Telithromycin

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Telithromycin
Telithromycin.svg
Clinical data
Trade names Ketek, others
AHFS/Drugs.com Monograph
MedlinePlus a604026
License data
Routes of
administration 		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 57%
Protein binding 66% to 79%
Metabolism Hepatic (50% CYP3A4-mediated)
Elimination half-life 10 hours
Excretion Biliary and renal
Identifiers
  • (1S,2R,5R,7R,8R,9S,11R,13R,14R)-8-[(2S,3R,4S,6R)-
    4-dimethylamino-3-hydroxy-6-methyl-oxan-2-yl]oxy-
    2-ethyl-9-methoxy-1,5,7,9,11,13-hexamethyl-15-
    [4-(4-pyridin-3-ylimidazol-1-yl)butyl]-3,17-dioxa-15-
    azabicyclo[12.3.0]heptadecane-4,6,12,16-tetrone
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.208.206 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C43H65N5O10
Molar mass 812.018 g·mol−1
3D model (JSmol)
Melting point 177 °C (351 °F)
  • O=C2[C@@H]([C@@H](O[C@@H]1O[C@@H](C[C@H](N(C)C)[C@H]1O)C)[C@@](OC)(C)C[C@H](C(=O)[C@H](C)[C@H]3N(C(=O)O[C@]3(C)[C@H](OC(=O)[C@@H]2C)CC)CCCCn4cc(nc4)c5cccnc5)C)C
  • InChI=1S/C43H65N5O10/c1-12-33-43(8)37(48(41(53)58-43)19-14-13-18-47-23-31(45-24-47)30-16-15-17-44-22-30)27(4)34(49)25(2)21-42(7,54-11)38(28(5)35(50)29(6)39(52)56-33)57-40-36(51)32(46(9)10)20-26(3)55-40/h15-17,22-29,32-33,36-38,40,51H,12-14,18-21H2,1-11H3/t25-,26-,27+,28+,29-,32+,33-,36-,37-,38-,40+,42-,43-/m1/s1 Yes check.svgY
  • Key:LJVAJPDWBABPEJ-PNUFFHFMSA-N Yes check.svgY
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Telithromycin is the first ketolide antibiotic to enter clinical use and is sold under the brand name of Ketek. It is used to treat community acquired pneumonia of mild to moderate severity. After significant safety concerns, the US Food and Drug Administration sharply curtailed the approved uses of the drug in early 2007.

Contents

Telithromycin is a semi-synthetic erythromycin derivative. It is created by substituting a ketogroup for the cladinose sugar and adding a carbamate ring in the lactone ring. An alkyl-aryl moiety is attached to this carbamate ring. Furthermore, the oxygen at the 6 position is methylated, as is the case with clarithromycin, to achieve better acid-stability.

It was patented in 1994 and approved for medical use in 2001. [1]

Adverse effects

Most common side-effects are gastrointestinal, including diarrhea, nausea, abdominal pain and vomiting. Headache and disturbances in taste also occur. Less common side-effects include palpitations, blurred vision, and rashes. Prolonged QTc intervals may also be caused by telithromycin. [2]

Rare but severe side-effects were initially reported in March 2006, involving damage to the liver. [3] Three different incidents were reported: one case of temporary drug-induced hepatitis, one ending in a liver transplant, and one ending in death.

In the United States, the FDA's Office of Epidemiology and Surveillance identified 12 cases of acute liver failure, resulting in four deaths, and an additional 23 cases of acute, serious liver injury, among 5.2 million patients taking telithromycin through April 2006. [4] [5]

In 2010, a published report described the likely mechanism of action underlying not only the cases of liver failure but also cases of visual disturbances and exacerbations of myasthenia gravis. The study showed that a pyridine moiety that is part of the telithromycin molecule acts as an antagonist on cholinergic receptors located in the neuromuscular junction, the ciliary ganglion of the eye and the vagus nerve innervating the liver. Other macrolides, such as azithromycin and clarithromycin and the fluoroketolide, solithromycin, do not contain the pyridine moiety and do not antagonize these cholinergic receptors significantly. [6]

