INTRODUCTION 13 hydrogen bond acceptor · Telithromycin has 11

INTRODUCTIONThe rising of bacterial strains thathave 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 haveresistance or  show  lower sensitivity to previous antimicrobialagents. Changing the chemical structure of molecules and introduction ofmolecules with new chemical structure have provided agents able to overcome thepresent resistance mechanism. These search workings are especially atpenicillins, quinolones and macrolides.Eritromycin, the typical macrolide, wasdiscovered in early 1950s.

After this, macrolide antibiotics used for thetherapy of Streptococcus pneumoniae infections.At the same time, macrolides showed broad spectrum antimicrobial activityagainst patogens.The one of the advantages of macrolides is that it is analternative treatment of b-lactam intolerant patients. But, in the last two decades, there isan increasing resistance to macrolides such as erythromycin, azithromycin andclathromycin. To overcome this problem, ketolides were developed. Ketolides arenew major class of semisynthetic eritromycin derivatives with 10-fold greaterribosomal binding affinity because of secondary interaction.The main chemicalcharacteristics of a ketolide is the displacement of cladinose attached to the macrolidering of 6-O-methylerytromycin ring atC-3 position with a ketone moiety.Telithromycin is the first availableoral ketolide.

It is approved by the US Food and Drug Administration (FDA) in2001 and it is introduced into clinical practice.. Telithromycin was developedat Aventis and reached the market as Ketek. Telithromycin is used for treatmentof respiratory tract infections such as mild-to-moderately-severe CAP, chronicbronchitis and acute bacterial sinusitis. Also it is quite effective againstmacrolide resistant Streptecoccuspneumoniae.

  2. CHEMICAL and PHYSICAL PROPERTIES of TELITHROMYCIN·        Molecular formula of telithromycin is C43H65N5O10·        Molecularweight 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 °C3.STRUCTURE and ACTIVITY RELATIONSHIP                             Figure 1. Chemical structure of telithromycin In thisfigure; (a)   corresponds to metoxy group at C6 , increasesacid stability and forestall internal hemiketalization. (b)  corresponds to 3-keto-function,prevents MLSBresistance induction and increases ribosome binding(c)  corresponds to C11/12 carbamate side chain,increases ribosome affinity and increases interaction with MLSB- resistantribosomes.

 Erythromycin is a macrolide antibioticthat have a 14-membered lactone ring with cladinose.In oral administration,erythromycin is sufficiently absorbed from the gastrointestinal tract.If pH ofthe environment is low, for instance in the stomach, erythromycin falls intosome internal changes.After these changes some products are occured and theyhave no antimicrobial activity. By replacing cladinose group ofmacrolides with a keto group, ketolides are obtained.Ketolides aresemisynthetic derivatives of macrolides. Telithromycin is a member of ketolidesand it has large aromatic N-substitued carbamate bridge at position C11-C12.  It also has imidazo-pyridyl group attachmentin 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 toerytromycin.On the other hand thesemodifications increases bioavailability and acid stability of molecule.4.

MECHANISM of ACTIONBacterial ribosomes have 50S and 30Sribosomal subunits. Subunits of ribosome consist protein and rRNA. The smallsubunit of ribosome have an interaction with mRNA and translates the geneticcode. The large subunit shows function as a catalytic center, peptide bondsbetween aminoacids is formed in this unit.

The elongated peptide enters apeptide exit channel within the 50S ribosomal subunit.Ketolides and macrolides inhibit proteinsynthesis with the identical mechanism, . They bind within the exit tunnel ofthe 50S subunit, so blocks the exit of rising polypeptides. 23S rRNA have somespecific residues (A2058 and A2059) on domain V. Macrolides and ketolides bindthese residues. In addition, telithromycin is a veryeffective inhibitor of the translation function at the level of the 50Sribosomal subunit. Telithromycin binds to a specific residue (A752) on domainII of the 23S rRNA, via the 11,12 carbamate bridge containing the alkyl-arylextension.

