Uncomplicated Skin and Soft Tissue Infections Caused by Community-Associated Methicillin-Resistant Staphylococcus Aureus

Clinical practice in the treatment of community-onset skin and soft tissue infections (SSTI)
has not kept pace with the emergence of methicillin-resistant Staphylococcus aureus (MRSA)
in the community. This clinical trial will evaluate clindamycin (CLINDA) and
trimethoprim-sulfamethoxazole (TMP-SMX) and wound care for the outpatient management of
uncomplicated skin and soft tissue infection (uSSTI) in 3 metropolitan areas, Chicago, Los
Angeles, and San Francisco, cities with high prevalence of community acquired (CA)-MRSA.
This is a phase IIb multicenter, stratified, randomized, double-blind trial in which
enrolled subjects with abscess or cellulitis will be treated with CLINDA, TMP-SMX, or
placebo. Participants will include 1310 non-immunocompromised out-patients age 6 months to
85 years with SSTIs not requiring hospital admission. Subjects will undergo a
screening/baseline evaluation, including determination of presence and size of abscess
and/or presence of cellulitis. Subjects will then be randomized to receive treatment with
either CLINDA, TMP-SMX, or placebo depending on whether they have: a larger drainable
abscess, defined as greater than 5 cm in diameter in adults and as greater than 3 cm in
diameter for ages 6-11 months, greater than 4 cm for ages 1-8 years, and greater than 5 cm
for age 9 years and older; a limited drainable abscess, defined as less than or equal to 5
cm for adults and as less than or equal to 3 cm for ages 6-11 months, less than or equal to
4 cm for ages 1-8 years, and less than or equal to 5 cm for age 9 years and older; or
cellulitis or erysipelas only. If the diameter of the abscess greater than 5 cm (smaller for
children depending on age) or 2 or more sites of skin infection are present the subject will
be randomized (1:1) to 10 days of therapy with TMP-SMX or CLINDA. If the diameter of the
abscess less than or equal to 5 cm (smaller for children depending on age) then the subject
will be randomized (1:1:1) to TMP-SMX, CLINDA or placebo for 10 days. Subjects with
cellulitis or erysipelas only will be randomized (1:1) to TMP-SMX or CLINDA for 10 days.
Subjects will be provided study drug, instructed in its use, and scheduled for 4 follow-up
visits including: wound check (24-48 hours after enrollment); end of therapy (48 hours after
completion of therapy); test of cure (7-10 days after completion of therapy); and a final
visit at one month after completion of therapy. The primary objectives of this study are: to
compare the cure rate of CLINDA to that of TMP-SMX for the treatment of patients with
cellulitis or larger abscess at the Test of Cure (TOC) visit and to compare the cure rate of
CLINDA, TMP-SMX, and placebo, each in conjunction with surgical drainage for the treatment
of subjects with limited abscess at the TOC visit.

Inclusion Criteria:

- Age 6 months to 85 years.

- Able to complete the informed consent process or, if a minor, a parent or guardian
who is able to complete the informed consent process; an assent form also will be
completed for children age 7 and older.

- Willing and able to complete the study protocol, study-related activities, and
visits.

- Diagnosis of uncomplicated skin and soft tissue infection (uSSTI), either cellulitis
(defined as an inflammation of skin and associated skin structures) or abscess
(defined as a circumscribed collection of pus), evidenced by at least 2 of the
following localized signs or symptoms on the skin for at least 24 hours:

1. Erythema

2. Swelling or induration

3. Local warmth

4. Purulent drainage

5. Tenderness to palpation or pain

- Able to take oral antibiotic therapy, either in pill or suspension form.

Exclusion Criteria:

- Hospital in-patient.

- Hospitalization within the prior 14 days.

- Residence in a long-term skilled nursing facility.

- Requirement for hospitalization for skin infection or other condition.

- Previous enrollment in this protocol.

- Participation in another clinical trial within the previous 30 days.

- Superficial skin infection only, including:

1. Impetigo

2. Ecthyma

3. Folliculitis

4. Infections that have a high cure rate after surgical incision alone (such as
isolated furunculosis) or after topical or local measures

- Unstable psychiatric or psychological condition rendering the subject unlikely to be
cooperative or to complete study requirements.

