Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: Actavis Group PTC ehf, Reykjavikurvegi 76-78, 220 Hafnarfjördur, Iceland
Pharmacotherapeutic group: Beta-lactamase resistant penicillins
ATC code: J01CF05
Flucloxacillin is a semisynthetic penicillin (beta-lactam antibiotic; isoxazolylpenicillin) with a narrow spectrum of activity primarily against Gram-positive organisms, including β-lactamase-producing strains.
There is evidence that the risk of flucloxacillin induced liver injury is increased in subjects carrying the HLA-B*5701 allele. Despite this strong association, only 1 in 500-1,000 carriers will develop liver injury. Consequently, the positive predictive value of testing the HLA-B*5701 allele for liver injury is very low (0.12%) and routine screening for this allele is not recommended.
Flucloxacillin inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) in the biosynthetic pathway of bacterial peptidoglycan, which is an integral structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, which is usually followed by cell lysis and death.
The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for flucloxacillin.
Resistance to isoxazolylpenicillins (so-called methicillin-resistance) is caused by the bacteria producing an altered penicillin binding protein. Cross resistance may occur in the beta-lactam group with other penicillins and cefalosporins. Methicillin-resistant staphylococci generally have low susceptibility for all beta-lactam antibiotics.
Flucloxacillin is active against both β-lactamase-positive and –negative strains of Staphylococcus aureus and other aerobic Gram-positive cocci, with the exception of Enterococcus faecalis. Gram-positive anaerobes are generally susceptible (MIC 0.25‑2 mg/l) but Gram-negative bacilli or anaerobes are moderately to fully resistant. Enterobacteria is fully resistant to flucloxacillin as well as methicillin-resistant staphylococci.
Strains of the following organisms are generally sensitive to the bactericidal action of flucloxacillin in vitro. The minimal inhibitory concentrations (MIC) of flucloxacillin are quoted below:
| Micro-organisms | MIC (mg/l) |
|---|---|
| Staphylococcus aureus | 0.1 to 0.25 |
| Staphylococcus aureus (beta-lactamase +) | 0.25 to 0.5 |
| Streptococcus pneumoniae | 0.25 |
| Streptococcus pyogenes (Group A beta-haemolytic) | 0.1 |
| Streptococcus viridans group | 0.5 |
| Clostridium tetani | 0.25 |
| Clostridium welchii | 0.25 |
| Neisseria meningitidis | 0.1 |
| Neisseria gonorrhoeae | 0.1 |
| Neisseria gonorrhoeae (beta-lactamase +) | 2.5 |
The Group A beta-haemolytic streptococci are less sensitive to the isoxazolyl penicillins than to penicillin G or penicillin V.
The peak serum levels of flucloxacillin reached after 1h are as follows:
Protein binding: the serum protein binding rate is 95%.
Flucloxacillin diffuses well into most tissues.
Crossing the meningeal barrier: flucloxacillin diffuses in only small proportion into the cerebrospinal fluid of subjects whose meninges are not inflamed.
Crossing into mother’s milk: flucloxacillin is excreted in small quantities in mothers milk.
In normal subjects approximately 10% of the flucloxacillin administered is metabolised to penicilloic acid. The elimination half life of flucloxacillin is on the order of 53min.
Excretion occurs mainly through the kidney. Sixty five per cent of the dose administered orally is recovered in unaltered active form in the urine within 8h. A small portion of the dose administered is excreted in the bile. The excretion of flucloxacillin is slowed in cases of renal failure.
The clearance of flucloxacillin is considerably slower in neonates compared with adults and a mean elimination half life of approximately four and a half hours has been reported in neonates. Special care should be taken during administration of flucloxacillin to the newborn (see section 4.4). Younger infants (<6 months) achieve higher plasma concentrations of flucloxacillin than older children when given the same dose.
In patients with severe renal impairment the elimination half life of flucloxacillin increases to values of between 135-173 min. Modified dosage is required if renal impairment is severe, with creatinin clearance <10 ml/min (see section 4.2).
Hepatic disease is thought unlikely to influence the pharmacokinetics of flucloxacillin as the antibiotic is cleared primarily via the renal route.
Not relevant.
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