Flucloxacillin

Flucloxacillin
Systematic (IUPAC) name
(2S,5R,6R)-6-({[3-(2-chloro-5-fluorophenyl)-5-methylisoxazol-4-yl]carbonyl}amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
Clinical data
AHFS/Drugs.com Micromedex Detailed Consumer Information
Oral, IM, IV, intrapleural, intraarticular
Pharmacokinetic data
Bioavailability 50–70%
Metabolism Hepatic
Half-life 0.75–1 hour
Excretion Renal
Identifiers
5250-39-5 Yes
J01CF05 QJ51CF05
PubChem CID 21319
DrugBank DB00301 Yes
ChemSpider 20037 Yes
UNII 43B2M34G2V Yes
KEGG D04196 Yes
ChEBI CHEBI:5098 Yes
ChEMBL CHEMBL222645 Yes
Chemical data
Formula C19H17ClFN3O5S
453.87 g/mol
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Flucloxacillin (INN) or floxacillin (USAN) is a narrow-spectrum beta-lactam antibiotic of the penicillin class. It is used to treat infections caused by susceptible Gram-positive bacteria. Unlike other penicillins, flucloxacillin has activity against beta-lactamase-producing organisms such as Staphylococcus aureus[1] as it is beta-lactamase stable. However, it is ineffective against MRSA. It is very similar to dicloxacillin and these two agents are considered interchangeable. Flucloxacillin is available under a variety of trade names, including Floxapen (Beecham, now GSK), Flopen (CSL), Staphylex (Alphapharm), Softapen (Rephco Pharmaceuticals Limited), and Flubex (Beximco Pharmaceuticals Ltd, Bangladesh).

Overview of common uses

It is most commonly used to treat infections such as:

Flucloxacillin can also be used to prevent infections during major surgical procedures, particularly in heart or orthopedic surgery.

Mechanism of action

Like other β-lactam antibiotics, flucloxacillin acts by inhibiting the synthesis of bacterial cell walls. It inhibits cross-linkage between the linear peptidoglycan polymer chains that make up a major component of the cell wall of Gram-positive bacteria.

Medicinal chemistry

Flucloxacillin is insensitive to beta-lactamase (also known as penicillinase) enzymes secreted by many penicillin-resistant bacteria. The presence of the isoxazolyl group on the side chain of the penicillin nucleus facilitates the β-lactamase resistance, since they are relatively intolerant of side chain steric hindrance. Thus, it is able to bind to penicillin-binding proteins and inhibit peptidoglycan crosslinking, but is not bound by or inactivated by β-lactamases.

Clinical use

Flucloxacillin is more acid-stable than many other penicillins and can be given orally, in addition to parenteral routes. However, like methicillin, it is less potent than benzylpenicillin against non-β-lactamase-producing Gram-positive bacteria.

Flucloxacillin has similar pharmacokinetics, antibacterial activity, and indications to dicloxacillin, and the two agents are considered interchangeable. It is believed to have higher incidence of severe hepatic adverse effects than dicloxacillin, but a lower incidence of renal adverse effects.[2]

Available forms

Flucloxacillin is commercially available as the sodium salt flucloxacillin sodium, in capsules (250 or 500 mg), oral suspensions (125 mg/5 ml]] or 250 mg/5 ml), and injections (powder for reconstitution, 250, 500 and 1000 mg per vial).

Indications

Flucloxacillin is indicated for the treatment of infections caused by susceptible bacteria. Specific approved indications include:[2][3]

Flucloxacillin has relatively poor activity against non-β-lactamase-producing bacteria including Streptococcus pyogenes. Therefore, empirical therapy for significant cellulitis often involves dual-therapy to cover both staphylococci and streptococci, using either penicillin or ampicillin in addition to flucloxacillin. The latter is available as a standardised combination preparation co-fluampicil (flucloxacillin+ampicillin).

Precautions/contraindications

Flucloxacillin is contraindicated in those with a previous history of allergy to penicillins, cephalosporins, or carbapenems. It should also not be used in the eye, or administered to those with a history of cholestatic hepatitis associated with the use of dicloxacillin or flucloxacillin.[2]

It should be used with caution in the elderly, patients with renal impairment where a reduced dose is required, and those with hepatic impairment, due to the risk of cholestatic hepatitis.[2]

Adverse effects

Common adverse drug reactions 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.[2] Rarely, cholestatic jaundice (also referred to as cholestatic hepatitis) has been associated with flucloxacillin therapy. The reaction may occur up to several weeks after treatment has stopped, and takes weeks to resolve. The estimated incidence is one in 15,000 exposures, and is more frequent in people >55 years, females, and those with treatment longer than two weeks.[2][3]

Resistance

Despite flucloxacillin's being insensitive to beta-lactamases, some organisms have developed resistance to it and other narrow-spectrum β-lactam antibiotics including methicillin. Such organisms include methicillin-resistant Staphylococcus aureus, which has developed resistance to flucloxacillin and other penicillins by having an altered penicillin-binding protein.

See also

References

  1. ↑ Sutherland R, Croydon EA, Rolinson GN (November 1970). "Flucloxacillin, a new isoxazolyl penicillin, compared with oxacillin, cloxacillin, and dicloxacillin". Br Med J 4 (5733): 455–60. doi:10.1136/bmj.4.5733.455. PMC 1820086. PMID 5481218.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
  3. ↑ 3.0 3.1 Joint Formulary Committee. British National Formulary, 50th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2005.