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Fusidic Acid

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Synonyms: Ácido fusídico; Acidum Fusidicum; Acidum Fusidicum Hemihydricum; Fucidinsyra; Fusídico, ácido; Fusidiinihappo; Fusidinsyra; Fuzidinsav; Fuzido rūgštis; Kyselina fusidová hemihydrát; SQ-16603
BAN: Fusidic Acid
USAN: Fusidic Acid
INN: Fusidic Acid [rINN (en)]
INN: Ácido fusídico [rINN (es)]
INN: Acide Fusidique [rINN (fr)]
INN: Acidum Fusidicum [rINN (la)]
INN: Фэузидовая Кислота [rINN (ru)]
Chemical name: ent-16α-Acetoxy-3β-dihydroxy-4β,8β,14α-trimethyl-18-nor-5β,10α-cholesta-(17Z)-17(20),24-dien-21-oic acid hemihydrate
Molecular formula: C31H48O6,1/2H2O =525.7
CAS: 6990-06-3 (anhydrous fusidic acid)
ATC code: D06AX01; D09AA02; J01XC01; S01AA13
Read code: y00kx [Eye]; y012G

Pharmacopoeias. In Europe. European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Fusidic Acid). An antimicrobial substance produced by the growth of certain strains of Fusidium coccineum or by any other means. A white or almost white crystalline powder. Practically insoluble in water; freely soluble in alcohol. Store at a temperature of 2° to 8°. Protect from light.

Sodium Fusidate

(British Approved Name Modified, US Adopted Name, rINNM)

Drug Nomenclature

INNs in main languages (French, Latin, Russian, and Spanish):

Synonyms: Fusidato sódico; Nátrium-fuzidát; Natrii Fusidas; Natrio fuzidatas; Natrium-fusidát; Natriumfusidaatti; Natriumfusidat; SQ-16360
BAN: Sodium Fusidate [BANM]
USAN: Fusidate Sodium
INN: Sodium Fusidate [rINNM (en)]
INN: Fusidato sódico [rINNM (es)]
INN: Fusidate de Sodium [rINNM (fr)]
INN: Natrii Fusidas [rINNM (la)]
INN: Натрий Фэузидат [rINNM (ru)]
Molecular formula: C31H47NaO6 =538.7
CAS: 751-94-0
ATC code: D06AX01; D09AA02; J01XC01; S01AA13
Read code: y02QO; y07jL

Pharmacopoeias. In Europe and Japan. European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Sodium Fusidate). A white or almost white, slightly hygroscopic, crystalline powder. Freely soluble in water and in alcohol. A 1.25% solution in water has a pH of 7.5 to 9.0. Store in airtight containers at a temperature of 2° to 8°. Protect from light. Incompatibility. UK licensed product information states that reconstituted sodium fusidate injection is incompatible with infusion solutions containing glucose 20% or more, lipid infusions, and peritoneal dialysis fluids; precipitation may occur in solutions with a pH of less than 7.4.

Adverse Effects and Precautions

Apart from mild gastrointestinal upsets, fusidic acid or sodium fusidate appear to be well tolerated when given orally. Treatment with fusidates, orally or especially by the intravenous route, has been associated with jaundice and changes in liver function; normal liver function is usually restored when treatment is stopped.

Therefore, fusidates should be given with caution to patients with hepatic impairment, and periodic monitoring of hepatic function is recommended in these patients and in those receiving high or prolonged oral doses. Caution is also required in biliary disease or biliary obstruction.

Venospasm, thrombophlebitis, and haemolysis have occurred in patients given fosidates intravenously. To reduce this it is recommended that solutions be buffered and that the solution should be given as a slow infusion into a large vein where there is a good blood flow. Hypocalcaemia has occurred after use of intravenous doses above those recommended, and has been attributed to the phosphate-citrate buffer in the preparation.

Intramuscular or subcutaneous use may lead to tissue necrosis and is contra-indicated. Hypersensitivity reactions in the form of rashes and irritation may occur with topical fusidates; rash is rare after systemic use. Fusidic acid competes with bilirubin for binding to albumin in vitro and caution has been advised if it is given to premature, jaundiced, acidotic, or seriously-ill neonates because of the risk of kernicterus.

