Duration of ANtibiotic Therapy for CEllulitis (DANCE)

• ClinicalTrials.gov Identifier: NCT02032654
• Recruitment Status: Terminated
• First Posted: January 10, 2014
• Last Update Posted: October 10, 2017
• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborator: ZonMw: The Netherlands Organisation for Health Research and Development
• Information provided by (Responsible Party): W.J. Wiersinga, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Cellulitis; Erysipelas	Drug: Flucloxacillin; Drug: Placebo (for flucloxacillin)	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 151 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Duration of Antibiotic Therapy for Cellulitis (DANCE): a Randomized Controlled Trial Comparing 6 to 12 Days of Antibiotic Therapy for Patients Hospitalized With Cellulitis
• Actual Study Start Date: August 26, 2014
• Actual Primary Completion Date: July 24, 2017
• Actual Study Completion Date: September 25, 2017

Arms and Interventions

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 Name: 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 Name: Floxapen; Drug: Placebo (for flucloxacillin); Sugar capsule manufactured to mimic flucloxacillin 500mg capsules

Outcome Measures

Primary Outcome Measures :

1. Part 1/2: Resolution... [ Time Frame: day 14 ]
   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
2. Part 2/2: ...without relapse [ Time Frame: day 28 ]
   No recurrence by day 28, defined as the need for additional antibiotic therapy for cellulitis

Secondary Outcome Measures :

1. Resolution without relapse [ Time Frame: day 28 ]
   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)
2. Recurrence at day 90 [ Time Frame: 90 days ]
   Recurrence of cellulitis by day 90, defined as the need for additional antibiotic therapy for cellulitis
3. Objective speed of recovery [ Time Frame: Up to 90 days ]
   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
4. Health related Quality of Life [ Time Frame: Up to 90 days ]
   Using questionnaires Dutch SF-36 and EQ-5D at day 1, day 28, and day 90
5. Health care resource utilisation [ Time Frame: Up to 90 days ]
   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.
6. Subjective speed of recovery [ Time Frame: Up to 90 days ]
   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
7. Additional antibiotic usage [ Time Frame: Up to 90 days ]
   Total usage of additional antibiotics for cellulitis between the end of treatment and day 90.
8. Time to relapse [ Time Frame: Up to 90 days ]
   Time between end of treatment and the need for additional antibiotics for cellulitis

Other Outcome Measures:

1. Cellulitis severity score subgroup analysis [ Time Frame: up to day 28 ]
   Analysis to see if the height of the cellulitis severity score influences outcome, using a regression analysis with interaction term for severity score.
2. Diabetes mellitus subgroup analysis [ Time Frame: up to day 28 ]
   Analysis to see if having diabetes mellitus influences outcome, using a regression analysis with interaction term for diabetes.
3. Per protocol analysis [ Time Frame: up to 28 days ]
   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.
4. Per protocol analysis of the "resolution without relapse" secondary outcome [ Time Frame: up to 28 days ]
   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.
5. Sensitivity analyses of the "resolution without relapse" secondary outcome [ Time Frame: up to 28 days ]
   Similar, but requiring further improvement of symptoms by either 1 or 2 points by day 28, instead of just stability of symptoms.
6. Adjustments for baseline covariates [ Time Frame: up to day 28 ]
   Sensitivity analysis, adjusting the primary outcome for baseline covariates

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

Netherlands

Flevoziekenhuis

Almere, Flevoland, Netherlands, 1300EG

Sint Lucas Andreas Ziekenhuis

Amsterdam, Noord-Holland, Netherlands, 1061AE

Slotervaartziekenhuis

Amsterdam, Noord-Holland, Netherlands, 1066EC

VU university medical center

Amsterdam, Noord-Holland, Netherlands, 1081HV

Onze Lieve Vrouwe Gasthuis

Amsterdam, Noord-Holland, Netherlands, 1087CH

Academic Medical Center - University of Amsterdam

Amsterdam, Noord-Holland, Netherlands, 1105AZ

Spaarne Gasthuis Locatie Haarlem Zuid

Haarlem, Noord-Holland, Netherlands, 2035RC

Tergooi

Hilversum, Noord-Holland, Netherlands, 1213XZ

St. Antonius Ziekenhuis locatie Utrecht

Utrecht, Netherlands, 3543AZ

Diakonessenhuis

Utrecht, Netherlands, 3582KE

University Medical Center Utrecht

Utrecht, Netherlands, 3584CX

Sponsors and Collaborators

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

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)

  Study Documents (Full-Text)

Documents provided by W.J. Wiersinga, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):

Study Protocol and Statistical Analysis Plan  [PDF] July 27, 2017

More Information

Additional Information:

Published study protocol in BMC Infectious Diseases 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: W.J. Wiersinga, MD, PhD, internist, infectious diseases specialist, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• ClinicalTrials.gov Identifier: NCT02032654
• 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) )
• First Posted: January 10, 2014
• Last Update Posted: October 10, 2017
• Last Verified: October 2017

Keywords provided by W.J. Wiersinga, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):

antibiotics; flucloxacillin; therapy duration; cellulitis; erysipelas; skin infections; hospital

Additional relevant MeSH terms:

Cellulitis; Erysipelas; Skin Diseases, Infectious; Infections; Suppuration; Connective Tissue Diseases; Inflammation; Pathologic Processes; Streptococcal Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Skin Diseases, Bacterial; Skin Diseases; Floxacillin; Anti-Bacterial Agents; Anti-Infective Agents