- Active drug or alcohol use or dependence that, in the opinion of the site
investigator, would interfere with the adherence or subject compliance with study
requirements.

- Systolic blood pressure > 180 mm Hg.

- Systolic blood pressure (SBP) less than an age-specific critical value:

1. Age 6 - 11 months: < 70 mm Hg

2. Age 1 to 8 years: < 80 mm Hg

3. Age 9 to 17 years: < 90 mm Hg

4. Age greater than or equal to 18 years: < 90 mm Hg

- Heart rate less than 45 beats per minute (BPM).

- Heart rate greater than an age-specific critical value:

1. Age 6 - 11 months: > 140 BPM

2. Age 1 to 8 years: > 120 BPM

3. Age 9 to 17 years: > 120 BPM

4. Age greater than or equal to 18 years: > 120 BPM.

- Oral temperature (or equivalent rectal, tympanic membrane, axillary) less than 35.5
degrees Celsius (95.9 degrees Fahrenheit).

- Oral temperature (or equivalent rectal, tympanic membrane, axillary) greater than
age-specific critical value:

1. Age 6 - 11 months: > 38.0 degrees Celsius (100.4 degrees Fahrenheit)

2. Age 1 to 8 years: > 38.5 degrees Celsius (101.3 degrees Fahrenheit)

3. Age 9 to 17 years: > 38.5 degrees Celsius (101.3 degrees Fahrenheit)

4. Age greater than or equal to 18 years: > 38.5 degrees Celsius (101.3 degrees
Fahrenheit).

- Documented human or witnessed animal bite in the past 30 days at the site of
infection.

- Systemic antibacterial therapy with antistaphylococcal activity within the prior 14
days.

- The following concomitant medications: warfarin, phenytoin, methotrexate,
rosiglitazone or sulfonylureas and systemically administered antibacterial agents
with activity against staphylococci.

- Diagnosed or suspected disseminated or severe Staphylococcus aureus or group A
streptococcal (GAS) infection, including lymphangitic spread of skin infection,
septicemia, bacteremia, pneumonia, endocarditis, osteomyelitis, septic arthritis,
gangrene, necrotizing fasciitis, myositis, or other serious infections.

- Infection at an anatomical skin site requiring specialized management or specialized
antimicrobial therapy, including:

1. Periauricular or orbital infection

2. Perirectal infection

3. Suspected deep space infection of the hand or foot

4. Genital infection

5. Mastitis

6. Bursitis

- Radiographic evidence or suspicion of gas in the tissue or foreign body infection
(note: radiography is not required for screening and can be performed at the
discretion of the treating physician).

- Gastrointestinal symptoms such as nausea, vomiting, or diarrhea of a severity that
would preclude consumption of oral antibiotics.

- Hypersensitivity or history of allergic reaction to study drug.

- History of glucose-6-phosphate dehydrogenase (G6PD) deficiency.

- Third trimester pregnancy: pregnant women must have gestational age estimated by an
objective means, e.g. ultrasound, fundal height, and women who are within 4 weeks of
the third trimester of pregnancy, defined as week 27 of pregnancy, are not eligible.

- Currently breast feeding.

- Severe or morbid obesity with a body mass index (BMI) >40 kg/m^2.

- Complicated skin or soft tissue infection, such as:

1. Catheter or catheter site infection within 30 days of placement

2. Surgical site infection

3. Known or suspected prosthetic device infection

4. Suspected Gram-negative or anaerobic pathogen

5. Unusual exposure history (e.g., underwater injury, fish-tank exposure, heavy
soil exposure, etc)

6. Infection at the site of an area of underlying skin disease such as chronic
eczema, psoriasis, atopic dermatitis, or chronic venous stasis

- History of underlying immunocompromising condition or immunodeficiency, for example:

1. Diabetes mellitus

2. Chronic renal failure, creatinine clearance <30 ml/min

3. Renal dialysis within the past 180 days

4. Human immunodeficiency virus (HIV)-positive with either cluster of
differentiation (CD)4 count <200 or <4 percent CD4 in the past 180 days or
HIV-positive and no documented CD4 count in the past 4 months

5. Organ or bone marrow transplantation (ever), immunosuppressive therapy within
the past 180 days, severe liver disease

6. Other serious underlying disease, as determined by the treating physician or the
investigator