Due to the binding to domain II, binding efficiency of telithromycin to ribosomes is 10-fold more thanerytromycin. Telithromycin can inhibit the formation of small ribosomal subunitand it can inhibit assembly of the large ribosomal subunit. Figure 2.Secondary structure models of the peptidyl transferase center in domain V of23S rRNA (a) and hairpin 35 in domain II (b) Positions of macrolideinteractions and of mutations that confer macrlide resistance are indicated andnucleotides are circled, respectively.5.

ANTIBACTERIAL ACTIVITYWhen the microbiological profile oftelithromycin is studied, it can be seen that, telithromycin has high in vitroactivity against many common respiratory tract infection pathogens such as S.pneumoniae, S. aureus, Enterococcus faecalis, Enterococcus faecium,Corynebacterium diphtheriae, Listeria monocytogenes, L.

pneumophila andBartonella spp. When the comparing in vitro activity of telithromycin withmacrolides and azolides, telithromycin has good activity  against gram (+) bacteria. Also it is 2-5times more active against gram (+ )bacteria, comparing to clarithromycin.Besides, telithromycin has activity against gram-negative bacteria. However, it has no activity againstMLSB-resistant Staphylococcus aureus,Enterobacteria and Acinetobacter baumanii.

In vitro pharmacodynamicstudies of telithromycin against extracellular or intracellular Helicobacterpylori showed promising results. In addition telithromycin have good invitro activity against intracellular pathogens, such as Rickettsia spp.and Bartonella spp.   Pneumococci are categorized that if the MIC issmaller than 1 µg/mL sensitive to telithromycin, if the MIC is 2 µg/mLintermediately resistant , and if the MIC is higher than 4 µg/mL resistant totelithromycin comparing  witherythromycin A, azithromycin, clarithromycin, roxithromycin, clindamycin,telithromycin is the most active agent.

Minium inhibitory concentration oftelithromycin (MIC50/90) is 0.06/4.0 mg/L against Enterococcus faecalis  MIC50values of telithromycin against Staphylococcus aereus  isolates ranged between 0.06 and 0.

12 mg/Land MIC90 values ranged between 0.12 and 0.25 mg/L. MIC50/90values of telithromycin values range from 0.

03 to 0.25 mg/L when the isolate issusceptible to Erytromycin A.                Table 1. Minimum inhibitory concentrations (MICs) oftelithromycin for key respiratorypathogens6.MECHANISM of RESISTANCE There are two main mechanismof resistance to macrolides: i) modification by methylation, ii) reducedintracellular accumulation due to decreasedinflux or increased efflux of thedrug Pneumococci andstaphylococci have an enzyme that can methylates a specific adenineresidue(A2058)..

After methlyation with A2058, bacteria can not bind macrolidesand bacteria resistant to these agents.Methylation of A2058 reasons resistance toclindamycin, a lincosamide, and to streptogramin type B antibiotics (e.g.,quinupristin) Methylation or substitution of A2058 changes the major contactsite forthe drugs. The erythromycin- resistancemethylase genes (erm genes) codes methylase. Lots of of bacteria such aspneumococci and staphylococci describes methylase genes . The erm genes areexpressed both constitutively and by induction.

If it is expressedconstitutively, the bac- teria test positive in terms of MLSB resistance. Otherwise,the isolates test positive in terms of resistance to macrolides. The resistanceof MLSB is showed by using a disk approximation test. In pneumococci  erm gene usually expressed constitutively.

 Reduced intracellularaccumulation due to decreased in flux or increased efflux of the drug is theother common mechanism of macrolide resistance in pneumococci. Strains thathave this resistance mechanism have the macrolide efflux pump, that uses energyto remove macrolides from the inside of the bacteria. Therefore, the macrolidecould not reach inside the cell (the ribosome). Macrolide efflux gene (meJ)codes the efflux pump.The mechanism of macrolide resistance  consist mutations that influence ribosomalproteins or RNA . For instance, the strains that include point mutations ofA2059 have  resistance because macrolidescan not bind to their ribosomes.

