Fidaxomicin

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Fidaxomicin
Fidaxomicin.svg
Clinical data
Trade names Dificid, Dificlir
Other namesClostomicin B1, lipiarmicin, lipiarmycin, lipiarmycin A3, OPT-80, PAR 01, PAR-101, tiacumicin B
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • AU:B1
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Minimal systemic absorption [2]
Elimination half-life 11.7 ± 4.80 hours [2]
Excretion Urine (<1%), faeces (92%) [2]
Identifiers
  • 3-(((6-Deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl)oxy)-methyl)-12(R)-[(6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxo-hexopyranosyl)oxy]-11(S)-ethyl-8(S)-hydroxy-18(S)-(1(R)-hydroxyethyl)-9,13,15-trimethyloxacyclooctadeca-3,5,9,13,15-pentaene-2-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.220.590 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C52H74Cl2O18
Molar mass 1058.05 g·mol−1
3D model (JSmol)
  • CC[C@H]1/C=C(/[C@H](C/C=C/C=C(/C(=O)O[C@@H](C/C=C(/C=C(/[C@@H]1O[C@H]2[C@H]([C@H]([C@@H](C(O2)(C)C)OC(=O)C(C)C)O)O)\C)\C)[C@@H](C)O)\CO[C@H]3[C@H]([C@H]([C@@H]([C@H](O3)C)OC(=O)C4=C(C(=C(C(=C4O)Cl)O)Cl)CC)O)OC)O)\C
  • InChI=1S/C52H74Cl2O18/c1-13-30-22-26(6)33(56)18-16-15-17-31(23-66-51-45(65-12)42(61)44(29(9)67-51)69-49(64)35-32(14-2)36(53)39(58)37(54)38(35)57)48(63)68-34(28(8)55)20-19-25(5)21-27(7)43(30)70-50-41(60)40(59)46(52(10,11)72-50)71-47(62)24(3)4/h15-17,19,21-22,24,28-30,33-34,40-46,50-51,55-61H,13-14,18,20,23H2,1-12H3/b16-15+,25-19+,26-22+,27-21+,31-17+/t28-,29-,30+,33+,34+,40-,41+,42+,43+,44-,45+,46+,50-,51-/m1/s1 X mark.svgN
  • Key:ZVGNESXIJDCBKN-UUEYKCAUSA-N X mark.svgN
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Fidaxomicin, sold under the brand name Dificid (by Merck) among others, is the first member of a class of narrow spectrum macrocyclic antibiotic drugs called tiacumicins. [3] It is a fermentation product obtained from the actinomycete Dactylosporangium aurantiacum subspecies hamdenesis. [4] [5] Fidaxomicin is minimally absorbed into the bloodstream when taken orally, is bactericidal, and selectively eradicates pathogenic Clostridioides difficile with relatively little disruption to the multiple species of bacteria that make up the normal, healthy intestinal microbiota. The maintenance of normal physiological conditions in the colon may reduce the probability of recurrence of Clostridioides difficile infection. [6] [7]

Contents

It is marketed by Merck, which acquired Cubist Pharmaceuticals in 2015, and had in turn bought the originating company, Optimer Pharmaceuticals. It is used for the treatment of Clostridioides difficile infection, which is also known as Clostridioides difficile-associated diarrhea or Clostridioides difficile-associated illness (CDI), and can develop into Clostridioides difficile colitis and pseudomembranous colitis.

