Benzyl penicillin (Penicillin G), Procaine penicillin & Benzathine penicillin, What’s The Difference? -Everything you need to know on these penicillin

Introduction

No doubt that penicillin antibiotics are a keystone in treatment of bacterial infections. Benzyl penicillin (Penicillin G), Procaine penicillin & Benzathine penicillin play a crucial role in treating various bacterial infections. Nonetheless, health practitioners may sometimes confuse these 3 which leads to prescribing, dispensing and administration error.

This confusion among these formulations also represents a significant source of adverse events in clinical practice. Such errors can lead to profound consequences, including therapeutic failure, delayed treatment of serious infections, or severe adverse reactions such as neurovascular damage, cardiac arrest, and even death. This article will discuss these 3 antibiotics, looking at their similarities, major difference and how best not to confuse the 3. Enjoy !

Similarities

1. Common Chemical Backbone

All these 3 agents share a common derivative which is the benzylpenicillin, also called Penicillin G. Penicillin G is a narrow-spectrum β-lactam antibiotic. As with all β-lactam antibiotics, they have a common bicyclic core structure, with variations on the side chains or formation of salt forms

 2.  Same mechanism of action

These antibiotics share same mechanism of action which is inhibition of bacterial cell wall synthesis. The antibiotic(s) crosses cell wall and peri plasmic space where it will bind to penicillin binding protein (PBP) on the cell membrane of bacteria. The PBP are responsible for mitosis and cell structure integrity. Inhibition of PBP results in prevention of cell division, resulting in filament formation which cause leakages of bacteria cell content, leading to cell lysis and ultimately cell death

3.  Consistent Antimicrobial Spectrum

They are all primarily active against Aerobic Gram-positive cocci, Anaerobic Gram-positive cocci, Gram-positive bacilli, Gram-negative cocci, Anaerobic Gram-negative cocci, Spirochetes

While their fundamental mechanism of action and general antimicrobial spectrum are shared, the delivery and duration of their therapeutic effect, which are profoundly influenced by their specific salt forms, are what truly distinguish their clinical utility.

This highlights a crucial point: a common mechanism of action does not equate to clinical interchangeability. The precise application of these agents in practice is determined by how their pharmacokinetic profiles are engineered to meet specific therapeutic needs. Understanding this distinction is vital for safe and effective prescribing, as it moves beyond a superficial appreciation of their shared antibacterial function to a deeper comprehension of their practical application.

Key Differences

1. Chemical Formulation and Solubility

●      Benzylpenicillin (Penicillin G): This formulation is typically available as sodium or potassium salts. These salt forms are highly soluble.

●      Procaine Penicillin: This compound is the procaine monohydrate salt of penicillin G. It is an equimolar salt of procaine and penicillin G. This unique formulation forms a crystalline complex that functions as a depot, designed to delay the rapid absorption of penicillin G into the bloodstream. It exhibits slight solubility in water.

●      Benzathine Penicillin: This formulation is formed by the reaction of dibenzoyl-ethylene diamine with two molecules of penicillin G. It presents as an opaque, viscous crystalline powder. It has a very low solubility in water

2. Pharmacokinetics: How They Behave in the Body

●      Benzylpenicillin (Penicillin G)

○      Absorption: This form is rapidly absorbed following intramuscular (IM) or Intravenous (IV) administration. Oral absorption is poor due to its susceptibility to inactivation by gastric acid.

○      Peak Concentration: Peak serum concentrations are typically achieved around 2 hours after IV injection.

○      Half-life: Benzylpenicillin has a short plasma half-life, approximately 30 minutes in adult humans.

○      Duration of Action: The drug is generally cleared from the bloodstream within 8 hours. Consequently, it necessitates frequent administration, typically every 4 to 6 hours, to maintain therapeutic concentrations.

○      Elimination: It is rapidly cleared from the blood primarily through the kidneys, excreted largely unchanged in the urine via both glomerular filtration and proximal tubular secretion.

●      Procaine Penicillin

○      Absorption: Upon IM injection, procaine penicillin is slowly hydrolyzed in the muscle, releasing benzylpenicillin and procaine, with subsequent gradual absorption of the benzylpenicillin component from the injection site. Absorption of an i.m.-injected dose continues for up to 24 hours, so that injections may be separated by this interval

○      Peak Concentration (Cmax): A peak serum level is reached in about 2–4 hours after IM injection, but lower serum levels are obtained when compared with Benzylpenicillin.

○      Half-life: The elimination half-life is 20-30 minutes. The procaine component has a short half-life (approximately 1 hour in humans) due to rapid hydrolysis by serum cholinesterase.

