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.

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.