Benzathine benzylpenicillin !

An intramuscular depot of penicillin G that releases the drug for weeks: the mainstay for syphilis and for preventing rheumatic fever.

Updated 2026-11-01

Class: Beta-lactams
Enzyme: Penicillin-binding proteins (bacterial DD-transpeptidases)
ATC code: J01CE08
WHO Model List of Essential Medicines

Also called: benzathine penicillin G, penicillin G benzathine

Penicillin-binding proteins (bacterial DD-transpeptidases)Benzathine benzylpenicillin

The figure shows the DD-peptidase of Streptomyces R61, the classic PBP model, acylated by penicillin G (the active molecule the benzathine salt releases).

Target in 3D: Penicillin-binding proteins (bacterial DD-transpeptidases). PDB structure 1PWC (RCSB PDB, public domain). View the structure at RCSB PDB

Mechanism of action

It is a poorly soluble salt of penicillin G. Injected into muscle it forms a depot that dissolves slowly and keeps low but long-lasting penicillin G levels, which acylate the PBPs and stop wall synthesis. Treponema pallidum and group A streptococcus remain susceptible, and the long action avoids relying on many doses.

The intramuscular injection forms a crystal depot
The depot releases penicillin G slowly for weeks
Penicillin G acylates the PBPs of Treponema and streptococci
Dividing bacteria lose their wall and die

Pharmacokinetics

Absorption: Very slow absorption from muscle; low, sustained levels.
Elimination: The released penicillin is eliminated by the kidney.
Onset and duration: Slow; not suitable when high levels are needed quickly, as in neurosyphilis or meningitis.

Indications

Primary, secondary and latent syphilis, including syphilis in pregnancy to prevent congenital syphilis. Syphilis →
Long-term secondary prophylaxis of rheumatic fever and rheumatic heart disease. Rheumatic heart disease →
Group A streptococcal pharyngitis, with a single injection. Streptococcal pharyngitis →

Adverse effects

Common

Pain, hardening or a lump at the injection site
Jarisch–Herxheimer reaction (fever, chills, headache, myalgia) in the first hours when treating early syphilis

Contraindications

History of a hypersensitivity reaction to any penicillin (in pregnancy with syphilis the patient is desensitised rather than switched)
Intravenous use: it is forbidden

Key interactions

Probenecid: Reduces tubular secretion: higher and longer-lasting β-lactam levels.
Tetracyclines and other bacteriostatic drugs: May reduce penicillin's bactericidal effect.

What is monitored

In syphilis, serial non-treponemal tests to confirm the response
Observe the patient after the injection for allergic reaction

Administration and safety

Deep intramuscular only, into a large muscle (gluteal in adults, lateral thigh in small children). Never intravenous.
Aspirate before injecting and stop if blood or severe immediate pain appears.
Do not confuse it with procaine benzylpenicillin or the benzathine–procaine mix: they are not interchangeable in syphilis.
It is a thick suspension: injected slowly and steadily.

Nursing care

Before the first dose: ask about allergy to penicillins, cephalosporins and other β-lactams, and what the reaction was.
Keep the patient under observation after the injection with anaphylaxis equipment ready.
Warn that fever and malaise may come a few hours later (Jarisch–Herxheimer); in pregnancy it can trigger contractions, but treatment is not delayed.
In rheumatic fever prophylaxis, schedule and remind each injection: adherence is what protects.
In syphilis, offer testing and treatment to sexual partners.

Pregnancy and breastfeeding

Parenteral penicillin G is the only treatment with documented efficacy for syphilis in pregnancy and prevents congenital syphilis; if there is allergy, the patient is desensitised.

Test yourself

Think of the answer, then tap the question to see it.

Why is benzathine penicillin not used for neurosyphilis?

Because it releases low penicillin levels that do not reach adequate concentrations in the cerebrospinal fluid; neurosyphilis needs intravenous penicillin G.

What is done for a pregnant woman with syphilis and penicillin allergy?

She is desensitised and treated with penicillin, because it is the only treatment with documented efficacy to prevent congenital syphilis.

Hours after treatment for secondary syphilis, the patient has fever, chills and myalgia. What is it?

Most likely a Jarisch–Herxheimer reaction, from products released by dying treponemes; it is not a penicillin allergy.

What is the most dangerous administration error with this drug?

Injecting it into a vein: it can cause cardiorespiratory arrest and death. It is given by deep intramuscular injection only.

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Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: Penicillin G Benzathine Injection: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2026); Syphilis - STI Treatment Guidelines (Centers for Disease Control and Prevention (CDC), 2021); Rheumatic heart disease (World Health Organization, 2024); Farmacología básica y clínica (Katzung), cap. 43 (McGraw Hill, 2025).

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Representative model, for educational purposes only.