The rising of bacterial strains that
have antibiotic resistance is causing the search for new antimicrobial agents.
In recent years, there is a number of new agents to treat patogenic diseases.
These agents show considerable improved activity against bacteria that have
resistance or show lower sensitivity to previous antimicrobial
agents. Changing the chemical structure of molecules and introduction of
molecules with new chemical structure have provided agents able to overcome the
present resistance mechanism. These search workings are especially at
penicillins, quinolones and macrolides.
Eritromycin, the typical macrolide, was
discovered in early 1950s. After this, macrolide antibiotics used for the
therapy of Streptococcus pneumoniae infections.
At the same time, macrolides showed broad spectrum antimicrobial activity
against patogens.The one of the advantages of macrolides is that it is an
alternative treatment of b-lactam intolerant patients.
But, in the last two decades, there is
an increasing resistance to macrolides such as erythromycin, azithromycin and
clathromycin. To overcome this problem, ketolides were developed. Ketolides are
new major class of semisynthetic eritromycin derivatives with 10-fold greater
ribosomal binding affinity because of secondary interaction.The main chemical
characteristics of a ketolide is the displacement of cladinose attached to the macrolide
ring of 6-O-methylerytromycin ring at
C-3 position with a ketone moiety.
Telithromycin is the first available
oral ketolide. It is approved by the US Food and Drug Administration (FDA) in
2001 and it is introduced into clinical practice.. Telithromycin was developed
at Aventis and reached the market as Ketek. Telithromycin is used for treatment
of respiratory tract infections such as mild-to-moderately-severe CAP, chronic
bronchitis and acute bacterial sinusitis. Also it is quite effective against
macrolide resistant Streptecoccus
2. CHEMICAL and PHYSICAL PROPERTIES of TELITHROMYCIN
Molecular formula of telithromycin is C43H65N5O10
weight of telithromycin is 812.018 g/mol.
Telithromycin has 1 hydrogen bond donor
Telithromycin has 13 hydrogen bond acceptor
Telithromycin has 11 rotatable bond
Formal charge of telithromycin is 0
Telithromycin has 13 defined atom stereocenter
Telithromycin has 1 covalently bonded unit
Telithromycin is canonicalized compound
Log P value of telithromycin is 3
Water solubility of telithromycin is 300 mg/L
Melting point of telithromycin is between 176 °C and 188 °C
STRUCTURE and ACTIVITY RELATIONSHIP
Figure 1. Chemical structure of telithromycin
(a) corresponds to metoxy group at C6 , increases
acid stability and forestall internal hemiketalization.
(b) corresponds to 3-keto-function,prevents MLSB
resistance induction and increases ribosome binding
(c) corresponds to C11/12 carbamate side chain,
increases ribosome affinity and increases interaction with MLSB- resistant
Erythromycin is a macrolide antibiotic
that have a 14-membered lactone ring with cladinose.In oral administration,
erythromycin is sufficiently absorbed from the gastrointestinal tract.If pH of
the environment is low, for instance in the stomach, erythromycin falls into
some internal changes.After these changes some products are occured and they
have no antimicrobial activity.
By replacing cladinose group of
macrolides with a keto group, ketolides are obtained.Ketolides are
semisynthetic derivatives of macrolides. Telithromycin is a member of ketolides
and it has large aromatic N-substitued carbamate bridge at position C11-C12. It also has imidazo-pyridyl group attachment
in this ring and it has 6-O CH3 group.Due to these specific modifications,
telithromycin has good activity on S.
Pneumoniae and some gram-positive bacteries that have resistance to
erytromycin.On the other hand these
modifications increases bioavailability and acid stability of molecule.
4.MECHANISM of ACTION
Bacterial ribosomes have 50S and 30S
ribosomal subunits. Subunits of ribosome consist protein and rRNA. The small
subunit of ribosome have an interaction with mRNA and translates the genetic
code. The large subunit shows function as a catalytic center, peptide bonds
between aminoacids is formed in this unit. The elongated peptide enters a
peptide exit channel within the 50S ribosomal subunit.
