Telithromycin
Encyclopedia
Telithromycin is the first ketolide antibiotic
to 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 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 carbon at position 6 has been methylated, as is the case in clarithromycin
, to achieve better acid-stability.
Hoechst Marion Roussel (later Sanofi-Aventis
) began phase II/III clinical trial
s 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 FDA
approval on April 1, 2004 .
. Telithromycin binds to the subunit 50S
of 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 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. Telithromycin can also inhibit the formation of ribosomal subunits 50S and 30S
.
s. 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.
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 transplant and one case of drug-induced hepatitis
.
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.
Telithromycin has been known to cause false positive readings in drug screenings for cocaine and amphetamines.
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.
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.
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.
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...
to 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 erythromycin
Erythromycin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...
derivative. It is created by substituting a ketogroup for the cladinose
Cladinose
Cladinose is a hexose deoxy sugar that in several antibiotics is attached to the macrolide ring.In ketolides, a relatively new class of antibiotics, the cladinose is replaced with a keto group.-External links:* *...
sugar and adding a carbamate
Carbamate
Carbamates are organic compounds derived from carbamic acid . A carbamate group, carbamate ester, and carbamic acids are functional groups that are inter-related structurally and often are interconverted chemically. Carbamate esters are also called urethanes.-Synthesis:Carbamic acids are derived...
ring in the lactone
Lactone
In chemistry, a lactone is a cyclic ester which can be seen as the condensation product of an alcohol group -OH and a carboxylic acid group -COOH in the same molecule...
ring. 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
Clarithromycin
Clarithromycin is a macrolide antibiotic used to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia , skin and skin structure infections...
, to achieve better acid-stability.
History
French pharmaceutical companyPharmaceutical company
The pharmaceutical industry develops, produces, and markets drugs licensed for use as medications. Pharmaceutical companies are allowed to deal in generic and/or brand medications and medical devices...
Hoechst Marion Roussel (later Sanofi-Aventis
Sanofi-Aventis
Sanofi S.A. is a multinational pharmaceutical company headquartered in Paris, France, the world's fourth-largest by prescription sales. Sanofi engages in the research and development, manufacturing and marketing of pharmaceutical products for sale principally in the prescription market, but the...
) began phase II/III clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s of telithromycin (HMR-3647) in 1998. Telithromycin was approved by the European Commission
European Commission
The European Commission is the executive body of the European Union. The body is responsible for proposing legislation, implementing decisions, upholding the Union's treaties and the general day-to-day running of the Union....
in July 2001 and subsequently went on sale in October 2001. In the US, telithromycin received FDA
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
approval on April 1, 2004 .
Available forms
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 synthesisProtein biosynthesis
Protein biosynthesis is the process in which cells build or manufacture proteins. The term is sometimes used to refer only to protein translation but more often it refers to a multi-step process, beginning with amino acid synthesis and transcription of nuclear DNA into messenger RNA, which is then...
. Telithromycin binds to the subunit 50S
50S
50S is the larger subunit of the 70S ribosome of prokaryotes. It is the site of inhibition for antibiotics such as macrolides, chloramphenicol, clindamycin, and the pleuromutilins. It includes the subunits 5S and 23S.-Structure:...
of the bacterial 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....
, 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. Telithromycin can also inhibit the formation of ribosomal subunits 50S and 30S
30S
30S is the smaller subunit of the 70S ribosome of prokaryotes. It is a complex of ribosomal RNA and ribonucleoproteins that functions in mRNA translation...
.
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 phagocytePhagocyte
Phagocytes are the white blood cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are...
s. 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.
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.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.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 transplant and one case of drug-induced hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
.
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.
Telithromycin has been known to cause false positive readings in drug screenings for cocaine and amphetamines.
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.
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
Solithromycin
Solithromycin is a novel ketolide antibiotic undergoing clinical development for the treatment of community acquired pneumonia and other infections...
, do not contain the pyridine moiety and do not antagonize these cholinergic receptors significantly.
FDA Warning
On February 12, 2007, the Food and Drug AdministrationFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
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
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
," their strongest form of warning. Ketek's warning states that it should not be used in patients with myasthenia gravis
Myasthenia gravis
Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
, a disease that causes muscle weakness.
External links
- FDA Public Health Advisory for Telithromycin (marketed as Ketek)
- Article in Annals of Internal Medicine regarding cases of hepatotoxicity induced by telithromycin
- New York Times article. Login is required
- FDA officials question safety of antibiotic 'Ketek'
- Drugs and Treatments - KETEK Oral - Patient Handout from WebMD