IUPAC_name = (1"S",2"R",5"R",7"R",8"R",9"S",11"R",13"R",14"R")-8- [(2"S",3"R",4"S",6"R")-
azabicyclo [12.3.0] heptadecane-4,6,12,16-tetrone
CAS_number = 191114-48-4
ATC_prefix = J01
ATC_suffix = FA15
PubChem = 5462516
DrugBank = APRD00483
C = 43 |H = 65 |N = 5 |O = 10
molecular_weight = 812.004 g/mol
bioavailability = 57%
protein_bound = 60% to 70%
metabolism = Hepatic (50%
elimination_half-life = 10 hours
excretion = Biliary and renal
pregnancy_category = C (U.S.)
legal_status = POM (UK), ℞-only (U.S.)
routes_of_administration = Oral
Telithromycin is the first
ketolide antibioticto enter clinical use. It is used to treat mild to moderate respiratory infections. Telithromycin is sold under the brand name of Ketek.
Telithromycin is a semi-synthetic
erythromycinderivative. It is created by substituting the cladinosesugar with a ketogroup and adding a carbamatering in the lactonering. An alkyl-aryl moiety is attached to this carbamate ring. Furthermore, the carbon at position 6 has been methylated, as is the case in clarithromycin, to achieve better acid-stability.
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 Commissionin July 2001 and subsequently went on sale in October 2001. In the US, telithromycin received FDA approval on April 1, 2004.
Telithromycin is administered as tablets. The standard dosing is two 400 mg tablets to be taken together daily, with or without food.
Mechanism of action
Telithromycin prevents bacteria from growing, by interfering with their protein synthesis. Telithromycin binds to the subunit
50Sof the bacterial ribosome, 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 binds simultaneously to two domains of 23S RNA of the 50 S ribosomal subunit, where older macrolides bind only to one. Telithromycin can also inhibit the formation of ribosomal subunits 50S and 30S.
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 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.
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.
Rare but severe side effects reported in January 2006 involve damage to the liver. Three different incidents have been reported: one ending in death, one in a
liver transplantand one case of drug-induced hepatitis.cite journal | author=Clay KD et al. | title=Brief communication: severe hepatotoxicity of telithromycin: three case reports and literature review | journal=Annals of Internal Medicine | year=2006 | volume=144(6) | pages=415–420 | pmid=16481451 ] .
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 in patients taking telithromycin up to April 2006. [http://www.fda.gov/ohrms/dockets/AC/06/slides/2006-4266s1-01-07-FDA-Brinker.ppt]
Telithromycin has been known to cause false positive readings in drug screenings for cocaine and amphetamines.Fact|date=April 2007
By April 2008, independent analysis using FDA data has linked Ketek (Telithromycin) to 18 deaths and at least 134 cases of liver damage. Some researchers say the total may be far greater. [http://www.rd.com/national-interest/consumer-safety/fda-approves-harmful-antibiotic/article.html]
Safety controversies and fraud
FDA staffers publicly complained that safety problems were ignored, 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 because Ketek seemed to cause liver problems, including liver failure, to a greater extent than would be expected of a common-use antibiotic. [cite journal
coauthors= Kerri Wachter
title= Liver toxicity reported with Ketek
journal= Internal Medicine News
accessdate= 2007-11-17] The House Committee on Energy and Commerce held hearings [ [http://energycommerce.house.gov/cmte_mtgs/110-oi_hrg.021307.FDA_drug_supply.shtml] 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.] .
Study 3014 was a key clinical trial of more than 24,000 patients which Sanofi-Aventis submitted to the FDA seeking approval for Ketek. The doctor who treated the most patients in Study 3014, Maria "Anne" Kirkman Campbell, is currently serving a 57-month sentence in federal prison after pleading guilty to defrauding Aventis and others. The indictment states that Dr. Campbell fabricated data she sent to the company [ [http://www.fda.gov/foi/nidpoe/n41l.htm] Food and Drug Administration, NOTICE OF INITIATION OF DISQUALIFICATION PROCEEDINGS AND OPPORTUNITY TO EXPLAIN (NIDPOE), Leslie Ball, 5/18/2006] . Documents including internal Sanofi-Aventis emails show that Aventis was worried about Dr. Campbell early in study 3014 but didn't tell the FDA until the agency's own inspectors discovered the problem independently [ [http://online.wsj.com/article/SB114644463095840108.html?mod=blogs] 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] .
In July 2006, the "New York Times"cite journal | author=Harris, G . | title=Approval of Antibiotic Worried Safety Officials | journal=New York Times | year=2006 | volume= 19 July 2006 | pages= | id= | url=http://www.nytimes.com/2006/07/19/health/19fda.html ] quoted e-mails from FDA safety official David Graham, arguing that 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. There were 14 cases of liver failure, including at least four deathscite journal | author=Clay KD et al. | title=Brief communication: severe hepatotoxicity of telithromycin: three case reports and literature review | journal=Annals of Internal Medicine | year=2006 | volume=144(6) | pages=415–420 | pmid=16481451 ] , vision problems, blackouts, syncope, and potentially fatal cases of
myasthenia gravis. Graham wrote, “It’s as if every principle governing the review and approval of new drugs was abandoned or suspended where telithromycin is concerned.” cite journal | author=Harris, G . | title=Approval of Antibiotic Worried Safety Officials | journal=New York Times | year=2006 | volume= 19 July 2006 | pages= | id= | url=http://www.nytimes.com/2006/07/19/health/19fda.html ] "The Times" said that the FDA was embroiled in a "fierce battle" over the approval, fueled by exposure in the press. Three other FDA officials also criticized the approval: Dr. Charles Cooper, Dr. David Ross, and Dr. Rosemary Johann-Liang, who wrote, "How does one justify balancing the risk of fatal liver failure against one day less of ear pain?". cite journal | author=Harris, G . | title=Approval of Antibiotic Worried Safety Officials | journal=New York Times | year=2006 | volume= 19 July 2006 | pages= | id= ] Senator Charles E. Grassley (R-Iowa, chairman, Senate Finance Committee), Representatives Edward J. Markey (D-Mass) and Henry A. Waxman (D-Calif) held hearings.
On February 12, 2007, the Food and Drug Administration announced a revision to the labeling of Ketek to improve patient safety. 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 will remain on the market for the treatment of community acquired 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. [http://www.fda.gov/bbs/topics/NEWS/2007/NEW01561.html]
* [http://www.fda.gov/cder/drug/advisory/telithromycin.htm FDA Public Health Advisory for Telithromycin (marketed as Ketek)]
* [http://www.annals.org/cgi/reprint/144/6/415.pdf Article in Annals of Internal Medicine regarding cases of hepatotoxicity induced by telithromycin]
* [http://www.nytimes.com/2006/07/19/health/19fda.html?ex=1169960400&en=30b585a30a671f03&ei=5070 New York Times article. Login is required]
* [http://www.webmd.com/drugs/drug-90375-Ketek.aspx?drugid=90375&drugname=Ketek Drugs and Treatments - KETEK Oral - Patient Handout from WebMD]
Wikimedia Foundation. 2010.