It is approved as a generic medication. [8]

Mechanism

Fidaxomicin binds to and prevents movement of the "switch regions" of bacterial RNA polymerase. Switch motion occurs during the opening and closing of the DNA:RNA clamp, a process that occurs throughout RNA transcription but is especially important in the opening of double-stranded DNA during the initiation of transcription. [9] It has minimal systemic absorption and a narrow spectrum of activity; it is active against Gram positive bacteria, especially clostridia. The minimal inhibitory concentration (MIC) range for C. difficile (ATCC 700057) is 0.03–0.25 μg/mL. [4]

Biosynthesis

The biosynthetic pathway of fidaxomicin, also known as tiacumicin B, was first proposed in 2011 by Zhang et al. based on the identification of and sequence analysis of the tiacumicin B tia-gene cluster. The biosynthesis begins with the formation of the core aglycone, tiacumicinone, done by a type I polyketide synthase (PKS) coded for by the tiaA1-tiaA4 genes. The PKS is composed of a loading domain and eight elongating domains. Tiacumicinone formation starts when the loading acyltransferase domain loads propionyl-CoA onto the loading acyl carrier protein (ACP) domain. The following eight modules extend and tailor the polyketide using malonyl-CoA, methylmalonyl-CoA, and ethylmalonyl-CoA. The final thioesterase domain hydrolyzes the polyketide to form the 18-membered tiacumicinone aglycone. [10] Modification to the aglycone begins with oxidation at the C(20) position by TiaP2, a cytochrome P450. This is followed by attachment of ᴅ-noviose at the OH-C(11) position by the glycotransferase TiaG1. Next, the glycotransferase TiaG2 binds ᴅ-rhamnose at the OH-C(20) position followed by the attachment of an isobutyric ester at the OH-C(4’’) position of the noviose. TiaB, which codes for another type I PKS, forms an homoorsellinic acid moiety from propionyl-CoA and three malonyl-CoA elongating units that is coupled to rhamnose at the OH-C(4’) position by the TiaF, a ketoacyl ACP synthase. This is followed by chlorination of the aryl moiety by the halogenase TiaM and methylation of the OH-C(2’) position of rhamnose by the methyltransferase TiaS5. Lastly, there is another oxidation by the cytochrome P450 TiaP1 that oxidizes at the C(18) position of the aglycone to give tiacumicin B. [11]

Biosynthetic pathway of fidaxomicin. The polyketide synthase modules and domains for the aglycone are shown above followed by the modifications that form fidaxomicin. Fidaxomicin biosynthetic pathway.gif
Biosynthetic pathway of fidaxomicin. The polyketide synthase modules and domains for the aglycone are shown above followed by the modifications that form fidaxomicin.

Clinical trials

Good results were reported by the company in 2009, from a North American Phase III clinical trial comparing it with oral vancomycin for the treatment of Clostridioides difficile infection. [12] [13] The study met its primary endpoint of clinical cure, showing that fidaxomicin was non-inferior to oral vancomycin (92.1% vs. 89.8%). In addition, the study met its secondary endpoint of recurrence: 13.3% of the subjects had a recurrence with fidaxomicin vs. 24.0% with oral vancomycin. The study also met its exploratory endpoint of global cure (77.7% for fidaxomicin vs. 67.1% for vancomycin). [14] Clinical cure was defined as patients requiring no further therapy for the treatment of C. difficile infection two days after completion of study medication. Global cure was defined as patients who were cured at the end of therapy and did not have a recurrence in the next four weeks. [15]

Fidaxomicin was shown to be as good as the standard-of-care, vancomycin, for treating Clostridioides difficile infection in a Phase III clinical trial published in February 2011. [16] The authors also reported significantly fewer recurrences of infection, a frequent problem with C. difficile, and similar drug side effects.

Based on a multicenter clinical trial, fidaxomicin was reported well tolerated in children with Clostridioides difficile–associated diarrhea and has a pharmacokinetic profile in children similar to that in adults. [17]

Regarding the high budget to spend for fidaxomicin, a systematic literature review published in 2017, showed that fidaxomicin was demonstrated to be cost-effective versus metronidazole and vancomycin in patients with Clostridioides difficile infection. [18]

Approvals and indications

On April 5, 2011, the drug won an FDA advisory panel's unanimous approval for the treatment of Clostridioides difficile infection, [19] and gained full FDA approval on May 27, 2011. [20] As of January 2020, fidaxomicin is FDA-approved for use in children aged 6 months and older for C. difficile associated diarrhea (CDAD). [21]

