Macrolides and Lincosamides

Macrolides, Ketolides and LincosamidesDr.Zulcaif Ahmad

MacrolidesHistoryChemistryClassificationMechanism of ActionAntibacterial SpectrumBacterial ResistancePharmacokineticsAdverse Effects

Introduction

The term Macrolide was originally given to antibiotics produced by species of Streptomyces.In 1950 the first drug of this class was isolated: PicromycinIn 1952 Erythromycin and Carbomycin were introduced into clinic.

General Structure

They all contain three characteristics parts in the molecule:A highly substituted macrocyclic lactone: aglycone.A ketone group.An amino desoxysugar: glycon, and in some of the macrolides, a neutral desoxysugar which are glycosisically attached to the aglycone ring.

The lactone ring usually has 12, 14, or 16 atoms and is often unsaturatedmacrolide antibiotics are weak bases and different salts with pKa range of 6.0-9.0 can be formed on the amino group.Macrolides are water-insoluble molecules. Salts prepared by glucoheptonic and lactobionic salts are water soluble, whereas stearic acid and laurylsulfuric acid salts are water-insoluble. Macrolides are stable in aqueous solutions at or below room temperature. They are unstable in acidic or basic conditions or at high temperatures.

It has been the subject of chemical manipulations to:Increase the water solubility of the drug for parenteral dosage forms.Increase the lipid solubility and hence chemical stability of the drug against aqueous acidic conditions as well as increase in oral absorption and masking the bitter taste of the drug.

Chemical Instability of Macrolide Antibiotics

Macrolides are unstable under acidic conditions and undergo an intramolecular reaction to form an inactive cyclic ketal.

Chemical Instability..The cyclic ketal is the cause of intestinal cramp which is reported after the use of erythromycin.Water-insoluble salts and enteric coated dosage forms of macrolides have less such a side effect.Water insoluble forms cannot take part in the reactions which occur in aqueous solutions.Stearate salt is an example of insoluble salts of erytromycin.

ClassificationMacrolidesErythromycinClarithromycinAzithromycinDirithromycinTelithromycinOleandomycinTylosinSpiramycin

Lincosamides Lincomycin Clindamycin

Mechanism of ActionMacrolides attach to the 50s portion of bacterial ribosomes and inhibit the protein synthesis. Prevent translocation during elongation of protein synthesisTheir binding site is either identical or in close proximity to that for clindamycin and chloramphenicol.

Mechanism of action of erythromycin and clindamycin.

Spectrum of Antibacterial ActivityMacrolides are similar to penicillins regarding their spectrum of activity.They are effective against penicillin-resistant strains.Macrolides are effective against most of the G(+) bacteria, cocci or bacillus, they have antibiotic activity against G(-) cocci ,especially Neisseria Spp too.Macrolide antibiotics are effective against Mycoplasma, Chlamydia, Campylobacter and Legionella in contrast to penicillins.They are less effective against G(-) bacteria, though some strains of H. influenza and Brucella are sensitive to the antibacterial activity of this class of antibiotics.

Typical therapeutic applications of macrolides.

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Bacterial Resistance Methylation of a guanine residue on ribosomal RNA leads to lower affinity toward macrolidesAn active efflux systempresence of a plasmid-associated erythromycin esterase.Clarithromycin and azithromycin show cross-resistance with erythromycin, but telithromycin can be effective against macrolide-resistant organisms.Lack of cell wall permeability to macrolides is the reason why G(-) bacteria are resistant to antibacterial effects of these agents.

PharmacokineticsAbsorption: Enteric coated preparations protect the antibiotic from gastric acid destruction allowing oral absorption Also when stable esterified salts are used.Fate: Widely distributed to all tissues except CNS.Excretion: Metabolized by liver and excreted by bile .Tylosin and telmicosin excreted unchanged in bile and urine.

Administration and fate of the macrolide antibiotics.

Some properties of the macrolide antibiotics.

Inhibition of the cytochrome P450 system by erythromycin, clarithromycin, and telithromycin.

Adverse EffectsEpigastric distress: Common with erythromycinCholestatic jaundice: Especially with the estolate form of erythromycinOtotoxicity: Transient deafness associated with erythromycin, at high dosages.Contraindications: Patients with hepatic dysfunction.Interactions: Inhibit the hepatic metabolism of a number of drugs

Some adverse effects of macrolide antibiotics.

Clinical Applicationof ErythromycinIt is used to treat The upper part of the respiratory tract infections, Soft tissue G(+) infections, Mycoplasma pneumonia caused pneumonia, Campylobacter jejuni enteritis, Chlamydia infections.Gonorrhoea.It is a good choice for penicillin-sensitive cases.

Clarithromycin

6-Methyl ether of erythromycin.Cannot undergo cyclic ketal formation, so doesnt cause cramp in GI.Higher blood concentrations. More lipophyl.Lower doses with less intervals.

Azithromycin

Azalide, a semisynthetic macrolide with a15 membered ring.Stable under acidic conditions, because it doesnt form cyclic ketal.In the treatment of urogenital infections caused by N. gonorrhoeae and Chlamidia trachomatis.Longer half-life.

Oleandomycin

Oleandomycin is isolated from Streptomyces antibuticus. Bacteriostatic effects the same as erythromycin.

Lincosamide

First lincosamide to be discovered is lincomycin, isolated from Streptomyces lincolnensisLincosamides are derivatives of an amino acid and a sulfur-containing octose. Lincosamides, macrolides, and chloramphenicol, although not structurally related, seem to act at this same site. The lincosamides are bacteriostatic or bactericidal depending on the concentration. Activity is enhanced at an alkaline pH.Lincomycin has been superseded by clindamycin, which exhibits improved antibacterial activity.

ClindamycinMechanism same as that of erythromycinGood for anaerobic organisms (Bacteroids)Resistance like erythromycinWell absorbed by the oral route.It distributes well into all body fluids except the CSF.Penetration into bone occurs even in the absence of inflammation.The drug is excreted into the bile or urine .Adverse effect:In addition to skin rashes, serious adverse effect is fatal pseudomembranous colitis caused by C. difficile, which is treated by metronidazole or vancomycin .

Administration and fate of clindamycin.

Ketolides

Ketolides are antibiotics belonging to the macrolides 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.

Ketolides are effective against macrolide-resistant bacteria as well as having a structural modification that makes them poor substrates for efflux-pump mediated resistance. 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.Other ketolides in development include Cethromycin and Solithromycin.

Macrolides and ketolides inhibit protein synthesis by the same mode of action. They bind within the exit tunnel of the large ribosomal subunit, thus blocking the exit of nascent polypeptides. The large ribosomal subunit consists of 2 pieces of rRNA (23S and 5S) and 31 ribosomal proteins. Macrolides and ketolides bind to specific residues of 23S rRNAnamely, the adenine at positions 2058 (A2058) and 2059 (A2059). These specific adenine residues are on domain V of 23S rRNA. In addition, telithromycin binds, via the 11,12 carbamate bridge containing the alkyl-aryl extension, to a specific adenine (A752) on domain II of the 23S rRNA, a region near domain V in the 3-dimensional structure of the ribosome (figure 2). In susceptible organisms, telithromycin binds 10-fold more tightly to ribosomes than erythromycin does, because of the binding to domain II 32