Strategies Using Off-Patent Antibiotics for Methicillin Resistant S. Aureus "STOP MRSA"
Strategies Using Off-Patent Antibiotics for Methicillin Resistant S. Aureus "STOP MRSA"
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.
Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has recently emerged
 as a cause of skin and soft-tissue infection (SSTI). In the current era of increasing CA-MRSA
 infections, the outpatient management of SSTIs has not been well studied. This will be a
 clinical trial to evaluate oral off-patent antibiotics for outpatient treatment of patients
 with any of the 3 main types of acute uncomplicated SSTI, i.e., abscesses, infected wounds,
 and cellulitis. Upon enrollment, subjects will be stratified by type of infection, and then
 randomized to various treatments. Subjects with an acute uncomplicated cutaneous abscess
 receiving incision and drainage (I&D) will be treated with Trimethoprim/Sulfamethoxazole
 (TMP/SMX) or placebo to determine whether the addition of an antibiotic with activity against
 CA-MRSA is more clinically efficacious than I&D alone. Subjects with an acute wound infection
 will be treated with TMP/SMX or clindamycin to determine if clindamycin, an antibiotic with
 activity against CA-MRSA, methicillin-susceptible Staphylococcus aureus (MSSA), and
 streptococci is more clinically efficacious than TMP/SMX, an antibiotic with activity against
 CA-MRSA and MSSA. Subjects with acute cellulitis will be treated with cephalexin/TMP/SMX or
 cephalexin/placebo to determine if cephalexin/TMP/SMX is more clinically efficacious than
 cephalexin alone. The primary objectives for each type of SSTI studied are to compare the
 cure rates in the per protocol (PP) population. Secondary objectives provide additional means
 of assessment for the clinical efficacy of the employed interventions and resolution of the
 infection and include describing microbiological cure, change in the dimension of erythema,
 composite cure, surgical procedures, invasive and recurrent infections, infections in
 household contacts, and time to normal activity and until analgesics are no longer used at
 various times in the PP/ modified intent-to-treat (mITT) populations. This is a multi-center,
 randomized, double-blind clinical trial in which subjects will be stratified by the type of
 infection and then randomized to various 7-day oral antibiotic treatments, including
 placebo-controlled and comparative designs. The study population will include children 13
 years of age and over and adults, who weigh greater than or equal to 40 kg presenting to 5
 large urban emergency departments. Therapy will start on the day of enrollment. Subjects will
 be evaluated upon enrollment, at 2-3 days after enrollment (OTV), at 1-3 days after the
 end-of-therapy (EOT), at 7-14 days after the end-of-therapy (TOC), and at 6-8 weeks after the
 end-of-therapy (EFV).
Inclusion Criteria:

 -  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:

 1. 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.

 2. 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

 3. 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.

 Exclusion Criteria:

 -  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;

 -  Prior enrollment in this study within 12 weeks;

 -  Another active infection of another organ system (e.g., pneumonia) or more than one
 active (i.e., currently on antibiotic treatment and/or requiring I&D) SSTI site (e.g.,
 a site noncontiguous with the infection under study). Note: Minor folliculitis at
 secondary site is not an exclusion;

 -  Presence of an abscess that has completely drained, either spontaneously or by a
 healthcare provider prior to enrollment;

 -  An infected wound or cellulitis that has been surgically explored (>1 cm incision) and
 does not reveal an abscess. Cellulitis that has been needled, minimally incised (less
 than or equal to 1 cm) or punch biopsied and no purulent drainage found can still be
 enrolled;

 -  Currently incarcerated in a detention facility or in police custody (note: patients
 wearing a monitoring device can be enrolled) at baseline/screening;

 -  For patients with an infected wound, history of C. difficile infection,
 pseudomembranous colitis, or active diarrhea at baseline/screening;

 -  For patients with an infected wound, severe liver disease based on patient history;

 -  An intravenous (IV) drug user in the last month with current presence of fever;

 -  Current residence in a nursing home or other long term care facility at
 baseline/screening;

 -  Expected use of other investigational drug or vaccine while on study drug;

 -  For patients with an abscess, cardiac conditions associated with the highest risk of
 adverse outcome from endocarditis for which prophylaxis is reasonable, including
 patients with prosthetic cardiac valve or prosthetic material used for cardiac valve
 repair, history of previous infective endocarditis, congenital heart disease
 (excluding mitral valve prolapse), and history of cardiac transplantation recipients
 who develop cardiac valvulopathy;

 -  Presence of an organic foreign body, e.g., wood (note: subjects with embedded
 non-organic materials, e.g., metal or glass, that can be completely removed can still
 be enrolled if physician is certain there is no foreign body left).