Benzathine Penicillin

Benzathine penicillin (benzathine benzylpenicillin) is a long-acting intramuscular depot of benzylpenicillin that gives low but prolonged serum levels for 2 to 4 weeks. It is the cornerstone for syphilis, secondary prevention of rheumatic fever and single-dose treatment of streptococcal pharyngitis. It must never be given intravenously.

Classification. Beta-lactam, natural penicillin, repository form. 1.2 MU equals 900 mg benzathine benzylpenicillin.

Mechanism. Slow hydrolysis from the injection site releases benzylpenicillin, which inhibits cell wall synthesis.

Pharmacokinetics. Peak serum levels occur 12 to 24 hours after injection, around 0.03 to 0.05 mg/L; levels stay detectable for 2 to 4 weeks. CSF penetration is negligible, so it does not treat neurosyphilis, meningitis or bacteraemia.

All use is by deep intramuscular injection. No loading, titration or maintenance split. Maximum for one session is 2.4 MU, given as two injections at separate sites.

Syphilis in adults.

• Primary, secondary and early latent: 2.4 MU once.
• Late latent or latent of unknown duration, and tertiary without neurological involvement: 2.4 MU once weekly for 3 weeks.
• In pregnancy and HIV: many services give a second 2.4 MU dose 1 week after the first for early syphilis; practice differs.

Congenital syphilis. Asymptomatic infants with normal examination and adequately treated mother: 50,000 units/kg once. Confirmed or probable disease needs intravenous benzylpenicillin.

Streptococcal pharyngitis. Single dose: 1.2 MU for 27 kg and over; 600,000 units under 27 kg.

Rheumatic fever secondary prevention. 1.2 MU every 4 weeks (every 3 weeks in high-risk patients or recurrences despite 4-weekly dosing); 600,000 units for children under 27 kg. Duration is 5 years or until age 21 without carditis, 10 years or until 21 after carditis, and up to age 40 or lifelong after severe valve disease.

Yaws, bejel and pinta. Adults and children 10 years and over: 1.2 MU once; children under 10 years: 600,000 units once.

Alternatives. Doxycycline for syphilis in penicillin allergy outside pregnancy; desensitisation for pregnancy. Procaine penicillin plus probenecid for neurosyphilis.

Contraindications. Immediate penicillin hypersensitivity; known procaine hypersensitivity if the product contains procaine (most do not).

Warnings.

• Never intravenous or intra-arterial: cardiopulmonary arrest and death have followed inadvertent IV injection.
• Intra-arterial or peri-arterial injection causes gangrene (Nicolau syndrome).
• Sciatic nerve injury can follow gluteal injection in infants and children.
• Jarisch-Herxheimer reaction within 24 hours in syphilis: fever, rigors, myalgia, hypotension.
• Anaphylaxis; deliver where resuscitation drugs and adrenaline are immediately available and observe for 30 minutes. Fear of anaphylaxis is a recognised reason for withholding it, but true reaction is rare.

Interactions. Methotrexate, oral typhoid vaccine, warfarin. Probenecid is not used with it.

Common prescribing errors. IV administration, using it for neurosyphilis, giving 1.2 MU instead of 2.4 MU in syphilis, missed weekly doses, and ignoring the 27 kg cut-off in children.

Special groups.

• Pregnancy: the only adequate treatment for syphilis; if allergic, desensitise then treat.
• Breastfeeding: compatible.
• Children: anterolateral thigh in infants; reduced dose under 27 kg for pharyngitis and prophylaxis.
• Older adults: usual dose.
• Kidney and liver impairment: no adjustment.
• Region: supply shortages and unequal product quality occur in East Africa; confirm the product is a registered benzathine benzylpenicillin and check expiry.

Preparation. Reconstitute powder with the diluent supplied or water for injection; shake to an even suspension. Use a wide-bore needle (18 to 21 gauge) in the upper outer buttock or anterolateral thigh. Aspirate before injecting and inject slowly. Do not use lidocaine as diluent unless the product allows it and never add adrenaline.

Baseline and monitoring. - Syphilis: baseline non-treponemal titre, HIV test and pregnancy test; repeat titres at 3, 6 and 12 months (also 24 months in latent disease). A fourfold fall is expected within 6 to 12 months in early disease. - Rheumatic prophylaxis: check adherence, injection dates and echocardiography.

Stop rules. Stop for anaphylaxis. Rising titres or lack of fourfold fall mean treatment failure or reinfection.

Referral and escalation. Neurological, ocular or otic symptoms, treatment failure, pregnancy, HIV and congenital syphilis need specialist input; neurosyphilis requires intravenous benzylpenicillin.