Natural Penicillins

Natural penicillins (benzylpenicillin, phenoxymethylpenicillin, procaine benzylpenicillin and benzathine benzylpenicillin) are the narrow-spectrum parent compounds of the class. They remain the drugs of choice for susceptible streptococcal infections, syphilis and several anaerobic and zoonotic infections, and carry the lowest ecological cost of any antibacterial.

Mechanism. Inhibition of PBPs and peptidoglycan cross-linking. Active against Gram-positive cocci (Group A, B, C and G streptococci, viridans streptococci, penicillin-susceptible pneumococci), Neisseria meningitidis (susceptibility variable), Treponema pallidum, Clostridium (non-difficile), Actinomyces, Leptospira, Bacillus anthracis (susceptible isolates), Corynebacterium diphtheriae and susceptible Listeria and E. faecalis.

Pharmacokinetics. Benzylpenicillin is given parenterally (half-life 30 minutes). Phenoxymethylpenicillin is acid-stable with about 60 percent absorption, best taken fasting. Procaine benzylpenicillin gives levels for 12 to 24 hours; benzathine benzylpenicillin gives low levels for 2 to 4 weeks, which is not sufficient for infection needing sustained tissue levels.

Resistance. Staphylococcal penicillinase; altered PBPs in pneumococcus (breakpoints are stricter for meningitis); reduced susceptibility in meningococci.

• Benzylpenicillin: intravenous or intramuscular, for serious infection.
• Phenoxymethylpenicillin: oral, for mild streptococcal infection, tonsillopharyngitis and secondary prevention.
• Procaine benzylpenicillin: intramuscular once daily, used where intravenous access or frequent dosing is impractical.
• Benzathine benzylpenicillin: deep intramuscular only, for syphilis and rheumatic fever prophylaxis. It must never be injected intravenously (cardiorespiratory arrest, gangrene).

Adult regimens.

• Severe streptococcal or pneumococcal infection, susceptible: benzylpenicillin 1.2 to 2.4 g IV every 4 to 6 hours.
• Streptococcal pharyngitis: phenoxymethylpenicillin 500 mg every 12 hours (or 250 mg every 6 hours) for 10 days, or benzathine benzylpenicillin 1.2 million units IM once.
• Early syphilis (primary, secondary, early latent): benzathine benzylpenicillin 2.4 million units IM once. Late latent or unknown duration: 2.4 million units IM weekly for 3 weeks.
• Neurosyphilis: benzylpenicillin 18 to 24 million units daily IV (3 to 4 million units every 4 hours or continuous infusion) for 10 to 14 days.
• Rheumatic fever secondary prevention: benzathine benzylpenicillin 1.2 million units IM every 3 to 4 weeks (600,000 units if under about 30 kg), or phenoxymethylpenicillin 250 mg orally twice daily. Duration is set by the number of attacks and carditis severity and may be lifelong in severe valve disease.
• Susceptible meningococcal or pneumococcal meningitis, and Listeria (with an aminoglycoside): benzylpenicillin 2.4 g IV every 4 hours.
• Anthrax, diphtheria and clostridial infection: benzylpenicillin high-dose as part of combination therapy; tetanus is managed with metronidazole, immunoglobulin and supportive care.

Selection. Empirical meningitis and sepsis cover usually uses a third generation cephalosporin; switch to benzylpenicillin once penicillin-susceptible organisms are confirmed. Procaine penicillin is useful where only intramuscular treatment is feasible.

Contraindications. Confirmed immediate hypersensitivity. Intravenous administration of benzathine or procaine preparations is contraindicated.

Serious effects. Anaphylaxis; Jarisch-Herxheimer reaction within 24 hours of starting treatment for syphilis, leptospirosis or relapsing fever (fever, rigors, hypotension; manage supportively); procaine reactions (Hoigne syndrome: panic, hallucinations); sciatic nerve injury from gluteal injection; seizures with high doses in renal failure; hyperkalaemia with potassium salts in renal impairment.

Interactions. Methotrexate, probenecid, warfarin.

Monitoring. Renal function; clinical response; for syphilis, quantitative non-treponemal titres at 6, 12 and 24 months (a fourfold fall is expected by 6 to 12 months in early disease).

Special groups.

• Pregnancy and breastfeeding: first line. Syphilis in pregnancy requires penicillin; penicillin-allergic women are desensitised, as no alternative reliably prevents congenital syphilis.
• Children: benzylpenicillin 25 to 50 mg/kg (maximum 2.4 g) every 4 to 6 hours; neonates are dosed by age and weight by a specialist.
• Renal impairment: reduce when creatinine clearance is under 20 mL/min; maximum about 6 g daily when under 10 mL/min.
• Region: rheumatic heart disease is common in East Africa, so adherence to benzathine prophylaxis and drug availability are major determinants of outcome; stock-outs should be anticipated and oral phenoxymethylpenicillin used as a bridge.