○      Duration of Action: The benzylpenicillin component is generally cleared from plasma about 24 hours after administration.

○      Elimination: The penicillin G component is rapidly excreted by tubular excretion. Procaine and its metabolites, such as para-aminobenzoic acid and diethylaminoethanol, are predominantly excreted in the urine.

●      Benzathine Penicillin

○      Absorption: This formulation is characterized by very slow absorption from the intramuscular injection site. It is slowly released from the depot and then hydrolyzed to active penicillin G.

○      Peak Concentration (Cmax) : Peak plasma levels of benzylpenicillin are reached significantly later: 24 hours in children or 48 hours in adults' post-injection

○      Half-life: The absorption half-life for Benzathine penicillin is considerably longer than the elimination half-life of the active penicillin G once absorbed due to the sustained release from the depot.

○      Duration of Action: Benzathine penicillin provides prolonged, low concentrations of benzylpenicillin, enabling sustained antibiotic action over 1-3 weeks. Detectable drug concentrations can persist for 14 days or longer after a 1.2-million-unit injection.

Elimination: It is primarily excreted through the kidneys

The pharmacokinetic engineering of these drugs helps to fulfill different therapeutic requirements. Benzylpenicillin, having a rapid onset is used for acute severe conditions which require high and rapid concentrations. Procaine penicillin offers moderate, sustained concentrations over approximately 24 hours. Benzathine penicillin, conversely, provides very low but prolonged concentrations for weeks, making it ideal for prophylaxis or treating slow-growing infections.

3. Routes of Administration: A Critical Safety Point

●      Benzylpenicillin (Penicillin G): This formulation is versatile and can be administered via intramuscular (IM) injection, intravenous (IV) bolus injection, or IV infusion

●      Procaine Penicillin: This formulation is strictly for intramuscular (IM) injection ONLY. It is formulated as a suspension that dissolves slowly at the injection site, forming a depot. Inadvertent IV administration of procaine penicillin carries severe risks, including neurovascular damage, localized edema, cardiorespiratory arrest, and even death.

●      Benzathine Penicillin: This formulation is also strictly for intramuscular (IM) injection ONLY. IV administration of Benzathine penicillin can lead to devastating consequences, including neurovascular damage, cardiorespiratory arrest, and death.

The strict "IM ONLY" restriction for Procaine and Benzathine penicillin is directly linked to their low solubility and their formulation as crystalline suspensions. If these insoluble particles are injected intravenously, they can act as emboli, leading to vascular occlusion and direct tissue damage. This can result in severe neurovascular compromise, profound edema, and ultimately, cardiorespiratory arrest and death

Contributing Factors To Errors (Prescribing, Dispensing & Administration)

•  Nomenclature Similarity: The names "Benzathine benzylpenicillin," "Benzylpenicillin," are strikingly similar, which frequently leads to confusion. The historical use of "Penicillin G" as a synonym for benzylpenicillin further complicates correct product selection.

• Similar Doses/Strengths: The numerical presentation of indicated doses and the available strengths (often as MIU) of injectable preparations can be similar across the different salts, adding to the potential for confusion.

• Product Labeling Inconsistencies: Product Summary of Product Characteristics (SPCs) and general product labeling may not always consistently reflect the International Non-proprietary Name (INN), and alternative nomenclature might be used, exacerbating the confusion.

Strategies To Reduce Errors

• Consistent Nomenclature: It is imperative to mandate and ensure that local clinical guidelines, protocols, electronic prescribing systems, and formularies consistently use distinct and unambiguous nomenclature for all benzylpenicillin salts

• Promoting Continuous Professional Education and Awareness: Ongoing education and awareness campaigns are vital for all healthcare professionals involved in prescribing, dispensing, and administering medications. These initiatives should highlight the availability of different benzylpenicillin salts and, critically, the severe risks associated with selecting the incorrect salt or route of administration.

• Double-Checking in Clinical Practice: Implementing mandatory independent double-checks for high-risk medications, especially injectable penicillin, is a foundational safety practice. This involves a second healthcare professional independently verifying the drug name, strength, dose, route, and patient identity before administration.

Conclusion

The main difference in these antibiotics is in their salt forms which profoundly alter their pharmacokinetic profiles, thus their optimal routes of administration and clinical applications.

The critical takeaway for healthcare professionals is that these formulations are not clinically interchangeable. Misadministration, particularly the inadvertent intravenous injection of the intramuscular-only Procaine or Benzathine penicillins, carries a severe risk of neurovascular damage, cardiac arrest, and even death due to their insoluble crystalline nature. The similarity in nomenclature and dosing units, despite vastly different clinical behaviors, creates a significant vulnerability for medication errors.