Flucloxacillin: Efficacy in Staphylococcal Infections

Flucloxacillin (brand names Staphylex and generics) is a narrow spectrum penicillin from the group of isoxazolyl penicillins. Its profile is tailored to gram positive pathogens, primarily methicillin susceptible Staphylococcus aureus (MSSA). Because of its stability against beta lactamases (penicillinases) produced by many staphylococci, flucloxacillin is considered the first line agent for proven or highly suspected MSSA infection.

Flucloxacillin plays an important role in the treatment of skin infections, bone and joint infections, endocarditis, and bacteremia caused by MSSA. In case of suspected methicillin resistant Staphylococcus aureus (MRSA) or severe penicillin allergy, flucloxacillin is not suitable; in these cases glycopeptides (vancomycin) or lipopeptides (daptomycin) are used. Careful indication assessment with pathogen identification and antibiogram is the basis of successful therapy.

Mechanism of Action

Like all beta lactams, flucloxacillin inhibits bacterial cell wall synthesis. It binds to penicillin binding proteins (PBPs) in the bacterial membrane and thereby blocks the cross linking of the peptidoglycan layer. Weakened cell wall and osmotic instability lead to bacterial lysis. Flucloxacillin acts primarily on gram positive pathogens including streptococci and staphylococci, which compared to gram negative bacteria have a significantly thicker peptidoglycan layer.

The decisive advantage over classical penicillin G and aminopenicillins is the structurally modified side chain with isoxazole ring. It protects the beta lactam from hydrolysis by penicillinases, which approximately 80 to 90 percent of Staphylococcus aureus strains produce. Methicillin resistant strains carry an altered PBP2a to which flucloxacillin no longer binds sufficiently. This makes the substance ineffective against MRSA.

Pharmacokinetically, flucloxacillin is characterized by high plasma protein binding (approximately 95 percent). The half life is around 1 hour, which is why multiple daily doses are common. The substance is eliminated predominantly via renal excretion in unchanged form. In renal insufficiency, levels and half life increase, requiring dose adjustment.

Indications

• Skin and soft tissue infections such as erysipelas, impetigo, phlegmon, wound infections caused by gram positive pathogens
• Osteomyelitis and septic arthritis in proven MSSA infection
• Endocarditis caused by MSSA, high dose intravenous, often in combination with other antibiotics
• Pneumonia caused by gram positive pathogens, especially community acquired with evidence of staphylococci
• Mastitis in nursing women, frequently methicillin susceptible Staphylococcus aureus
• Sepsis and bacteremia caused by MSSA, intravenous administration, high dose, long treatment duration
• Periorbital cellulitis and tonsillar abscess in specialized settings

Flucloxacillin is insufficient for MRSA, anaerobes, Streptococcus pneumoniae with reduced penicillin susceptibility, mixed flora in intra abdominal infections, and gram negative pathogens.

Dosage and Administration

Adults orally: 500 mg to 1 g four times daily for 7 to 10 days in uncomplicated infections.

Adults intravenously: 1 to 2 g every four to six hours, in endocarditis up to 12 g per day divided into four to six individual doses.

Pediatric: 12.5 to 25 mg per kg body weight four times daily orally, intravenously up to 50 mg per kg in four to six individual doses, depending on infection severity.

Oral administration: on an empty stomach, at least 30 to 60 minutes before or two hours after a meal, because food significantly reduces absorption. Take with plenty of water.

Renal insufficiency: dose reduction (extending the dosing interval) required when eGFR is below 30 ml per minute. Hepatic insufficiency: caution due to risk of hepatotoxicity.

Treatment duration: 7 to 10 days for simple skin infections, four to six weeks for osteomyelitis, four to six weeks for endocarditis, individualized based on clinical course and pathogen identification.

Adverse Effects

Common: nausea, diarrhea, abdominal pain, rash, allergic reactions.

Occasional: elevation of liver transaminases, eosinophilia, mild leukopenia, local irritation at infusion site, phlebitis with intravenous administration.

Rare but relevant: cholestatic hepatitis, often with latency of up to eight weeks after treatment ends. Risk factors include age over 55 years, female sex, longer and higher doses, and genetic predisposition (HLA B 5701). Symptoms include nausea, fatigue, pruritus, jaundice, dark urine, and pale stool. Discontinue immediately if suspected.

Allergic reactions: immediately occurring anaphylaxis is rare but life threatening. Do not attempt flucloxacillin in patients with known penicillin allergy. Severe cutaneous reactions such as Stevens Johnson syndrome or DRESS are very rare.

Kidneys: acute interstitial nephritis is described, clinically characterized by eosinophilia, rash, and creatinine elevation.

With intravenous high dose therapy: hypokalemia, hypernatremia, and occasionally neurological symptoms with accumulation. Plasma levels and electrolytes are an important part of monitoring in endocarditis therapy.

Drug Interactions

• Probenecid: inhibits tubular secretion and increases flucloxacillin levels and duration of action.
• Methotrexate: penicillins may reduce renal clearance of methotrexate and increase toxicity, especially in oncological high dose regimens.
• Oral anticoagulants (warfarin, phenprocoumon): individual reports of INR changes, clinically relevant only in isolated cases, INR monitoring in first week of therapy.
• Bacteriostatic antibiotics (tetracyclines, erythromycin): theoretical antagonism, clinically rarely relevant, avoid combination in practice.
• Paracetamol in high dose therapy: very rarely formation of 5 oxoproline and metabolic acidosis in critically ill patients with reduced glutathione reserves.
• Oral contraceptives: theoretical reduction in efficacy, clinical significance with standard use is low, with prolonged antibiotic therapy and diarrhea use additional contraception as precaution.

Special Precautions

Pregnancy: flucloxacillin is considered safe in pregnancy based on long term experience and is the drug of choice for MSSA infections, such as mastitis. Breast feeding: minimal transfer into breast milk, breast feeding during therapy is possible.

Children: established in pediatrics, dosage adjusted for weight. Liquid formulations are available.

Penicillin allergy: known penicillin allergy is a contraindication. In unclear history, detailed questioning and if necessary allergy testing should be performed before first administration, because many reported penicillin allergies cannot be confirmed.

Therapy monitoring: with high dose therapy and prolonged intravenous administration, liver values, kidney values, differential blood count, and electrolytes must be regularly monitored. In patients over 55 years and therapy longer than two weeks, special attention to cholestatic hepatitis is recommended.

Resistance situation: in Germany approximately 1 to 2 percent of Staphylococcus aureus isolates are MRSA, slightly higher in hospitals. With locally higher prevalence or special risk factors (hospital, long term care facility, hemodialysis, prior MRSA colonization), empirical therapy must be adjusted.

Antibiotic stewardship: no antibiotic without indication and suspected pathogen. Therapy should be adjusted specifically according to antibiogram and strictly limited in duration.

You may also be interested in

• Cefaclor, second generation cephalosporin
• Clindamycin, lincosamide for gram positive pathogens and anaerobes
• Vancomycin, glycopeptide for MRSA and severe gram positive infection
• Clavulanic acid, beta lactamase inhibitor in combination preparations
• Erythromycin, macrolide for penicillin allergy

Frequently Asked Questions

Sources

• Gelbe Liste, Flucloxacillin active substance profile
• BfArM, Federal Institute for Drugs and Medical Devices
• AWMF, Guidelines for skin, bone, and endocarditis infections
• Robert Koch Institute, antibacterial resistance surveillance