Some mutations or amino acid insertionsinfluence ribosomal proteins and can produce macrolide resistance .7.PHARMACOKINETICS and PHARMACODYNAMICSAccording to an in vivomodel of infections in mice, macrolides can be seperated into two classes. Firstis time above MIC for some macrolides such as erytromycin A, clarithromycin androdixromycin. Second is concentration-dependent killing for azithromycin.Applying the same way, it is demonstratedthat using the area under the serum concentrationsto MIC ratio (AUC/MIC), the best correlation is acquired without regarding thesensitivity of S.

pneumoniae strains to erythromycin A.The pharmacokinetic characteristicsof telithromycin has been defined in patients after single or repeated oraldoses of 800 mg. Thus metabolism and drug interactions of telithromycin hasbeen discovered.After a 800 mg of telithromycin, in one hourthe mean peak plasma concentration (Cmax) was 1.9 mg/L. Afterdosing,the plasma concentration was 0.

03 mg/L at 24 hour. The mean area underthe curve (AUC) was 8.4 mg.h/L, and the terminal  half-life ranges from 10 to 12 hour.

Repeatingthe doses during 10 days, using the AUC ratio, the mean accumulation ratiocalculated as 1.5.Telithromycin is bound to serum proteins,approximately 70% of the molecule is protein bound. The main protein involvedis human serum albumin (45-49%), accounting for a concentration of 2.4 mg/L,with ?1-acid glycoprotein (12-30%) and liporoteins being responsiblefort he remaining part. Thebig part of the metabolism is made by the cytochrome P450 3A4 system, and theother part is made by cytochrome P450-independent mechanisms. Of the systemicallyavailable drug, 7% is excreted in the feces, 13% is excreted in the urine, and37% is metabolized by the liver.

There is an increase in renalelimination in patients with hepatic insufficiency. But, patients that havehepatic impairment and  renal impairment ,the dosage should be decreased to half of the previous dosage. The availability of multiple routes of eliminationreduces the impact of isolated renal or hepatic insufficiency on drugaccumulation. Higher intracellular concentrations of telithromycin can help forcuring  intracellular pathogens.

8.DRUG-DRUG INTERACTIONSTelithromycin has inhibitory effect ofthe cytochrome P450 system. Therefore, levels of lots of drugs are enhanced bytelithromycin.  It is contraindicated togive telithromycin to patients taking pimozide or cisapride. When telithromycinis gived to patients, later simvastatin, lovastatin, and atorvastatin should bestopped during the telithromycin treatment. Administration of telithromycin andtheophylline with together couldaggravate gastrointestinal adverse effects such as nausea and vomiting.If coadministration of drugs is necessary, they could be administered 1 hourapart.

Telithromycin reduces sotalol level by reducing its absorption.           Tablo 2. Drug-drug interactions withtelithromycin 9.CONCLUSIONSTelithromycin is a ketolidethat has some chemical differents from the classic macrolide antibiotics.

Ithas more activity than erythromycin against macrolide-sensitive organisms.Telithromycin has a good activity on several erythromycin resistant patogen strainssuch as S. aureus and S. Pyogenes.In vitro studies showed thattelithromycin has similar activity with azithromycin.Clinical studies supportthe using of telithromycin to treatment of mild-to-moderate CAP, AECB, andacute bacterial sinusitis. FDA is confirmed telithromycin for the treatment of mild-to-moderateCAP.

Gemifloxacin, gatifloxacin, and levofloxacin are also agents that usingthe treatment of CAP. The activity profile of telithromycin is similar to othercommonly used oral antimicrobial agents. The concentrations of telithromycin inrespiratory tissues and fluids suggest that it will offer an effectivetreatment for lower RTIs caused by common pathogens.