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Chloramphenicol
……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………
Chemotherapy (VPT-411)
(Lecture-15)
Dr. Kumari Anjana
Asstt. Professor
Deptt. of Veterinary Pharmacology & Toxicology
Bihar Veterinary College, Bihar Animal Sciences University, Patna
Content of the chapter
Chloramphenicol
Introduction,
Source
chemistry,
classification
spectrum of activity
MOA
Applications
Side effects
Chloramphenicol
• The isolation of chloramphenicol was reported by Ehrlich,
Burkholder and coworkers in the year 1947.
• It was naturally obtained from Streptomyces venezuelae
and was the first antibiotic to be manufactured
synthetically for clinical use.
• Chloramphenicol is used in a variety of infections in
veterinary medicine, particularly those caused by anaerobic
bacteria.
• It is a highly effective broad spectrum antibiotic.
• But this drug causes severe blood dyscracias in human so
carefully used in pet animals and not approved for use in
food animals in many countries.
• Two chloramphenicol congeners viz.
thiamphenicol and florefenicol
(less toxic to bone marrow)
Thiamphenicol:
• Is produced by replacing the nitrophenblic group of
chloramphenicol by a methylsulphonyl group.
• It is less effective but safer than chloramphenicol.
Florfenicol:
• It is a fluorinate derivative of thiamphenicol more effective
than chloramphenicol, resists bacterial destruction and
approved for use in cattle.
Properties
• Chloramphenicol is a highly lipid soluble antibiotic that exists as a
yellowish white crystalline solid.
• It has a nitrobenzene substitution, which is probably responsible
for the antibacterial activity and its intensely bitter taste.
• It is freely soluble is alcohol and acetone, fairly soluble in ether,
less soluble in water, and insoluble in benzene.
• Aqueous solutions of chloramphenicol are neutral and quite
stable, but need protection from light.
• Chloramphenicol is marketed either as a free base or in ester
forms (e.g., palmitate, succinate, or panthothenate salts).
• Chloramphenicol palmitate is insoluble is water and sparingly
soluble in alcohol, so is used for oral administration.
• chloramphenicol succinate (sodium succinate) is freely soluble in
both acetone and water and, therefore, is used for parenteral
injection.
• The inert chloramphenicol esters are hydrolysed in vivo to free
biologically active chloramphenicol.
Chemistry and SAR
• Chloramphenicol (D-threo-2-dichloroacetamido-l
-p-nitrophenyl-l, 3-propanediol) is a derivative of
nitrobenzene and dichloroacetic acid.
• It is unique among natural compounds having a
nitrobenzene moiety in its structure.
• The para-nitro group is not important for
antibacterial activity.
• The p- nitrophenyl group may be changed to
ortho- or meta-nitro compounds or even be
replaced by halogens without significant loss of
activity.
Source : Google image
• Although chloramphenicol exists in 4 stereoisomers, only D-
threo form has antibacterial activity.
• Therefore, in the formation of derivatives such as
palmitate ester, the stereo chemical configuration of the
propanediol side chain must be retained.
• The p-nitro group has been implicated in the irreversible
suppression of bone marrow.
Mechanism of action
• Chloramphenicol inhibits protein synthesis.
• Chloramphenicol readily penetrates into bacterial cells,
probably both by passive and facilitated diffusions.
• Once inside the bacterial cell, it binds reversibly to the 50 S
ribosomal subunit and prevents the activity of peptidyl
transferase enzyme.
• This interferes with transfer of elongating polypeptide chain in
the newly attached aminoacyl t-RNA at ribosome-mRNA
complex.
• By binding specifically to 50 S ribosomal subunit,
chloramphenicol also appears to hinder the access of
aminoacyl tRNA to acceptor site of the ribosomal—mRNA
complex.
• The binding of tRNA to its codon is not affected, but
failure of aminoacyl-tRNA to associate properly with the
acceptor site prevents the subsequent transpeptidation
reaction catalysed by peptidyl transferase.
Source :Pharmacology by Rang and Dale
• Although host ribosomes do not bind as effectively as do
bacterial ribosomes, some host ribosomal protein synthesis
is impaired.
• At high doses, it can inhibit mammalian mitochondrial
protein synthesis as well.
• Bone marrow cell are especially susceptible.
Antimicrobial spectrum
• It is a broad spectrum antibiotic effective against
both Gram positive and Gram negative bacteria and
several anerobes (Bacteroidesfragilis),
as well as Rickettsia, Chlamidia and Mycoplasma like tetracycline.
• It has special efficacy against Salmonella including S. typthi, but less
action on Gram positive cocci.
• Like tetracycline it is inactive against Mycobacteria,
Pseudomonas, many Proteus spp, viruses and fungi.
• Florfenicol also has broad antimicrobial spectrum.
• Bacterial resistance is due to synthesis of chloramphenicol
acetyltransferase (plasmid mediated).
Therapeutic uses
• The use of chloramphenicol should be reserved for serious infections in which the
benefit of the drug is greater than the risk of toxicity.
• It is used for both local and systemic infections in animals: Drug of choice in
Salmonella and Bacteroides septicaemia.
• Also used in Bacterial meningoencephalitis,
Brain abscess,
Ophthalmitis,
Mastitis (Intramammarily and/or parenterally),
Intraocular infections,
Equine dermatophilus infections (haematogenus delivery),
Superficial skin and eye infections and
Otitis externa (as 1% topical preparation).
• In human it is effective in typhoid and paratyphoid fever
but ciprofloxacin or amoxicillin and cotrimoxazole (in adult)
or cefixime/cefoperazone/ceftriaxone (in children) are
similarly effective and less toxic drugs.
Toxicity
Chloramphenicol in man (but not florfenicol) produces two
types syndrome related to bone marrow depression.