Mechanism of action

Telithromycin prevents bacteria from growing, by interfering with their protein synthesis. Telithromycin binds to the subunit 50S of the bacterial ribosome, [7] and blocks the progression of the growing polypeptide chain. Telithromycin has over 10 times higher affinity to the subunit 50S than erythromycin. In addition, telithromycin strongly bind simultaneously to two domains of 23S RNA of the 50 S ribosomal subunit, where older macrolides bind strongly only to one domain and weakly to the second domain. Like many other protein synthesis inhibitors, telithromycin can also inhibit the formation of ribosomal subunits 50S and 30S.

Pharmacokinetics

Unlike erythromycin, telithromycin is acid-stable and can therefore be taken orally while being protected from gastric acids. It is fairly rapidly absorbed, and diffused into most tissues and phagocytes. Due to the high concentration in phagocytes, telithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations of telithromycin is released. The concentration of telithromycin in the tissues is much higher than in plasma. Telithromycin fulfills a role that has arisen due to the rise of microbial resistance to existing macrolides and appears to be effective against macrolide-resistant Streptococcus pneumoniae. The defining differentiating characteristic of the ketolides as opposed to other macrolides is the removal of the neutral sugar, L-cladinose from the 3 position of the macrolide ring and the subsequent oxidation of the 3-hydroxyl to a 3-keto functional group. [8]

Metabolism

Telithromycin is metabolized mainly in the liver, the main elimination route being the bile, a small portion is also excreted into the urine. About one third is excreted unchanged in bile and urine, the biliary route being favoured. Telithromycin's half-life is approximately ten hours.

History

French pharmaceutical company Hoechst Marion Roussel (later Sanofi-Aventis) began phase II/III clinical trials of telithromycin (HMR-3647) in 1998. Telithromycin was approved by the European Commission in July 2001 and subsequently went on sale in October 2001. In the US, telithromycin received U.S. Food and Drug Administration (FDA) approval on April 1, 2004.

Safety controversies and fraud

FDA staffers publicly complained that safety problems and some data integrity issues were ignored prior to approval, and the House Committee on Energy and Commerce held hearings to examine these complaints. One doctor went to prison because she falsified data in her portion of the clinical trials (about 400 patients out of 24,000). Further, Ketek seemed to cause liver problems, including "liver failure", to a greater extent than would be expected of a common-use antibiotic. [9] The House Committee on Energy and Commerce held hearings. [10]

Study 3014 was a key clinical trial of approximately 24,000 patients which Sanofi-Aventis submitted to the FDA to seek approval for Ketek. The doctor who treated the most patients in Study 3014 (about 400), Maria "Anne" Kirkman Campbell, served a 57-month sentence in federal prison after pleading guilty to mail fraud, by defrauding Aventis and others. The indictment states that Campbell fabricated data she sent to the company. [11] Documents, including internal Sanofi-Aventis emails show that Aventis was worried about Campbell early in study 3014 but didn't tell the FDA until the agency's own inspectors discovered the problem independently. [12]

In January 2006, an article [3] in the March issue of Annals of Internal Medicine was published, citing three recent drug-induced liver injury cases likely due to telithromycin, one resulting in a liver transplant and one in death.

In July 2006, according to the New York Times, unpublished e-mails from FDA safety official David Graham argued telithromycin had not been proven safe, that safer drugs were available for the same indications, and that the approval was a mistake and should be immediately withdrawn. [13]

Between the start of telithromycin's marketing in mid-2004 and September 2006, there were 13 cases of liver failure, including at least four deaths, vision problems, blackouts, syncope, and potentially fatal cases of myasthenia gravis. The Times said that the FDA was embroiled in a "fierce battle" over the approval, fueled by exposure in the press. Senator Charles E. Grassley (R-Iowa, chairman, Senate Finance Committee), Representatives Edward J. Markey (D-Mass) and Henry A. Waxman (D-Calif) held hearings.