Adverse effects

The most common side effects reported in adults with the use of fidaxomicin include nausea, abdominal pain, vomiting, anemia, neutropenia, and gastrointestinal hemorrhage. [21] In children the most common side effects include fever, vomiting, diarrhea, constipation, abdominal pain, rash, and increased aminotransferases. [21]

Related Research Articles

<span class="mw-page-title-main">Vancomycin</span> Antibiotic medication

Vancomycin is a glycopeptide antibiotic medication used to treat certain bacterial infections. It is administered intravenously to treat complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and meningitis caused by methicillin-resistant Staphylococcus aureus. Blood levels may be measured to determine the correct dose. Vancomycin is also taken orally to treat Clostridioides difficile infections. When taken orally, it is poorly absorbed.

<span class="mw-page-title-main">Metronidazole</span> Antibiotic and antiprotozoal medication

Metronidazole, sold under the brand name Flagyl among others, is an antibiotic and antiprotozoal medication. It is used either alone or with other antibiotics to treat pelvic inflammatory disease, endocarditis, and bacterial vaginosis. It is effective for dracunculiasis, giardiasis, trichomoniasis, and amebiasis. It is an option for a first episode of mild-to-moderate Clostridioides difficile colitis if vancomycin or fidaxomicin is unavailable. Metronidazole is available orally, as a cream or gel, and by slow intravenous infusion.

<i>Clostridioides difficile</i> infection Disease caused by C. difficile bacteria

Clostridioides difficile infection, also known as Clostridium difficile infection, is a symptomatic infection due to the spore-forming bacterium Clostridioides difficile. Symptoms include watery diarrhea, fever, nausea, and abdominal pain. It makes up about 20% of cases of antibiotic-associated diarrhea. Antibiotics can contribute to detrimental changes in gut microbiota; specifically, they decrease short-chain fatty acid absorption which results in osmotic, or watery, diarrhea. Complications may include pseudomembranous colitis, toxic megacolon, perforation of the colon, and sepsis.

<span class="mw-page-title-main">Rifamycin</span> Group of antibiotics

The rifamycins are a group of antibiotics that are synthesized either naturally by the bacterium Amycolatopsis rifamycinica or artificially. They are a subclass of the larger family of ansamycins. Rifamycins are particularly effective against mycobacteria, and are therefore used to treat tuberculosis, leprosy, and mycobacterium avium complex (MAC) infections.

<span class="mw-page-title-main">Fecal microbiota transplant</span> Process of transplantation of fecal bacteria from a healthy individual into a recipient

Fecal microbiota transplant (FMT), also known as a stool transplant, is the process of transferring fecal bacteria and other microbes from a healthy individual into another individual. FMT is an effective treatment for Clostridioides difficile infection (CDI). For recurrent CDI, FMT is more effective than vancomycin alone, and may improve the outcome after the first index infection.

<span class="mw-page-title-main">Rifaximin</span> Antibiotic medication

Rifaximin, is a non-absorbable, broad spectrum antibiotic mainly used to treat travelers' diarrhea. It is based on the rifamycin antibiotics family. Since its approval in Italy in 1987, it has been licensed in over more than 30 countries for the treatment of a variety of gastrointestinal diseases like irritable bowel syndrome, and hepatic encephalopathy. It acts by inhibiting RNA synthesis in susceptible bacteria by binding to the RNA polymerase enzyme. This binding blocks translocation, which stops transcription. It is marketed under the brand name Xifaxan by Salix Pharmaceuticals.

<span class="mw-page-title-main">Oritavancin</span> Pharmaceutical drug

Oritavancin, sold under the brand name Orbactiv among others, is a semisynthetic glycopeptide antibiotic medication for the treatment of serious Gram-positive bacterial infections. Its chemical structure as a lipoglycopeptide is similar to vancomycin.

