Rifabutin Based Therapy for the Eradication of Staphylococcus Aureus Colonization in HIV Infected Adults

Study Overview
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Brief Summary
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DESIGN: This single center, double-blinded, randomized phase II study is being conducted to assess the efficacy of a rifabutin based regimen to eliminate S. aureus colonization in HIV infected individuals. Individuals must have HIV infection and a skin and skin structure infection (SSSI) in the prior 6 months to be eligible for screening. Prior to enrollment, subjects will be cultured for evidence of S. aureus colonization. Individuals who are culture positive at ≥ one body site will be eligible for enrollment. Subjects who meet inclusion and exclusion criteria and consent to participate in the study will be randomized to seven days of rifabutin plus trimethoprim-sulfamethoxazole (TMP-SMX) or TMP-SMX alone. Following completion of treatment subjects will be screened seven days, 30 days, and 60 days post-treatment for colonization at multiple body-sites. Subjects will also be actively followed for evidence of SSSI. SUBJECT PARTICIPATION DURATION: 12 weeks SAMPLE SIZE: 88 total subjects POPULATION: 200 HIV infected individuals who receive care at San Francisco General Hospital HIV clinic (Ward 86) with a history of SSSI in the prior 6 months will be screened for S. aureus colonization. DESCRIPTION OF AGENT OR INTERVENTION: This is a double-blind trial comparing rifabutin plus TMP-SMX versus placebo plus TMP-SMX. Placebo will be administered at a dose of 300 mg p.o. daily or an equivalent dose depending on co-administration of other drugs that may adjust the serum level of rifabutin. TMP-SMX will be administered at a dose of trimethoprim 160 mg and sulfamethoxazole 800 mg p.o. twice daily or adjusted per CrCl. Study drug will be provided by the study and administered for 7 days.

Official Title
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Randomized, Double-Blinded Evaluation of Rifabutin Based Therapy for Eradication of Staphylococcus Aureus Carriage in HIV Infected Individuals With Prior Skin and Skin Structure Infections

Conditions
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Staphylococcus Aureus, HIV Infections

Intervention / Treatment
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* Drug: rifabutin plus trimethoprim sulfamethoxazole
* Drug: placebo plus trimethoprim-sulfamethoxazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years HIV infection as reported by the subject's physician Physician-reported SSSI within the prior 6 months. S. aureus colonization at ≥ 1 body site as defined as a positive culture for S. aureus at minimum one of five cultures taken at pre-enrollment screening. Subjects (or their legally acceptable representatives) must have signed an informed consent documentation indicating that they understand the purpose of and procedures required for the study, and are willing to participate in the study Exclusion Criteria: Female subjects who are pregnant or lactating. Known or suspected hypersensitivity to rifabutin, a rifamycin class antimicrobial, TMP-SMX or another sulfa based medication. Known or suspected condition or concurrent treatment that would be contraindicated by the prescribing of rifabutin or TMP-SMX. Receipt of an anti-staphylococcal antimicrobial within 14 days prior to administration of study drug (TMP-SMX, clindamycin, any macrolide, any tetracycline, any rifamycin, any fluoroquinolone, vancomycin, linezolid, daptomycin, any penicillin, any carbapenem, or any cephalosporin). Diagnosis of an active SSSI or other signs and symptoms of S. aureus infection at the time of study enrollment Physician-reported diagnosis of active or untreated latent mycobacterial infection CrCl < 30 ml/min as determined by the Cockcroft-Gault Method using a serum creatinine from a value obtained within the last 6 months. No serum creatinine value available for the subject in the SFGH clinical laboratory system (LCR) within 6 months prior to enrollment. Physician-reported diagnosis of end-stage liver disease Physician-reported diagnosis of uveitis in the past or at time of enrollment Concomitant use of medications with unknown pharmacokinetic interactions with rifabutin or contraindicated with rifabutin (unboosted indinavir, unboosted saquinavir, delavirdine, atovaquone, azithromycin, Bacillus of Calmette and Guerin [only if recent administration for bladder cancer treatment], dapsone, dasatinib, erlotininb, ethinyl estradiol, fluconazole, imatinab, itinotecan, itraconazole, ixabepilone, lapatinib, levonorgestrel, mestranol, nilotininb, norelgestromin, norethindrone, posaconazole, ranolazine, sirolimus, sunitinib, tacrolimus, temsirolimus, trimetrexate, voriconazole, warfarin) Colonizing S. aureus isolate resistant to TMP-SMX Colonizing S. aureus isolate resistant to rifampin (rifampin resistance will serve as a surrogate for rifabutin resistance at initial screening) Subjects who are unlikely to be able to comply with the mandated study visits

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rifabutin<br>Subjects will be assigned to 7 days of treatment with rifabutin plus trimethoprim-sulfamethoxazole | Drug: rifabutin plus trimethoprim sulfamethoxazole<br>* rifabutin 300 mg PO daily or equivalent depending on concomitant medications plus trimethoprim-sulfamethoxazole 1 DS tab twice daily both for 7 days<br>|
| Placebo Comparator: Placebo<br>Subjects will be assigned to 7 days of treatment with placebo plus trimethoprim-sulfamethoxazole | Drug: placebo plus trimethoprim-sulfamethoxazole<br>* placebo plus trimethoprim-sulfamethoxazole 1 DS tab twice daily both for 7 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Eradication of S. Aureus Colonization | Eradication was measured by performing cultures for S aureus at the nose, throat, and groin | 30 days following completion of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Eradication of S. Aureus Colonization | Eradication was measured by performing cultures for S aureus at the nose, throat, and groin | 7 days following completion of treatment | 
| Eradication of S. Aureus Colonization | Eradication was measured by performing cultures for S aureus at the nose, throat, and groin | 60 days following completion of treatment | 
| Recurrent Skin and Skin Structure Infections (SSTI) | recurrent SSTI was by self-report and exam, followed until positive colonization | up to 30 days following completion of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Staphylococcus aureus, colonization, eradication, rifabutin