FLUCLOXACILLIN

Muhammad Junaid Iqbal

MS Chemistry, MSF2100851
Flucloxacillin
Flucloxacillin, ( IUPAC name (2S,5R,6R)-6-[[3-(2-chloro-6-fluorophenyl)-5-methyl-1,2-oxazole-4-
carbonyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid )[1] a
new isoxazole penicillin, is active against penicillinase-producing strains of Staphylococcus
aureus and is well absorbed in human after oral and intramuscular administration.[2] It’s Non-
FDA approved, and is not available in USA[3]. Flucloxacillin was first marketed in Europe in the
1970s[4]. There are two forms of Flucloxacillin: Flucloxacillin sodium and Flucloxacillin
magnesium octahydrate. Flucloxacillin sodium (FLU) is the form used in pharmaceutical
formulations.

Flucloxacillin Structure

Flucloxacillin is used for both staphylococcal and streptococcal skin infections.[5] These include
folliculitis, carbuncles,[6] impetigo, ecthyma, cellulitis, erysipelas, necrotising fasciitis, and
infections of skin conditions such as eczema, scabies, ulcers and acne.[5][7][8] Due to the
widespread belief that dual-therapy is needed to cover both Staphylococcus and Streptococcus
in cellulitis, Flucloxacillin is sometimes given with the addition of benzylpenicillin for more
severe cellulitis.[9] Infections of leg ulcers can be treated with Flucloxacillin.[10] With diabetic
foot infections the dose is adjusted according to whether the infection appears mild, moderate
or severe.[10] Despite having a lower than optimum drug penetration into bone ratio of 10-
20%, flucloxacillin appears effective in treating osteomyelitis.[11][12] Depending on local
guidance it may be used in the treatment of infection of joints while waiting for culture results.
[9][13]

The mechanisms of action of antimicrobials can act on the interference of cell wall synthesis,
inhibition of protein synthesis, interference in DNA synthesis and inhibition of metabolic
pathway.[14]
FLU inhibits the cell wall biosynthesis of Gram positive microorganisms, being a bactericidal
drug. The penicillin’s in general act in this way, preventing the reproduction of bacteria, more
specifically inhibiting the synthesis of peptideoglycan, by inhibiting the enzymes trans
peptidases.[15] It should be noted that the indiscriminate use of antimicrobials contributes to
bacterial resistance, which has become a worldwide health problem.[16]

FLU is used in the treatment of infections of susceptible micro-organisms; its bioavailability is

50–70% after oral administration and its absorption by the intestine is rapid. This drug, can be
used orally, intravenously, intramuscularly, intrapleural, intra-articularly and by nebulization.
[17,18] FLU is an organic compound, acid in aqueous solution with pKa 2.76, determined at 37C
in 0.15 M KCl.[19] It has a half-life of approximately 1 hour. FLU can be found in bone tissues,
breast milk, pleural and sinuvial fluid; it crosses the placenta and does not diffuse easily in
cerebrospinal fluid.[20]

FLU is a semi-synthetic product derived from fermentation, white or almost white, hygroscopic
and crystalline. The solubility of FLU is characterized as very soluble in water and methanol, and
soluble in ethanol (96%). The chemical name of FLU is (2S,5R,6R)-6-[[3-(2-chloro-6-
fluorophenyl)-5-methyl-1,2- oxazole-4-carbonyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-
azabicyclo[3.2.0] heptane-2-carboxylic acid. Its molecular formula is C19H16ClFN3NaO5S.H2O
and molecular weight is 493.869 mol/L.[21] It has LogP 2.58 and pKa (acid) 3.75.[19]

In normal subjects approximately 10% of the flucloxacillin administered is metabolised to

penicilloic acid. The elimination half-life of flucloxacillin is in the order of 53 minutes. 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. The excretion of flucloxacillin is slowed
in cases of renal failure.[22]

Common side effects associated with the use of flucloxacillin include: diarrhoea, nausea, rash,
urticaria, pain and inflammation at injection site, superinfection (including candidiasis), allergy,
and transient increases in liver enzymes and bilirubin.[24]

A kind of synthetic method of Sodium flucloxacillin take 3-(2-chloro-6-fluorophenyl)-5-methyl-

isoxazole-4-formic acid as raw material, comprises the steps:

Raw material is placed in organic solvent, under the catalysis of organic amine, descend and
phosphorus oxychloride reaction in 0 ~ 50 ℃, obtain 3-(2-chloro-6-fluorophenyl)-5-methyl-
isoxazole-4-formyl chloride solution, wherein, the mol ratio of raw material, organic amine and
phosphorus oxychloride is 1:2 ~ 5:1 ~ 4.

6-amino-penicillanic acid and mineral alkali are added in the suitable quantity of water, be
cooled to 5 ~ 10 ℃ after the stirring and dissolving, drip the solution of acid chloride that
obtains in the step (1), the mol ratio of 6-amino-penicillanic acid, mineral alkali and raw
material is 1:2 ~ 5:1 ~ 2, react complete rear dropping hcl acidifying, then layering, water layer
merge organic layer after with organic solvent extraction.

The organic layer solution decompression that obtains is concentrated, resistates adds alcoholic
solvent, stir slowly to drip water down, and crystallization, crystallization is 0 ~ 4 ℃ of lower
growing the grain 1 hour, filters, washing, oven dry obtain Flucloxacillin acid.

Flucloxacillin acid is dissolved in organic solvent, at 17 ~ 25 ℃ of lower Sodium isooctanoate

solution that drip, the reaction salify is cooled to 0 ~ 5 ℃ and stirred 1 hour behind the
crystallization, and filtration, oven dry obtain product Flucloxacillin sodium-hydrate. [23]
References:

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