<span class="mw-page-title-main">Dalbavancin</span> Antibiotic used to treat MRSA

Dalbavancin, sold under the brand names Dalvance in the US and Xydalba in the EU among others, is a second-generation lipoglycopeptide antibiotic medication. It belongs to the same class as vancomycin, the most widely used and one of the treatments available to people infected with methicillin-resistant Staphylococcus aureus (MRSA).

<span class="mw-page-title-main">Ramoplanin</span> Antibiotic chemical

Ramoplanin (INN) is a glycolipodepsipeptide antibiotic drug derived from strain ATCC 33076 of Actinoplanes. It is effective against Gram-positive bacteria.

<span class="mw-page-title-main">Tolevamer</span> Chemical compound

Tolevamer is a medication developed to combat Clostridioides difficile associated diarrhea. It is a potassium sodium polystyrene sulfonate. It was never marketed.

<span class="mw-page-title-main">Ceftaroline fosamil</span> Chemical compound

Ceftaroline fosamil (INN), brand name Teflaro in the US and Zinforo in Europe, is a cephalosporin antibiotic with anti-MRSA activity. Ceftaroline fosamil is a prodrug of ceftaroline. It is active against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria. It retains some activity of later-generation cephalosporins having broad-spectrum activity against Gram-negative bacteria, but its effectiveness is relatively much weaker. It is currently being investigated for community-acquired pneumonia and complicated skin and skin structure infection.

Bezlotoxumab, sold under the brand name Zinplava, is a human monoclonal antibody designed for the prevention of recurrence of Clostridioides difficile infections. Bezlotoxumab binds to Clostridioides difficile toxin B.

<span class="mw-page-title-main">Rifalazil</span> Antibiotic

Rifalazil is an antibiotic substance that kills bacterial cells by blocking off the β-subunit in RNA polymerase. Rifalazil is used as a treatment for many different diseases. The most common are Chlamydia infection, Clostridioides difficile associated diarrhea (CDAD), and tuberculosis (TB). Using rifalazil and the effects that coincide with taking rifalazil for treating a bacterial disease vary from person to person, as does any drug put into the human body. Food interactions and genetic variation are a few causes for the variation in side effects from the use of rifalazil. Its development was terminated in 2013 due to severe side effects.

<span class="mw-page-title-main">Cadazolid</span> Chemical compound

Cadazolid is an experimental antibiotic of the oxazolidinone class made by Actelion Pharmaceuticals Ltd. which is effective against Clostridioides difficile, a major cause of drug resistant diarrhea in the elderly. Current drug treatments for this infection involve orally delivered antibiotics, principally fidaxomicin, metronidazole and vancomycin; the last two drugs are the principal therapeutic agents in use, but fail in approximately 20 to 45% of the cases. The drug works by inhibiting the synthesis of proteins in the bacteria, thus inhibiting the production of toxins and the formation of spores. Cadazolid progressed through to Phase III clinical trials, but in its financial results for Q1 2018, Idorsia mentions that Actelion informed them that "following completion of Phase 3 data analysis of cadazolid - it has decided to discontinue the development of the compound."

<span class="mw-page-title-main">Surotomycin</span> Investigational oral antibiotic

Surotomycin was an investigational oral antibiotic. This macrolide antibiotic was under investigation by Merck & Co for the treatment of life-threatening diarrhea, commonly caused by the bacterium Clostridioides difficile. After reaching phase III in clinical trials, its production was discontinued in 2017 due to its non-superiority to current therapies.

Bacteriotherapy is the purposeful use of bacteria or their products in treating an illness. Forms of bacteriotherapy include the use of probiotics, microorganisms that provide health benefits when consumed; fecal matter transplants (FMT) /intestinal microbiota transplant (IMT), the transfer of gut microorganisms from the fecal matter of healthy donors to recipient patients to restore microbiota; or synbiotics which combine prebiotics, indigestible ingredients that promote growth of beneficial microorganisms, and probiotics. Through these methods, the gut microbiota, the community of 300-500 microorganism species that live in the digestive tract of animals aiding in digestion, energy storage, immune function and protection against pathogens, can be recolonized with favorable bacteria, which in turn has therapeutic effects.

