What if penicillin (Penicillin) cannot be administered for syphilis?

From the Guidelines

If you can't give penicillin for syphilis, the recommended alternative is doxycycline 100 mg orally twice daily for 14 days (for early syphilis) or 28 days (for late syphilis), as supported by the most recent study 1. This recommendation is based on the limited data available on alternative treatments for syphilis.

• Doxycycline is a suitable alternative for non-pregnant, penicillin-allergic patients with primary or secondary syphilis.
• Other options include tetracycline 500 mg orally four times daily for the same durations, or ceftriaxone 1-2 grams daily intramuscularly or intravenously for 10-14 days, as mentioned in earlier studies 1.
• For pregnant patients with penicillin allergy, desensitization to penicillin is recommended rather than using alternatives, as penicillin is the only proven effective therapy for preventing congenital syphilis, as noted in several studies 1. Before starting alternative treatments, it is essential to confirm the penicillin allergy with testing if possible, as many reported allergies are not true allergies, as highlighted in the 2022 study 1. These alternative regimens work by inhibiting bacterial protein synthesis or cell wall formation, though they may be less effective than penicillin, which remains the gold standard. Patients on alternative regimens require careful follow-up with repeat serologic testing at 6 and 12 months to ensure adequate treatment response, as emphasized in the 2022 study 1.

From the FDA Drug Label

Syphilis–early: Patients who are allergic to penicillin should be treated with doxycycline 100 mg, by mouth, twice a day for 2 weeks Syphilis of more than one year’s duration: Patients who are allergic to penicillin should be treated with doxycycline 100 mg, by mouth, twice a day for 4 weeks. If you can’t give penicillin for syphilis, doxycycline can be used as an alternative treatment. The recommended dosage is:

• 100 mg, twice a day for 2 weeks for early syphilis
• 100 mg, twice a day for 4 weeks for syphilis of more than one year’s duration 2

From the Research

Alternative Treatments for Syphilis

If penicillin cannot be used to treat syphilis, there are alternative treatment options available.

• Doxycycline is an acceptable alternate option for treating early and late latent syphilis, as stated in the study 3.
• According to the study 4, doxycycline appears to be an effective agent for the treatment of early syphilis, with no serological failures reported in the doxycycline group.
• Other alternative regimens for nonpregnant patients with no evidence of central nervous system involvement include tetracycline, ceftriaxone, and azithromycin, as mentioned in the study 5.
• However, it is essential to note that azithromycin resistance in Treponema pallidum subsp. pallidum has been reported, which may preclude its routine use as a second-line drug, as discussed in the study 6.

Comparison of Serological Response to Alternative Treatments

Studies have compared the serological response to doxycycline versus benzathine penicillin G in the treatment of early syphilis.

• A multi-center observational study 7 found that the serological response rates to a 14-day course of doxycycline and a single dose of benzathine penicillin were similar in HIV-infected patients with early syphilis at 6 and 12 months of follow-up.
• The study 7 also found that patients with secondary syphilis were more likely to achieve serological response than those with other stages, regardless of the treatment regimen used.