Strategies Using Off-Patent Antibiotics for Methicillin Resistant S. Aureus "STOP MRSA"

NCT00729937 | Completed Phase 2 Results

• 1 other identifier: 07-0040
• Study Type: interventional
• Target: 2,265
• Locations: 1 country
• Sites: 5

Brief Summary

The purpose of this study is to determine the optimal outpatient treatment strategy of uncomplicated skin and soft tissue infection (SSTI) in areas of the United States where the prevalence of Community-Acquired Methicillin-Resistant Staphylococcus (S.) aureus (CA-MRSA) is high. Infection with the S. aureus bacteria that is resistant to antibiotics is a cause of SSTIs. Three oral antibiotics will be tested for off patent treatment. Patients will receive Trimethoprim/Sulfamethoxazole (TMP/SMX), placebo (substance containing no medication), clindamycin, or cephalexin or some combination of these. The study population will include 2,235 volunteers, children 13 years of age and over and adults presenting to 5 large urban Emergency Departments. Therapy for acute uncomplicated SSTIs, including abscess, infected wound, and cellulitis will start on the day of enrollment. Participants may be involved in study related procedures for about 9 weeks.

Conditions

Staphylococcal Infection

Keywords

Methicillin, Staphylococcus aureus, MRSA

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Clinical Cure as of the Test-of-Cure (TOC) Visit in the Per Protocol Population

  Clinical cure at TOC was defined as no failure on any previous visit up through the TOC, absence of fever, and resolution or minimal presence of all the following signs and symptoms from baseline based on clinician assessment of erythema, swelling, and tenderness. A participant would have been a clinical failure at the On Therapy (OTV) visit with presence of fever attributable to the infection being studied, increase in erythema by 25% or more, or worsening of both swelling and tenderness based on clinical assessment. A participant would have been a clinical failure at the End of Therapy (EOT) visit with presence of fever attributable to the infection being studied, increase or no improvement in erythema, or no improvement in either swelling or tenderness based on clinical assessment.

  Days 14-21

Secondary Outcomes (30)

• Number of Participants With Clinical Cure as of the TOC Visit in the Intent to Treat Population

  Days 14-21

• Number of Participants With Reduction in Erythema Dimensions by 5% Intervals at the On-therapy Visit in the Per Protocol Population

  Day 1 to Day 3-4

• Number of Participants With Reduction in Erythema Dimensions by 5% Intervals at the On-therapy Visit in the Intent to Treat Population

  Day 1 to Day 3-4

• Number of Participants With Reduction in Erythema Dimensions by 5% Intervals at the End-of-therapy Visit in the Per Protocol Population

  Day 1 to Day 8-10

• Number of Participants With Reduction in Erythema Dimensions by 5% Intervals at the End-of-therapy Visit in the Intent to Treat Population

  Day 1 to Day 8-10

Study Arms (3)

TMP/SMX vs. Placebo

EXPERIMENTAL

Subjects with an acute uncomplicated cutaneous abscess will be randomized to receive either Trimethoprim/Sulfamethoxazole (TMP/SMX) (4 single strength pills, 80 mg/400 mg each, twice per day) or 4 placebo pills (twice per day).

Other: Placebo; Drug: Trimethoprim-sulfamethoxazole

TMP/SMX vs. Clindamycin

EXPERIMENTAL

Subjects with an acute uncomplicated wound infection will be randomized to receive Trimethoprim/Sulfamethoxazole (TMP/SMX) (4 single strength pills, 80 mg/400 mg each, twice per day, with alternating 1 identical placebo pill, twice per day) or clindamycin (300 mg, four times per day, with 3 placebo pills on alternating doses).

Drug: Clindamycin; Other: Placebo; Drug: Trimethoprim-sulfamethoxazole

Cephalexin and TMP/SMX vs. Cephalexin

EXPERIMENTAL

Subjects with acute uncomplicated cellulitis will be randomized to receive cephalexin (500 mg, four times per day) and Trimethoprim/Sulfamethoxazole (TMP/SMX) (4 single strength pills, 80 mg/400 mg each, twice per day) or cephalexin (500 mg, four times per day) and placebo (4 pills, twice per day).

Drug: Cephalexin; Other: Placebo; Drug: Trimethoprim-sulfamethoxazole

Interventions

Cephalexin DRUG

500 mg, four times per day.

Cephalexin and TMP/SMX vs. Cephalexin

Clindamycin DRUG

300 mg, four times per day.

TMP/SMX vs. Clindamycin

Placebo OTHER

Placebo tablet administered orally.

