Penicillins

Penicillins are beta-lactam antibiotics built on the 6-aminopenicillanic acid nucleus and are among the safest and most effective antibacterials available. Side-chain changes create four working subclasses with different spectra: natural penicillins, aminopenicillins, antistaphylococcal penicillins and antipseudomonal penicillins, with beta-lactamase inhibitors added to extend several of them.

Mechanism. Binding to PBPs blocks peptidoglycan cross-linking, leading to lysis of dividing cells. Activity is time-dependent.

Pharmacokinetics. Bioavailability varies: phenoxymethylpenicillin about 60 percent, amoxicillin 70 to 90 percent, flucloxacillin and cloxacillin about 50 to 70 percent (food reduces absorption), benzylpenicillin not absorbed orally. Half-lives are 0.5 to 1 hour with renal tubular secretion. Benzathine and procaine formulations give slow release.

Resistance. Staphylococcal penicillinase (over 90 percent of S. aureus), TEM and SHV beta-lactamases in Gram-negatives, altered PBPs in pneumococci, MRSA and E. faecium.

Representative adult regimens (normal renal function).

• Benzylpenicillin 1.2 to 2.4 g IV every 4 to 6 hours; up to 2.4 g every 4 hours for meningitis and endocarditis.
• Phenoxymethylpenicillin 250 to 500 mg orally every 6 hours; pharyngitis 500 mg every 12 hours for 10 days.
• Amoxicillin 500 mg to 1 g orally every 8 hours; ampicillin 1 to 2 g IV every 4 to 6 hours (maximum 12 g daily).
• Cloxacillin or flucloxacillin 500 mg to 1 g orally every 6 hours; 1 to 2 g IV every 4 to 6 hours (maximum 12 g daily).
• Piperacillin-tazobactam 4.5 g IV every 6 hours (4 g piperacillin).

Selection. Use the narrowest active penicillin once the organism is known. Penicillins are first line for streptococcal infection, syphilis, meningococcal and pneumococcal disease where susceptible, Listeria, MSSA, enterococcal infection and (with an inhibitor) mixed aerobic and anaerobic infection. Oral options suit mild disease; intravenous therapy is needed in bacteraemia, endocarditis, CNS and bone infection.

Contraindications. Confirmed immediate hypersensitivity or severe cutaneous reaction to a penicillin. Benzathine and procaine preparations are never given intravenously.

Serious effects. Anaphylaxis; seizures at high doses or in renal failure; cholestatic hepatitis (flucloxacillin, amoxicillin-clavulanate); interstitial nephritis; neutropenia and haemolytic anaemia with prolonged use; C. difficile infection; hypokalaemia and sodium load with high-dose antipseudomonal agents; high anion gap metabolic acidosis with flucloxacillin plus paracetamol.

Common prescribing errors. Using benzathine benzylpenicillin intravenously; omitting the dose reduction in severe renal impairment; labelling remote benign rash as allergy; giving amoxicillin for presumed infectious mononucleosis (non-allergic rash).

Interactions. Methotrexate (reduced renal clearance), warfarin, probenecid, allopurinol with amoxicillin (rash), oral typhoid vaccine (inactivated by antibiotics).

Monitoring. Renal function; liver tests and full blood count weekly in courses over 14 days; electrolytes with high-dose therapy.

Special groups. Safe in pregnancy and breastfeeding. Renal impairment: lengthen the interval when creatinine clearance is under 30 mL/min and reduce the dose in severe impairment. Children: weight-based doses (amoxicillin 25 to 30 mg/kg every 12 hours or 40 to 90 mg/kg daily in divided doses depending on indication).