Fusidic acid

Fusidic acid is an antibiotic that is often used topically in creams and eyedrops but may also be given
systemically as tablets or injections. The global problem of advancing antimicrobial resistance has led to
a renewed interest in its use recently.[1]

Pharmacology

Fusidic acid acts as a bacterial protein synthesis inhibitor by preventing the turnover of elongation factor
G (EF-G) from the ribosome. Fusidic acid is effective primarily on Gram-positive bacteria such as
Staphylococcus species, Streptococcus species,[2] and Corynebacterium species. Fusidic acid inhibits
bacterial translation and does not kill the bacteria, and is therefore termed "bacteriostatic".

Fusidic acid is an antibiotic, derived from the fungus Fusidium coccineum and was developed by Leo
Pharma in Ballerup, Denmark and released for clinical use in the 1960s. It has also been isolated from
Mucor ramannianus and Isaria kogana. The drug is licensed for use as its sodium salt sodium fusidate,
and it is approved for use under prescription in South Korea, Japan, UK, Canada, Europe, Australia, New
Zealand, Thailand, India and Taiwan. A different oral dosing regimen, based on the compound's
pharmacokinetic/pharmacodynamic (PK-PD) profile is in clinical development in the U.S.[3] as Taksta.

Uses

Fusidic acid is active in vitro against Staphylococcus aureus, most coagulase-positive staphylococci, Beta-
hemolytic streptococci, Corynebacterium species, and most clostridium species. Fusidic acid has no
known useful activity against enterococci or most Gram-negative bacteria (except Neisseria, Moraxella,
Legionella pneumophila, and Bacteroides fragilis). Fusidic acid is active in vitro and clinically against
Mycobacterium leprae but has only marginal activity against Mycobacterium tuberculosis.

One important clinical use of fusidic acid is its activity against methicillin-resistant Staphylococcus aureus
(MRSA).[4] Although many strains of MRSA remain sensitive to fusidic acid, there is a low genetic barrier
to drug resistance (a single point mutation is all that is required), fusidic acid should never be used on its
own to treat serious MRSA infection and should be combined with another antimicrobial such as
rifampicin when administering oral or topical dosing regimens approved in Europe, Canada, and
elsewhere. However, resistance selection is low when pathogens are challenged at high drug exposure.
[5] An orally-administered mono-therapy with a high loading dose is under development in the United
States.[3]

Topical fusidic acid is occasionally used as a treatment for acne vulgaris.[6] As a treatment for acne,
fusidic acid is often partially effective at improving acne symptoms.[7] However, research studies have
indicated that fusidic acid is not as highly active against Propionibacterium acnes as many other
antibiotics that are commonly used as acne treatments.[8] Fusidic acid is also found in several additional
topical skin and eye preparations (e.g. Fucibet), although its use for these purposes is controversial.[9]
Fusidic acid is being tested for indications beyond skin infections. There is evidence from compassionate
use cases that fusidic acid may be effective in the treatment of patients with prosthetic joint-related
chronic osteomyelitis.[10]

Dose

Fusidic acid should not be used on its own to treat S. aureus infections when used at low drug dosages.
However, it may be possible to use fusidic acid as monotherapy when used at higher doses.[3] The use of
topical preparations (skin creams and eye ointments) containing fusidic acid is strongly associated with
the development of resistance,[11] and there are voices advocating against the continued use of fusidic
acid monotherapy in the community.[9] Topical preparations used in Europe often contain fusidic acid
and gentamicin in combination, which helps to prevent the development of resistance.

Depending on the reason for which sodium fusidate is prescribed, the adult dose can be 250 mg twice a
day and or up to 750 mg three times a day. (Skin conditions normally need the smaller dose). It is
available in tablet and suspension form.[12] A oral dosing regimen is in clinical development in the U.S.
based on the pharmacokinetic/pharmacodynamic profile of the compound. It incorporates a dose of
1,500 mg twice on the first day followed by 600 mg twice-daily. It has been demonstrated in an in vitro
model to have a low potential for selection of resistant organisms.[3]

There is an intravenous preparation available, but it is irritant to veins, causing phlebitis. Most people
absorb the drug extremely well after taking it orally, so, if a patient can swallow, there is not much need
to administer it intravenously, even if used to treat endocarditis (infection of the heart chambers).

Cautions

There is inadequate evidence of safety in human pregnancy. Animal studies and many years of clinical
experience suggest that fusidic acid is devoid of teratogenic effects (birth defects), but fusidic acid can
cross the placental barrier.[13]

Side-effects

Fucidin tablets and suspension, whose active ingredient is sodium fusidate, occasionally cause liver
upsets, which can produce jaundice (yellowing of the skin and the whites of the eyes). This condition will
almost always get better after the patient finishes taking Fucidin tablets or suspension. Other related
side-effects include dark urine and lighter-than-usual feces. These, too, should normalize when the
course of treatment is completed.[14] Patients taking the drug should tell their doctors if they notice
these side effects.
Resistance

In vitro susceptibility studies of U.S. strains of several bacterial species such as S. aureus, including MRSA
and coagulase negative Staphylococcus, indicate potent activity against these pathogens[15][16][17]

In the UK and Australia, susceptibility is defined as a minimum inhibitory concentration (MIC) of 0.25
mg/l or 0.5 mg/l or less. Resistance is defined as an MIC of 2 mg/l or more. In laboratories using disc
diffusion methods, susceptibility for a 2.5 µg disc is defined as a zone of 22 mm or more, and resistance
is defined as a zone of 17 mm or less; intermediate values are defined as intermediate resistance. These
susceptibility criteria are based on lower dosing regimens used outside of the U.S. Clinical trials in the
U.S. incorporate a different dosing regimen that results in higher blood levels. Therefore, the U.S. dosing
regimen may warrant different susceptibility criteria.

Mechanisms of resistance have been extensively studied only in Staphylococcus aureus. The most
important mechanism is the development of point mutations in fusA, the chromosomal gene that codes
for EF-G. The mutation alters EF-G so that fusidic acid is no longer able to bind to it.[18][19] Resistance is
readily acquired when fusidic acid is used alone and commonly develops during the course of treatment.
As with most other antibiotics, resistance to fusidic acid arises less frequently when used in combination
with other drugs. For this reason, fusidic acid should not be used on its own to treat serious Staph.
aureus infections. However, at least in Canadian hospitals, data collected between 1999-2005 showed
rather low rate of resistance of MSSA and MRSA to fusidic acid, and mupirocin was found to be the more
problematic topical antibiotic for the aforementioned conditions.[20]

Some bacteria also display 'fusB-type' resistance. This resistance mechanism is mediated by fusB, fusC,
and fusD genes found on plasmids.[21] The product of fusB-type resistance genes is a 213-residue
cytoplasmic protein which interacts in a 1:1 ratio with EF-G. FusB-type proteins bind in a region distinct
from fusidic acid to induce a conformational change which results in liberation of EF-G from fusidic acid,
allowing the elongation factor to participate in another round of ribosome translocation.[22]

FusB-type resistance is common in clinical MRSA isolates and is observed in over 70% of some cohorts