Benzylpenicillin

Benzylpenicillin is the natural, narrow-spectrum penicillin given by injection. It remains the drug of choice for fully susceptible streptococci, Neisseria meningitidis, Treponema pallidum, Clostridium species and Actinomyces, and its activity depends on how long free drug stays over the MIC.

Classification. Beta-lactam, natural penicillin. Acid labile, so oral absorption is unreliable. Doses are written in grams or units: 600 mg equals 1 million units (1 MU).

Mechanism. Binds penicillin-binding proteins and blocks peptidoglycan cross-linking, causing lysis of dividing bacteria. Hydrolysed by staphylococcal and many Gram-negative beta-lactamases.

Spectrum. Active against Streptococcus pyogenes, Streptococcus agalactiae, penicillin-susceptible Streptococcus pneumoniae, meningococci, Treponema pallidum, Leptospira, Corynebacterium diphtheriae, Bacillus anthracis (susceptible strains), Pasteurella multocida and non-difficile Clostridium species. Most Staphylococcus aureus, gonococci and enteric Gram-negative bacilli are resistant. Penicillin-nonsusceptible pneumococci occur and local susceptibility data decide use in meningitis.

Pharmacokinetics. Given IV or IM. Half-life is about 30 minutes with normal kidney function, so frequent dosing or continuous infusion is needed. Protein binding is about 50%. Renal elimination is largely by tubular secretion, which probenecid blocks. CSF penetration is low but adequate in inflamed meninges.

No loading dose is needed. Titration is not used; the dose is set by site of infection and kidney function. Maximum adult dose is 14.4 g (24 MU) daily.

Adult regimens (IV unless stated).

• Suspected meningococcal disease before hospital transfer: 1.2 g IM or IV once.
• Meningococcal meningitis: 2.4 g every 4 hours for 7 days.
• Susceptible pneumococcal meningitis: 2.4 g every 4 hours for 10 to 14 days.
• Pneumococcal pneumonia, susceptible strain, severe: 1.2 to 2.4 g every 4 to 6 hours for 5 to 7 days, then oral step-down once stable.
• Streptococcal endocarditis, highly susceptible viridans group streptococci: 12 to 18 MU (7.2 to 10.8 g) daily as continuous infusion or in 4 to 6 divided doses, for 4 weeks in native valve disease.
• Necrotising soft tissue infection with group A streptococci or clostridia: 2.4 g every 4 hours with clindamycin, until debrided and clinically stable.
• Neurosyphilis, ocular and otic syphilis: 18 to 24 MU daily, as 3 to 4 MU every 4 hours or continuous infusion, for 10 to 14 days.
• Leptospirosis, severe: 1.5 MU (900 mg) every 6 hours for 7 days.

Children (1 month to 17 years).

• Usual: 25 mg/kg every 6 hours.
• Severe infection: 50 mg/kg (maximum 2.4 g a dose) every 4 to 6 hours.
• Meningitis: 150 to 240 mg/kg/day divided every 4 to 6 hours, maximum 24 MU daily.
• Pre-hospital suspected meningococcal disease: under 1 year 300 mg, 1 to 9 years 600 mg, 10 years and over 1.2 g.

Neonates. Group B streptococcal bacteraemia: 50 mg/kg every 12 hours in the first week and every 8 hours from 7 to 28 days. Meningitis: up to 75 mg/kg every 8 to 12 hours. Dosing varies with gestation and weight.

Alternatives and specialist use. Procaine penicillin and benzathine penicillin are depot forms for intramuscular use. Amoxicillin covers listeria and enterococci. Ceftriaxone is used for presumptive meningitis where penicillin resistance is likely.

Contraindications. Previous immediate hypersensitivity (anaphylaxis, urticaria, angioedema, bronchospasm) to any penicillin. Cross-reactivity with cephalosporins is about 1 to 2% and with carbapenems under 1%.

Serious adverse effects. Anaphylaxis (about 1 to 5 in every 10,000 courses), seizures with high dose or renal impairment, interstitial nephritis, haemolytic anaemia, neutropenia and thrombocytopenia with courses over 2 weeks, Clostridioides difficile infection, and Jarisch-Herxheimer reaction in syphilis and leptospirosis.

Electrolytes. Each 600 mg contains about 1.7 mmol sodium, so high doses add a sodium load. Hypokalaemia occurs with large doses.

Interactions.

• Probenecid raises levels, usually used deliberately.
• Methotrexate toxicity increases because renal clearance falls.
• INR can change in patients on warfarin.
• Oral typhoid vaccine (live) may be less effective.

Common prescribing errors. Giving fast IV bolus of large doses, confusing units with grams, and omitting dose reduction in renal failure.

Special groups.

• Pregnancy: safe at all stages and the treatment of choice for syphilis and group B streptococcal prophylaxis (5 MU load then 2.5 MU every 4 hours until delivery).
• Breastfeeding: compatible; watch the infant for diarrhoea and thrush.
• Older adults: seizure and sodium-load risk is higher.
• Kidney impairment: with creatinine clearance 10 to 50 mL/min give the usual dose every 6 to 8 hours. Under 10 mL/min reduce the daily dose by 50% or give every 8 to 12 hours, and cap high-dose regimens at about 6 g daily.
• Haemodialysis: give the dose after the session.
• Liver impairment: no adjustment unless combined with severe renal failure.
• Obesity: use actual doses in grams; no weight adjustment in adults.

Preparation. Dissolve each 600 mg vial in 5 mL water for injection for IV use; give up to 1.2 g slowly over 3 to 5 minutes, and larger doses by infusion over 30 minutes in 0.9% sodium chloride or 5% glucose. For IM use, reconstitute to the volume on the label. Fast bolus of high doses can cause CNS irritation.

Continuous infusion. Used for endocarditis and neurosyphilis; stability of the diluted solution is limited, so renew the bag every 12 to 24 hours as the product allows.

Baseline and monitoring. - Baseline: allergy history, creatinine, full blood count. - During therapy: renal function and electrolytes at least twice weekly in high-dose treatment; full blood count weekly beyond 2 weeks; watch for myoclonus or confusion as an early sign of neurotoxicity. - No therapeutic drug monitoring.

Stop rules. Stop for anaphylaxis, new rash with fever or eosinophilia, unexplained cytopenia, or seizures. Step down to oral phenoxymethylpenicillin or amoxicillin when afebrile, improving and tolerating oral intake, if the organism is susceptible.

Referral and escalation. Involve infectious diseases for endocarditis, neurosyphilis, and any penicillin allergy label that needs formal assessment.