Effects on the blood

There have been occasional reports of granulocytopenia and thrombocytopenia after the use of fusidic acid systemically. Sideroblastic anaemia has also been reported. UK licensed product information also states that there have been isolated cases of neutropenia, agranulocytosis, and pancytopenia.

Interactions

Although the exact metabolic pathways of fusidic acid are not known, an interaction has been suspected with drugs metabolised by the hepatic cytochrome P450 isoenzyme CYP3A4, and UK licensed product information suggests avoiding their use with fusidic acid.

Antivirals

An HIV-infected patient had fusidic acid toxicity after taking fusidic acid orally for one week with his usual antiretroviral treatment of ritonavir, saquinavir, and stavudine. The plasma-fusidic acid concentration was about twice that expected and the ritonavir and saquinavir concentrations were also elevated. Fusidic acid was stopped and the patient initially improved.

However, 4 days later he presented with jaundice, nausea, weakness, and further increases in liver function tests and hence all medications were stopped. The fusidic acid concentration, as well as those of ritonavir and saquinavir, were found to be still significantly elevated 6 days after fusidic acid had been stopped. The patient was able to restart his antiretroviral therapy later with no problems. The authors suggested that this interaction may be due to mutual inhibition of metabolism between the HlV-protease inhibitors and fusidic acid, and recommended that use of fusidic acid with either saquinavir or ritonavir should be avoided.

Statins

For reference to the effect of fusidic acid in patients receiving statins.

Antimicrobial Action

Fusidic acid is a steroidal antibacterial with a bacteriostatic or bactericidal activity, mainly against Gram-positive bacteria. Fusidic acid inhibits bacterial protein synthesis although, in contrast to drugs such as the macrolides or tetracyclines, it does not bind to the bacterial ribosome, but inhibits a factor necessary for translocation of peptide subunits and elongation of the peptide chain. It is capable of inhibiting protein synthesis in mammalian cells but exerts a selective action against susceptible infecting organisms because of poor penetration into the host cell. Fusidic acid is very active against staphylococci, notably Staph. aureus and Staph. epidermidis (including meticillin-resistant strains). Nocardia asteroides and many clostridial strains are also highly susceptible. The streptococci and enterococci are less susceptible.

Most Gram-negative bacteria are intrinsically resistant but fusidic acid is active against Neisseria spp. and Bacteroides fragilis. It has some activity against strains of Mycobacterium tuberculosis and is highly active against M. leprae.

Fungi are resistant, but fusidic acid has some activity against a range of protozoa including Giardia lamblia and Plasmodium falciparum. High concentrations of fusidate are reported to inhibit viral growth in vitro, including that of HIV, although it is unclear whether this represents a surfactant effect, a general cytotoxic effect, or a genuine antiviral action.

No synergy has been shown in vitro in most studies between fusidic acid and rifampicin or vancomycin, and antagonism of the effects of ciprofloxacin has been reported. Interactions with the penicillins are complex, with either antagonism of the effect of one or both drugs, or no interaction.

However, use of an antistaphylococcal penicillin with fusidic acid may prevent the emergence of fusidic acid-resistant staphylococcal mutants, and such combinations may be clinically effective. Resistance. Resistance may be chromosomally mediated, representing altered protein synthesis, or plasmid-mediated, which appears to be due to reduced penetration of active drug into the cell. For further details on the increase of resistance to fusidic acid, see below.

Fusidic Acid

Resistance

There has been an increase in the number of reports of fusidic acid resistance in Staphylococcus aureus particularly in dermatological isolates. The number of clinical isolates of initially resistant staphylococci has historically been low at about 1 to 2% overall. However, in the UK the rate of fusidic acid resistance in staphylococcal isolates increased by up to 200% during the 1990s, and over half of all isolates are resistant in some samples.