Ketolides and macrolides inhibit protein
synthesis with the identical mechanism, . They bind within the exit tunnel of
the 50S subunit, so blocks the exit of rising polypeptides. 23S rRNA have some
specific residues (A2058 and A2059) on domain V. Macrolides and ketolides bind
In addition, telithromycin is a very
effective inhibitor of the translation function at the level of the 50S
ribosomal subunit. Telithromycin binds to a specific residue (A752) on domain
II of the 23S rRNA, via the 11,12 carbamate bridge containing the alkyl-aryl
extension.Due to the binding to domain II,
binding efficiency of telithromycin to ribosomes is 10-fold more than
erytromycin. Telithromycin can inhibit the formation of small ribosomal subunit
and it can inhibit assembly of the large ribosomal subunit.
Secondary structure models of the peptidyl transferase center in domain V of
23S rRNA (a) and hairpin 35 in domain II (b) Positions of macrolide
interactions and of mutations that confer macrlide resistance are indicated and
nucleotides are circled, respectively.
When the microbiological profile of
telithromycin is studied, it can be seen that, telithromycin has high in vitro
activity against many common respiratory tract infection pathogens such as S.
pneumoniae, S. aureus, Enterococcus faecalis, Enterococcus faecium,
Corynebacterium diphtheriae, Listeria monocytogenes, L. pneumophila and
Bartonella spp. When the comparing in vitro activity of telithromycin with
macrolides and azolides, telithromycin has good activity against gram (+) bacteria. Also it is 2-5
times more active against gram (+ )bacteria, comparing to clarithromycin.
Besides, telithromycin has activity
against gram-negative bacteria. However, it has no activity against
MLSB-resistant Staphylococcus aureus,Enterobacteria and Acinetobacter baumanii.
In vitro pharmacodynamic
studies of telithromycin against extracellular or intracellular Helicobacter
pylori showed promising results. In addition telithromycin have good in
vitro activity against intracellular pathogens, such as Rickettsia spp.
and Bartonella spp. Pneumococci are categorized that if the MIC is
smaller than 1 µg/mL sensitive to telithromycin, if the MIC is 2 µg/mL
intermediately resistant , and if the MIC is higher than 4 µg/mL resistant to
telithromycin comparing with
erythromycin A, azithromycin, clarithromycin, roxithromycin, clindamycin,
telithromycin is the most active agent. Minium inhibitory concentration of
telithromycin (MIC50/90) is 0.06/4.0 mg/L
against Enterococcus faecalis
values of telithromycin against Staphylococcus aereus isolates ranged between 0.06 and 0.12 mg/L
and MIC90 values ranged between 0.12 and 0.25 mg/L. MIC50/90
values of telithromycin values range from 0.03 to 0.25 mg/L when the isolate is
susceptible to Erytromycin A.
Table 1. Minimum inhibitory concentrations (MICs) of
telithromycin for key respiratory
6.MECHANISM of RESISTANCE
There are two main mechanism
of resistance to macrolides: i) modification by methylation, ii) reduced
intracellular accumulation due to decreasedinflux or increased efflux of the
staphylococci have an enzyme that can methylates a specific adenine
residue(A2058)..After methlyation with A2058, bacteria can not bind macrolides
and bacteria resistant to these agents.
Methylation of A2058 reasons resistance to
clindamycin, a lincosamide, and to streptogramin type B antibiotics (e.g.,
quinupristin) Methylation or substitution of A2058 changes the major contact
the drugs. The erythromycin- resistance
methylase genes (erm genes) codes methylase. Lots of of bacteria such as
pneumococci and staphylococci describes methylase genes . The erm genes are
expressed both constitutively and by induction. If it is expressed
constitutively, the bac- teria test positive in terms of MLSB resistance. Otherwise,
the isolates test positive in terms of resistance to macrolides. The resistance
of MLSB is showed by using a disk approximation test. In pneumococci erm gene usually expressed constitutively.
accumulation due to decreased in flux or increased efflux of the drug is the
other common mechanism of macrolide resistance in pneumococci. Strains that
have this resistance mechanism have the macrolide efflux pump, that uses energy
to remove macrolides from the inside of the bacteria. Therefore, the macrolide
could not reach inside the cell (the ribosome). Macrolide efflux gene (meJ)
codes the efflux pump.The mechanism of macrolide resistance consist mutations that influence ribosomal
proteins or RNA . For instance, the strains that include point mutations of
A2059 have resistance because macrolides
can not bind to their ribosomes. Some mutations or amino acid insertions
influence ribosomal proteins and can produce macrolide resistance .
