Fusidic acid
Encyclopedia
Fusidic acid is a bacteriostatic 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.
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 replication 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 Laboratories 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 sodium fusidate, and it is approved for use under prescription in South Korea, Japan, UK, Canada, Europe, Australia, New Zealand, and Taiwan. A different oral dosing regimen, based on the compound's PK-PD profile is in clinical development in the U.S. as Taksta
.
against Staphylococcus aureus, most coagulase-negative 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.
Fusidic acid is often found in topical skin and eye preparations (e.g., Fucibet), a use that has been contested.
Fusidic acid is being testing 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.
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 agitating 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 front-loading 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).
(birth defects), but fusidic acid can cross the placental barrier.
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.
.
It has been reported on August 8, 2008, that the Irish Medicines Board is 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 drop
s, or in tablet
form.
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
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.
Pharmacology
Fusidic acid acts as a bacterial protein synthesis inhibitorProtein synthesis inhibitor
A protein synthesis inhibitor is a substance that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins....
by preventing the turnover of elongation factor
Elongation factor
Elongation factors are a set of proteins that facilitate the events of translational elongation, the steps in protein synthesis from the formation of the first peptide bond to the formation of the last one.Elongation is the most rapid step in translation:...
G (EF-G
EF-G
EF-G or elongation factor G is one of the prokaryotic elongation factors.-Function:The factor EF-G catalyzes the translocation of the tRNA and mRNA down the ribosome at the end of each round of polypeptide elongation. Homologous to EF-Tu + tRNA, EF-G also binds to the ribosome in its GTP-bound...
) from the ribosome
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....
. Fusidic acid is effective primarily on gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...
bacteria such as Staphylococcus
Staphylococcus
Staphylococcus is a genus of Gram-positive bacteria. Under the microscope they appear round , and form in grape-like clusters....
species, Streptococcus
Streptococcus
Streptococcus is a genus of spherical Gram-positive bacteria belonging to the phylum Firmicutes and the lactic acid bacteria group. Cellular division occurs along a single axis in these bacteria, and thus they grow in chains or pairs, hence the name — from Greek στρεπτος streptos, meaning...
species, and Corynebacterium
Corynebacterium
Corynebacterium is a genus of Gram-positive rod-shaped bacteria. They are widely distributed in nature and are mostly innocuous. Some are useful in industrial settings such as C. glutamicum. Others can cause human disease. C...
species. Fusidic acid inhibits bacterial replication 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 Laboratories in Ballerup, Denmark
Denmark
Denmark is a Scandinavian country in Northern Europe. The countries of Denmark and Greenland, as well as the Faroe Islands, constitute the Kingdom of Denmark . It is the southernmost of the Nordic countries, southwest of Sweden and south of Norway, and bordered to the south by Germany. Denmark...
and released for clinical use in the 1960s. It has also been isolated from Mucor
Mucor
Mucor is a microbial genus of about 3000 species of moulds commonly found in soil, digestive systems, plant surfaces, and rotten vegetable matter.-Description:...
ramannianus and Isaria kogana. The drug is licensed for use as sodium fusidate, and it is approved for use under prescription in South Korea, Japan, UK, Canada, Europe, Australia, New Zealand, and Taiwan. A different oral dosing regimen, based on the compound's PK-PD profile is in clinical development in the U.S. as Taksta
Taksta
Taksta is a front-loaded oral dosing regimen of sodium fusidate under development in the U.S. as an antibiotic for gram-positive infections including drug-resistant strains such as methicillin-resistant Staphylococcus aureus ....
.
Uses
Fusidic acid is active in vitroIn vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
against Staphylococcus aureus, most coagulase-negative 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
Neisseria
The Neisseria is a large genus of commensal bacteria that colonize the mucosal surfaces of many animals. Of the 11 species that colonize humans, only two are pathogens. N. meningitidis and N. gonorrhoeae often cause asymptomatic infections, a commensal-like behavior...
