Fusidic Acid
An antimicrobial substance produced by the growth of certain
strains of Fusidium coccineum.
A white or almost white crystalline powder. Practically Insol-
uble in water; freely soluble in alcohol. Store at a tempera-
ture of 2Β° to 8Β°. Protect from light.
Incompatibility. The UK manufacturers state that the re-
constituted sodium fusidate injection is incompatible with in-
fusion solutions containing glucose 20% or more. and that
precipitation may occur in solutions with a pH of less than
7.4.
Adverse Effects and Precautions
Apart from mild gastro-intestinal upsets fusidic acid
or sodium fusidate appear to be well tolerated when
given by mouth. Treatment with fusidates. by mouth
or especially by the intravenous route, has been as-
sociated with jaundice and changes in liver function:
normal liver function is usually restored when treat-
ment is discontinued. Therefore, fusidates should be
given with caution to patients with impaired liver
function, and periodic monitoring of hepatic func-
tion is recommended in these patients and in those
receiving high or prolonged oral doses.
Venospasm, thrombophlebitis and haemolysis have
occurred in patients given fusidates 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 intra-
venous administration of doses above those recom-
mended, and has been attributed to the phosphate-
citrate buffer in the preparation. Intramuscular or
subcutaneous administration may lead to tissue
necrosis and is contra-indicated.
Hypersensitivity reactions in the form of rashes and
irritation may occur after the topical administration
of fusidates; rash is rare after systemic administra-
tion. Fusidic acid or its derivatives should be avoid-
ed in patients known to be hypersensitive to
fusidates.
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 possible risk of kernicter-
us.
Effects on the Mood. There have been occasional reports
of granulocytopenia and one case of thrombocytopenia
following the use of systemic doses of fusidic acid.
Antimicrobial Action
Fusidic acid is a steroidal antibiotic with a bacterio-
static or bactericidal activity mainly against Gram-
positive bacteria.
Mechanism of action. 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 neces-
sary for translocation of peptide subunits and elon-
gation of the peptide chain. It is capable of inhibiting
protein synthesis in mammalian cells but exerts a se-
lective action against susceptible infecting organ-
isms because of poor penetration into the host cell.
Spectrum of activity. Fusidic acid is very active
against staphylococci. notably Staph. aureus and
Staph. epidermidis (including methicillin-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 resist-
ant but fusidic acid is active against Neisseria spp.
and Bacteroides fragilis. It has some activity against
strains of Mycobacterium tuberculosis and M. lep-
rae.
Fungi are resistant, but fusidic acid has some activi-
ty against a range of protozoa including Giardia
lambia and Plasmodium falciparum. High concen-
trations 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 ac-
tion.
Minimum inhibitory concentrations (MICs) for sus-
ceptible Staph. aureus isolates are reported to range
from about 0.03 to O.I ng per mL; up to 16 iig per
mL may be required to inhibit streptococci. The ac-
tivity is reduced in the presence of protein. Fusidic
acid is bactericidal for many strains at concentra-
tions close to the MIC, but in most methicillin-re-
sistant Staph. aureus the ratio of the bactericidal to
the inhibitory concentration is much greater.
Activity with other antimicrobials. No synergy has
been demonstrated in vitro in most studies between
fusidic acid and rifampicin or vancomycin, and an-
tagonism of the effects of ciprofloxacin has been re-
ported. Interactions with the penicillins are
complex, with either antagonism of the effect of one
or both drugs, or no interaction. However, the com-
bination of an antistaphylococcal penicillin with fu-
sidic acid may prevent the emergence of fusidic
acid-resistant staphylococcal mutants, and such
combinations may be clinically effective.
Resistance. Resistant strains of staphylococci are
readily selected in vitro, and occasionally during
therapy, but the number of clinical isolates that are
initially resistant remains relatively low at about I to
2% overall, despite widespread topical use. Resist-
ance 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.
Pharmacokinetics
Sodium fusidate is well absorbed from the gastro
intestinal tract, and a single 500-mg dose is reported
to produce mean plasma concentrations of about
30 ng per mL 2 to 4 hours after administration, al
though there is considerable interindividual varia
tion. Oral suspensions of fusidic acid are less well
absorbed, and a 500-mg dose of such a suspension is
reported to produce peak plasma concentrations of
about 23 ng per mL. Absorption may be delayed by
food, but may be more rapid in children than adults
Some accumulation occurs with repeated adminis
tration and plasma concentrations of 100 ng per ml
or more have been reported following 500 mg of so
dium fusidate 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 fe-
tal circulation and in breast milk. About 95% or
more of fusidate in the circulation is bound to plas-
ma protein.
Fusidate has a plasma half-life that has been vari-
ously reported as 5 to 6 and 10 to 15 hours. It is ex-
creted 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 antibiotics used mainly
in the treatment of staphylococcal infections, often
in conjunction with other drugs. They have been
used in the treatment of abscess, including brain ab-
scess. in bone and joint infections, in staphylococcal
infections in patients with cystic fibrosis,
in the treatment of staphylococcal endocarditis, and topi-
cally in eye infections and infections of the skin.
Administration and dosage. The fusidates are given
by mouth or topically as fusidic acid or sodium fusi-
date, or intravenously as sodium fusidate. The dieth-
anolamine salt has also been used intravenously.
Sodium fusidate is administered as tablets in
usual dose of 500 mg by mouth every 8 hours, although
this dose may be doubled in severe infection. Be-
cause of differences in absorption (see Phannacoki-
netics, above) 250 mg of fusidic acid is
therapeutically equivalent to only 175 mg of the so-
dium salt, so doses of fusidic acid suspension appear
relatively higher. Suggested doses are: up to I year,
50 mg per kg body-weight daily in 3 divided doses;
1 to 5 years, 250 mg three times daily; 5 to 12 years.
500 mg three times daily: over 12 years. 750 mg
three times daily.
In severe infections sodium fusidate 500 mg is given
three times daily by slow intravenous infusion. Each
500-mg dose is usually administered as a buffered
solution (pH 7.4 to 7.6) diluted to 500 mL with so-
dium chloride or other suitable intravenous solution.
For children and adults weighing less than 50 kg a
dose of 6 to 7 mg per kg body-weight three times
daily is recommended.
Sodium fusidate as an ointment (2%) or medicated
dressing, or fusidic acid as a cream or gel (2%), are
used in the local treatment of skin infections. A ster-
ile gel of fusidic acid (2%) has been used for the
treatment of abscesses and 1% eye drops of fusidic
acid may be used in eye infections. Topical use may
lead to problems of resistance.