Clinical trial NCT02922686: Penicillin for the Emergency Department Outpatient Treatment of CELLulitis
Official title: Oral Flucloxacillin Alone Versus Flucloxacillin and Phenoxymethylpenicillin for the Emergency Department Outpatient Treatment of Cellulitis: a Non-inferiority Randomised Controlled Trial.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Cellulitis
Wound Infection
Abscess
Lead sponsor: Royal College of Surgeons, Ireland
Sponsor class: OTHER
Collaborators: name: Health Research Board, Ireland
First posted: 2016-10-04
Enrollment: 414
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The main objective of this study is to investigate the non-inferiority of oral flucloxacillin alone compared with a combination of oral flucloxacillin and phenoxymethylpenicillin for the emergency department directed outpatient treatment of cellulitis, wound infections and abscesses, recently renamed by the Food and Drug Administration (FDA) as acute bacterial skin and skin structure infections (ABSSSIs). Half of the trial participants will receive flucloxacillin and placebo in combination, and the remaining half will be treated will flucloxacillin and phenoxymethylpenicillin.

In a secondary objective the trial aims to measure adherence and persistence of trial patients with outpatient antibiotic therapy. In addition a within-trial evaluation of the cost per quality adjusted life year (QALY) gained from the use of oral flucloxacillin compared with combination therapy from the perspective of the health-care payer (direct costs) the patient and government. Finally the study will externally validate the Extremity Soft Tissue Infection-score, a Health Related Quality of Life (HRQL) questionnaire designed to quantify the impact of cellulitis, wound infections and abscesses on patient HRQL in clinical trials.

Detailed description: There is obvious clinical equipoise between the use of oral flucloxacillin alone or combined with phenoxymethylpenicillin for the emergency department treatment of cellulitis, wound infections and abscesses as evidenced by current disparate prescribing practice and hospital guidelines. Feasibility studies for the planned trial have shown that 45-50% of emergency department patients with these infections in Ireland are discharged on oral antibiotics which is consistent with findings in other jurisdictions. Despite the significant healthcare and economic costs associated with cellulitis, there is a paucity of scientific evidence concerning the appropriate antibiotic treatment for these conditions. Additionally, "less severe" infections tend to be over-treated and severe infections under-treated, indicating unjustifiable levels of antibiotic misuse, insufficient knowledge of therapeutics and a lack of evidence to risk-stratify patients with cellulitis to different treatments.The planned trial is therefore likely to be definitive due to the current clinical equipoise between the use of both penicillins for the emergency department outpatient treatment of this group of infections

Eligibility criteria: Inclusion Criteria:

* Clinically diagnosed cellulitis, wound infections or abscess (ABSSSI) affecting any body part, excluding the perineum, and having any two of the following signs:

  * Erythema
  * Warmth
  * Tenderness / Pain of affected area
  * Oedema / Induration
  * Regional lymphadenopathy
* Cellulitis, wound infection and abscess deemed treatable with oral outpatient antibiotics in which either combination of antibiotic is likely to produce a clinical response (Eron Class 1-2)
* Written informed consent obtained.
* 16 years of age or older.
* Fluency in written and spoken English.
* Willing to return for study follow-up or to have the research nurse visit their home.
* Willing to receive a telephone call from a study investigator.

Exclusion Criteria:

* Penicillin allergy (self-reported or confirmed).
* Any cellulitis, wound infection and abscess that treating clinicians deem treatable with intravenous (IV) antibiotics.
* Any cellulitis, wound infection and abscess that is more severe than Eron Class 2 (Appendix 2)
* Any cellulitis, wound infection and abscess of the perineal region.
* Patients who have received more than 24 hours of effective antibiotics for the current episode of acute cellulitis, wound infection or abscess
* Any medical condition, based on clinical judgment, that may interfere with interpretation of the primary outcome measures (e.g. chronic skin condition at the lesion site)
* Immunodeficiency from primary or secondary causes (e.g. corticosteroids, chemotherapeutic agents).
* Previous history of renal dysfunction or known chronic kidney disease under care of a nephrologist. - Previous history of liver dysfunction defined as chronically deranged liver function tests elicited from medical notes or history.
* Suspected or confirmed septic arthritis.
* Suspected or confirmed osteomyelitis.
* Infection involving prosthetic material.
* Pregnant or lactating women.
* Patients with a previous history of flucloxacillin- associated jaundice/hepatic dysfunction
* Patients with a previous history of MRSA colonization/infection.
* Patients with lactose intolerance diagnosed by a medical professional