, Moraxella
Moraxella
Moraxella is a genus of Gram-negative bacteria in the Moraxellaceae family. It is named after the Swiss ophthalmologist Victor Morax. The organisms are short rods, coccobacilli or, as in the case of Moraxella catarrhalis, diplococci in morphology, with asaccharolytic, oxidase-positive and...
, Legionella pneumophila
Legionella pneumophila
Legionella pneumophila is a thin, ærobic, pleomorphic, flagellated, non-spore forming, Gram-negative bacterium of the genus Legionella. L. pneumophila is the primary human pathogenic bacterium in this group and is the causative agent of legionellosis or Legionnaires' disease.-Characterization:L...
, and Bacteroides fragilis
Bacteroides fragilis
Bacteroides fragilis is a Gram-negative bacillus bacterium species, and an obligate anaerobe of the gut.B. fragilis group is the most commonly isolated bacteriodaceae in anaerobic infections especially those that originate from the gastrointestinal flora. B. fragilis is the most prevalent organism...
). Fusidic acid is active in vitro and clinically against Mycobacterium leprae
Mycobacterium leprae
Mycobacterium leprae, also known as Hansen’s coccus spirilly, mostly found in warm tropical countries, is a bacterium that causes leprosy . It is an intracellular, pleomorphic, acid-fast bacterium. M. leprae is an aerobic bacillus surrounded by the characteristic waxy coating unique to mycobacteria...
but has only marginal activity against Mycobacterium tuberculosis
Mycobacterium tuberculosis
Mycobacterium tuberculosis is a pathogenic bacterial species in the genus Mycobacterium and the causative agent of most cases of tuberculosis . First discovered in 1882 by Robert Koch, M...
.
One important clinical use of fusidic acid is its activity against methicillin-resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus is a bacterium responsible for several difficult-to-treat infections in humans. It is also called multidrug-resistant Staphylococcus aureus and oxacillin-resistant Staphylococcus aureus...
. Many strains of MRSA remain sensitive to fusidic acid, but, because there is a low genetic barrier to drug resistance
Drug resistance
Drug resistance is the reduction in effectiveness of a drug such as an antimicrobial or an antineoplastic in curing a disease or condition. When the drug is not intended to kill or inhibit a pathogen, then the term is equivalent to dosage failure or drug tolerance. More commonly, the term is used...
(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
Rifampicin
Rifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ...
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.
Fusidic acid is often found in topical skin and eye preparations (e.g., Fucibet), a use that has been contested.
Fusidic acid is being testing 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.
Dosing
Fusidic acid should not be used on its own to treat S. aureusStaphylococcus aureus
Staphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...
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 agitating against the continued use of fusidic acid monotherapy in the community. Topical preparations used in Europe often contain fusidic acid and gentamicin
Gentamicin
Gentamicin is an aminoglycoside antibiotic, used to treat many types of bacterial infections, particularly those caused by Gram-negative organisms. However, gentamicin is not used for Neisseria gonorrhoeae, Neisseria meningitidis or Legionella pneumophila...
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 front-loading 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
Phlebitis
Phlebitis is an inflammation of a vein, usually in the legs.When phlebitis is associated with the formation of blood clots , usually in the deep veins of the legs, the condition is called thrombophlebitis...
. 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
Endocarditis
Endocarditis is an inflammation of the inner layer of the heart, the endocardium. It usually involves the heart valves . Other structures that may be involved include the interventricular septum, the chordae tendineae, the mural endocardium, or even on intracardiac devices...
(infection of the heart chambers).
Pregnancy caution
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 effectsTeratology
Teratology is the study of abnormalities of physiological development. It is often thought of as the study of human birth defects, but it is much broader than that, taking in other non-birth developmental stages, including puberty; and other non-human life forms, including plants.- Etymology :The...
(birth defects), but fusidic acid can cross the placental barrier.
Side-effects
- Fucidin Tablets and Suspension 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 that their urine is 'very dark', if their feces are 'very pale', or if their skin or the whites of their eyes become yellow, the Australian data sheet for patients adds.
