High-dose vs. Standard-dose Cephalexin for Cellulitis

NCT04471246 | Completed Phase 4 Results

• 1 other identifier: 20200175
• Study Type: interventional
• Target: 69
• Locations: 1 country
• Sites: 1

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.

Conditions

Cellulitis

Outcome Measures

Primary Outcomes (2)

• Patient Recruitment Rate

  % of patients recruited into the trial

  6 months

• 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)

  Each patient was assessed for oral antibiotic treatment failure at the day 3 and day 7 follow-ups

Secondary Outcomes (7)

• Ability to Approach Eligible Patients

  6 months

• Assessment of Blinding

  Patient were asked which dose of cephalexin they believe they received during the day 7 follow-up

• Protocol Adherence

  7 days

• Loss to Follow-up

  Determined at final follow-up (day 14) if lost to follow-up

• Clinical Cure

  Assessed for clinical cure at day 7and day 14 follow-up

Study Arms (2)

High Dose Cephalexin

EXPERIMENTAL

The intervention is high-dose cephalexin (1000mg PO QID) for seven days

Drug: Cephalexin

Standard Dose Cephalexin

ACTIVE COMPARATOR

The comparator is standard-dose cephalexin (500mg PO QID) plus oral placebo for seven days

Drug: Cephalexin + placebo

Interventions

Cephalexin DRUG

1000 mg PO QID for 7 days

Also known as: High-dose cephalexin

High Dose Cephalexin

Cephalexin + placebo DRUG

500 mg PO QID plus oral placebo for 7 days

Also known as: Standard-dose cephalexin

Standard Dose Cephalexin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Ottawa Hospital Research Institute: lead
• The Ottawa Hospital Academic Medical Association: collaborator
• Canadian Association of Emergency Physicians: collaborator

Study Sites (1)

The Ottawa Hospital

Ottawa, Ontario, K1y 4E9, Canada

Location

Related Publications (15)

• Stevens DL, Eron LL. In the clinic. Cellulitis and soft-tissue infections. Ann Intern Med. 2009 Jan 6;150(1):ITC11. doi: 10.7326/0003-4819-150-1-200901060-01001.

  PMID: 19124814 RESULT

• 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):430-8. doi: 10.1017/s1481803500011623.

  PMID: 19788787 RESULT

• 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 Jan;26(1):51-59. doi: 10.1111/acem.13492. Epub 2018 Jul 4.

  PMID: 29869364 RESULT

• 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. 2015 Apr;48(4):508-19. doi: 10.1016/j.jemermed.2014.12.001. Epub 2015 Jan 17.

  PMID: 25605319 RESULT

• 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 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014 Jul 15;59(2):e10-52. doi: 10.1093/cid/ciu444.

  PMID: 24973422 RESULT

• 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.

  PMID: 29299899 RESULT

• 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.

  PMID: 25992781 RESULT

• 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.

  PMID: 24799810 RESULT

• 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.

  PMID: 27531595 RESULT

• 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. doi: 10.1002/j.1552-4604.1979.tb01650.x. No abstract available.

  PMID: 438352 RESULT

• Wise R. The pharmacokinetics of the oral cephalosporins--a review. J Antimicrob Chemother. 1990 Dec;26 Suppl E:13-20. doi: 10.1093/jac/26.suppl_e.13.

  PMID: 2292525 RESULT

• Murray H, Stiell I, Wells G. Treatment failure in emergency department patients with cellulitis. CJEM. 2005 Jul;7(4):228-34. doi: 10.1017/s1481803500014342.

  PMID: 17355677 RESULT

• 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.

  PMID: 24842503 RESULT

• 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.

  PMID: 31378847 RESULT

• Yadav K, Eagles D, Perry JJ, Taljaard M, Sandino-Gold G, Nemnom MJ, Corrales-Medina V, Suh KN, Stiell IG. High-dose cephalexin for cellulitis: a pilot randomized controlled trial. CJEM. 2023 Jan;25(1):22-30. doi: 10.1007/s43678-022-00433-7. Epub 2023 Jan 2.

  PMID: 36592299 DERIVED

MeSH Terms

Conditions

Cellulitis

Interventions

Cephalexin

Condition Hierarchy (Ancestors)

Skin Diseases, Infectious; Infections; Suppuration; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cephalosporins; beta-Lactams; Lactams; Amides; Organic Chemicals; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

A small proportion of participants who reported clinical cure at the end-of-therapy visit. We have recently published a systematic review that demonstrates that symptoms such as pain and erythema can persist beyond 14 days. We were unable to assess for infection recurrence beyond 14 days. We will mitigate this in a future trial by including a 30-day telephone follow-up. Secondary feasibility target of \< 10% missed eligible patients not met.

Results Point of Contact

• Title: Krishan Yadav
• Organization: Ottawa Hospital Research Institute

kyadav@toh.ca

613-798-5555

Study Officials

• Krishan Yadav, MD, MSc

  Ottawa Hospital Research Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Eligible patients will be randomized (1:1) to high-dose versus standard-dose arms. The randomization sequence will be computer-generated by a statistician
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The Investigators will conduct a parallel arm double-blind randomized controlled pilot trial.

Study Record Dates

• First Submitted: June 30, 2020
• First Posted: July 15, 2020
• Study Start: August 16, 2021
• Primary Completion: February 23, 2022
• Study Completion: February 23, 2022
• Last Updated: January 17, 2025
• Results First Posted: January 17, 2025

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)