Flucloxacillin

Flucloxacillin is a penicillinase-resistant penicillin and the first-line drug for methicillin-susceptible Staphylococcus aureus (MSSA) and streptococcal skin, bone and bloodstream infection in settings where it is licensed.

Classification. Beta-lactam, isoxazolyl penicillin (anti-staphylococcal penicillin). Intrinsically inactive against MRSA.

Mechanism. Binds penicillin-binding proteins; its side chain protects against staphylococcal beta-lactamase.

Spectrum. MSSA, beta-haemolytic streptococci and pneumococci (less active than benzylpenicillin). Not active against MRSA, enterococci, Gram-negative bacilli or anaerobes.

Pharmacokinetics. Oral bioavailability about 50 to 70%, reduced by food. Half-life 45 to 60 minutes. Protein binding about 95%. Eliminated by kidneys and bile.

No loading dose. Maximum 12 g IV daily (some products limit to 8 g) and 4 g orally daily.

Mild skin and soft tissue infection (impetigo, cellulitis, abscess after drainage). 500 mg to 1 g orally every 6 hours for 5 to 7 days.

Severe skin and soft tissue infection. 1 to 2 g IV every 6 hours, switch to oral when improving, total 7 days.

MSSA bacteraemia. 2 g IV every 6 hours (or 12 g/24 hours as continuous infusion) for at least 14 days from the first negative blood culture in uncomplicated disease and 4 to 6 weeks if complicated.

Endocarditis. 2 g IV every 4 to 6 hours for 4 to 6 weeks; prosthetic valve disease adds rifampicin and gentamicin.

Osteomyelitis and septic arthritis. 2 g IV every 6 hours for 2 to 6 weeks, then oral therapy under specialist advice; total 6 weeks for osteomyelitis.

Children 1 month to 17 years. - Oral: 12.5 to 25 mg/kg every 6 hours (maximum 1 g). - IV: 25 mg/kg every 6 hours, up to 50 mg/kg (maximum 2 g a dose) in severe infection. - Neonates: 25 to 50 mg/kg every 12 hours in the first week and every 8 hours after, depending on gestation.

Alternatives. Cefazolin, cloxacillin, nafcillin or oxacillin by region; vancomycin or teicoplanin if MRSA or penicillin allergy; clindamycin or doxycycline for mild infection in allergy.

Contraindications. Penicillin hypersensitivity; previous hepatic dysfunction or jaundice caused by flucloxacillin.

Cholestatic jaundice and hepatitis. May occur up to 2 months after stopping. Risk rises with age over 50, courses over 14 days and existing liver disease; HLA-B*57:01 is associated. Use with caution and avoid prolonged courses in liver disease.

High anion gap metabolic acidosis. Reported with regular paracetamol use, especially in sepsis, renal impairment, malnutrition or low body weight. Measure arterial or venous blood gas and consider pyroglutamic acid if acidosis is unexplained.

Other adverse effects. Diarrhoea, rash, hypokalaemia with high doses, interstitial nephritis, neutropenia, Clostridioides difficile infection.

Interactions. Paracetamol (acidosis), warfarin (INR changes), methotrexate (reduced clearance), voriconazole and other CYP3A4 substrates (levels may fall), oral typhoid vaccine.

Common prescribing errors. Giving it with food, under-dosing bacteraemia, using it for MRSA, long courses without liver tests.

Special groups. - Pregnancy and breastfeeding: acceptable. - Older adults: higher risk of cholestasis; limit course length. - Kidney impairment: creatinine clearance 10 to 50 mL/min give usual dose every 6 to 8 hours; under 10 mL/min maximum 1 g every 8 hours. - Liver impairment: avoid in significant disease; if essential, monitor weekly. - Obesity: use full doses; maximum applies. - Region: widely used in East Africa as flucloxacillin or cloxacillin; check local supply.

Preparation. Oral: take 1 hour before or 2 hours after food. IV: dissolve in water for injection, give 1 to 2 g by slow injection over 3 to 4 minutes or by infusion over 30 to 60 minutes in 0.9% sodium chloride or 5% glucose. Continuous infusion needs a bag that remains stable for the infusion period; renew every 12 to 24 hours.

Baseline and monitoring. - Baseline: allergy history, liver tests, creatinine, cultures. - During treatment: liver tests weekly, creatinine and potassium twice weekly in high-dose therapy, full blood count weekly beyond 2 weeks, acid-base status when paracetamol is given. - No therapeutic drug monitoring.

Stop rules. Stop for jaundice or rising alanine aminotransferase over 3 times the upper limit of normal, severe rash, anaphylaxis or unexplained acidosis.

Referral and escalation. Infectious diseases for any Staphylococcus aureus bacteraemia, endocarditis, prosthetic joint infection, and for repeated positive cultures after 72 hours of treatment.