose Cephalexin for Cellulitis

Cellulitis Clinical Trial

Official title:

High-dose Cephalexin for Cellulitis: A Pilot Randomized Controlled Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04471246
• Other study ID #: 20200175
• Status: Completed
• Phase: Phase 4
• Start date: August 16, 2021
• Est. completion date: February 23, 2022

Study information

• Verified date: April 2022
• Source: Ottawa Hospital Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 66
• Est. completion date: February 23, 2022
• Est. primary completion date: February 23, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cellulitis

Intervention

Drug:
• Cephalexin
1000 mg PO QID for 7 days
• Cephalexin
500 mg PO QID plus oral placebo for 7 days

Locations

Country	Name	City	State
Canada	The Ottawa Hospital	Ottawa	Ontario

Sponsors (3)

Lead Sponsor	Collaborator
Ottawa Hospital Research Institute	Canadian Association of Emergency Physicians, The Ottawa Hospital Academic Medical Association

Country where clinical trial is conducted

Canada, 

References & Publications (14)

Chow M, Quintiliani R, Cunha BA, Thompson M, Finkelstein E, Nightingale CH. Pharmacokinetics of high-dose oral cephalosporins. J Clin Pharmacol. 1979 Apr;19(4):185-94. — View Citation

Cyriac JM, James E. Switch over from intravenous to oral therapy: A concise overview. J Pharmacol Pharmacother. 2014 Apr;5(2):83-7. doi: 10.4103/0976-500X.130042. Review. — View Citation

Kwak YG, Choi SH, Kim T, Park SY, Seo SH, Kim MB, Choi SH. Clinical Guidelines for the Antibiotic Treatment for Community-Acquired Skin and Soft Tissue Infection. Infect Chemother. 2017 Dec;49(4):301-325. doi: 10.3947/ic.2017.49.4.301. — View Citation

Li HK, Agweyu A, English M, Bejon P. An unsupported preference for intravenous antibiotics. PLoS Med. 2015 May 19;12(5):e1001825. doi: 10.1371/journal.pmed.1001825. eCollection 2015 May. — View Citation

Murray H, Stiell I, Wells G. Treatment failure in emergency department patients with cellulitis. CJEM. 2005 Jul;7(4):228-34. — View Citation

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 May;21(5):526-31. doi: 10.1111/acem.12371. — View Citation

Pollack CV Jr, Amin A, Ford WT Jr, Finley R, Kaye KS, Nguyen HH, Rybak MJ, Talan D. Acute bacterial skin and skin structure infections (ABSSSI): practice guidelines for management and care transitions in the emergency department and hospital. J Emerg Med. — View Citation

Stenstrom R, Grafstein E, Romney M, Fahimi J, Harris D, Hunte G, Innes G, Christenson J. Prevalence of and risk factors for methicillin-resistant Staphylococcus aureus skin and soft tissue infection in a Canadian emergency department. CJEM. 2009 Sep;11(5) — View Citation

Stevens DL, Bisno AL, Chambers HF, Dellinger EP, Goldstein EJ, Gorbach SL, Hirschmann JV, Kaplan SL, Montoya JG, Wade JC; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 — View Citation

Stevens DL, Eron LL. In the clinic. Cellulitis and soft-tissue infections. Ann Intern Med. 2009 Jan 6;150(1):ITC11. Review. — View Citation

Wise R. The pharmacokinetics of the oral cephalosporins--a review. J Antimicrob Chemother. 1990 Dec;26 Suppl E:13-20. Review. — View Citation

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 May;19(3):175-180. doi: 10.1017/cem.2016.347. Epub 2016 Aug 17. — View Citation

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. 2020 Feb;48(1):75-83. doi: 10.1007/s15010-019-01347-w. Epub 2019 Aug 5. — View Citation

Yadav K, Suh KN, Eagles D, MacIsaac J, Ritchie D, Bernick J, Thiruganasambandamoorthy V, Wells G, Stiell IG. Predictors of Oral Antibiotic Treatment Failure for Nonpurulent Skin and Soft Tissue Infections in the Emergency Department. Acad Emerg Med. 2019 — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Patient recruitment rate	% of patients recruited into the trial	6 months
Primary	Oral antibiotic treatment failure	% of patients with oral antibiotic treatment failure	6 months
Secondary	Ability to approach eligible patients	% of eligible patients that are approached for consent to enter into the trial	6 months
Secondary	Assessment of blinding	Assessment of blinding via a patient questionnaire (participant will be asked to indicate which treatment they believe they received) at end of therapy (7 days)	7 days
Secondary	Protocol adherence	% of patients that are adherent to allocated treatment for 7 days	7 days
Secondary	Loss to follow up	% of patients lost to follow up at 14 days	14 days
Secondary	Clinical cure	% of patients with clinical cure (no erythema, pain and fever) at days 3 and 7	7 days
Secondary	Adverse events	% of patients with adverse events (e.g. vomiting, diarrhea, rash) at 14-days measured via telephone follow-up	14 days
Secondary	Unplanned ED Visits or Hospitalization	% of patients with unplanned i) return ED visits; and ii) hospitalization, measured via 14-day telephone follow-up	14 days