Cephalexin and TMP/SMX vs. Cephalexin; TMP/SMX vs. Clindamycin; TMP/SMX vs. Placebo

Trimethoprim-sulfamethoxazole DRUG

4 single strength Trimethoprim/Sulfamethoxazole (TMP/SMX), 80 mg/400 mg each, twice per day.

Cephalexin and TMP/SMX vs. Cephalexin; TMP/SMX vs. Clindamycin; TMP/SMX vs. Placebo

Eligibility Criteria

• Age: 13 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult or child 13 years of age and older (who weighs greater than or equal to 40 kg);
• Have a skin and soft tissue infection (SSTI) with all three local findings of erythema (\> 2 cm across the lesion or from a discrete wound edge), tenderness, and swelling/induration. Fever, leukocytosis, and lymphangitis will be noted, but are not enrollment criteria. SSTI with these local findings will be further categorized and defined as one of:
• Abscess - a fluctuant and/or indurated lesion, or findings of a fluid-filled cavity on soft tissue ultrasound evaluation that, when opened reveals purulent material, receiving incision and drainage (I\&D) (considered standard care for abscess) and having a minimum diameter (along any axis) of at least 2 cm (measured from the borders of induration, if a fluctuant lesion, or borders of the abscess cavity on ultrasound, if not fluctuant).
• Note: Although I\&D of an abscess is considered standard care (i.e., patients will receive I\&D whether or not they are enrolled in the study), the procedure may be performed after enrollment into the study so that prior measurements of the area of erythema and swelling/induration can be obtained unless it is an occult abscess in which the I\&D will be performed prior to enrollment to verify infection type and ensure correct classification of the subject.
• Infected Wound - a wound (defined as any apparent break in the skin) with any apparent drainage limited in depth to only involving skin and subcutaneous tissue, including sutured cutaneous wounds not involving intra-abdominal surgeries contaminated with bacterial or bowel contents (e.g., colon surgery and empyema drainage), and
• Cellulitis - an area of erythema without the presence of a wound with drainage or abscess; Cellulitis associated with an abscess will be categorized as an abscess. Cellulitis associated with an infected wound will be classified as an infected wound. Patients with cellulitis and an abscess less than 2 cm will be excluded. Infected wound associated with an abscess that may require I\&D, will be classified as an infected wound.
• Have the infected lesion for 7 days or less duration;
• Are to receive outpatient treatment at enrollment/baseline;
• Express willingness and ability to be contacted and return for re-evaluation according to the study protocol;
• Provide written informed consent (and for subjects ages 13-17, consent from their guardian and assent);
• Negative pregnancy test for subjects who are women of childbearing potential.

You may not qualify if:

• Severe allergy or reaction to study drug or drugs similar to the study drug relevant to whichever study sub-trial the subject would be assigned to (e.g., patients with severe or life-threatening penicillin allergies, allergy to any cephalosporin, clindamycin, or sulfonamides, or any other drug containing sulfur such as thiazides, furosemide, and oral sulfonylureas);
• Concomitant treatment (i.e., while on study drug therapy) with coumadin, phenytoin, or methotrexate, or suspected G-6-PD or folic acid deficiency;
• Expected inability to swallow or absorb the study drug (assessed by patient history);
• Pregnancy, nursing, or expectation of becoming pregnant while on study drug;
• Perirectal (within 5 cm of anus), perineal non-skin lesions (i.e., mucosal), or paronychial location of infection. Scrotal and labial abscesses will not be excluded.
• An infection due to a mammalian bite;
• Treatment with a study drug relevant to their infection type, or another systemic antibiotic in the previous 48 hours (i.e., before screening/baseline) unless associated with treatment failure which is defined as a patient who has been on prior (non study drug) antibiotics for at least 72 hours and failed.
• Expected concurrent treatment with a topical antibiotic or another systemic antibiotic up to Test-of-Cure Visit (TOC) (note: if patient was using a topical antibiotic previously, they can still be enrolled if they agree to stop using it);
• Immunodeficiency \[e.g., absolute neutrophil count \<500/mm\^3, chronic immunosuppressive drugs, active chemotherapy, or known acquired immunodeficiency syndrome (AIDS) (CD4 count \<200 or AIDS-defining illness within the last year) assessed by patient history\]. Note: patients who had prior AIDS-defining illness or CD4 count \<200 in the past may be enrolled if most recent CD4 count \>200;
• Burn or active chronic skin condition (e.g., including rash or eczema) related to the skin and soft-tissue infection (SSTI) at screening/baseline;
• Infection related to currently indwelling device (e.g., intravenous line), excepting sutures associated with qualifying infected wounds which will be removed upon enrollment;
• Infection for which prior cultures reveal in vitro resistance of a pathogen to a study drug in the previous month prior to screening/baseline;
• Known or suspected osteomyelitis or septic arthritis;
• Infection related to diabetic foot, decubitus, or ischemic ulcer;
• Known severe renal insufficiency (creatinine clearance \< 50 mL/min) calculated by measurement of serum creatinine if patient provides this history or based on past studies at baseline/enrollment;