<i>Clostridioides difficile</i> Species of bacteria

Clostridioides difficile is a bacterium known for causing serious diarrheal infections, and may also cause colon cancer. It is known also as C. difficile, or C. diff, and is a Gram-positive species of spore-forming bacteria. Clostridioides spp. are anaerobic, motile bacteria, ubiquitous in nature and especially prevalent in soil. Its vegetative cells are rod-shaped, pleomorphic, and occur in pairs or short chains. Under the microscope, they appear as long, irregular cells with a bulge at their terminal ends. Under Gram staining, C. difficile cells are Gram-positive and show optimum growth on blood agar at human body temperatures in the absence of oxygen. C. difficile is catalase- and superoxide dismutase-negative, and produces up to three types of toxins: enterotoxin A, cytotoxin B and Clostridioides difficile transferase. Under stress conditions, the bacteria produce spores that are able to tolerate extreme conditions that the active bacteria cannot tolerate.

<span class="mw-page-title-main">Ridinilazole</span> Chemical compound

Ridinilazole is an investigational small molecule antibiotic being evaluated for oral administration to treat Clostridioides difficile infection (CDI). In vitro, it is bactericidal against C. difficile and suppresses bacterial toxin production; the mechanism of action is thought to involve inhibition of cell division. It has properties which are desirable for the treatment of CDI, namely that it is a narrow-spectrum antibiotic which exhibits activity against C. difficile while having little impact on other normal intestinal flora and that it is only minimally absorbed systemically after oral administration. At the time ridinilazole was developed, there were only three antibiotics in use for treating CDI: vancomycin, fidaxomicin, and metronidazole. The recurrence rate of CDI is high, which has spurred research into other treatment options with the aim to reduce the rate of recurrence.

Fecal microbiota, sold under the brand name, Rebyota is used for the prevention of recurrence of Clostridioides difficile infection.

Live fecal microbiota spores, sold under the brand name Vowst, is a fecal microbiota product used to prevent the recurrence of Clostridioides difficile infection.

