Fusidic acid

Fusidic acid
Names
Trade namesFucidin, Fucithalmic, Stafine
Other namesSodium fusidate
IUPAC name
  • 2-[(1S,2S,5R,6S,7S,10S,11S,13S,14Z,15R,17R)-13-(acetyloxy)-5,17-dihydroxy-2,6,10,11-tetramethyltetracyclo[8.7.0.02,7.011,15]heptadecan-14-ylidene]-6-methylhept-5-enoic acid
Clinical data
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
External links
AHFS/Drugs.comMicromedex Detailed Consumer Information
Legal
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetics
Bioavailability91% oral bioavailability
Protein binding97 to 99%
Elimination half-lifeApproximately 5 to 6 hours in adults
Chemical and physical data
FormulaC31H48O6
Molar mass516.719 g·mol−1
3D model (JSmol)
SMILES
  • O=C(O)/C(=C3/[C@@H]2C[C@@H](O)[C@H]1[C@@]4(C)CC[C@@H](O)[C@@H](C)[C@@H]4CC[C@@]1([C@]2(C[C@@H]3OC(=O)C)C)C)CC\C=C(/C)C
InChI
  • InChI=1S/C31H48O6/c1-17(2)9-8-10-20(28(35)36)26-22-15-24(34)27-29(5)13-12-23(33)18(3)21(29)11-14-30(27,6)31(22,7)16-25(26)37-19(4)32/h9,18,21-25,27,33-34H,8,10-16H2,1-7H3,(H,35,36)/b26-20-/t18-,21-,22-,23+,24+,25-,27-,29-,30-,31-/m0/s1 checkY
  • Key:IECPWNUMDGFDKC-MZJAQBGESA-N checkY

Fusidic acid, sold under the brand names Fucidin among others, is an antibiotic that is often used topically in creams and eyedrops but may also be given systemically as tablets or injections.
As of October 2008, the global problem of advancing antimicrobial resistance has led to a renewed interest in its use.[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, 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]

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).[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]

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

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,[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]


  • Fucidin (of Leo in Canada)
  • Fucidin H (topical cream with hydrocortisone - Leo)
  • Fucidin (of Leo in UK/ Leo-Ranbaxy-Croslands in India)
  • Fucidine (of Leo in France)
  • Fucidin (of Leo in Norway and Israel)
  • Fucidin (of Adcock Ingram, licensed from Leo, in South Africa)
  • Fucithalmic (of Leo in the UK, the Netherlands, Denmark and Portugal)
  • Fucicort (topical mixture with hydrocortisone)
  • Fucibet (fusidic acid/betamethasone valerate topical cream)
  • Ezaderm (topical mixture with betamethasone)(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 (fusidic acid/betamethasone valerate topical cream in Greece)
  • Betafucin (2% fusidic acid/1% betamethasone valerate topical cream in Egypt)(of Delta Pharma S.A.E., A.R.E. (Egypt))
  • Fusimax (of Roussette in India)
  • Fusiderm (topical cream and ointment by Indi Pharma in India)
  • Fusid (in Nepal)
  • Fudic (topical cream in India)
  • Fucidin (후시딘, of Donghwa Pharm in South Korea)
  • Dermy (Topical cream of W. Woodwards in Pakistan)
  • Fugen Cream (膚即淨軟膏 in Taiwan)
  • Phudicin Cream (in China; 夫西地酸[34])
  • Fucidin Fusidic Acid (in China;夫西地酸 of Leo Laoratories Limited)
  • Dermofucin cream, ointment and gel (in Jordan)
  • Optifucin viscous eye drops (of API in Jordan)
  • Verutex (of Roche in Brazil)
  • Taksta (of Cempra in U.S. For export only in US)
  • Futasole (of Julphar in Gulf and north Africa)
  • Stanicid (2% ointment of Hemofarm in Serbia)
  • Staphiderm Cream (Israel By Trima).
  • Fuzidin (tablets of Biosintez in Russia)
  • 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