Primary outcomes:
measure: Investigator-determined clinical response
timeFrame: Test Of Cure visit (Day 14-21 post randomization)
Secondary outcomes:
measure: Early Clinical Response (ECR)
timeFrame: Day 2-3 post randomization
measure: Clinical Treatment Failure
timeFrame: Up to 21 days post randomization
measure: Adherence to Medication
timeFrame: End of Treatment (EOT) visit Day 8-10 post randomization
measure: Adherence to medication using an electronic medication event monitoring system (MEMS®)
timeFrame: Day 2-3 and day 8-10 post randomization and initiation of therapy
measure: Measurement of Health Related Quality of Life
timeFrame: Day 2-3 post-randomization, Day 8-10 post randomization, Day 14 -21 post randomization
measure: Validation of the Extremity Soft Tissue Infections (ESTI)- score
timeFrame: Day 2-3 post-randomization, Day 8-10 post randomization, Day 14 -21 post randomization
measure: Cost-effectiveness analysis
timeFrame: Day 14 - 21 post randomization
measure: Measurement of Health Resource Use
timeFrame: Day 2-3 post-randomization, Day 8-10 post randomization, Day 14 -21 post randomization
Other outcomes:
Locations:
city: Blanchardstown
country: Ireland
facility: Department of Emergency Medicine, Connolly Hospital,
state: Dublin
city: Cork
country: Ireland
facility: Department of Emergency Medicine, Mercy University Cork
state: Greenville Place
city: Cork
country: Ireland
facility: Department of Emergency Medicine, Cork University Hospital
state: Wilton
city: Dublin
country: Ireland
facility: Department of Emergency Medicine, Mater Misericordiae University Hospital
city: Dublin
country: Ireland
facility: Beaumont Hospital,
Study officials:
affiliation: Mater Misericordiae University Hospital
name: Adrian Moughty
role: PRINCIPAL_INVESTIGATOR
affiliation: Connolly Hospital Blanchardstown
name: Joseph McKeever
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Emergency Medicine, Cork University Hopsital, Cork
name: Conor Deasy
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Emergency Medicine, Mercy University, Cork
name: Chris Luke
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Emergency Medicine, Beaumont Hospital, Dublin
name: Abel Wakai, MD FRCEM
role: PRINCIPAL_INVESTIGATOR
References:
citation: Quirke M, Saunders J, O'Sullivan R, Milenkovski H, Wakai A. A pilot cross-sectional study of patients presenting with cellulitis to emergency departments. Ir Med J. 2014 Nov-Dec;107(10):316-8.
citation: Dong SL, Kelly KD, Oland RC, Holroyd BR, Rowe BH. ED management of cellulitis: a review of five urban centers. Am J Emerg Med. 2001 Nov;19(7):535-40. doi: 10.1053/ajem.2001.28330.
citation: Kilburn SA, Featherstone P, Higgins B, Brindle R. Interventions for cellulitis and erysipelas. Cochrane Database Syst Rev. 2010 Jun 16;2010(6):CD004299. doi: 10.1002/14651858.CD004299.pub2.
citation: Storck AJ, Laupland KB, Read RR, Mah MW, Gill JM, Nevett D, Louie TJ. Development of a Health-Related Quality of Life Questionnaire (HRQL) for patients with Extremity Soft Tissue Infections (ESTI). BMC Infect Dis. 2006 Oct 11;6:148. doi: 10.1186/1471-2334-6-148.
citation: Quirke M, O'Sullivan R, McCabe A, Ahmed J, Wakai A. Are two penicillins better than one? A systematic review of oral flucloxacillin and penicillin V versus oral flucloxacillin alone for the emergency department treatment of cellulitis. Eur J Emerg Med. 2014 Jun;21(3):170-4. doi: 10.1097/MEJ.0b013e328360d980.
citation: Boland F, Quirke M, Gannon B, Plunkett S, Hayden J, McCourt J, O'Sullivan R, Eustace J, Deasy C, Wakai A. The Penicillin for the Emergency Department Outpatient treatment of CELLulitis (PEDOCELL) trial: update to the study protocol and detailed statistical analysis plan (SAP). Trials. 2017 Aug 24;18(1):391. doi: 10.1186/s13063-017-2121-2.