7.PHARMACOKINETICS and PHARMACODYNAMICS
According to an in vivo
model of infections in mice, macrolides can be seperated into two classes. First
is time above MIC for some macrolides such as erytromycin A, clarithromycin and
rodixromycin. Second is concentration-dependent killing for azithromycin.
Applying the same way, it is demonstrated
that using the area under the serum concentrations
to MIC ratio (AUC/MIC), the best correlation is acquired without regarding the
sensitivity of S. pneumoniae strains to erythromycin A.
The pharmacokinetic characteristics
of telithromycin has been defined in patients after single or repeated oral
doses of 800 mg. Thus metabolism and drug interactions of telithromycin has
After a 800 mg of telithromycin, in one hour
the mean peak plasma concentration (Cmax) was 1.9 mg/L. After
dosing,the plasma concentration was 0.03 mg/L at 24 hour. The mean area under
the curve (AUC) was 8.4 mg.h/L, and the terminal half-life ranges from 10 to 12 hour. Repeating
the doses during 10 days, using the AUC ratio, the mean accumulation ratio
calculated as 1.5.
Telithromycin is bound to serum proteins,
approximately 70% of the molecule is protein bound. The main protein involved
is human serum albumin (45-49%), accounting for a concentration of 2.4 mg/L,
with ?1-acid glycoprotein (12-30%) and liporoteins being responsible
fort he remaining part.
big part of the metabolism is made by the cytochrome P450 3A4 system, and the
other part is made by cytochrome P450-independent mechanisms. Of the systemically
available drug, 7% is excreted in the feces, 13% is excreted in the urine, and
37% is metabolized by the liver.
There is an increase in renal
elimination in patients with hepatic insufficiency. But, patients that have
hepatic impairment and renal impairment ,
the dosage should be decreased to half of the previous dosage.
The availability of multiple routes of elimination
reduces the impact of isolated renal or hepatic insufficiency on drug
accumulation. Higher intracellular concentrations of telithromycin can help for
curing intracellular pathogens.
Telithromycin has inhibitory effect of
the cytochrome P450 system. Therefore, levels of lots of drugs are enhanced by
telithromycin. It is contraindicated to
give telithromycin to patients taking pimozide or cisapride. When telithromycin
is gived to patients, later simvastatin, lovastatin, and atorvastatin should be
stopped during the telithromycin treatment. Administration of telithromycin and
theophylline with together could
aggravate gastrointestinal adverse effects such as nausea and vomiting.
If coadministration of drugs is necessary, they could be administered 1 hour
apart. Telithromycin reduces sotalol level by reducing its absorption.
Tablo 2. Drug-drug interactions with
Telithromycin is a ketolide
that has some chemical differents from the classic macrolide antibiotics. It
has more activity than erythromycin against macrolide-sensitive organisms.
Telithromycin has a good activity on several erythromycin resistant patogen strains
such as S. aureus and S. Pyogenes.
In vitro studies showed that
telithromycin has similar activity with azithromycin.Clinical studies support
the using of telithromycin to treatment of mild-to-moderate CAP, AECB, and
acute bacterial sinusitis. FDA is confirmed telithromycin for the treatment of mild-to-moderate
CAP. Gemifloxacin, gatifloxacin, and levofloxacin are also agents that using
the treatment of CAP. The activity profile of telithromycin is similar to other
commonly used oral antimicrobial agents. The concentrations of telithromycin in
respiratory tissues and fluids suggest that it will offer an effective
treatment for lower RTIs caused by common pathogens.