Flucloxacillin

Description

Chemically this is 3(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolyl penicillin; this differs from dicloxacillin only by the substitution of a fluorine for a chlorine atom (Sutherland et al., 1970). It comes as oral capsules of 250 and 500 mg, as a suspension of 25 and 50 mg/ml, and in an injectable formulation of 500 mg and 1 g.

Originator

Floxapen,Beecham,UK,1970

Uses

Antibacterial.

Definition

ChEBI: A penicillin compound having a 6beta-[3-(2-chloro-6-fluorophenyl)-5-methyl-1,2-oxazole-4-carboxamido] side-chain.

Manufacturing Process

3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylicacid, MP 206° to 207°C, was obtained by chlorinating 2-chloro-6-fluorobenzaldoxime, then condensing the resulting hydroxamoyl chloride with methyl acetoacetate in methanolic sodium methoxide and hydrolyzing the resulting ester with hot alkali. The acid chloride resulted from treatment of the acid with thionyl chloride
A suspension of 6-aminopenicillanic acid (36.4 grams) in water was adjusted to pH 7.2 by the addition of N aqueous sodium hydroxide and the resulting solution was treated with a solution of 3-(2-chloro-6-fluorophenyl)-5- methylisoxazole-4-carbonyl chloride (46.1 grams) in isobutyl methyl ketone. The mixture was stirred vigorously for 1? hours and then filtered through Dicalite. The layers were separated and the isobutyl methyl ketone layer was shaken with saturated brine. Then, precipitation of the sodium salt only took place after dilution of the mixture with ether. In this way there was obtained 60.7 grams of the penicillin sodium salt having a purity of 88% as determined by alkalimetric assay.

Therapeutic Function

Antibacterial

Antimicrobial activity

There is complete cross-resistance with other penicillinase-stable penicillins.

General Description

Flucloxacillin was synthesized by Beecham Research Laboratories in 1962 as a penicillinase-stable and orally active semisynthetic penicillin. It shows almost the same activity as dicloxacillin, and it has slightly higher serum and tissue concentrations than dicloxacillin. This drug has been used to treat pyoderma, sepsis, and postoperative infections as well as ear and nose, respiratory tract, and other infections caused by Staphylococcus and Streptococcus, including benzylpenicillin-resistant strains.

Pharmacokinetics

Oral absorption: c. 80%
C_max 250 mg (oral): 11 mg/L after 0.5–1 h
Plasma half-life: 2 h
Plasma protein binding: 95%
Absorption and distribution
It is well absorbed after oral administration and penetrates rapidly into extravascular exudates. Its high protein binding limits its diffusion, notably into the normal CSF.
Metabolism and excretion
Flucloxacillin is partly metabolized in the liver and about 10% of the plasma concentration is made up of metabolites. It is more slowly eliminated than cloxacillin. Some appears in the bile but about 50–80% of an oral dose is recovered from the urine, about 20% as metabolites.

Clinical Use

Uses are those of group 3 penicillins.

Side effects

In patients treated by intravenous infusion, about 5% developed phlebitis by the first and 15% by the second day, after which the proportion rose dramatically. Side effects are otherwise those common to penicillins.

Drug interactions

Potentially hazardous interactions with other drugs
Reduces excretion of methotrexate.

Metabolism

In normal subjects approximately 10% of the flucloxacillin administered is metabolised to penicilloic acid. Excretion occurs mainly through the kidney. Between 65.5% (oral route) and 76.1% (parenteral route) of the dose administered is recovered in unaltered active form in the urine within 8 hours. A small portion of the dose administered is excreted in the bile.