Short and Long Term Outcomes of Doxycycline Versus Trimethoprim-Sulfamethoxazole for Skin and Soft Tissue Infections Treatment
Short and Long Term Outcomes of Doxycycline Versus Trimethoprim-Sulfamethoxazole for Skin and Soft Tissue Infections Treatment
The purpose of this study is to compare how well two different antibiotics, doxycycline
 (DOXY) and trimethoprim/sulfamethoxazole (TMP/SMX), work at curing uncomplicated skin and
 soft tissue infection (uSSTI) such as 1.Boils (pus in the skin, also known as abscesses and
 furuncles) or 2. Infections that appear only on the skin surface (called cellulitis and
 erysipelas) that have pus.
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

 7. For women of childbearing potential, the participant agrees to use birth control for
 the 7 days on the study medication and 7 days after completion of study medication

 Patients who have received prior antibacterial therapy with anti-staphylococcal
 activity within the prior 14 days:

 8. Received prior systemic antibacterial therapy with anti-staphylococcal activity for a
 skin infection and are not on it currently, and have relapse/recurrence of skin
 infection.

 9. Received prior systemic antibacterial therapy with anti-staphylococcal activity for a
 skin infection (including those currently on it) without adequate source control of
 their skin infection and lack of response (i.e., persistence or progression of the
 lesion) to pre-study antibacterial therapy with on-going evidence of skin infection.

 10. Received prior antibiotics with anti-staphylococcal activity for non-skin infections
 and who developed a skin infection while on these antibiotics or shortly after
 completing these antibiotics.

 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 9 to 17 years: < 90 mm Hg

 2. 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 9 to 17 years: > 120 BPM

 2. 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:

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

 2. 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. Received prior systemic antibacterial therapy with anti-staphylococcal activity within
 the prior 14 days who do not meet inclusion criteria 8, 9 and 10.

 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. Genital infection

 5. Mastitis

 6. 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) >45 kg/m2; patients above BMI
 >45 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