Antistaphylococcal Penicillins

Antistaphylococcal penicillins (flucloxacillin, cloxacillin, dicloxacillin, oxacillin, nafcillin) carry bulky side chains that shield the beta-lactam ring from staphylococcal penicillinase. They are the reference treatment for infections caused by methicillin-susceptible S. aureus (MSSA). Methicillin itself is no longer used.

Mechanism. PBP inhibition with activity against MSSA, beta-haemolytic streptococci and pneumococci (less potent than benzylpenicillin). No activity against MRSA (PBP2a), enterococci or Gram-negative bacilli.

Pharmacokinetics. Oral absorption is 50 to 70 percent and falls with food, so doses are taken 1 hour before or 2 hours after meals. Highly protein-bound (about 95 percent), half-life under 1 hour, with mixed renal and hepatic clearance. Intravenous therapy is needed for serious infection because oral levels are unreliable.

• Flucloxacillin and cloxacillin: the usual agents outside North America; interchangeable in practice. Cloxacillin is the more widely stocked agent in much of East Africa; availability of each varies.
• Dicloxacillin: oral only, better absorbed than cloxacillin.
• Oxacillin and nafcillin: intravenous agents in North America; nafcillin is hepatically cleared and induces CYP enzymes.
• Cefazolin (a cephalosporin): an alternative for MSSA bacteraemia and endocarditis with fewer discontinuations for toxicity.

Adult regimens.

• Cellulitis, impetigo, infected eczema, abscess with cellulitis (mild to moderate): cloxacillin or flucloxacillin 500 mg to 1 g orally every 6 hours for 5 to 7 days.
• MSSA bacteraemia, severe soft tissue infection, pyomyositis, septic arthritis, osteomyelitis: 2 g IV every 4 to 6 hours (maximum 12 g daily). Duration: at least 14 days for uncomplicated bacteraemia from the first negative culture; 4 to 6 weeks for complicated bacteraemia, osteomyelitis and native valve endocarditis; oral step-down for bone infection is increasingly used after the early intravenous phase.
• Staphylococcal endocarditis: 2 g IV every 4 hours for 4 to 6 weeks.
• Children: 12.5 to 25 mg/kg every 6 hours orally; 25 to 50 mg/kg every 6 hours IV in serious infection (maximum 12 g daily); neonatal dosing is by weight and gestation.

Selection. Change vancomycin to an antistaphylococcal penicillin or cefazolin as soon as MSSA is confirmed; vancomycin is inferior for MSSA. In penicillin allergy, cefazolin (unique side chain) is usually acceptable unless the reaction was severe cutaneous.

Contraindications. Immediate hypersensitivity to penicillin; previous flucloxacillin-associated cholestatic jaundice or hepatic dysfunction.

Serious effects.

• Cholestatic hepatitis, onset up to 2 months after stopping; commoner in courses over 14 days, older adults and with HLA-B*57:01.
• High anion gap metabolic acidosis (5-oxoproline) with regular paracetamol, particularly in sepsis, malnutrition, women, and renal or hepatic impairment.
• Hypokalaemia from sodium load; phlebitis; interstitial nephritis; neutropenia in courses over 2 weeks.

Interactions. Warfarin (reduced effect with dicloxacillin and nafcillin), methotrexate, probenecid, paracetamol.

Monitoring. Liver tests and full blood count at least weekly in prolonged courses; potassium on high intravenous doses; avoid regular paracetamol in at-risk patients.

Special groups.

• Pregnancy and breastfeeding: acceptable.
• Hepatic impairment: use with caution; cefazolin is often preferred.
• Renal impairment: little adjustment until creatinine clearance is under 10 mL/min, when dose is reduced (accumulation can cause neurotoxicity).
• Older adults: higher cholestatic risk; limit duration or choose cefazolin.