Flucloxacillin

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IUPAC_name = 6-(("S")-3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-
4-carboxamido)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo
[3.2.0] heptane-2-carboxylic acid
CAS_number = 5250-39-5
ATC_prefix = J01
ATC_suffix = CF05
PubChem = 21319
DrugBank = APRD00609
C = 19 | H = 17 | Cl = 1 | F = 1 | N = 3 | O = 5 | S = 1
molecular_weight = 453.87 g/mol
bioavailability = 50–70%
metabolism = Hepatic
elimination_half-life = 0.75–1 hour
excretion = Renal
pregnancy_AU = B1
pregnancy_US =
legal_AU = S4
legal_UK = POM
legal_US =
routes_of_administration = Oral, IM, IV, intrapleural, intraarticular

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. Nowadays, it is no longer recommended against beta-lactamase-producing organisms such as "Staphylococcus aureus", since like in other penicillins, it has become not active against such infections. It is very similar to dicloxacillin and these two agents are considered interchangeable. Flucloxacillin is also available under a variety of trade names including Flopen (CSL) and Floxapen (GSK).

Mode 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 (PBPs) 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.Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.]

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:Joint Formulary Committee. British National Formulary, 50th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2005.]
*Staphylococcal skin infections and cellulitis – including impetigo, otitis externa, folliculitis, boils, carbuncles, and mastitis
*Pneumonia (adjunct)
*Osteomyelitis, septic arthritis
*Septicaemia
*Empirical treatment for endocarditis
*Surgical prophylaxis

Flucloxacillin has relatively poor activity, as noted above, 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 those with a history of cholestatic hepatitis associated with the use of dicloxacillin or flucloxacillin.

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.

Adverse effects

Common adverse drug reactions (ADRs) 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.

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 1 in 15,000 exposures, and is more frequent in people >55 years, females, and those with treatment longer than 2 weeks.

Resistance

Despite flucloxacillin 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" (MRSA).

ee also

*Beta-lactam antibiotic
*Dicloxacillin

References