Benzylpenicillin (penicillin G) !

The original penicillin, given by injection. Its slow-release benzathine form treats syphilis and prevents rheumatic fever from coming back.

Updated 2026-11-01

Class: Beta-lactams
Enzyme: Penicillin-binding proteins (bacterial DD-transpeptidases)
ATC code: J01CE01
WHO Model List of Essential Medicines

Also called: penicillin G, benzathine benzylpenicillin (long-acting form), procaine benzylpenicillin (long-acting form)

Penicillin-binding proteins (bacterial DD-transpeptidases)Benzylpenicillin (penicillin G)

The figure shows the DD-peptidase of Streptomyces R61, the classic model of a PBP, acylated by penicillin G: the opened β-lactam ring is bonded to the active-site serine.

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

Benzylpenicillin binds the penicillin-binding proteins that cross-link peptidoglycan. Its β-lactam ring is opened by the enzyme's serine and stays attached, so the transpeptidase is out of action. Without new cross-links the wall weakens and the growing bacterium lyses. It is narrow-spectrum (streptococci, Treponema pallidum, meningococcus, Leptospira) and is not active against penicillinase-producing bacteria such as many staphylococci.

The β-lactam ring mimics the D-Ala–D-Ala end of the wall precursor
The PBP serine opens the ring and stays acylated
Peptidoglycan cross-links stop forming
The weak wall gives way and the bacterium bursts

Pharmacokinetics

Absorption: Given IV or IM; the long-acting benzathine form only IM. Oral use relies on a different penicillin, phenoxymethylpenicillin.
Distribution: Wide in body fluids; reaches the cerebrospinal fluid poorly unless the meninges are inflamed.
Elimination: Kidney, mostly by active tubular secretion, which probenecid blocks.
Half-life: Under an hour for the IV form with normal kidneys (longer in newborns and in kidney failure); the benzathine form, given only IM, is released slowly from the muscle, so one injection keeps acting for a long time.

Indications

Syphilis: benzathine benzylpenicillin is the treatment of choice for early and latent syphilis, and the only drug proven in pregnancy (key to preventing congenital syphilis); neurosyphilis needs the IV aqueous form. Syphilis →
Group A streptococcal pharyngitis (a single benzathine injection is one option). Streptococcal pharyngitis →
Secondary prevention of rheumatic fever: benzathine injections at regular intervals for years protect the heart valves from new attacks. Rheumatic heart disease →
Leptospirosis: Leptospira is sensitive to penicillin G, which is used in severe disease (IV form). Leptospirosis →
Meningococcal meningitis, streptococcal endocarditis and neurosyphilis (IV form).

Adverse effects

Common

Allergic rash or hives
Pain or a lump at the injection site
Diarrhoea
Jarisch–Herxheimer reaction: fever, chills, headache and muscle aches within hours of the first dose for syphilis or leptospirosis, caused by dying spirochaetes, not by allergy

Contraindications

Previous anaphylaxis or a severe reaction to a penicillin (in pregnancy with syphilis, desensitisation is used instead of another drug)
Benzathine and procaine forms must never be given intravenously

Key interactions

Probenecid: Blocks tubular secretion, so penicillin levels rise and last longer.
Tetracyclines, macrolides, chloramphenicol and sulfonamides: These bacteriostatic drugs may blunt the bactericidal effect of penicillin.

What is monitored

Observation after the injection for allergic reactions
Nontreponemal titres (VDRL or RPR) after syphilis treatment to confirm response
Kidney function and level of consciousness with high IV doses

Test yourself

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

A patient with secondary syphilis has fever, chills and myalgia a few hours after a benzathine penicillin injection. What is it, and is it an allergy?

A Jarisch–Herxheimer reaction from the release of products of dying treponemes. It is not a penicillin allergy and does not mean the drug must be avoided.

A pregnant woman with syphilis reports a penicillin allergy. Why is she usually desensitised rather than given another antibiotic?

Penicillin is the only treatment proven to cure syphilis in pregnancy and prevent congenital syphilis, so desensitisation is used to allow it safely.

Why is benzathine benzylpenicillin used to prevent recurrences of rheumatic fever?

It releases penicillin slowly from muscle over a long period, so regular injections keep group A streptococcus from causing new infections that would trigger further valve damage.

Why does probenecid raise penicillin levels?

Penicillin G leaves the body mainly by active tubular secretion in the kidney, and probenecid blocks that secretion, so levels stay higher for longer.

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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); DailyMed - PENICILLIN G POTASSIUM injection, powder, for solution (DailyMed (U.S. National Library of Medicine), 2026); Syphilis - STI Treatment Guidelines (Centers for Disease Control and Prevention (CDC), 2021); ATCDDD - ATC/DDD Index (WHO Collaborating Centre for Drug Statistics Methodology, 2026).

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Representative model, for educational purposes only.