Duration of ANtibiotic Therapy for CEllulitis (DANCE)

Duration of Antibiotic Therapy for Cellulitis (DANCE): a Randomized Controlled Trial Comparing 6 to 12 Days of Antibiotic Therapy for Patients Hospitalized With Cellulitis

Cellulitis is among the most common infections leading to hospitalization, yet the optimal duration of therapy remains ill defined. Pragmatically, Dutch guidelines advise 10-14 days of antibiotics, which is the current standard of care. Recently it has been shown that antibiotic treatment for pneumonia and urinary tract infections can safely and significantly be shortened. Importantly, in an outpatient setting, treatment of uncomplicated cellulitis with 5 days of antibiotics was as effective as 10 days. We hypothesize that there is no difference in outcomes when patients hospitalized with cellulitis are treated with either a short-course (6 days) or standard-course (12 days) of antibiotics.

Study Overview

• Status: Terminated
• Conditions: Cellulitis; Erysipelas
• Intervention / Treatment: Drug: Flucloxacillin; Drug: Placebo (for flucloxacillin)

• Study Type: Interventional
• Enrollment (Actual): 151
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Utrecht, Netherlands, 3584CX
    • University Medical Center Utrecht
  • Utrecht, Netherlands, 3582KE
    • Diakonessenhuis
  • Utrecht, Netherlands, 3543AZ
    • St. Antonius Ziekenhuis locatie Utrecht
  • Flevoland
    • Almere, Flevoland, Netherlands, 1300EG
      • Flevoziekenhuis
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1081HV
      • VU University Medical Center
    • Amsterdam, Noord-Holland, Netherlands, 1061AE
      • Sint Lucas Andreas Ziekenhuis
    • Amsterdam, Noord-Holland, Netherlands, 1066EC
      • Slotervaartziekenhuis
    • Amsterdam, Noord-Holland, Netherlands, 1087CH
      • Onze Lieve Vrouwe Gasthuis
    • Amsterdam, Noord-Holland, Netherlands, 1105AZ
      • Academic Medical Center - University of Amsterdam
    • Haarlem, Noord-Holland, Netherlands, 2035RC
      • Spaarne Gasthuis Locatie Haarlem Zuid
    • Hilversum, Noord-Holland, Netherlands, 1213XZ
      • Tergooi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Admitted to receive intravenous antibiotics for cellulitis/erysipelas
• 18 years of age or older
• Capable of giving written informed consent, able to comply with study requirements and restrictions

Exclusion Criteria:

• Allergy for flucloxacillin, other beta-lactam antibiotics or one of the additives, or flucloxacillin induced hepatitis or liver enzyme disorders.
• Concurrent use of antibiotics for other indications
• Alternative diagnosis accounting for the clinical presentation.

• All cases involving any of the following complicating factors:

  • Use of antibiotics with Gram-positive activity for more than 4 days in the past 7 days
  • Intensive care unit admission during the last 7 days
  • Severe peripheral arterial disease (Fontaine IV)
  • Severe cellulitis necessitating surgical debridement or fascial biopsy
  • Necrotizing fasciitis
  • Periorbital or perirectal involvement
  • Surgery
  • Life expectancy less than one month

  • Risk factors associated with Gram-negative pathogens as a causative agent:

    • Chronic or macerated infra-malleolar ulcers, or infra-malleolar ulcers with previous antibiotic treatment, in patients with diabetes mellitus.
    • Neutropenia
    • Cirrhosis (Child-Pugh class B or C)
    • Intravenous drug use
    • Human or animal bite
    • Skin laceration acquired in fresh or salt open water
    • Fish fin or bone injuries

