Benzylpenicillins and Isoxazolylpenicillins

Cell Wall Inhibitors

Natural penicillins and penicillins stable to staphylococcal penicillinases (isoxazolylpenicillins) represent the original therapeutic pillars of beta-lactam therapy. Its bactericidal action requires active bacterial replication.

Mechanism

💊 Generic and Commercial Names

Penicilina G Sódica, Penicilina G Benzatina (Penibenzatina), Cloxacilina (Anaclosil), Oxacilina.

🔬 Pharmacological Group

Beta-lactámicos. Penicilinas naturales e isoxazolilpenicilinas resistentes a betalactamasas de bajo espectro.

Mechanism of Action

Su diana molecular es el paso final de la transpeptidación de la pared celular:

Unión e Inhibición Covalente de PBPs: Presentan una analogía estructural con el residuo terminal D-alanyl-D-alanina del peptidoglicano en formación. El anillo beta-lactámico es atacado por el residuo de serina activo de las PBPs (especialmente PBP1 y PBP3), formando un complejo éster peniciloil-enzima inactivo de disociación extremadamente lenta. Al bloquearse la transpeptidación, se detiene el entrecruzamiento de las cadenas de peptidoglicano.
Activación de Autolisinas: La inhibición de la síntesis de la pared celular provoca la liberación secundaria de autolisinas bacterianas endógenas (hidrolasas de peptidoglicano), induciendo la lisis osmótica celular de la bacteria.
Resistencia de Cloxacilina: Posee un anillo isoxazólico con sustituyentes voluminosos que ejercen un impedimento estérico que protege al enlace amida del anillo beta-lactámico de la hidrólisis por las penicilinasas de Staphylococcus aureus (pero es vulnerable a BLEE y carbapenemasas).

Pharmacokinetics

Key Pharmacokinetics

Parameter	Quantitative Pharmacokinetic Profile
Routes of Administration	Penicillin G Sodium: IV; Penicillin G Benzathine: IM (slow deposition); Cloxacillin: IV and Oral (poor oral bioavailability, ~30-50%, severely affected by food).
Absorption and Onset	Penicillin G Benzathine IM generates very low but persistent plasma concentrations for 14-21 days (useful in prophylaxis of rheumatic fever and syphilis). IV Cloxacillin reaches peak levels within 30 minutes after completing the infusion.
Volume of Distribution (V_d)	Low (0.15 - 0.25 L/kg). Mainly confined to the extracellular space. It presents poor tissue penetration in an intact blood-brain barrier, but it increases in a clinically significant manner in the presence of active meningeal inflammation. Protein binding: Penicillin G ~60%; Extremely high cloxacillin ~90-95%.
Metabolism	Minimal hepatic metabolism (10-20% to inactive metabolites of penicilloic acid).
Excretion and Half-Life	Predominant renal excretion (70-90% unchanged): Through glomerular filtration and active tubular secretion through the organic anion transporter OAT1/OAT3. Plasma half-life (t_1/2) very short: 30 to 60 minutes in healthy adults with preserved kidney function. Renal clearance decreases drastically with age and in neonates.

Antimicrobial Spectrum

Penicillin G: Excellent activity against Streptococcus pyogenes (Group A), Streptococcus pneumoniae (susceptible to penicillin), Neisseria meningitidis, Treponema pallidum, Clostridium perfringens and other anaerobes of the oral cavity (except Bacteroides fragilis).
Cloxacillin / Oxacillin: Specifically designed for the management of methicillin-sensitive Staphylococcus aureus (MSSA) and sensitive coagulase-negative staphylococci. It lacks useful activity against Gram-negative or enterococci.

Indicators and dose

Dosage and Adjustment

Penicillin G Sodium (Adults): 12 to 24 million IU/day IV, divided every 4 hours (or administered as a continuous infusion after loading dose).
Penicillin G Benzathine: 1.2 to 2.4 million IU single dose via deep IM in the upper outer quadrant of the gluteus.
Cloxacillin: 1 to 2 g IV every 4 to 6 hours (maximum dose 12 g/day for severe endovascular infections such as bacterial endocarditis).
Adjustment in Kidney Failure:
- Cl_cr > 30 mL/min: No change.
- Cl_cr 10-30 mL/min: Space Penicillin G every 8 hours or reduce the daily dose by 50%. Cloxacillin does not require routine dose adjustment due to its high excretion and secondary compensatory biliary metabolism.
- Cl_cr < 10 mL/min: Space Penicillin G every 12 hours.

Security

Contraindications and Precautions

Absolute: Demonstrated immediate type I hypersensitivity (anaphylaxis, angioedema, bronchospasm) to penicillins or other beta-lactams in a cross-linked manner.
Relative: Severe renal failure (systemic accumulation that can induce neurotoxicity due to blockade of cortical GABAergic receptors); active epilepsy that is difficult to control.

Adverse Effects (ADR)

Immunoallergic (Common): Maculopapular rash, urticaria, drug fever. Immediate type reactions (anaphylactic shock <0.05% of cases). Immune-mediated acute interstitial nephritis (fever, eosinophilia, hematuria).
Neurotoxicity (Dose-dependent): Myoclonus, mental confusion, generalized tonic-clonic seizures (favored by massive IV doses of sodium penicillin in patients with uncorrected renal failure).
Hematological: Reversible neutropenia in prolonged treatments (>2 weeks of cloxacillin); hemolytic anemia with positive direct Coombs test.

Risk of Intravascular Injection of Penicillin G Benzathine

Penicillin G Benzathine is a viscous, insoluble depot formulation designed exclusively for deep intramuscular administration. Its accidental injection into the arterial or venous stream can cause catastrophic distal microvascular occlusion, focal tissue necrosis, gangrene and permanent neurological damage (Nicolau syndrome). Aspiration should always be performed prior to injection and avoid the vicinity of major neurovascular bundles.

Epistemis is educational review material. It is not a medical device, does not diagnose or prescribe treatment, and does not replace formal medical training, current clinical guidelines, or professional clinical judgment.

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System: Antimicrobial and Infectious
Cluster: Cell Wall Inhibitors

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