Mechanism of antibacterial action
The action of penicillins is bactericidal and is realized through two interrelated pathways that destroy the bacterial cell wall.
- Disruption of peptidoglycan synthesis. The basis of the cell wall consists of chains of N-acetylmuramic acid and N-acetylglucosamine. Penicillins bind to the transpeptidase enzyme and block it. Normally, this enzyme cross-links the pentaglycine bridge of one chain with the penultimate D-alanine residue of another chain (cleaving off the terminal D-alanine). Without transpeptidase activity, cross-links do not form, and the synthesis of a complete framework ceases.
- Activation of autolysis. Bacteria have their own enzymes — autolysins, which cleave peptidoglycan to ensure cell division. Normally, they are held in check by an endogenous inhibitor. Penicillins suppress this inhibitor, leading to uncontrolled activation of autolysins and hydrolysis (self-destruction) of the cell wall.
Spectrum of activity and clinical use
Natural penicillins have a relatively narrow spectrum of activity, directed primarily against gram-positive flora.
- Gram-positive bacteria: streptococci, pneumococci, pathogens of diphtheria (Corynebacterium diphtheriae) and anthrax (Bacillus anthracis), listeria. Staphylococci are sensitive only if they do not produce $\beta$-lactamases.
- Gram-negative cocci: meningococci and gonococci.
- Anaerobes and spirochetes: clostridia, Treponema pallidum, leptospira, borrelia.
Drugs of this group remain drugs of choice for the treatment of syphilis and year-round bicillin prophylaxis of rheumatism. They are also prescribed for tonsillitis, scarlet fever, pneumonia, erysipelas, bacterial endocarditis, meningitis, gas gangrene, and tick-borne borreliosis (Lyme disease).
Drug classification
Depending on their resistance to the acidic environment of the stomach and the duration of effect, natural penicillins are divided into two large groups.
A. Parenteral (acid-labile) Destroyed by hydrochloric acid, therefore administered only by injection.
- Short-acting (3–4 hours): sodium and potassium salts of benzylpenicillin. Rapidly absorbed, create high peak concentrations in the blood. Used for acute and severe infections.
- Prolonged-acting (depot penicillins): procaine benzylpenicillin (acts 12–18 hours), benzathine benzylpenicillin (Bicillin-1, acts 7–10 days), and Bicillin-5 (acts 1 month). These are poorly soluble suspensions administered strictly intramuscularly. They do not create high concentrations and do not cross the blood-brain barrier, but maintain a therapeutic level for a long time. Used for chronic mild to moderate infections.
B. Enteral (acid-stable)
- Phenoxymethylpenicillin. Due to the phenoxymethyl group, it is not destroyed in the stomach and is used orally (per os). The spectrum of action is identical to benzylpenicillin.
Pharmacokinetic features and safety profile
Soluble salts of benzylpenicillin are well distributed in the lungs, kidneys, joints, and serous cavities. Normally, they penetrate the blood-brain barrier (BBB) poorly, but during inflammation of the meninges, permeability increases sharply, making it possible to treat meningitis.
Side effects and toxicity:
- Allergic reactions occur most frequently (rash, urticaria, angioedema, anaphylaxis).
- Organotoxicity is rare: acute interstitial nephritis is possible, and with ultra-high doses, neurotoxicity (convulsions).
Drug interactions:
- With warfarin: penicillins suppress intestinal microflora, reducing vitamin K synthesis, which enhances the anticoagulant effect and increases the risk of bleeding.
- With probenecid: competition for renal transport systems occurs. Tubular secretion of the antibiotic decreases, while its plasma concentration increases.
To avoid confusing the routes of administration of benzylpenicillin salts: the Sodium salt can be given Nearly anywhere (intravenously, endolumbally, into cavities). The Potassium salt — only intramuscularly, otherwise Kalium will cause a Katastrophe (seizures and cardiac depression).
Class and exam questions
Why are natural penicillins ineffective against most staphylococci?
Many strains of staphylococci have acquired the ability to produce $\beta$-lactamase enzymes (penicillinases). They hydrolyze the antibiotic structure before it can bind to transpeptidase.
Can benzylpenicillin potassium salt be administered intravenously?
Categorically no. The rapid release of a large amount of potassium ions into the bloodstream can lead to severe arrhythmias, cardiac depression, and convulsions. It is administered strictly intramuscularly.
What is the rationale for creating depot penicillins (bicillins)?
Soluble salts are eliminated from the body in 3–4 hours, requiring up to 6 injections per day. Depot drugs are poorly soluble in water, slowly absorbed from muscle tissue, and allow the injection frequency to be reduced to once a week or even once a month.
What else to study on this topic
- Chemical structure of peptidoglycan and detailed transpeptidation process
- Mechanisms of acquired resistance: modification of penicillin-binding proteins (PBPs)
- Pharmacokinetics and tissue distribution of benzylpenicillin salts
- Organotoxicity of penicillins: pathogenesis of interstitial nephritis and neurotoxicity
- Depot drug regimens in the treatment of syphilis and prevention of rheumatism
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