The study aims to evaluate the efficacy of linezolid for the treatment of syphilis.

This will be a randomized, open-label, non-comparative, pilot trial to evaluate the efficacy of linezolid 600mg orally, twice a day, for ten days, using a contemporaneous historical control group benzathine penicillin G (single dose of 2.4 million units) in participants with and without HIV infection.

In total, 24 participants will be enrolled across multiple clinical sites in the United States. Participants will participate in follow-ups to monitor clinical outcomes and serological response (RPR titer) at 1 month, 3 months, and 6 months. A 5 and 10-day phone call will ensure adherence to treatment and evaluate safety.

Study findings may identify an efficacious alternative syphilis treatment to penicillin that is effective for people living with HIV. Study findings may also help address the crisis of penicillin shortages, difficulty in administration, and offer options for those with penicillin allergy.

Inclusion Criteria: To be eligible for this study, participants must be:

1. Diagnosed cases of primary, secondary or early latent syphilis with RPR titer ≥1:8 within 3 weeks prior to enrollment
2. 16 years of age or older
3. Able to provide informed consent/assent.
4. Individuals with HIV infection must be on treatment for HIV-infection and virologically suppressed (viral load < 200 copies/mL) or have a CD4 count ≥ 350 cells/mm3 as of their most recent test prior to enrollment.

Exclusion Criteria include:

1. Pregnancy or a positive pregnancy test on the day of enrollment
2. Patients showing signs and symptoms of neurosyphilis.
3. Participants who receive certain psychotropic medications, e.g., MAO inhibitors, SNRIs, SSRIs
4. Serofast RPR titer, defined as persistently positive RPR titer without more than 4-fold (2-titer level) change for 12 months or greater.
5. Recent (within the past 7 days) or concomitant antimicrobial therapy with activity against syphilis, namely azithromycin, tetracycline, doxycycline, cefixime, ceftriaxone or other beta lactam antibiotics (e.g. amoxicillin)
6. Individuals with HIV infection who report HIV treatment interruption for more than 4 weeks since their most recent viral load or CD4 test.
7. Individuals with known myelosuppressive conditions or receiving myelosuppressive medication
8. Individuals weighing 150kg (330 lbs) or more.
9. Individuals with known end renal stage disease, for example individuals in hemodialysis.
10. Self-reported allergy to linezolid or penicillin.
11. Unwilling or unable to attend follow-up visits.

No IPD will be shared with other researchers