Randomized Clinical Trial to Compare a Regimen of Trimethoprim-sulfamethoxazole Plus Rifampicin With a Regimen of Linezolid in the Treatment of Methicillin-Resistant Staphylococcus Aureus (MRSA) Infection

Randomized Clinical Trial to Compare a Regimen of Trimethoprim-sulfamethoxazole (TMP-SMX) Plus Rifampicin With a Regimen of Linezolid in the Treatment of Infections Caused by Methicillin-resistant Staphylococcus Aureus (MRSA)

MRSA infections often require systemic antibiotic therapy and represent an important healthcare burden. Currently available treatment options are either only available in parenteral form (vancomycin) or expensive (linezolid). Thus, there is an urgent, unmet need to better investigate in-expensive but highly active alternatives to currently recommended standard treatment options. The purpose of the proposed study is to test the hypothesis that a combination of TMP-SMX and rifampicin is not inferior to linezolid for treatment of MRSA infections.

Study Overview

• Status: Completed
• Conditions: MRSA Infection
• Intervention / Treatment: Drug: trimethoprim-sulfamethoxazole (TMP-SMX); Drug: Rifampicin; Drug: Linezolid

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 4

Contacts and Locations

Study Locations

• Switzerland
  • Geneva, Switzerland, 1211
    • Geneva University Hospitals

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. Patients with clinical signs and symptoms of MRSA-related infection

3. Culture of MRSA (predominant microorganism in culture) susceptible to all of the following:

   • TMP-SMX
   • rifampicin
   • linezolid
4. Patient must give written informed consent to participate in the study.

Exclusion Criteria:

1. Women who are pregnant or nursing
2. Women who refuse to substitute oral contraception during treatment
3. Known or suspected hypersensitivity to linezolid, TMP-SMX or rifampicin

4. Clinical or laboratory evidence of significant impairment of hepatic function, as demonstrated by any of the following criteria:

   • Bilirubin > 3 x upper limit of normal range
   • AST or ALT > 5 x upper limit of normal range
   • Acute hepatitis or proven liver cirrhosis by liver histology
5. Treatment with other antimicrobials with activity against MRSA for > 72 hours prior to study inclusion
6. Patients with a high probability of death within the week following study entry
7. Patients who, in the opinion of the investigator, cannot be relied upon for post-therapy follow-up
8. Patients requiring alternative antibiotic therapy with anti-MRSA activity. However, if another antibiotic treatment without antistaphylococcal activity is necessary, the patient is acceptable for randomization. In that sense, the use of aztreonam (against Gram negative microorganisms) or metronidazole (against anaerobes) is allowed
9. Hemodialyzed patients
10. History of pheochromocytoma, carcinoid syndrome, untreated hyperthyroidism, uncontrolled hypertension, or patients receiving serotonin uptake inhibitors
11. Severe thrombocytopenia (< 50.000 platelets)
12. Left-sided endocarditis with a poor prognosis (patients aged over 50; cerebral embolism)
13. Chronic osteomyelitis without surgical debridement; superinfected indwelling foreign body, deliberately kept in place
14. Patients with severe sepsis or septic shock due to MRSA bacteremia
15. Patients who receive any of the following drugs, which cannot be substituted or temporarily withdrawn: adrenergic and serotonergic agents, tramadol, pethidine, duloxetine, venlafaxine, milnacipran, sibutramine, chlorpheniramine, brompheniramine, cyproheptadine, citalopram, and paroxetine.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; trimethoprim-sulfamethoxazole (TMP-SMX) plus rifampicin	Drug: trimethoprim-sulfamethoxazole (TMP-SMX); TMP-SMX (160 mg TMP/ 800 mg SMX IV or PO 3x daily); Drug: Rifampicin; Rifampicin (600 mg IV or PO once daily)
Active Comparator: 2; Linezolid	Drug: Linezolid; Linezolid (600 mg IV or PO twice daily)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Bacteriological and clinical cure	6 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Treatment costs	6 weeks

Collaborators and Investigators

• Sponsor: University Hospital, Geneva
• Investigators: Principal Investigator: Stephan Harbarth, MD, MS, University Hospital, Geneva

Publications and helpful links

General Publications

• Harbarth S, von Dach E, Pagani L, Macedo-Vinas M, Huttner B, Olearo F, Emonet S, Uckay I. Randomized non-inferiority trial to compare trimethoprim/sulfamethoxazole plus rifampicin versus linezolid for the treatment of MRSA infection. J Antimicrob Chemother. 2015 Jan;70(1):264-72. doi: 10.1093/jac/dku352. Epub 2014 Sep 10.

Helpful Links

• MRSA research center, Geneva University Hospitals and Medical School

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: July 3, 2008
• First Submitted That Met QC Criteria: July 3, 2008
• First Posted (Estimate): July 9, 2008

Study Record Updates

• Last Update Posted (Estimate): August 5, 2014
• Last Update Submitted That Met QC Criteria: August 4, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: Staphylococcal infection
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Communicable Diseases; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Leprostatic Agents; Protein Synthesis Inhibitors; Cytochrome P-450 Enzyme Inducers; Antiprotozoal Agents; Antiparasitic Agents; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antimalarials; Folic Acid Antagonists; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Anti-Dyskinesia Agents; Anti-Infective Agents, Urinary; Renal Agents; Cytochrome P-450 CYP2C8 Inhibitors; Linezolid; Rifampin; Trimethoprim; Sulfamethoxazole; Trimethoprim, Sulfamethoxazole Drug Combination
• Other Study ID Numbers: 08-059