References

  1. ↑ "Dificlir EPAR". European Medicines Agency (EMA). September 17, 2018. Retrieved January 18, 2021.
  2. 1 2 3 "Dificid" (PDF). TGA eBusiness Services. Specialised Therapeutics Australia Pty Ltd. April 23, 2013. Retrieved March 31, 2014.
  3. ↑ Revill P, Serradell N, Bolos J (2006). "Tiacumicin B". Drugs of the Future. 31 (6): 494. doi:10.1358/dof.2006.031.06.1000709.
  4. 1 2 "Dificid- fidaxomicin tablet, film coated Dificid- fidaxomicin granule, for suspension". DailyMed. February 18, 2020. Retrieved March 26, 2020.
  5. ↑ "Fidaxomicin: Difimicin; Lipiarmycin; OPT 80; OPT-80; PAR 101; PAR-101". Drugs in R&D. 10 (1): 37–45. 2012. doi:10.2165/11537730-000000000-00000. PMC   3585687 . PMID   20509714.
  6. ↑ Louie TJ, Emery J, Krulicki W, Byrne B, Mah M (January 2009). "OPT-80 eliminates Clostridium difficile and is sparing of bacteroides species during treatment of C. difficile infection". Antimicrobial Agents and Chemotherapy. 53 (1): 261–263. doi:10.1128/AAC.01443-07. PMC   2612159 . PMID   18955523.
  7. ↑ Johnson S (June 2009). "Recurrent Clostridium difficile infection: a review of risk factors, treatments, and outcomes". The Journal of Infection. 58 (6): 403–410. doi:10.1016/j.jinf.2009.03.010. PMID   19394704.
  8. ↑ "First-Time Generic Drug Approvals 2024". U.S. Food and Drug Administration (FDA). March 8, 2024. Retrieved March 9, 2024.
  9. ↑ Srivastava A, Talaue M, Liu S, Degen D, Ebright RY, Sineva E, et al. (October 2011). "New target for inhibition of bacterial RNA polymerase: 'switch region'". Current Opinion in Microbiology. 14 (5): 532–543. doi:10.1016/j.mib.2011.07.030. PMC   3196380 . PMID   21862392.
  10. ↑ Xiao Y, Li S, Niu S, Ma L, Zhang G, Zhang H, et al. (February 2011). "Characterization of tiacumicin B biosynthetic gene cluster affording diversified tiacumicin analogues and revealing a tailoring dihalogenase". Journal of the American Chemical Society. 133 (4): 1092–1105. doi:10.1021/ja109445q. PMID   21186805.
  11. ↑ Dorst A, Jung E, Gademann K (April 2020). "Recent Advances in Mode of Action and Biosynthesis Studies of the Clinically Used Antibiotic Fidaxomicin". CHIMIA. 74 (4): 270–273. doi: 10.2533/chimia.2020.270 . PMID   32331545. S2CID   216130499.
  12. ↑ "Optimer's North American phase 3 Fidaxomicin study results presented at the 49th ICAAC" (Press release). Optimer Pharmaceuticals. September 16, 2009. Retrieved May 7, 2013.
  13. ↑ "Optimer Pharmaceuticals Presents Results From Fidaxomicin Phase 3 Study for the Treatment" (Press release). Optimer Pharmaceuticals. May 17, 2009. Archived from the original on November 14, 2012. Retrieved May 7, 2013.
  14. ↑ Golan Y, Mullane KM, Miller MA (September 12–15, 2009). Low recurrence rate among patients with C. difficile infection treated with fidaxomicin. 49th interscience conference on antimicrobial agents and chemotherapy. San Francisco.
  15. ↑ Gorbach S, Weiss K, Sears P, Pullman J (September 12–15, 2009). Safety of fidaxomicin versus vancomycin in treatment of Clostridium difficile infection. 49th interscience conference on antimicrobial agents and chemotherapy. San Francisco.
  16. ↑ Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, et al. (February 2011). "Fidaxomicin versus vancomycin for Clostridium difficile infection". The New England Journal of Medicine. 364 (5): 422–431. doi: 10.1056/NEJMoa0910812 . PMID   21288078.
  17. ↑ O'Gorman MA, Michaels MG, Kaplan SL, Otley A, Kociolek LK, Hoffenberg EJ, et al. (August 2018). "Safety and Pharmacokinetic Study of Fidaxomicin in Children With Clostridium difficile-Associated Diarrhea: A Phase 2a Multicenter Clinical Trial". Journal of the Pediatric Infectious Diseases Society. 7 (3): 210–218. doi: 10.1093/jpids/pix037 . PMID   28575523.
  18. ↑ Burton HE, Mitchell SA, Watt M (November 2017). "A Systematic Literature Review of Economic Evaluations of Antibiotic Treatments for Clostridium difficile Infection". PharmacoEconomics. 35 (11): 1123–1140. doi:10.1007/s40273-017-0540-2. PMC   5656734 . PMID   28875314.
  19. ↑ Peterson M (April 5, 2011). "Optimer wins FDA panel's backing for antibiotic fidaxomicin". Bloomberg.
  20. ↑ Nordqvist C (May 27, 2011). "Dificid (fidaxomicin) approved for Clostridium difficile-associated diarrhea". Medical News Today.
  21. 1 2 3 "Dificid (fidaxomicin)" (PDF). U.S. Food and Drug Administration (FDA). January 2020. Retrieved April 21, 2022.
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