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard course; Flucloxacillin (1000mg iv OR, later, 500mg capsules), every 6 hours, for 6 days, followed by: Flucloxacillin 500mg capsules, every 6 hours, for 6 days	Drug: Flucloxacillin; Other Names: Floxapen
Experimental: Short course; Flucloxacillin (1000mg iv OR, later, 500mg capsules), every 6 hours, for 6 days, followed by: Placebo (for flucloxacillin 500mg) 500mg capsules, every 6 hours, for 6 days	Drug: Flucloxacillin; Other Names: Floxapen; Drug: Placebo (for flucloxacillin); Sugar capsule manufactured to mimic flucloxacillin 500mg capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1/2: Resolution...	Resolution of cellulitis at day 14, defined as disappearance of warmth and tenderness at the site of infection, with substantial improvement in erythema and edema	day 14
Part 2/2: ...without relapse	No recurrence by day 28, defined as the need for additional antibiotic therapy for cellulitis	day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Resolution without relapse	Other operators used to define resolution at day 14 (no fever; reduction in combined erythema/edema/warmth/tenderness score of at least 2 points, or reach 0) and relapse at day 28 (no fever; stable or further improved combined score; no new antibiotics for cellulitis)	day 28
Recurrence at day 90	Recurrence of cellulitis by day 90, defined as the need for additional antibiotic therapy for cellulitis	90 days
Objective speed of recovery	Improvement in cellulitis severity score (a 7 item scoring system, each with a score between 0-3; items are erythema, warmth, tenderness, edema, ulceration, drainage and fluctuance). Determined at day 1, day 2-3, day 5-6, day 14, and day 28	Up to 90 days
Health related Quality of Life	Using questionnaires Dutch SF-36 and EQ-5D at day 1, day 28, and day 90	Up to 90 days
Health care resource utilisation	Determined by total antibiotic use and effect on direct and indirect health-care associated costs, using modified versions of iMTA's Productivity Cost Questionnaire (iPCQ) and Medical Consumption Questionnaire (iMCQ). Measured at day 5-6, day 28 and day 90.	Up to 90 days
Subjective speed of recovery	Visual Analog Scales (0-10) on pain and on swelling. Determined at day 1, day 2-3, day 5-6, day 14, day 28, and day 90	Up to 90 days
Additional antibiotic usage	Total usage of additional antibiotics for cellulitis between the end of treatment and day 90.	Up to 90 days
Time to relapse	Time between end of treatment and the need for additional antibiotics for cellulitis	Up to 90 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cellulitis severity score subgroup analysis	Analysis to see if the height of the cellulitis severity score influences outcome, using a regression analysis with interaction term for severity score.	up to day 28
Diabetes mellitus subgroup analysis	Analysis to see if having diabetes mellitus influences outcome, using a regression analysis with interaction term for diabetes.	up to day 28
Per protocol analysis	Like main outcome, but the following will be included: (i) patients with treatment failure, who have received at least 24 hours of study medication, and (ii) patients with treatment success, who have received at least 80% of study medication. Treatment failure is defined as the persistence or progression of signs and symptoms of the acute process after randomization, or the inability to complete the study owing to adverse events. The response is deemed indeterminate when the patients (i) received less than 80% of the study drug for reasons other than treatment failure, (ii) acquired a concomitant infection outside of the skin requiring antibiotic treatment, (iii) were lost to follow-up, or (iv) died unrelated to the primary diagnosis.	up to 28 days
Per protocol analysis of the "resolution without relapse" secondary outcome	Like secondary outcome, but the following will be included: (i) patients with treatment failure, who have received at least 24 hours of study medication, and (ii) patients with treatment success, who have received at least 80% of study medication. Cured is defined as above (under secondary outcome). Indeterminate is (i) receiving <80% of study drug for reasons other than unblinding/requiring new AB for cellulitis/being unable to continue due to adverse effects, (ii) acquired a concomitant infection outside of the skin requiring antibiotic treatment, (iii) were lost to follow-up, or (iv) died unrelated to the primary diagnosis. Patients who are not cured nor indeterminate are failures.	up to 28 days
Sensitivity analyses of the "resolution without relapse" secondary outcome	Similar, but requiring further improvement of symptoms by either 1 or 2 points by day 28, instead of just stability of symptoms.	up to 28 days
Adjustments for baseline covariates	Sensitivity analysis, adjusting the primary outcome for baseline covariates	up to day 28

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development
• Investigators: Principal Investigator: W. Joost Wiersinga, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Principal Investigator: Jan M. Prins, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Publications and helpful links

General Publications

• Cranendonk DR, Hugenholtz F, Prins JM, Savelkoul PHM, Budding AE, Wiersinga WJ; DANCE Consortium. The Skin Microbiota in Patients Hospitalized for Cellulitis and Association With Outcome. Clin Infect Dis. 2019 Apr 8;68(8):1292-1299. doi: 10.1093/cid/ciy709.
• Cranendonk DR, Opmeer BC, Prins JM, Wiersinga WJ. Comparing short to standard duration of antibiotic therapy for patients hospitalized with cellulitis (DANCE): study protocol for a randomized controlled trial. BMC Infect Dis. 2014 May 5;14:235. doi: 10.1186/1471-2334-14-235.

Helpful Links

• Published study protocol in BMC Infectious Diseases

Study record dates

Study Major Dates

• Study Start (Actual): August 26, 2014
• Primary Completion (Actual): July 24, 2017
• Study Completion (Actual): September 25, 2017

Study Registration Dates

• First Submitted: January 8, 2014
• First Submitted That Met QC Criteria: January 9, 2014
• First Posted (Estimate): January 10, 2014

Study Record Updates

• Last Update Posted (Actual): October 10, 2017
• Last Update Submitted That Met QC Criteria: October 9, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: antibiotics; hospital; cellulitis; flucloxacillin; skin infections; erysipelas; therapy duration
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Infections; Inflammation; Connective Tissue Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Streptococcal Infections; Gram-Positive Bacterial Infections; Skin Diseases, Infectious; Suppuration; Skin Diseases, Bacterial; Cellulitis; Erysipelas; Anti-Infective Agents; Anti-Bacterial Agents; Floxacillin
• Other Study ID Numbers: NL44512.018.13; 4360 (Registry Identifier: Netherlands Trial Register); 2013-002106-31 (EudraCT Number); 836011024 (Other Grant/Funding Number: Netherlands Organisation for Health Research and Development (ZonMw))