This has been attributed to the widespread topical use of fusidic acid. The rate of resistance to short courses of fusidic acid used in systemic monotherapy is reported to be about 5%. In contrast, when given systemically with other antibacterials, the rate of resistance remains low at 0.8% Therefore, it has been suggested that systemic fusidic acid should be restricted to use with other antibacterial agents where clinically indicated in order to reduce the rate of resistance.

Pharmacokinetics

Sodium fusidate is well absorbed from the gastrointestinal tract, and a single oral 500-mg dose is reported to produce mean plasma concentrations of about 30 micrograms/mL within 2 to 4 hours, although there is considerable interindividual variation. Oral suspensions of fusidic acid are less well absorbed, with a bio-availability reported to be about 70% of that for sodium fusidate.

Absorption may be delayed by food and may be more rapid in children than adults. Some accumulation occurs with repeated dosage and plasma concentrations of 100 micrograms/mL or more have been reported after 500 mg of sodium fusidate given three times daily for 4 days.

Fusidate is widely distributed into tissues and body fluids, including bone, pus, and synovial fluid; it penetrates cerebral abscesses but does not enter CSF in appreciable amounts. It has been found in the fetal circulation and in breast milk.

About 95% or more of fusidate in the circulation is bound to plasma proteins. Fusidate has a plasma half-life of about 10 to 15 hours. It is excreted in the bile, almost entirely as metabolites, some of which have weak antimicrobial activity. About 2% appears unchanged in the faeces. Little is excreted in the urine or removed by haemodialysis.

Uses and Administration

Fusidic acid and its salts are antibacterials used mainly in the treatment of staphylococcal infections, often with other drugs. They have been used in the treatment of abscess, including brain abscess, in bone and joint infections, in staphylococcal infections in patients with cystic fibrosis, in the treatment of staphylococcal endocarditis, and topically in eye infections and infections of the skin.

For details of these infections and their treatment, see under Choice of Antibacterial.

The fusidates are given orally or topically as fusidic acid or sodium fusidate, or intravenously as sodium fusidate. Sodium fusidate 1 g is equivalent to about 0.98 g of fusidic acid. Because of differences in absorption (see Pharmacokinetics, above) 250 mg of fusidic acid is therapeutically equivalent to only 175 mg of the sodium salt, so doses of fusidic acid suspension (commonly used in children) appear relatively higher (see below).

The diolamine salt was formerly used intravenously in humans but is still used in topical preparations in veterinary medicine. Sodium fusidate is given as tablets in a usual oral adult dose of 500 mg every 8 hours, although this dose may be doubled in severe infection. For cutaneous staphylococcal infections, a dose of 250 mg twice daily is suitable.

When given orally as the suspension the usual adult dose is 750 mg of fusidic acid three times daily. In severe infections in adults weighing over 50 kg, sodium fusidate 500 mg is given three times daily by slow intravenous infusion. Each 500-mg dose is usually given as a buffered solution (pH 7.4 to 7.6) diluted to 500 mL with sodium chloride or other suitable intravenous solution. For those weighing less than 50 kg, a dose of 6 to 7 mg/kg three times daily is used. For details of doses in children, see below. Sodium fusidate as a 2% ointment or medicated dressing, or fusidic acid as a 2% cream or gel, are used in the local treatment of skin infections. Eye drops containing fusidic acid 1% are used in eye infections. Topical use may lead to problems of resistance (see Antimicrobial Action, above).

Administration in children

In the UK, the licensed oral doses of fusidic acid suspension, given three times daily, are:

  • up to 1 year old: about 15 mg/kg
  • 1 to 5 years: 250 mg
  • 5 to 12 years: 500 mg
  • over 12 years: usual adult doses (see above)

Suggested doses of sodium fusidate by intravenous infusion are:

  • 1 month and above: if weighing less than 50 kg, 6 to 7 mg/kg three times daily; heavier children may be given usual adult doses (see above)

The BNFC suggests that neonates up to 1 month of age may be given an intravenous dose of 10 mg/kg every 12 hours.

