antibiotics targeting the 50 s ribosomal subunit
TRANSCRIPT
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Antibiotics targeting the 50S ribosomal subunit
Jeevan JacobJR, Pharmacology
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Introduction Chloramphenicol Macrolides Clindamycin Linezolid Streptogramins
Contents
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Introduction
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Chloramphenicol was initially obtained from Streptomyces venezuelae in 1947.
The nitrobenzene moiety of chloramphenicol is probably responsible for the antibacterial activity as well as its intensely bitter taste.
CHLORAMPHENICOL
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It specifically attaches to the 50S ribosome near the acceptor (A) site and prevents peptide bond formation between the newly attached aminoacid and the nascent peptide chain.
Mechanism of action
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Chloramphenicol is primarily bacteriostatic, though high concentrations exert cidal effect on some bacteria, e.g. H. influenzae and N. meningitidis.
It is a broad-spectrum antibiotic, active against gram-positive and negative cocci and bacilli, rickettsiae, mycoplasma.
Antimicrobial spectrum
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Resistance is generally due to acquisition of R plasmid encoded for an acetyl transferase— an enzyme which inactivates chloramphenicol.
Acetyl-chloramphenicol does not bind to the bacterial ribosome.
Resistance
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Decreased permeability into the resistant bacterial cells and lowered affinity of bacterial ribosome for chloramphenicol are the other mechanisms of resistance.
Resistance contd.
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Chloramphenicol is rapidly and completely absorbed after oral ingestion.
It is 50–60% bound to plasma proteins and very widely distributed: volume of distribution 1 L/kg.
It freely penetrates serous cavities and blood-brain barrier: CSF concentration is nearly equal to that of unbound drug in plasma.
It crosses placenta and is secretedin bile and milk
Pharmacokinetics
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Chloramphenicol is primarily conjugated with glucuronic acid in the liver and little is excreted unchanged in urine.
The metabolite is excreted mainly in urine.
Plasma t½ of chloramphenicol is 3–5 hours
Pharmacokinetics contd.
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The commonest route of administration of chloramphenicol is oral—as capsules; 250–500 mg 6 hourly
Preparations and administration
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Bone marrow depression
Hypersensitivity reactions Rashes, fever, atrophic glossitis, angioedema are infrequent.
Nausea, vomiting, diarrhoea, pain on injection.
Adverse effects
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Gray baby syndrome
The baby stopped feeding, vomited, became hypotonic and hypothermic, abdomen distended, respiration became irregular; an ashen gray cyanosis developed in many, followed by cardiovascular collapse and death.
Adverse effects contd.
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It occurs because of inability of the newborn to adequately metabolize and excrete chloramphenicol.
At higher concentration, chloramphenicol blocks electron transport in the liver, myocardium and skeletal muscle, resulting in the above symptoms.
Adverse effects contd.
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Chloramphenicol inhibits metabolism of tolbutamide, chlorpropamide, warfarin, cyclophosphamide and phenytoin.
Phenobarbitone, phenytoin, rifampin enhance chloramphenicol metabolism → reduce its concentration → failure of therapy may occur.
Interactions
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Pyogenic meningitis Anaerobic Infections Intra ocular infections UTI Enteric fever. The dose is 0.5 g 6 hourly (children 50 mg/kg/day) till fever subsides, then 0.25 g 6 hourly for another 5–7 days, because bacteriological cure takes longer
USES
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These are antibiotics having a macrocyclic lactone ring with attached sugars.
Erythromycin is the first member discovered in the 1950s, Roxithromycin, Clarithromycin and Azithromycin are the later additions.
Spiramycin and telithromycin are of minor utility.
Macrolides
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It was isolated from Streptomyces erythreus in 1952.
ERYTHROMYCIN
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Mechanism of action
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It is narrow, includes mostly gram-positive and a few gram negative bacteria.
Enterobacteriaceae, other gram-negative bacilli and B. fragilis are not inhibited.
Antimicrobial spectrum
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All cocci readily develop resistance to erythromycin, mostly by acquiring the capacity to pump it out.
Resistant Enterobacteriaceae have been found to produce an erythromycin esterase.
Alteration in the ribosomal binding site for erythromycin by a plasmid encoded methylase enzyme is an important mechanism of resistance in gram-positive bacteria.
Resistance
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Bacteria that develop resistance to erythromycin are cross resistant to other macrolides as well.
Cross resistance with clindamycin and chloramphenicol also occurs, because the
ribosomal binding sites for all these antibiotics are proximal to each other.
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Erythromycin base is acid labile.
To protect it from gastric acid, it is given as enteric coated tablets, from which absorption is incomplete and food delays absorption by retarding gastric emptying.
Its acid stable esters are better absorbed.
Erythromycin is widely distributed in the body, enters cells and into abscesses, crosses serous membranes and placenta, but not bloodbrain barrier.
Pharmacokinetics
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Therapeutic concentration is attained in the prostate.
It is 70–80% plasma protein bound, partly metabolized and excreted primarily in bile in the active form.
Renal excretion is minor; dose need not be altered In renal failure.
The plasma t½ is 1.5 hr, but erythromycin persists longer in tissues.
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Gastrointestinal -Mild-to-severe epigastric pain is experienced by many patients, especially children, on oral ingestion.
Adverse effects
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Erythromycin stimulates motilin receptors in the g.i.t.—thereby induces gastric contractions, hastens gastric emptying and promotes intestinal motility without significant effect on colonic motility.
On the basis of this action erythromycin has been occasionally used to afford short-term symptomatic relief in diabetic gastroparesis.
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Very high doses of erythromycin have caused reversible hearing impairment.
