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

L

Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

Status and phase

Completed
Phase 2

Conditions

Methicillin-resistant Staphylococcus Aureus
Skin Infection

Treatments

Drug: TMP-SMX
Drug: DOXY

Study type

Interventional

Funder types

Other
NIH

Identifiers

Details and patient eligibility

About

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.

Full description

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.

Enrollment

269 patients

Sex

All

Ages

9 to 85 years old

Volunteers

No Healthy Volunteers

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

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

Quadruple Blind

269 participants in 2 patient groups

Trimethoprim/sulfamethoxazole (TMP-SMX)
Experimental group
Description:
TMP-SMX will be dosed as follows: for adults, 160/800 mg administered as two single strength (SS) over-encapsulated tablets (equivalent to one double strength (DS) tablet) twice daily. As dosages of these medications may be lower in children with lower body weight (\<40 kg), we will use weight based liquid medications for children \< 40 kg (TMP/SMX dosed based on 8-10 mg/kg of TMP daily, divided into two daily doses) for those children who are under 40 kg in weight. As dosages of these medications are higher in persons with high body weight (\>100 kg), we will use TMP/SMX 160/800 mg administered as four single strength (SS) over-encapsulated tablets (equivalent to two double strength (DS) tablet) twice daily.
Treatment:
Drug: TMP-SMX
Doxycycline (DOXY)
Experimental group
Description:
DOXY will be dosed as follows: for adults, two 50 mg tabs (100 mg total) given twice daily. As dosages of these medications may be lower in children with lower body weight (\<40 kg), we will use weight based liquid medications for children \< 40 kg (DOXY 2.2 mg/kg twice daily) for those children who are under 40 kg in weight. The doxycycline dose will remain the same for persons with high body weight (\>100 kg) and four additional placebo tabs will be given to subjects \> 100 kg randomized to doxycycline.
Treatment:
Drug: DOXY

Trial contacts and locations

3

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Central trial contact

Donna Phan Tran, MPH

Data sourced from clinicaltrials.gov

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