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (5)

Maricopa Medical Center - Emergency Medicine

Phoenix, Arizona, 85008-4973, United States

Location

University of California Los Angeles - Olive View Medical Center

Sylmar, California, 91342-1437, United States

Location

Johns Hopkins University at Mount Washington - Emergency Medicine

Baltimore, Maryland, 21209-3652, United States

Location

Truman Medical Center - Hospital Hill

Kansas City, Missouri, 64108-2640, United States

Location

Temple University Hospital

Philadelphia, Pennsylvania, 19140-5103, United States

Location

Related Publications (5)

• Mower WR, Crisp JG, Krishnadasan A, Moran GJ, Abrahamian FM, Lovecchio F, Karras DJ, Steele MT, Rothman RE, Talan DA. Effect of Initial Bedside Ultrasonography on Emergency Department Skin and Soft Tissue Infection Management. Ann Emerg Med. 2019 Sep;74(3):372-380. doi: 10.1016/j.annemergmed.2019.02.002. Epub 2019 Mar 27.

  PMID: 30926187 DERIVED

• Talan DA, Moran GJ, Krishnadasan A, Abrahamian FM, Lovecchio F, Karras DJ, Steele MT, Rothman RE, Mower WR. Subgroup Analysis of Antibiotic Treatment for Skin Abscesses. Ann Emerg Med. 2018 Jan;71(1):21-30. doi: 10.1016/j.annemergmed.2017.07.483. Epub 2017 Oct 5.

  PMID: 28987525 DERIVED

• Moran GJ, Krishnadasan A, Mower WR, Abrahamian FM, LoVecchio F, Steele MT, Rothman RE, Karras DJ, Hoagland R, Pettibone S, Talan DA. Effect of Cephalexin Plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis: A Randomized Clinical Trial. JAMA. 2017 May 23;317(20):2088-2096. doi: 10.1001/jama.2017.5653.

  PMID: 28535235 DERIVED

• Talan DA, Lovecchio F, Abrahamian FM, Karras DJ, Steele MT, Rothman RE, Krishnadasan A, Mower WR, Hoagland R, Moran GJ. A Randomized Trial of Clindamycin Versus Trimethoprim-sulfamethoxazole for Uncomplicated Wound Infection. Clin Infect Dis. 2016 Jun 15;62(12):1505-1513. doi: 10.1093/cid/ciw177. Epub 2016 Mar 29.

  PMID: 27025829 DERIVED

• Talan DA, Mower WR, Krishnadasan A, Abrahamian FM, Lovecchio F, Karras DJ, Steele MT, Rothman RE, Hoagland R, Moran GJ. Trimethoprim-Sulfamethoxazole versus Placebo for Uncomplicated Skin Abscess. N Engl J Med. 2016 Mar 3;374(9):823-32. doi: 10.1056/NEJMoa1507476.

  PMID: 26962903 DERIVED

MeSH Terms

Conditions

Staphylococcal Infections

Interventions

Cephalexin; Clindamycin; Trimethoprim, Sulfamethoxazole Drug Combination

Condition Hierarchy (Ancestors)

Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Cephalosporins; beta-Lactams; Lactams; Amides; Organic Chemicals; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lincomycin; Lincosamides; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Glycosides; Carbohydrates; Sulfamethoxazole; Benzenesulfonamides; Sulfonamides; Sulfanilamides; Aniline Compounds; Amines; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Trimethoprim; Pyrimidines; Drug Combinations; Pharmaceutical Preparations

Results Point of Contact

• Title: David A. Talan, MD
• Organization: Olive View-UCLA Medical Center

dtalan@ucla.edu

818-364-3107

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 7, 2008
• First Posted: August 8, 2008
• Study Start: April 1, 2009
• Primary Completion: May 1, 2013
• Study Completion: June 1, 2013
• Last Updated: February 18, 2015
• Results First Posted: May 28, 2014

Record last verified: 2013-09

Locations

US (5)