Mechanism of Antibacterial Action
The action of penicillins is bactericidal and occurs via two interrelated pathways that disrupt the bacterial cell wall.
- Inhibition of peptidoglycan synthesis. The cell wall framework consists of N-acetylmuramic acid and N-acetylglucosamine chains. Penicillins bind to and inhibit the transpeptidase enzyme (penicillin-binding protein, PBP). Normally, this enzyme cross-links the pentaglycine bridge of one glycan chain to the penultimate D-alanine residue of another (cleaving the terminal D-alanine). Without transpeptidase activity, cross-linking fails, halting the synthesis of a structurally sound cell wall.
- Activation of autolysins. Bacteria possess endogenous enzymes called autolysins that cleave peptidoglycan to allow for cell division. Normally, these are kept in check by an endogenous inhibitor. Penicillins suppress this inhibitor, leading to the uncontrolled activation of autolysins and subsequent hydrolysis (self-destruction) of the cell wall.
Spectrum of Activity and Clinical Uses
Natural penicillins have a relatively narrow spectrum of activity, directed primarily against gram-positive organisms.
- Gram-positive bacteria: Streptococcus species, Streptococcus pneumoniae, Corynebacterium diphtheriae, Bacillus anthracis, and Listeria. Staphylococci are sensitive only if they do not produce $\beta$-lactamases.
- Gram-negative cocci: Neisseria meningitidis and Neisseria gonorrhoeae.
- Anaerobes and spirochetes: Clostridium species, Treponema pallidum, Leptospira, and Borrelia.
Drugs in this group remain the drugs of choice for treating syphilis and for year-round secondary prophylaxis of rheumatic fever. They are also indicated for streptococcal pharyngitis, scarlet fever, pneumonia, erysipelas, infective endocarditis, meningitis, gas gangrene, and Lyme disease.
Classification of Drugs
Depending on their resistance to gastric acid and the duration of their effect, natural penicillins are divided into two major groups.
A. Parenteral (Acid-Labile) Destroyed by gastric hydrochloric acid, therefore administered exclusively via injection.
- Short-acting (3–4 hours): Benzylpenicillin sodium and potassium salts. Rapidly absorbed, producing high peak serum concentrations. Used for acute, severe infections.
- Long-acting (depot penicillins): Procaine penicillin (duration 12–18 hours), benzathine benzylpenicillin (Bicillin-1, duration 7–10 days), and long-acting benzathine penicillin combinations (duration up to 1 month). These are poorly soluble suspensions administered intramuscularly only. They do not produce high peak levels or cross the blood-brain barrier well, but they maintain low therapeutic levels over extended periods. Used for chronic, mild-to-moderate infections and prophylaxis.
B. Enteral (Acid-Stable)
- Phenoxymethylpenicillin (Penicillin V). Due to its phenoxymethyl side chain, it is acid-stable and can be administered orally (per os). Its antimicrobial spectrum is identical to that of benzylpenicillin.
Pharmacokinetics and Safety Profile
Soluble salts of benzylpenicillin distribute well into the lungs, kidneys, joints, and serous cavities. Under normal conditions, they cross the blood-brain barrier (BBB) poorly, but inflammation of the meninges dramatically increases BBB permeability, allowing for the treatment of meningitis.
Adverse Effects and Toxicity:
- Allergic reactions are most common (rash, urticaria, angioedema, anaphylaxis).
- Organ toxicity is rare: acute interstitial nephritis may occur, and administration of ultra-high doses can cause neurotoxicity (seizures).
Drug Interactions:
- Warfarin: Penicillins suppress gut flora, reducing vitamin K synthesis, which potentiates the anticoagulant effect and increases bleeding risk.
- Probenecid: Competes with penicillins for renal tubular secretion. This decreases antibiotic renal clearance and elevates plasma drug concentrations.