High-dose vs. Standard-dose Cephalexin for Cellulitis

Overview

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.

Full Title of Study: “High-dose Cephalexin for Cellulitis: A Pilot Randomized Controlled Trial”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Triple (Participant, Care Provider, Investigator)
  • Study Primary Completion Date: February 23, 2022

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

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

Arms, Groups and Cohorts

  • Experimental: High Dose Cephalexin
    • The intervention is high-dose cephalexin (1000mg PO QID) for seven days
  • Active Comparator: Standard Dose Cephalexin
    • The comparator is standard-dose cephalexin (500mg PO QID) plus oral placebo for seven days

Clinical Trial Outcome Measures

Primary Measures

  • Patient recruitment rate
    • Time Frame: 6 months
    • % of patients recruited into the trial
  • Oral antibiotic treatment failure
    • Time Frame: 6 months
    • % of patients with oral antibiotic treatment failure

Secondary Measures

  • Ability to approach eligible patients
    • Time Frame: 6 months
    • % of eligible patients that are approached for consent to enter into the trial
  • Assessment of blinding
    • Time Frame: 7 days
    • 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)
  • Protocol adherence
    • Time Frame: 7 days
    • % of patients that are adherent to allocated treatment for 7 days
  • Loss to follow up
    • Time Frame: 14 days
    • % of patients lost to follow up at 14 days
  • Clinical cure
    • Time Frame: 7 days
    • % of patients with clinical cure (no erythema, pain and fever) at days 3 and 7
  • Adverse events
    • Time Frame: 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
    • Time Frame: 14 days
    • % of patients with unplanned i) return ED visits; and ii) hospitalization, measured via 14-day telephone follow-up

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Ottawa Hospital Research Institute
  • Collaborator
    • The Ottawa Hospital Academic Medical Association
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Krishan Yadav, MD, MSc, Principal Investigator, Ottawa Hospital Research Institute

Citations Reporting on Results

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.

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. Erratum In: CJEM. 2009 Nov;11(6):570.

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.

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.

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. Erratum In: Clin Infect Dis. 2015 May 1;60(9):1448. Dosage error in article text.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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