  1. ↑ Falagas ME, Grammatikos AP, Michalopoulos A (October 2008). "Potential of old-generation antibiotics to address current need for new antibiotics". Expert Review of Anti-Infective Therapy. 6 (5): 593–600. doi:10.1586/14787210.6.5.593. PMID 18847400. S2CID 13158593.
  2. ↑ Leclercq R, Bismuth R, Casin I, Cavallo JD, Croizé J, Felten A, et al. (January 2000). "In vitro activity of fusidic acid against streptococci isolated from skin and soft tissue infections". The Journal of Antimicrobial Chemotherapy. 45 (1): 27–29. doi:10.1093/jac/45.1.27. PMID 10629009.
  3. 1 2 3 4 Moriarty SR, Clark K, Scott D, Degenhardt TP, Fernandes P, Craft JC, Corey GR, Still JG and Das A (2010). 50th Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract L1-1762
  4. ↑ Bodley, James W.; Zieve, Franklin J.; Lin, Lillian; Zieve, Sandra T. (1969-10-22). "Formation of the ribosome-G factor-GDP complex in the presence of fusidic acid". Biochemical and Biophysical Research Communications. 37 (3): 437–443. doi:10.1016/0006-291X(69)90934-6. ISSN 0006-291X. PMID 4900137. Archived from the original on 2023-07-01. Retrieved 2023-05-10.
  5. ↑ Gao YG, Selmer M, Dunham CM, Weixlbaumer A, Kelley AC, Ramakrishnan V (October 2009). "The structure of the ribosome with elongation factor G trapped in the posttranslocational state". Science. 326 (5953): 694–699. Bibcode:2009Sci...326..694G. doi:10.1126/science.1179709. PMC 3763468. PMID 19833919.
  6. ↑ Seo HS, Abedin S, Kamp D, Wilson DN, Nierhaus KH, Cooperman BS (February 2006). "EF-G-dependent GTPase on the ribosome. conformational change and fusidic acid inhibition". Biochemistry. 45 (8): 2504–2514. doi:10.1021/bi0516677. PMID 16489743.
  7. ↑ Savelsbergh A, Rodnina MV, Wintermeyer W (May 2009). "Distinct functions of elongation factor G in ribosome recycling and translocation". RNA. 15 (5): 772–780. doi:10.1261/rna.1592509. PMC 2673078. PMID 19324963.
  8. ↑ Existing drug will cure hospital superbug MRSA, say scientists – The Guardian, 17 January 2007 Archived 9 February 2018 at the Wayback Machine.Accessed 2008-01-17.
  9. ↑ O'Neill AJ, Chopra I (August 2004). "Preclinical evaluation of novel antibacterial agents by microbiological and molecular techniques". Expert Opinion on Investigational Drugs. 13 (8): 1045–1063. doi:10.1517/13543784.13.8.1045. PMID 15268641. S2CID 24016698.
  10. ↑ Spelman D (August 1999). "Fusidic acid in skin and soft tissue infections". International Journal of Antimicrobial Agents. 12 (Suppl 2): S59–S66. doi:10.1016/s0924-8579(98)00074-0. PMID 10528787.
  11. ↑ "Fusidic Acid and Acne Vulgaris". ScienceOfAcne.com. 2011-09-11. Archived from the original on 2012-11-02. Retrieved 2012-08-14.
  12. ↑ Sommer S, Bojar R, Cunliffe WJ, Holland D, Holland KT, Naags H (September 1997). "Investigation of the mechanism of action of 2% fusidic acid lotion in the treatment of acne vulgaris". Clinical and Experimental Dermatology. 22 (5): 211–215. doi:10.1046/j.1365-2230.1997.2530670.x. PMID 9536540.
  13. 1 2 Howden BP, Grayson ML (February 2006). "Dumb and dumber--the potential waste of a useful antistaphylococcal agent: emerging fusidic acid resistance in Staphylococcus aureus". Clinical Infectious Diseases. 42 (3): 394–400. doi:10.1086/499365. PMID 16392088.
  14. ↑ Wolfe, CR (2011) Case report: treatment of chronic osteomyelitis. Clinical Infectious Diseases 52(Supplement 7): S538-S541
  15. ↑ Mason BW, Howard AJ, Magee JT (April 2003). "Fusidic acid resistance in community isolates of methicillin-susceptible Staphylococcus aureus and fusidic acid prescribing". The Journal of Antimicrobial Chemotherapy. 51 (4): 1033–1036. doi:10.1093/jac/dkg190. PMID 12654748.
  16. ↑ "Fucidin data sheet". New Zealand Government. December 2005. Archived from the original on 2007-10-26.
  17. ↑ "Fucidin UK data sheet". Electronic Medicines Compendium. June 1997. Archived from the original on 2008-06-11.
  18. ↑ "Fucidin patient information leaflet" (PDF). Government of Victoria, Australia. Archived from the original (PDF) on 2011-07-20.
  19. ↑ Castanheira M, Watters AA, Bell JM, Turnidge JD, Jones RN (September 2010). "Fusidic acid resistance rates and prevalence of resistance mechanisms among Staphylococcus spp. isolated in North America and Australia, 2007-2008". Antimicrobial Agents and Chemotherapy. 54 (9): 3614–3617. doi:10.1128/aac.01390-09. PMC 2934946. PMID 20566766.