Hypersensitivity : Rashes and fever are infrequent.
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Hepatitis with cholestatic jaundice resembling viral hepatitis or extrahepatic biliary obstruction occurs with the estolate ester (rarely with ethyl succinate or stearate ester) after 1–3 weeks.
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Incidence is higher in pregnant women.
It clears on discontinuation of the drug, and is probably due to hypersensitivity to the estolate ester; erythromycin base or other esters can be given to these patients without recurrence.
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The clinically significant interactions are—rise in plasma levels of theophylline, carbamazepine, valproate, ergotamine and warfarin.
Several cases of Q-T prolongation, serious ventricular arrhythmias and death have been reported due to inhibition of CYP3A4 by erythromycin/ clarithromycin resulting in high blood levels of concurrently administered terfenadine/ astemizole/cisapride
Drug Interaction
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Clinical Uses of Erythromycin
“Drug of Choice” for
Mycoplasma pneumoniaeLegionella pneumophila Chlamydia pneumoniae, C. trachomatisBordetella pertussis (whooping cough)C. diphtheriae
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New macrolides antibiotics
Advantages :◦Broader spectrum, higher activity◦Orally effective◦High blood concentration◦Longer t 1/2◦Less toxicity◦Mainly used in respiratory tract infection
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Chlorine-substituted derivative of lincosamide called lincomycin
Elaborated by Streptomyces lincolnensis
Clindamycin
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Inhibits protein synthesis – interfering with the formation of initiation complexes and with aminoacyl translocation reactions
Binding site on the 50S subunit of the bacterial ribosome is identical with that for erythromycin.
Mech. Of Action
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Mutation of ribosomal receptor site
Modification of the receptor by a constitutively expressed methylase
Resistance
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Streptococci, staphylococci, and pneumococci
Both gram-positive and gram-negative anaerobes - susceptible
Enterococci and gram negative aerobic organisms (poor permeability) are resistant
Cross resistance to macrolides
Antibacterial spectrum
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Penetrates well into most tissues, with brain and cerebrospinal fluid as well as abscesses
Metabolized by the liver
Excreted in bile and urine
Half-life - 2.5 hours
Pharmacokinetics
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Treatment of skin and soft-tissue infections caused by streptococci and staphylococci
Community-acquired strains of MRSA.
Anaerobic infections caused by Bacteroides sp
Combination with an aminoglycoside or cephalosporin – treat penetrating wounds of the abdomen and the gut
Clinical Uses
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Alternative to Penicillin allergy – prophylaxis of endocarditis in patients with valvular heart disease undergoing certain dental procedures
Clindamycin plus primaquine – effective alternative to trimethoprim-sulfamethoxazole
Uses contd.
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Diarrhea, nausea, and skin rashes.
Impaired liver function
Neutropenia
Risk factor for diarrhea and colitis due to C difficile
Adverse Effects
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This is the first member of a new class of synthetic AMAs ‘Oxazolidinones’ useful in the treatment of resistant gram-positive coccal (aerobic and anaerobic) and bacillary infections.
Linezolid
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It binds to the 23S fraction (P site) of the 50S ribosome and interferes with formation of the ternary N-formylmethioninetRNA (tRNAfMet) -70S initiation complex.
Mech. Of action
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Linezolid is rapidly and completely absorbed orally, partly metabolized nonenzymatically and excreted in urine. Plasma t½ is 5 hrs.
Pharmacokinetics
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Linezolid given orally or i.v. is used for uncomplicated and complicated skin and soft tissue infections
community and hospital acquired pneumonias
bacteraemias and other drug-resistant gram-positive infections.
Uses
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Side effects to linezolid have been few; mostly mild abdominal pain, nausea, taste disturbance and diarrhoea.
Neutropenia, anaemia and thrombocytopenia are infrequent and mostly associated with prolonged use.
Optic neuropathy has occurred after linezolid is given for >4 weeks.
Side Effects
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Quinupristin/dalfopristin is a combination of quinupristin, a streptogramin B, with dalfopristin, a streptogramin A, in a 30:70 ratio.
These compounds are semisynthetic derivatives of naturally occurring pristinamycins, produced by Streptomyces pristinaespiralis.
Streptogramins
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Dalfopristin binds to the 23S portion of the 50S ribosomal subunit, and changes the conformation of it, enhancing the binding of quinupristin.
Quinupristin prevents elongation of the polypeptide,as well as causing incomplete chains to be released.
Dalfopristin directly interferes with polypeptide-chain formation
Mech. Of Action
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It is active against most gram-positive cocci including MRSA, some VRSA and some VRE; as well as certain Neisseria, Legionella and Chlamydia pneumoniae
spectrum
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The combination is bactericidal against strepto and staphylococci but bacteriostatic against E. faecium.
It is being used for serious nosocomial MRSA, VRE and other resistant gram-positive infections.
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The most common side effects are infusion-related events, such as pain and phlebitis at the infusion site and arthralgias and myalgias
Side Effects
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Drug MoA Spectrum ResistanceChloramphenicol Inhibit peptide
bond formationbroad Acetyl
transferaseErythromycin Inhibit
translocationnarrow G –ve esterase
G+ve methylase
Clindamycin Inhibit translocation
Gram positive and negative anaerobes
Methylase modify the receptor
Linezolid Inhibit formation of tRNAfMet 70 S complex
Gram Positive point mutations in 23S ribosomal RNA (rRNA)
Streptogramins inhibition of polypeptide elongation and early termination of protein synthesisnslocation
MRSAVRSAVRE
ribosomal methylase that prevents binding of drug to its target
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Thank You