Short and Long Term Outcomes of Doxycycline Versus Trimethoprim-Sulfamethoxazole for Skin and Soft Tissue Infections Treatment

This is a phase IIb multicenter, randomized, double-blind trial in which enrolled subjects
with abscess or cellulitis will be treated with either DOXY or TMP-SMX.

The overall objective is to provide a clinically relevant treatment strategy for uSSTI in
children and adults in areas where CA-MRSA is prevalent. Out-patient subjects, both children
and adults with abscess and/or purulent cellulitis will be enrolled into a randomized,
double-blind trial in which enrolled subjects will be treated with either DOXY or TMP-SMX.

Background: Staphylococcus aureus is the most commonly identified cause of skin infections.
In the last 15 years, there also has been an large increase in Staphylococcus aureus skin
infection attributable to CA-MRSA (Methicillin-resistant Staphylococcus aureus) throughout
the United States. However, optimal treatment remains unclear and several commonly used
antibiotics such as doxycycline are commonly used but understudied. As resistance among
CA-MRSA strains to commonly used antibiotics such as clindamycin continues to increase, there
is a need to understand the relative safety and efficacy of alternative treatments, such as
doxycycline. This clinical trial will evaluate DOXY and TMP-SMX for the outpatient management
of uSSTI in two metropolitan areas, Los Angeles and St. Louis, cities with high prevalence of
CA-MRSA. This trial will test important unanswered hypotheses relating to the treatment of
CA-MRSA uSSTI and it will advance healthcare providers' ability to successfully manage adults
and children with uSSTIs in areas where CA-MRSA is prevalent.

Methods: Out-patient subjects, both children and adults with abscess and/or purulent
cellulitis will be enrolled into a randomized, double-blind trial in which enrolled subjects
will be treated with either DOXY or TMP-SMX. Using a 1:1 randomized controlled trial of 462
subjects, the investigators aim to 1) compare the cure rate of DOXY to that of TMP-SMX for
the treatment of patients throughout the study 2) compare rates of adverse events and of
adverse events that are treatment limiting between DOXY and TMP-SMX 3) estimate relapse and
recurrence of uSSTI among patients treated with DOXY and of TMP-SMX 4) estimate treatment
failure among patients with uSSTI colonized with S. aureus at the anterior nares and
oropharynx.

Inclusion Criteria:

1. Age 9 years to 85 years

2. 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 9 and older

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

4. Diagnosis of uSSTI, either purulent 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

5. Pus or drainage from wound that can be sent for clinical culture.

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

Exclusion Criteria:

1. Cellulitis without abscess, drainage, or other culturable exudate.

2. Hospital inpatient

3. Hospitalization within the prior 14 days

4. Residence in a long-term skilled nursing facility

5. Requirement for hospitalization for skin infection or other condition

6. Previous enrollment in this protocol

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

8. 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

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

10. 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

11. Systolic blood pressure > 180 mm Hg

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

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

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

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

4. Age ≥ 18 years: < 90 mm Hg

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

14. 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 ≥ 18 years: > 120 BPM

15. Oral temperature (or equivalent rectal, tympanic membrane, axillary defined in Table
2) less than 35.5° C (95.9° F)

16. Oral temperature (or equivalent rectal, tympanic membrane, axillary defined in Table
2) greater than age-specific critical value:

- Age 6 -11 months: > 38.0° C (100.4° F)

- Age 1 to 8 years: > 38.5° C (101.3° F)

- Age 9 to 17 years: > 38.5° C (101.3° F)

- Age ≥ 18 years: > 38.5° C (101.3° F)

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

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

19. The following concomitant medications: warfarin, phenytoin, methotrexate, dofetilide,
methanamine, amiodarone, leucovorin, pyrimethamine, acitretin, atovaquone,
atovaquone/proguanil, isotretinoin, or sulfonylureas and systemically administered
antibacterial agents with activity against staphylococci

20. Diagnosed or suspected disseminated or severe S. aureus or GAS infection, including
lymphangitic spread of skin infection, septicemia, bacteremia, pneumonia,
endocarditis, osteomyelitis, septic arthritis, gangrene, necrotizing fasciitis,
myositis, or other serious or infections

21. Infection at an anatomical site skin 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. Suspected deep space infection of the hand or foot

5. Genital infection

6. Mastitis

7. Bursitis

22. 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)

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

24. Hypersensitivity or history of allergic reaction to study drug

25. History of G6PD deficiency

26. Pregnant or lactating, or intending to become pregnant within 3 months after screening
Women of childbearing potential must have a negative urine or serum pregnancy test
result within 1 day prior to initiation of study drug.

27. Severe or morbid obesity with a body mass index (BMI) >40 kg/m2; patients above BMI
>40 can be enrolled if their weight is < 100 kg kg/m2.

28. 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)

29. History of drug-induced thrombocytopenia and documented megaloblastic anemia due to
folate deficiency.

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

31. History of severe underlying immunocompromising condition or immunodeficiency, for
example

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

2. Renal dialysis within the past 180 days

3. HIV-positive with either CD4 count <200 or <4% CD4 in the past 180 days or
HIV-positive and no documented CD4 count in the past 4 months

4. Cancer or malignancy with receipt of systemic chemotherapy in the prior 180 days

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