  20. ↑ Pfaller MA, Castanheira M, Sader HS, Jones RN (March 2010). "Evaluation of the activity of fusidic acid tested against contemporary Gram-positive clinical isolates from the USA and Canada". International Journal of Antimicrobial Agents. 35 (3): 282–287. doi:10.1016/j.ijantimicag.2009.10.023. PMID 20036520.
  21. ↑ Castanheira M, Mendes RE, Rhomberg PR and Jones RN (2010). Activity of fusidic acid tested against contemporary Staphylococcus aureus collected from United States hospitals. Infectious Diseases Society of America, 48th Annual Meeting, Abstract 226.
  22. ↑ Turnidge J, Collignon P (August 1999). "Resistance to fusidic acid". International Journal of Antimicrobial Agents. 12 (Suppl 2): S35–S44. doi:10.1016/S0924-8579(98)00072-7. PMID 10528785.
  23. ↑ Besier S, Ludwig A, Brade V, Wichelhaus TA (January 2003). "Molecular analysis of fusidic acid resistance in Staphylococcus aureus". Molecular Microbiology. 47 (2): 463–469. doi:10.1046/j.1365-2958.2003.03307.x. PMID 12519196. S2CID 31240369.
  24. ↑ Rennie RP (2006). "Susceptibility of Staphylococcus aureus to fusidic acid: Canadian data". Journal of Cutaneous Medicine and Surgery. 10 (6): 277–280. doi:10.2310/7750.2006.00064. PMID 17241597. S2CID 22919577.
  25. ↑ Castanheira M, Watters AA, Mendes RE, Farrell DJ, Jones RN (July 2010). "Occurrence and molecular characterization of fusidic acid resistance mechanisms among Staphylococcus spp. from European countries (2008)". The Journal of Antimicrobial Chemotherapy. 65 (7): 1353–1358. doi:10.1093/jac/dkq094. PMID 20430787.
  26. ↑ McLaws FB, Larsen AR, Skov RL, Chopra I, O'Neill AJ (March 2011). "Distribution of fusidic acid resistance determinants in methicillin-resistant Staphylococcus aureus". Antimicrobial Agents and Chemotherapy. 55 (3): 1173–1176. doi:10.1128/AAC.00817-10. PMC 3067117. PMID 21149625.
  27. ↑ Castanheira M, Watters AA, Bell JM, Turnidge JD, Jones RN (September 2010). "Fusidic acid resistance rates and prevalence of resistance mechanisms among Staphylococcus spp. isolated in North America and Australia, 2007-2008". Antimicrobial Agents and Chemotherapy. 54 (9): 3614–3617. doi:10.1128/AAC.01390-09. PMC 2934946. PMID 20566766.
  28. ↑ O'Neill AJ, McLaws F, Kahlmeter G, Henriksen AS, Chopra I (May 2007). "Genetic basis of resistance to fusidic acid in staphylococci". Antimicrobial Agents and Chemotherapy. 51 (5): 1737–1740. doi:10.1128/AAC.01542-06. PMC 1855526. PMID 17325218.
  29. ↑ O'Neill AJ, Larsen AR, Henriksen AS, Chopra I (September 2004). "A fusidic acid-resistant epidemic strain of Staphylococcus aureus carries the fusB determinant, whereas fusA mutations are prevalent in other resistant isolates". Antimicrobial Agents and Chemotherapy. 48 (9): 3594–3597. doi:10.1128/AAC.48.9.3594-3597.2004. PMC 514786. PMID 15328136.
  30. ↑ Cox G, Thompson GS, Jenkins HT, Peske F, Savelsbergh A, Rodnina MV, et al. (February 2012). "Ribosome clearance by FusB-type proteins mediates resistance to the antibiotic fusidic acid". Proceedings of the National Academy of Sciences of the United States of America. 109 (6): 2102–2107. Bibcode:2012PNAS..109.2102C. doi:10.1073/pnas.1117275109. PMC 3277530. PMID 22308410.
  31. ↑ Pushkin R, Iglesias-Ussel MD, Keedy K, MacLauchlin C, Mould DR, Berkowitz R, et al. (December 2016). "A Randomized Study Evaluating Oral Fusidic Acid (CEM-102) in Combination With Oral Rifampin Compared With Standard-of-Care Antibiotics for Treatment of Prosthetic Joint Infections: A Newly Identified Drug-Drug Interaction". Clinical Infectious Diseases. 63 (12): 1599–1604. doi:10.1093/cid/ciw665. PMID 27682068.
  32. ↑ Riegel, Ralph (2008-08-08). "Man died after rare medical reaction to cholesterol drug". Irish Independent. Archived from the original on 2012-10-11. Retrieved 2023-05-10.
  33. ↑ "Systemic fusidic acid and interaction with statins". gov.uk. Archived from the original on 2023-05-10. Retrieved 2023-05-10.
  34. ↑ "奥络说明书, 奥络疗效,作用机制,副作用--广州皮肤病专科药房". Archived from the original on 2011-07-07. Retrieved 2010-09-28.
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