Classify penicillins. Describe their mechanism of action, pharmacokinetics, uses and adverse effects.

Mechanism of Action

Penicillins share a beta-lactam ring, structurally resembling the terminal D-alanyl-D-alanine of the peptidoglycan precursor → They bind penicillin-binding proteins (PBPs) in the bacterial membrane → The key enzyme inhibited is transpeptidase, which cross-links peptidoglycan strands → The wall becomes mechanically weak → autolysins are also activated → The organism lyses under its own osmotic pressure — bactericidal, and only against actively dividing organisms

• Because they act only on dividing cells, penicillins are ineffective against dormant organisms and may be antagonised by a bacteriostatic drug given simultaneously
• The wall is absent in man, which is why penicillins have an enormous therapeutic index — the only serious hazard is allergy

Classification

Pharmacokinetics

• Benzylpenicillin is acid-labile and must be given parenterally; phenoxymethylpenicillin and amoxicillin are acid-stable and orally active
• Amoxicillin is better absorbed than ampicillin and is less affected by food — the reason it largely replaced it
• Widely distributed; poor CSF penetration normally, but adequate when the meninges are inflamed — hence high-dose penicillin works in meningitis
• Excreted rapidly and unchanged by the kidney, largely by tubular secretion; probenecid blocks this and prolongs the level, an interaction once used deliberately when penicillin was scarce
• Short half-life of about 30 minutes, hence frequent dosing or depot preparations
• Dose reduction is needed in renal failure for high-dose regimens

Therapeutic Uses

• Streptococcal infections — pharyngitis, cellulitis, erysipelas, scarlet fever; Streptococcus pyogenes has never developed penicillin resistance, which is remarkable after eighty years of use
• Pneumococcal pneumonia and meningitis (where sensitive)
• Meningococcal disease — benzylpenicillin, including a pre-hospital dose
• Syphilis — benzathine penicillin remains the drug of choice at every stage, with no resistance recorded
• Rheumatic fever — treatment and long-term secondary prophylaxis with benzathine penicillin, which matters enormously in India
• Infective endocarditis — with an aminoglycoside for synergy
• Anthrax, diphtheria, tetanus, gas gangrene, actinomycosis, leptospirosis
• Amoxicillin — otitis media, sinusitis, urinary infection, typhoid, H. Pylori eradication, and endocarditis prophylaxis

Adverse Effects

• Hypersensitivity — the principal hazard, in 1 to 10%: rashes, urticaria, serum sickness, and anaphylaxis in about 0.05%, which is fatal in a proportion. Cross-reactivity exists across the whole class
• A history of "penicillin allergy" must be interrogated — most reported reactions are nausea or a non-specific rash, and wrongly labelling a patient denies them the safest and most effective antibiotic for life; skin testing and formal de-labelling are worthwhile
• The ampicillin rash in infectious mononucleosis — a maculopapular rash occurs in most patients given ampicillin during EBV infection; it is not a true allergy and does not preclude later penicillin use
• Gastrointestinal — diarrhoea, nausea; Clostridioides difficile colitis, particularly with co-amoxiclav
• Neurotoxicity — myoclonus and seizures with very high doses or in renal failure, especially if given intrathecally
• Jarisch–herxheimer reaction when treating syphilis
• Cholestatic hepatitis with co-amoxiclav; interstitial nephritis with methicillin

Resistance to Penicillins

• The distinction matters clinically — beta-lactamase-mediated resistance is defeated by an inhibitor, whereas altered-target resistance is not, and requires an entirely different drug

Applied Aspects

• Benzathine penicillin every 3 to 4 weeks prevents recurrent rheumatic fever and progressive valve damage; adherence over years is the difficulty, and a register-based programme with reminders is what makes it work
• Penicillin remains first-line for streptococcal sore throat, and there is no reason to use a broader agent; treating it prevents rheumatic fever, which is still common in India
• Ask what the "penicillin allergy" actually was — nausea, diarrhoea and a family history are not allergies, and de-labelling restores access to the safest antibiotics
• Amoxicillin is preferred to ampicillin orally because absorption is better and less affected by food
• Co-amoxiclav is over-used — plain amoxicillin suffices for most community infections, and the clavulanate adds diarrhoea, cholestatic hepatitis and selection pressure
• Keep adrenaline immediately available wherever parenteral penicillin is given, and observe the patient for 20 to 30 minutes afterwards
• Warn about the Jarisch–Herxheimer reaction before treating syphilis or leptospirosis, so that the patient and staff do not mistake it for an allergic reaction and stop effective treatment
• Intrathecal penicillin must never be given — it causes convulsions and arachnoiditis; systemic high dose penetrates inflamed meninges adequately
• Amoxicillin remains first-line for otitis media, sinusitis and community-acquired pneumonia in most guidelines, and its low cost matters greatly in India
• Penicillin allergy labels are carried for life and rarely reviewed; formal assessment should be arranged for anyone likely to need beta-lactams repeatedly