FDA Warning

On February 12, 2007, after an advisory committee discussion and vote in December 2006, the FDA announced a revision to the labeling of Ketek. The changes included the removal of two of the three previously approved indications: acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis. The agency determined that the balance of benefits and risks no longer supported approval of the drug for these indications. Ketek remained on the market for the treatment of community acquired bacterial pneumonia of mild to moderate severity (acquired outside of hospitals or long-term care facilities). In addition, the FDA worked with the manufacturer to update the product labeling with a "black box warning," their strongest form of warning. Ketek's warning states that it should not be used in patients with myasthenia gravis, a disease that causes muscle weakness. [14] Following this decision, Sanofi-Aventis withdrew the drug from active sales in the United States.

Available forms

Telithromycin is administered as tablets. The standard dosing is two 400 mg tablets to be taken together daily, with or without food.

Related Research Articles

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

Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used during pregnancy to prevent Group B streptococcal infection in the newborn, as well as to improve delayed stomach emptying. It can be given intravenously and by mouth. An eye ointment is routinely recommended after delivery to prevent eye infections in the newborn.

<span class="mw-page-title-main">Macrolide</span> Class of natural products

The Macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Macrolides belong to the polyketide class of natural products. Some macrolides have antibiotic or antifungal activity and are used as pharmaceutical drugs. Rapamycin is also a macrolide and was originally developed as an antifungal, but is now used as an immunosuppressant drug and is being investigated as a potential longevity therapeutic.

<span class="mw-page-title-main">Tacrolimus</span> Immunosuppressive drug

Tacrolimus, sold under the brand name Prograf among others, is an immunosuppressive drug. After allogeneic organ transplant, the risk of organ rejection is moderate. To lower the risk of organ rejection, tacrolimus is given. The drug can also be sold as a topical medication in the treatment of T-cell-mediated diseases such as eczema and psoriasis. For example, it is prescribed for severe refractory uveitis after a bone marrow transplant, exacerbations of minimal change disease, Kimura's disease, and vitiligo. It can be used to treat dry eye syndrome in cats and dogs.

<span class="mw-page-title-main">Clarithromycin</span> Type of antibiotic

Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, H. pylori infection, and Lyme disease, among others. Clarithromycin can be taken by mouth as a pill or liquid.

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

Clindamycin is an antibiotic medication used for the treatment of a number of bacterial infections, including osteomyelitis (bone) or joint infections, pelvic inflammatory disease, strep throat, pneumonia, acute otitis media, and endocarditis. It can also be used to treat acne, and some cases of methicillin-resistant Staphylococcus aureus (MRSA). In combination with quinine, it can be used to treat malaria. It is available by mouth, by injection into a vein, and as a cream or a gel to be applied to the skin or in the vagina.

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

Roxithromycin is a semi-synthetic macrolide antibiotic. It is used to treat respiratory tract, urinary and soft tissue infections. Roxithromycin is derived from erythromycin, containing the same 14-membered lactone ring. However, an N-oxime side chain is attached to the lactone ring. It is also currently undergoing clinical trials for the treatment of male-pattern hair loss.

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

Ketolides are antibiotics belonging to the macrolide group. Ketolides are derived from erythromycin by substituting the cladinose sugar with a keto-group and attaching a cyclic carbamate group in the lactone ring. These modifications give ketolides much broader spectrum than other macrolides. Moreover, ketolides are effective against macrolide-resistant bacteria, due to their ability to bind at two sites at the bacterial ribosome as well as having a structural modification that makes them poor substrates for efflux-pump mediated resistance.

