What is benzyl penicillin (Penicillin G)?

What is Benzyl Penicillin (Penicillin G)?

Benzyl penicillin (penicillin G) is a natural, water-soluble beta-lactam antibiotic that remains the gold standard treatment for serious streptococcal, pneumococcal, meningococcal, gonococcal, and treponemal infections due to its bactericidal activity, excellent tissue distribution, and lack of documented resistance among Group A streptococci. 1

Chemical Structure and Formulation

• Benzyl penicillin is chemically designated as 4-Thia-1-azabicyclo(3.2.0)-heptane-2-carboxylic acid, 3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-, monosodium salt 1
• It is a bicyclic ring compound containing a 4-membered beta-lactam ring (penam) fused to a 5-membered thiazolidine ring 2
• Available as a white to almost white crystalline powder that forms a colorless solution when reconstituted, with pH ranging from 5.0 to 7.5 1
• Supplied in vials containing 5 million units of penicillin G as the sodium salt, with 1.68 mEq of sodium per million units 1

Mechanism of Action

• Penicillin G is bactericidal against susceptible microorganisms during their active multiplication phase 1
• It acts by inhibiting biosynthesis of bacterial cell-wall mucopeptide, leading to cell death 1
• It is not active against penicillinase-producing bacteria, which includes many staphylococcal strains 1

Pharmacokinetics

• Absorption and Distribution: Following intramuscular administration of benzathine penicillin G, the drug is absorbed slowly with a median time to peak concentration (tmax) of 48 hours 3

• Penicillin G distributes widely to lung, liver, kidney, muscle, bone, and placenta 1

• In the presence of inflammation, therapeutic levels are achieved in abscesses, middle ear, pleural, peritoneal, and synovial fluids 1

• Penetration into the eye, brain, cerebrospinal fluid (CSF), or prostate is poor without inflammation, but improves significantly with inflamed meninges (CSF/serum ratio of 2-6%) 1

• Elimination: Renal clearance is extremely rapid, occurring through glomerular filtration and predominantly active tubular transport 1

• Urinary recovery is 58-85% of the administered dose 1

• The serum half-life ranges from 3.2 hours in neonates 0-6 days old to 1.4 hours in infants ≥14 days old 1

• For benzathine penicillin G, the apparent terminal half-life is approximately 189 hours, maintaining therapeutic concentrations above 18 ng/mL for a median of 561 hours (18-25 days) 3

• Probenecid blocks renal tubular secretion, prolonging penicillin elimination and increasing serum concentrations 1

Spectrum of Activity

• Highly susceptible organisms: Streptococci (Groups A, B, C, G, H, L, M), pneumococci, Neisseria meningitidis, Neisseria gonorrhoeae, Corynebacterium diphtheriae, Bacillus anthracis, Clostridium species, Actinomyces species, Listeria monocytogenes, Leptospira, and Treponema pallidum (extremely susceptible) 1
• No documented resistance: Group A streptococci remain universally susceptible to penicillin worldwide, with no clinical isolate ever documented to be resistant 4, 5
• Not active against: Penicillinase-producing staphylococci and most gram-negative bacilli (no longer considered first-line for Escherichia coli, Proteus mirabilis, Salmonella, Shigella, or Enterobacter) 1, 2

Clinical Formulations and Uses

Benzathine Penicillin G (Long-Acting)

• Provides sustained antibiotic levels for several weeks following a single intramuscular injection 6
• Dosing: 1.2 million units IM as a single dose for adolescents/adults; 600,000 units IM for children <27 kg 4
• Ideal for single-session therapy in streptococcal pharyngitis, syphilis treatment, and rheumatic fever prophylaxis 4, 6
• For early syphilis, one dose of 2.4 million units is noninferior to three weekly doses, with 76% serologic response at 6 months 7
• For rheumatic fever prophylaxis, administered every 4 weeks in the United States (every 3 weeks in high-incidence areas or for recurrent cases) 4

Penicillin V (Oral)

• Acid-stable formulation for oral administration 4
• Dosing: Children: 250 mg 2-3 times daily; Adolescents/adults: 250 mg 3-4 times daily or 500 mg twice daily for 10 days 4, 5
• Amoxicillin is often substituted in young children due to better palatability, with equivalent efficacy 4

Aqueous Penicillin G (IV/IM)

• For serious infections requiring immediate high serum levels 1
• Administered intravenously or intramuscularly for severe pneumococcal, streptococcal, meningococcal infections, and neurosyphilis 4

Clinical Advantages

• Proven efficacy: Remains the only antimicrobial therapy proven in controlled studies to prevent initial attacks of rheumatic fever 4
• Safety profile: Sensitivity reactions from benzathine penicillin G are less frequent and less severe than those from aqueous or procaine penicillin G 6
• Narrow spectrum: Minimizes disruption of normal flora and reduces selection pressure for resistance 4
• Low cost: Remains one of the most cost-effective antibiotics available 4
• No resistance development: After 50+ years of use, no resistance has emerged among target pathogens like Group A streptococci 4, 5, 2

Special Populations

• Renal impairment: The beta-phase serum half-life is prolonged (1-2 hours with creatinine <3 mg/100 mL; up to 20 hours in anuric patients), requiring dosage reduction 1
• Hepatic impairment: Further alters elimination when combined with renal dysfunction (half-life up to 30.5 hours in anuric patients with cirrhosis) 1
• Pregnancy: Penicillin is the only proven safe and effective treatment for syphilis in pregnant women; no alternatives exist 4
• HIV infection: Penicillin is recommended whenever possible for HIV-infected patients with syphilis or streptococcal infections 4
• Neonates: Renal clearance is delayed due to decreased renal function, requiring adjusted dosing 1

Critical Pitfalls to Avoid

• Penicillin allergy: Only 10% of patients reporting severe penicillin allergy remain truly allergic; skin testing with major determinant (benzylpenicilloyl poly-L-lysine) and penicillin G can identify 90-97% of currently allergic patients 4
• Desensitization required: For neurosyphilis, congenital syphilis, or syphilis in pregnancy, no proven alternatives exist; penicillin-allergic patients must undergo desensitization 4
• Inadequate dosing: Residual drug may remain in the syringe due to high viscosity of benzathine penicillin G formulations, potentially leading to underdosing 3
• Treatment duration: A full 10-day course is essential for oral therapy to prevent rheumatic fever and achieve maximal pharyngeal eradication 4, 5
• Not for MRSA: Penicillin G has no activity against methicillin-resistant staphylococci, which are now a major cause of hospital sepsis 2