Resistance to the second line treatment regimen for syphilis reported from a large London sexual health clinic is causing concern. Macrolide antibiotics are used as second line treatment for early syphilis which is caused by a bacterium Treponema pallidum, in patients allergic to penicillin. Fortunately penicillin resistance has never been reported in syphilis and penicillin remains an effective treatment against this disease worldwide. The problem arises in patients with penicillin allergy who for some reason (eg pregnancy) cannot be treated with tetracyclines, the best alternative therapy.