<span class="mw-page-title-main">Ofloxacin</span> Antibiotic to treat bacterial infections

Ofloxacin is a quinolone antibiotic useful for the treatment of a number of bacterial infections. When taken by mouth or injection into a vein, these include pneumonia, cellulitis, urinary tract infections, prostatitis, plague, and certain types of infectious diarrhea. Other uses, along with other medications, include treating multidrug resistant tuberculosis. An eye drop may be used for a superficial bacterial infection of the eye and an ear drop may be used for otitis media when a hole in the ear drum is present.

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

Terfenadine is an antihistamine formerly used for the treatment of allergic conditions. It was brought to market by Hoechst Marion Roussel and was marketed under various brand names, including Seldane in the United States, Triludan in the United Kingdom, and Teldane in Australia. It was superseded by fexofenadine in the 1990s due to the risk of a particular type of disruption of the electrical rhythms of the heart and has been withdrawn from markets worldwide.

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

Tigecycline, sold under the brand name Tygacil, is an tetracycline antibiotic medication for a number of bacterial infections. It is a glycylcycline administered intravenously. It was developed in response to the growing rate of antibiotic resistant bacteria such as Staphylococcus aureus, Acinetobacter baumannii, and E. coli. As a tetracycline derivative antibiotic, its structural modifications has expanded its therapeutic activity to include Gram-positive and Gram-negative organisms, including those of multi-drug resistance.

<span class="mw-page-title-main">Norfloxacin</span> Chemical compound, antibiotic

Norfloxacin, sold under the brand name Noroxin among others, is an antibiotic that belongs to the class of fluoroquinolone antibiotics. It is used to treat urinary tract infections, gynecological infections, inflammation of the prostate gland, gonorrhea and bladder infection. Eye drops were approved for use in children older than one year of age.

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

Moxifloxacin is an antibiotic, used to treat bacterial infections, including pneumonia, conjunctivitis, endocarditis, tuberculosis, and sinusitis. It can be given by mouth, by injection into a vein, and as an eye drop.

<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">Azalide</span>

Azalides such as azithromycin are a class of macrolide antibiotics that were originally manufactured in response to the poor acid stability exhibited by original macrolides (erythromycin). Following the clinical overuse of macrolides and azalides, ketolides have been developed to combat surfacing macrolide-azalide resistance among streptococci species. Azalides have several advantages over erythromycin such as more potent gram negative antimicrobial activity, acid stability, and side effect tolerability. Although there are few drug interactions with azithromycin, it weakly inhibits the CYP4A4 enzyme.

<span class="mw-page-title-main">Dronedarone</span> Drug

Dronedarone, sold under the brand name Multaq, is a medication by Sanofi-Aventis, mainly for the indication of cardiac arrhythmias. It was approved by the FDA on July 2, 2009. It was recommended as an alternative to amiodarone for the treatment of atrial fibrillation and atrial flutter in people whose hearts have either returned to normal rhythm or who undergo drug therapy or electric shock treatment i.e. direct current cardioversion (DCCV) to maintain normal rhythm. It is a class III antiarrhythmic drug. In the United States, the FDA approved label includes a claim for reducing hospitalization, but not for reducing mortality, as a reduction in mortality was not demonstrated in the clinical development program. A trial of the drug in heart failure was stopped as an interim analysis showed a possible increase in heart failure deaths, in patients with moderate to severe CHF.

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

Tylosin is a macrolide antibiotic and bacteriostatic feed additive used in veterinary medicine. It has a broad spectrum of activity against Gram-positive organisms and a limited range of Gram-negative organisms. It is found naturally as a fermentation product of Streptomyces fradiae.

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

Delafloxacin sold under the brand name Baxdela among others, is a fluoroquinolone antibiotic used to treat acute bacterial skin and skin structure infections.

<span class="mw-page-title-main">Tedizolid</span> Oxazolidinone-class antibiotic

Tedizolid, is an oxazolidinone-class antibiotic. Tedizolid phosphate is a phosphate ester prodrug of the active compound tedizolid. It was developed by Cubist Pharmaceuticals, following acquisition of Trius Therapeutics, and is marketed for the treatment of acute bacterial skin and skin structure infections.

