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Penicillin is the preferred drug for treating syphilis at present, although penicillin allergy has been a serious problem. For penicillin-allergic patients with syphilis, macrolides, tetracyclines and third-generation cephalosporins can be applied. Of these alternatives, doxycycline and ceftriaxone can serve as the primary choice for their strong antimicrobial activity. However, ceftriaxone should be used with caution for the possible cross allergy with penicillin. Macrolides, especially azithromycin, can only serve as a second-line treatment in specific conditions for the high resistance rate in clinical practice. The resistance of Treponema pallidum to these alternative drugs is associated with antimicrobial mechanisms of drugs and gene mutations in some Treponema pallidum strains.

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