Fusidic acid is a
tetracyclic, naturally occurring steroid 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
sodiumsaltsodium fusidate, and it is approved for use under prescription in South Korea, Japan, Canada, the EU, Australia, New Zealand, Colombia, 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.
Mechanism of action
Fusidic acid binds to EF-G after translocation and GTP (
guanosine-5'-triphosphate) hydrolysis.[4] This interaction prevents the necessary conformational changes for EF-G release from the ribosome, effectively blocking the protein synthesis process. Fusidic acid can only bind to EF-G in the ribosome after GTP hydrolysis.[5][6]
Since translocation is a part of elongation and ribosome recycling, fusidic acid can block either or both steps of protein synthesis.[7]
One important clinical use of fusidic acid is its activity against
methicillin-resistant Staphylococcus aureus (MRSA).[8] 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.[9] 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.[10] As a treatment for acne, fusidic acid is often partially effective at improving acne symptoms.[11] However, research studies have indicated that fusidic acid is not as highly active against Cutibacterium acnes as many other antibiotics that are commonly used as acne treatments.[12] Fusidic acid is also found in several additional topical skin and eye preparations (e.g.
Fucibet), although its use for these purposes is controversial.[13]
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.[14]
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,[15] and there are voices advocating against the continued use of fusidic acid monotherapy in the community.[13] 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.[16] An 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.[17]
Side-effects
Fucidin tablets and suspension, whose active ingredient is sodium fusidate, occasionally cause liver damage, 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.[18]
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.[19][20][21]
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 studied 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.[22][23] 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 and 2005 showed rather low rate of resistance of both methicillin-susceptible and methicillin-resistant to fusidic acid, and
mupirocin was found to be the more problematic topical antibiotic for the aforementioned conditions.[24]
Some bacteria also display 'FusB-type' resistance, which has been found to be the most prevalent in Staphylococcus spp. in many clinical isolates.[25][26][27] This resistance mechanism is mediated by fusB, fusC, and fusD genes found primarily on plasmids,[28] but have also been found in chromosomal DNA.[29] 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 the ribosome, allowing the elongation factor to participate in another round of ribosome translocation.[30]
Interactions
Fusidic acid should not be used with
quinolone antibiotics, with which it is antagonistic. Although clinical practice over the past decade has supported the combination of fusidic acid and
rifampicin, a recent clinical trial showed that there is an antagonistic interaction when both antibiotics are combined.[31]
On August 8, 2008, it was reported that the Irish Medicines Board was investigating the death of a 59-year-old Irish man who developed
rhabdomyolysis after combining
atorvastatin and fusidic acid, and three similar cases.[32] 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."[33]
Fuzimet (ointment with methyluracil of Biosintez in Russia)
Axcel Fusidic Acid (2% cream and ointment of Kotra Pharma, Malaysia)
Ofusidic (eye drops produced by Orchidia pharmaceutical in Egypt
References
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