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

Solithromycin is a ketolide antibiotic undergoing clinical development for the treatment of community-acquired pneumonia and other infections.

<span class="mw-page-title-main">Quinolone antibiotic</span> Class of antibacterial drugs, subgroup of quinolones

A quinolone antibiotic is a member of a large group of broad-spectrum bacteriocidals that share a bicyclic core structure related to the substance 4-quinolone. They are used in human and veterinary medicine to treat bacterial infections, as well as in animal husbandry, specifically poultry production.

References

  1. ↑ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 499. ISBN   9783527607495.
  2. ↑ Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor Basic & Clinical Pharmacology, 11e McGraw-Hill 2009 via "accessmedicine.com"
  3. 1 2 Clay KD, et al. (2006). "Brief communication: severe hepatotoxicity of telithromycin: three case reports and literature review". Annals of Internal Medicine. 144 (6): 415–420. doi: 10.7326/0003-4819-144-6-200503210-00121 . PMID   16481451.
  4. ↑ "Archived copy". Food and Drug Administration . Archived from the original on 2017-05-17. Retrieved 2019-12-16.{{cite web}}: CS1 maint: archived copy as title (link)
  5. ↑ Mathews, Anna Wilde (May 2006). "Fraud, Errors Taint Key Study Of Widely Used Sanofi Drug - WSJ". Wall Street Journal.
  6. ↑ Bertrand, D; Bertrand, S; Neveu, E; Fernandes, P (2010). "Molecular Characterization of Off-Target Activities of Telithromycin: a Potential Role for Nicotinic Acetylcholine Receptors". Antimicrobial Agents and Chemotherapy. 54 (12): 5399–5402. doi:10.1128/aac.00840-10. PMC   2981250 . PMID   20855733.
  7. ↑ Eyal, Z.; Matzov, D.; Krupkin, M.; Wekselman I.; Paukner S.; Zimmerman, E.; Rozenberg, H.; Bashan, A.; Yonath, A. (2015). "Structural insights into species-specific features of the ribosome from the pathogen Staphylococcus aureus". Proc Natl Acad Sci U S A. 112 (43): E5805–14. Bibcode:2015PNAS..112E5805E. doi: 10.1073/pnas.1517952112 . PMC   4629319 . PMID   26464510.
  8. ↑ Scheinfeld, N (2004). "Telithromycin: A brief review of a new ketolide antibiotic". J Drug Dermat. 3 (4): 409–13. PMID   15303785.
  9. ↑ Splete, Heidi; Kerri Wachter (March 2006). "Liver toxicity reported with Ketek". Internal Medicine News.
  10. ↑ "The House Committee on Energy and Commerce :: Hearing". Archived from the original on 2007-04-26. Retrieved 2007-04-20. House of Representatives, The House Committee on Energy and Commerce, Honorable John D. Dingell, Chairman, Subcommittee on Oversight and Investigations, "The Adequacy of FDA Efforts to Assure the Safety of the Drug Supply", February 13, 2007.
  11. ↑ Food and Drug Administration, NOTICE OF INITIATION OF DISQUALIFICATION PROCEEDINGS AND OPPORTUNITY TO EXPLAIN (NIDPOE), Leslie Ball, 5/18/2006
  12. ↑ Infected Data: Fraud, Errors Taint Key Study Of Widely Used Sanofi Drug Despite Some Faked Results, FDA Approves Antibiotic; One Doctor's Cocaine Use; Company Defends Safety, By ANNA WILDE MATHEWS, Wall Street Journal, May 1, 2006
  13. ↑ Gardiner Harris (2006-07-19). "Approval of Antibiotic Worried Safety Officials". New York Times . Retrieved 2010-05-25.
  14. ↑ "FDA Announces Label and Indication Changes for the Antibiotic Ketek". Food and Drug Administration . Archived from the original on 2007-02-14.
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