Treatment of tertiary syphilis

For features of tertiary syphilis, see Features of the clinical stages of syphilis.

Repeat serology on the day of treatment so that an accurate peak rapid plasma reagin [RPR] test titre is recorded to enable monitoring of the treatment responseOng, 2023.

Patients with central nervous system, eye or ear involvement require treatment with intravenous benzylpenicillin; see Treatment of neurosyphilis, ocular syphilis and otosyphilis.

Benzathine benzylpenicillin is long acting and the drug of choice for cardiovascular or gummatous tertiary syphilis without central nervous system, eye or ear involvement. UseBritish Association for Sexual Health and HIV (BASHH), 2019Workowski, 2021:

benzathine benzylpenicillin 2.4 million units intramuscularly1, every 7 days for 3 weeks. benzathine benzylpenicillin benzathine benzylpenicillin benzathine benzylpenicillin

Do not confuse benzathine benzylpenicillin with benzylpenicillin, which is short acting.

If a dose of benzathine benzylpenicillin for the treatment of tertiary syphilis is delayed, seek expert advice as soon as possible.

There are limited data supporting the use of nonpenicillin regimens for the treatment of syphilisOng, 2023. For patients who report penicillin hypersensitivity, verify their allergy. In some patients it may be appropriate to directly delabel their allergy by taking an extensive allergy history (see Clinical history for initial assessment of patients reporting penicillin hypersensitivity); in these patients benzathine benzylpenicillin should be used.

Seek expert advice for patients with a verified allergy. For patients who have had a nonsevere (immediate or delayed) or a severe (immediate)2 hypersensitivity reaction to a penicillin, options that an infectious diseases physician or clinical microbiologist may use include:

For patients who have had a severe (delayed)3 hypersensitivity reaction to a penicillin, desensitisation should not be performed; seek expert advice for alternative treatment.

Warn patients that they may experience a Jarisch–Herxheimer reaction – see Approach to managing syphilis for more information.

Corticosteroids have been used in combination with antibiotic therapy for complicated presentations, but clinical evidence to support this practice is limited. For cardiovascular syphilis, prednisolone (or prednisone) can be administered initially, starting 24 hours before penicillin to reduce the likelihood of a Jarisch–Herxheimer reaction and resultant worsening of symptomsBritish Association for Sexual Health and HIV (BASHH), 2019.

For follow-up investigations to check treatment response, see Follow-up investigations for syphilis.

If there is a possibility that the patient has early syphilis, perform contact tracing; see Management of sexual contacts of patients with early syphilis. For patients with tertiary syphilis, perform serological testing for current sexual partners and treat according to the results. Tertiary syphilis may have been acquired many years ago, so use the sexual history to determine if further contact tracing is required and seek expert advice. See also STI contact tracing.

1 The ventrogluteal site is preferred for administration of intramuscular benzathine benzylpenicillin because of reduced pain and risk of nerve injury. For instructions on intramuscular injection at the ventrogluteal site, see Instructions for intramuscular injection at the ventrogluteal site.Return
2 Severe immediate hypersensitivity reactions include anaphylaxis, compromised airway, airway angioedema, hypotension and collapse.Return
3 Severe delayed hypersensitivity reactions include cutaneous adverse drug reactions (eg drug rash with eosinophilia and systemic symptoms [DRESS], Stevens–Johnson syndrome/toxic epidermal necrolysis [SJS/TEN], severe blistering or desquamative rash), and significant internal organ involvement (eg acute interstitial nephritis).Return