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Flucloxacillin

Flucloxacillin 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 b-lactamase-producing organisms such as Staphylococcus aureus [1]. It is very similar to dicloxacillin and these two agents are considered interchangeable. 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.

Therapeutic use

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

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

Dosage and Administration

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).

Toxicology

Rat acute toxicity 2.0834 LD50, mol/kg

Cholestatic liver disease of unknown origin occurring in flucloxacillin users has been reported since the beginning of its use, and numerous similar reports including several case series from Australia [315]. From these reports a well-defined clinical picture of flucloxacillin-associated liver disease was described, which consisted of prolonged painless jaundice with elevation of cholestatic liver enzymes diagnosed within 26 weeks after prescription, and as much as 3 weeks after the drug was stopped. Although most patients eventually recovered within several months, a chronic vanishing bile duct syndrome was reported in some patients [7, 11-12, 16], and fatal cases were also described [7, 9].

Though one case of cholestatic liver disease per 12 000 first-time users may be considered to be a relatively rare event, it must be taken into account, that the risk is apparently higher in older patients, that flucloxacillin-induced liver disease is a potentially irreversible and lethal disease [7, 9, 17], and that the cases identified in a recent study [18] only represent a small proportion of the absolute number of cases that occur each year in the UK, where flucloxacillin is a frequently used drug with about two million prescriptions per year [19].

Pharmacokinetic

 

Bioavailability 5070%
Protein binding  
Metabolism hepatic
Half-life 0.751 hr
Cmax (mg/ml)  
tmax (hrs)  
Distribution volume Vd  
Clearance  
Excretion renal

Absorption

 

Distribution


Excretion

 

Metabolism

 

Mechanism of Action

Like other β-lactam antibiotics, flucloxacillin (fluclox) 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.

Other pharmacological effects

 


Medicinal Chemistry

CAS number: 5250-39-5  EINECS: 226-051-0

Molecular Formula:  C19H17ClFN3O5S 

Average mass: 493.869 Da

Monoisotopic mass:  493.0486566 Da

Systematic name: (2S,5R,6R)-6-({[3-(2-chloro-5-fluorophenyl)-5-methylisoxazole-4-yl]carbonyl}amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

SMILES: H][C@]12SC(C)(C)[C@@H](N1C(=O)[C@H]2NC(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl)C(O)=O

Std. InChI: 1S/C19H17ClFN3O5S/c1-7-10(12(23-29-7)11-8(20)5-4-6-9(11)21)15(25)22-13-16(26)24-14(18(27)28)19(2,3)30-17(13)24/h4-6,13-14,17H,1-3H3,(H,22,25)(H,27,28)/t13-,14+,17-/m1/s1

ACD/LogP: 2.600.45 # of Rule of 5 Violations: 0
ACD/LogD (pH 5.5): -0.46 ACD/LogD (pH 7.4): -1.13
ACD/BCF (pH 5.5): 1.00 ACD/BCF (pH 7.4): 1.00
ACD/KOC (pH 5.5): 1.00 ACD/KOC (pH 7.4): 1.00
#H bond acceptors: 8 #H bond donors: 2
#Freely Rotating Bonds: 4 Polar Surface Area: 138.04 2
Index of Refraction: 1.672 Molar Refractivity: 106.30.4 cm3
Molar Volume: 283.75.0 cm3 Polarizability: 42.10.5 10-24cm3
Surface Tension: 77.05.0 dyne/cm Density: 1.60.1 g/cm3
Flash Point: 363.431.5 C Enthalpy of Vaporization: 104.43.0 kJ/mol
Boiling Point: 677.355.0 C at 760 mmHg Vapour Pressure: 0.02.2 mmHg at 25C

 

Major Impurities:

Appearance:

Melting point:

Optical rotation:

Solubility: 8.820 mg/L

logP: 2.58

pKa: 3.75

Stability:

 


1. Sutherland R., Croydon E.A., Rolinson G.N. "Flucloxacillin, a new isoxazolyl penicillin, compared with oxacillin, cloxacillin, and dicloxacillin". Br. Med. J. 4, (5733): 45560, (1970).

2. Rossi S., editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; (2006).

3. Australian Adverse Drug Reactions Advisory Committee (ADRAC). "Flucloxacillin hepatitis!. Australian Adverse Drug Reactions Bulletin  9: 2, (1990).

4. Bengtsson F., Floren C.H., Hagerstrand I., Soderstrom C., Aberg T. "Flucloxacillin-induced cholestatic liver damage". Scand. J. Infect. Dis. 17: 1258, (1985).

5. Deboever G. "Cholestatic jaundice due to derivatives of oxacillin". Am. J. Gastroenterol. 82: 483, (1987).

6. Devereaux B.M., Crawford D.H., Purcell P., Powell L.W., Roeser H.P. "Flucloxacillin associated cholestatic hepatitis. An Australian and Swedish epidemic?" Eur. J. Clin. Pharmacol. 49: 815, (1995).

7. Eckstein R.P., Dowsett J.F., Lunzer M.R. "Flucloxacillin induced liver disease: histopathological findings at biopsy and autopsy".
Pathology 25: 2238, (1993).

8. Gotell P., Loof L. "[Effects of floxacillin on the liver: 3 cases of floxacillin-induced cholestatic liver disease]". Lakartidningen 84: 9545, (1987).

9. Koek G.H., Stricker B.H., Blok A.P., Schalm S.W., Desmet V.J. "Flucloxacillin-associated hepatic injury". Liver 14: 2259, (1994).

10. Lobatto S., Dijkmans B.A., Mattie H., Van Hooff J.P. "Flucloxacillin associated liver damage". Neth. J. Med. 25: 478, (1982).

11. Miros M., Kerlin P., Walker N., Harris O. "Flucloxacillin induced delayed cholestatic hepatitis". Aust. N, Z. J. Med. 20: 2513, (1990).

12. Turner I.B., Eckstein R.P., Riley J.W., Lunzer M.R. "Prolonged hepatic cholestasis after flucloxacillin therapy". Med. J. Aust. 151: 7015, (1989).

13. Tauris P., Jorgensen N.F., Petersen C.M., Albertsen K. "Prolonged severe cholestasis induced by oxacillin derivatives. A report on two cases". Acta Med. Scand. 217: 5679, (1985).

14. Victorino R.M., Maria V.A., Correia A.P., de Moura C. "Floxacillin-induced cholestatic hepatitis with evidence of lymphocyte sensitization". Arch. Intern. Med. 147: 9879, (1987).

15. Fairley C.K., McNeil J.J., Desmond P., et al. "Risk factors for development of flucloxacillin associated jaundice". Br. Med. J. 306: 2335, (1993).

16. Davies M.H., Harrison R.F., Elias E., Hubscher S.G. "Antibiotic associated acute vanishing bile duct syndrome: a pattern associated with severe, prolonged, intrahepatic cholestasis". J. Hepatol. 20: 1126, (1994).

17. Australian Adverse Drug Reactions Advisory Committee (ADRAC). "Fatal hepatic reactions to flucloxacillin". Australian Adverse Drug Reactions Bulletin 13: 101, (1994).

18. Stefan Russmann, James A. Kaye, Susan S. Jick & Hershel Jick. "Risk of cholestatic liver disease associated with flucloxacillin and flucloxacillin prescribing habits in the UK: Cohort study using data from the UK General Practice Research Database". Br. J. Clin. Pharmacol. 60:1 7682. (2005).

19.


 

 

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