Fusidic acid

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, and Corynebacterium species. Fusidic acid inhibits bacterial translation and does not kill the bacteria, and is therefore termed "bacteriostatic".

Fusidic acid is a true 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. 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. Many strains of MRSA remain sensitive to fusidic acid, but, because there is a low genetic barrier to drug resistance (a single point mutation is all that is required), fusidic acid must 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. An orally-administered mono-therapy with a high loading dose is under development in the United States.

Topical fusidic acid is occasionally used as a treatment for acne vulgaris. As a treatment for acne, fusidic acid is often partially effective at improving acne symptoms. 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. Fusidic acid is also found in several additional topical skin and eye preparations (e.g. Fucibet), although its use for these purposes is controversial.

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.

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. The use of topical preparations (skin creams and eye ointments) containing fusidic acid is strongly associated with the development of resistance, and there are voices advocating against the continued use of fusidic acid monotherapy in the community. 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. 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.

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.

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. 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

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. 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.

Some bacteria also mediate resistance via the fusB gene, which is carried on a plasmid; the mechanism by which fusB causes resistance is unknown.

Interactions

Fusidic acid should not be used with quinolones, with which they are antagonistic. When combined with rifampicin, the action of fusidic acid is additive or synergistic.
It has been reported on August 8, 2008, that the Irish Medicines Board was investigating the death of a 59-year-old Irish man who developed rhabdomyolysis after combining Lipitor and Fusidic Acid, and three similar cases. In August, 2011, the UK's Medicines and Healthcare products Regulatory Agency issued a Drug Safety Update warning that "Systemic fusidic acid (Fucidin) should not be given with statins because of a risk of serious and potentially fatal rhabdomyolysis. "

It is delivered as an ointment, as a cream, as eye drops, or in tablet form.

Trade names and preparations