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

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

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.

Study Overview

• Status: Terminated
• Conditions: HIV Infections; Staphylococcus Aureus
• Intervention / Treatment: Drug: rifabutin plus trimethoprim sulfamethoxazole; Drug: placebo plus trimethoprim-sulfamethoxazole

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94110
      • San Francisco General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age > 18 years
2. HIV infection as reported by the subject's physician
3. Physician-reported SSSI within the prior 6 months.
4. 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.
5. 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:

1. Female subjects who are pregnant or lactating.
2. Known or suspected hypersensitivity to rifabutin, a rifamycin class antimicrobial, TMP-SMX or another sulfa based medication.
3. Known or suspected condition or concurrent treatment that would be contraindicated by the prescribing of rifabutin or TMP-SMX.
4. 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).
5. Diagnosis of an active SSSI or other signs and symptoms of S. aureus infection at the time of study enrollment
6. Physician-reported diagnosis of active or untreated latent mycobacterial infection
7. CrCl < 30 ml/min as determined by the Cockcroft-Gault Method using a serum creatinine from a value obtained within the last 6 months.
8. No serum creatinine value available for the subject in the SFGH clinical laboratory system (LCR) within 6 months prior to enrollment.
9. Physician-reported diagnosis of end-stage liver disease
10. Physician-reported diagnosis of uveitis in the past or at time of enrollment
11. 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)
12. Colonizing S. aureus isolate resistant to TMP-SMX
13. Colonizing S. aureus isolate resistant to rifampin (rifampin resistance will serve as a surrogate for rifabutin resistance at initial screening)
14. Subjects who are unlikely to be able to comply with the mandated study visits

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Investigators: Principal Investigator: Henry F Chambers, MD, University of Califronia, San Francisco; Principal Investigator: Brian S Schwartz, MD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (ACTUAL): December 1, 2010
• Study Completion (ACTUAL): December 1, 2010

Study Registration Dates

• First Submitted: March 24, 2009
• First Submitted That Met QC Criteria: March 25, 2009
• First Posted (ESTIMATE): March 26, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): May 14, 2014
• Last Update Submitted That Met QC Criteria: April 23, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: HIV; Staphylococcus aureus; colonization; eradication; rifabutin
• Additional Relevant MeSH Terms: Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Infections; Staphylococcal Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Antitubercular Agents; Antimalarials; Folic Acid Antagonists; Antibiotics, Antitubercular; Anti-Dyskinesia Agents; Anti-Infective Agents, Urinary; Renal Agents; Cytochrome P-450 CYP2C8 Inhibitors; Rifabutin; Trimethoprim; Sulfamethoxazole; Trimethoprim, Sulfamethoxazole Drug Combination
• Other Study ID Numbers: 08033578