Preparations

British Pharmacopoeia 2008: Fusidic Acid Cream; Fusidic Acid Eye Drops; Fusidic Acid Oral Suspension; Sodium Fusidate Ointment.

Proprietary Preparations

Argentina: Drum; Fucidin; Fucithaimic; Fusimed; Fusitop; Gelbiotic; Australia: Fucidin; Austria: Fucidin; Fucithaimic; Belgium: Fucidin; Fucithaimic; Brazil: Verutex; Canada: Fucidin; Fucithaimic; Chile: Fucidin; Fucithaimic; Czech Republic: Fucidin; Fucithaimic; Denmark: Fucidin; Fucithaimic; Finland: Fucidin; Fucithaimic; France: Fucidine; Fucithaimic; Germany: Fucidine; Fucithaimic; Greece: Flusterix; Fucidin; Hong Kong: Fucidin; Fucithaimic; Fusidate; Qualifutin; Hungary: Fucidin; Fucithaimic; India: Fusibact; Fusiwal; Indonesia: Fucidin; Fucilex; Fucithaimic; Fuladic; Fuson; Fusycom; Futaderm; Ireland: Fucidin; Fucithaimic; Israel: Fucidin; Fucithaimic; Italy: Dermomycin; Fucidin; Fucithaimic; Malaysia: Foban; Fucidin; Fucithaimic; Germacid; Mexico: Fucidin; Uniderm; The Netherlands: Fucidin; Fucithaimic; Norway: Fucidin; Fucithaimic; New Zealand: Foban; Fucidin; Fucithaimic; Philippines: Flexid; Fucidin; Fucithaimic; Hopaq; Poland: Fucidin; Portugal: Desdelc Fucidine; Fucithaimic; Fusextrine; Infloc; Nadiclox; Russia: Fucidin; Fucithaimic; South Africa: Fucidin; Fucithaimic; Singapore: Balad; Duzen; Foban; Forsuderm; Fucidin; Fucithaimic; Fudikin; Spain: Fucidine; Fucithaimic; Sweden: Fucidin; Fucithaimic; Switzerland: Fucidin; Fucithaimic; Thailand: Foban; Fucidin; Fucithaimic; Fusid; Turkey: Fucidin; Fucithaimic; Stafine; United Arab Emirates (UAE): Futasole; United Kingdom (UK): Fucidin; Fucithaimic.

Multi-ingredient

Argentina: Drum B; Fucicort; Fusimed B; Gelbiotic Plus; Austria: Fucicort; Belgium: Fucicort; Fucidin Hydrocortisone; Brazil: Verutex B; Canada: Fucidin H; Chile: Fucicort; Fucidin H; Czech Republic: Fucicort; Fucidin H; Denmark: Fucicort; Fucidin-Hydrocortison; Finland: Fucicort; Fuddin-Hydrocortison; Germany; Fucicort; Fucidine plus; Greece: Alpider; Befucil; Betacort; Betafusin; Betasid; Betfu; Fubecot; Fucicort; Fucicream; Fucidin H; Fusibet; Hydrofusin; Roseti; Sensibio; Staficort; Hong Kong; Fucicort; Fucidin H; Hungary: Fucicort; Fucidin H; Indonesia: Fucicort; Israel: Fucicort; Fucidin H; Italy: Fucicort; Fucidin H; Piodermina; Malaysia: Axcel Fusi-Corte; Foban-Hydro; Fobancort; Fucicort; Fucidin H; Fusidic B; Mexico: Fucicort; Norway: Fucidin-Hydrocortison; New Zealand: Fucicort; Philippines: Fucicort; Fucidin H; Hoebedic; Portugal: Fucicort; Fucidine H; Russia: Fucicort; Fucidin H; South Africa: Fucidin H; Singapore: Fobancort; Fucicort; Fucidin H; Spain: Fucibet; Fucidine H; Sweden: Fucidin-Hydrocortison; Switzerland: Fucicort; Fucidin H; Thailand: Fucicort; Fucidin H; UAE: Futasone; United Kingdom (UK): Fucibet; Fucidin H.

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