Ketolides

Telithromycin

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.
Ketolides block protein synthesis by binding to ribosomal subunits and may also inhibit
the formation of newly forming ribosomes.

The only ketolide on the market at this moment is telithromycin, which is sold under the
brand name of Ketek.

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

the cladinose sugar with a ketogroup 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

Telithromycin (marketed as Ketek) Information

On February 12, 2007, the FDA and the sponsor agreed on an updated label for Ketek
(telithromycin), an antibiotic, and to distribute a Medication Guide (MedGuide) for
patients.

The new label narrows the usage for Ketek by dropping two previously approved
indications (acute bacterial exacerbation of chronic bronchitis due to Streptococcus
pneumoniae, Haemophilus, influenzae, or Moraxella catarrhalis; and acute bacterial
sinusitis due to Streptococcus pneumoniae, Haemophilus influenzae, Moraxella
catarrhalis, or Staphylococcus aureus.)
Ketek is now indicated for the treatment of community-acquired pneumonia (of mild to
moderate severity) due to Streptococcus pneumoniae, (including multi-drug resistant
isolates, Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, or
Mycoplasma pneumoniae, for patients 18 years and older.

The updated label includes a boxed warning and a contraindication stating that no one
with myasthenia gravis should take Ketek. In addition, warnings were strengthened for
hepatotoxicity (liver injury), loss of consciousness, and visual disturbances.

On June 29, 2006, the Food and Drug Administration notified healthcare professionals
and patients that it completed its safety assessment of Ketek (telithromycin). FDA
determined that additional warnings about the risk of liver toxicity are required and the
manufacturer has revised the drug labeling to address this safety concern. In addition, the
WARNINGS for patients with myasthenia gravis are being strengthened.

On January 20, 2006, the FDA advised the public that the Annals of Internal Medicine
had published an article reporting three patients who experienced serious liver toxicity
following administration of Ketek (telithromycin). These cases had also been reported to
FDA MedWatch. Telithromycin is marketed and used extensively in many other
countries, including countries in Europe and Japan.
 Telithromycin
Systematic (IUPAC) name
(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
Identifiers
CAS number 191114-48-4
ATC code J01FA15
PubChem 5462516
DrugBank APRD00483
Chemical data
Formula C43H65N5O10
Mol. mass 812.004 g/mol
Pharmacokinetic data
Bioavailability 57%
Protein binding 60% to 70%
Metabolism Hepatic (50% CYP3A4-
mediated)
Half life 10 hours
Excretion Biliary and renal
Therapeutic considerations
Pregnancy cat. C (U.S.)
Legal status POM (UK), ℞-only (U.S.)
Routes Oral

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 FDA 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 synthesis.
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 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.

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.

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.

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.[1].

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.[4]
Telithromycin has been known to cause false positive readings in drug screenings for
cocaine and amphetamines.[citation needed]

By April of 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.[5]

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.[2] The House Committee on Energy
and Commerce held hearings[3].

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[4].
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[5].

In July 2006, the New York Times[6] 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
deaths[1], 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.” [6] 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?". [6]
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, 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. [6]

Another promising ketolide is cethromycin

Cethromycin (initially known as ABT-773) is a macrolide antibiotic undergoing research

for the treatment of community acquired pneumonia (CAP) and for the prevention of
post-exposure inhalational anthrax, and was given an "orphan drug" status for this
indication.[1] Originally discovered and developed by Abbott, it was acquired by
Advanced Life Sciences Inc. for further development.

On April 10, 2008, Advanced Life Sciences announced that, based on a productive
meeting with the U.S. Food and Drug Administration (FDA), it plans to submit a New
Drug Application (NDA) in the third quarter of 2008 for cethromycin to treat mild-to-
moderate community acquired pneumonia.[2]