Resistance
Because the drug is not licensed for use in the U.S., there are no Clinical and Laboratory Standards Institute standard definitions of fusidic acid resistance. However, in vitro susceptibility studies of U.S. strains of several bacterial species such as S. aureus, including MRSA and coagulase negative Stahylococcus, indicate potent activity against these pathogensIn the UK and Australia, susceptibility is defined as a minimum inhibitory concentration
Minimum inhibitory concentration
In microbiology, minimum inhibitory concentration is the lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation. Minimum inhibitory concentrations are important in diagnostic laboratories to confirm resistance of microorganisms...
(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 synergisticSynergy
Synergy may be defined as two or more things functioning together to produce a result not independently obtainable.The term synergy comes from the Greek word from , , meaning "working together".-Definitions and usages:...
.
It has been reported on August 8, 2008, that the Irish Medicines Board is investigating the death of a 59-year-old Irish man who developed rhabdomyolysis
Rhabdomyolysis
Rhabdomyolysis is a condition in which damaged skeletal muscle tissue breaks down rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure...
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
Rhabdomyolysis
Rhabdomyolysis is a condition in which damaged skeletal muscle tissue breaks down rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure...
. "
It is delivered as an ointment, as a cream
Cream (pharmaceutical)
A cream is a topical preparation usually for application to the skin. Creams for application to mucus membranes such as those of the rectum or vagina are also used. Creams may be considered pharmaceutical products as even cosmetic creams are based on techniques developed by pharmacy and...
, as eye drop
Eye drop
Eye drops are saline-containing drops used as a route to administer medication in the eye. Depending on the condition being treated, they may contain steroids, antihistamines, sympathomimetics, beta receptor blockers, parasympathomimetics, parasympatholytics, prostaglandins, non-steroidal...
s, or in tablet
Tablet
A tablet is a pharmaceutical dosage form. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose...
form.
Trade names and preparations
- Fucidin (of Leo in US)
- Fucidin (of Leo in Canada)
- Fucidin (of Leo in UK/ Leo-Ranbaxy-Croslands in India)
- Fucidine (of Leo in France)
- Fucithalmic (of Leo in the UK, the Netherlands, Denmark and Portugal)
- Fucicort (topical mixture with hydrocortisone)
- Fucibet (topical mixture with betamethasoneBetamethasoneBetamethasone is a potent glucocorticoid steroid with anti-inflammatory and immunosuppressive properties. Unlike other drugs with these effects, betamethasone does not cause water retention. It is applied as a topical cream, ointment, foam, lotion or gel to treat itching...
) - Ezaderm (topical mixture with betamethasoneBetamethasoneBetamethasone is a potent glucocorticoid steroid with anti-inflammatory and immunosuppressive properties. Unlike other drugs with these effects, betamethasone does not cause water retention. It is applied as a topical cream, ointment, foam, lotion or gel to treat itching...
)(of United Pharmaceutical "UPM" in Jordan) - Fuci (of pharopharm in Egypt)
- Fucizon (topical mixture with hydrocortisone of pharopharm in Egypt)
- Foban (topical cream in New Zealand)
- Betafusin (cream mixture with betamethasone valerate in Greece)
- Fusiderm (topical cream and ointment by indi pharma in India)
- Fusid (in Nepal)
- Fudic (topical cream in India)
- Fucidin
- Stanicid (in SerbiaSerbiaSerbia , officially the Republic of Serbia , is a landlocked country located at the crossroads of Central and Southeast Europe, covering the southern part of the Carpathian basin and the central part of the Balkans...
) - Dermy (Topical cream of W.Woodwards in Pakistan)
- Fugen Cream (in Taiwan)
- Phudicin Cream (in China; http://www.pfb.org.cn/catalog/antimicrobial/20100204085231859.htm)
- Fusimax (of schwartz)
- Dermofucin (in Jordan)
- Verutex (of Roche in Brazil)
- TAKSTATakstaTaksta is a front-loaded oral dosing regimen of sodium fusidate under development in the U.S. as an antibiotic for gram-positive infections including drug-resistant strains such as methicillin-resistant Staphylococcus aureus ....
(of Cempra in U.S.) - Futasole (of Julphar in Gulf and north Africa)
- Stanicid (2% ointment of Hemofarm in Serbia)