Non regenerative anaemia
Reversible aplastic anaemia
Non regenerative anaemia:
• Such blood dyscrsias may also be seen in susceptible
neonatal animals treated with adult doses of
chloramphenicol.
• This is the direct toxic effect of drug related to the
interference with mRNA and protein synthesis in rapidly
multiplying bone marrow cells.
Reversible aplastic anaemia:
• It is sometimes seen in dogs and cats, much more serious
and related to idiosyncratic reaction.
• Thiamphencol and florfenicol, without the nitro group, do
not produce aplastic anaemia.
Gray baby syndrome:
• Chloramphenicol should be used with great care in newborns
because inadequate inactivation and execration of the drug
result in such toxic syndrome – vomiting flaccidity,
hypothermia, and an ashen grey cyanosis followed by CV
collapse and death.
• GI disturbances : Oral administration of chlormphenicol in
monogastric animals causes GI disturbances.
• Hypersensitivity reactions to the antibiotic are uncommon.
• The antibiotic causes immunosuppression so animal should
not be vaccinated while being treated with chloramphenicol.
• In large animal rapid IV injection of preparations containing
propylene glycol may result in haemolysis, collaspse and
death.
Drug interactions
• Chloramphenicol (a potent microsomal enzyme inhibitor) inhibits
the metabolism of many other drugs like phenytoin, barbiturates,
primidone, local anaesthetics and thereby either prolong their
action or precipitate toxicity.
• Phenobarbitone and phenytoin enhance chloramphenicol
metabolism, reduce therapeutic concentration and cause failure
of chemotherapy.
• It should not be combined with bactericidal drugs and drugs that
bind to 50S ribosomal subunit (macrolides and lincosamides).
Dosage and withdrawal
• Chloramphenicol: Oral administration (as capsule or as
palmitate suspension): Calves & foals: 0.5g 2-3 times daily.
• Chloramphenicol –Not approved in food animal
• Chloramphenicol-withdrawal period 14 days
• Florfenicol -withdrawal period 28 days
Summary
• Chloramphenicol was reported by Ehrlich, Burkholder and
coworkers in the year 1947.
• Once inside the bacterial cell, it binds reversibly to the 50
S ribosomal subunit and prevents the activity of peptidyl
transferase enzyme.
• Chloramphenicol
Lecture_15_Chloramphenicol (1).pptx

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Lecture_15_Chloramphenicol (1).pptx

  • 2. Content of the chapter Chloramphenicol Introduction, Source chemistry, classification spectrum of activity MOA Applications Side effects
  • 3. Chloramphenicol • The isolation of chloramphenicol was reported by Ehrlich, Burkholder and coworkers in the year 1947. • It was naturally obtained from Streptomyces venezuelae and was the first antibiotic to be manufactured synthetically for clinical use. • Chloramphenicol is used in a variety of infections in veterinary medicine, particularly those caused by anaerobic bacteria.
  • 4. • It is a highly effective broad spectrum antibiotic. • But this drug causes severe blood dyscracias in human so carefully used in pet animals and not approved for use in food animals in many countries. • Two chloramphenicol congeners viz. thiamphenicol and florefenicol (less toxic to bone marrow)
  • 5. Thiamphenicol: • Is produced by replacing the nitrophenblic group of chloramphenicol by a methylsulphonyl group. • It is less effective but safer than chloramphenicol. Florfenicol: • It is a fluorinate derivative of thiamphenicol more effective than chloramphenicol, resists bacterial destruction and approved for use in cattle.
  • 6. Properties • Chloramphenicol is a highly lipid soluble antibiotic that exists as a yellowish white crystalline solid. • It has a nitrobenzene substitution, which is probably responsible for the antibacterial activity and its intensely bitter taste. • It is freely soluble is alcohol and acetone, fairly soluble in ether, less soluble in water, and insoluble in benzene. • Aqueous solutions of chloramphenicol are neutral and quite stable, but need protection from light.
  • 7. • Chloramphenicol is marketed either as a free base or in ester forms (e.g., palmitate, succinate, or panthothenate salts). • Chloramphenicol palmitate is insoluble is water and sparingly soluble in alcohol, so is used for oral administration. • chloramphenicol succinate (sodium succinate) is freely soluble in both acetone and water and, therefore, is used for parenteral injection. • The inert chloramphenicol esters are hydrolysed in vivo to free biologically active chloramphenicol.
  • 8. Chemistry and SAR • Chloramphenicol (D-threo-2-dichloroacetamido-l -p-nitrophenyl-l, 3-propanediol) is a derivative of nitrobenzene and dichloroacetic acid. • It is unique among natural compounds having a nitrobenzene moiety in its structure. • The para-nitro group is not important for antibacterial activity. • The p- nitrophenyl group may be changed to ortho- or meta-nitro compounds or even be replaced by halogens without significant loss of activity. Source : Google image
  • 9. • Although chloramphenicol exists in 4 stereoisomers, only D- threo form has antibacterial activity. • Therefore, in the formation of derivatives such as palmitate ester, the stereo chemical configuration of the propanediol side chain must be retained. • The p-nitro group has been implicated in the irreversible suppression of bone marrow.
  • 10. Mechanism of action • Chloramphenicol inhibits protein synthesis. • Chloramphenicol readily penetrates into bacterial cells, probably both by passive and facilitated diffusions. • Once inside the bacterial cell, it binds reversibly to the 50 S ribosomal subunit and prevents the activity of peptidyl transferase enzyme. • This interferes with transfer of elongating polypeptide chain in the newly attached aminoacyl t-RNA at ribosome-mRNA complex.
  • 11. • By binding specifically to 50 S ribosomal subunit, chloramphenicol also appears to hinder the access of aminoacyl tRNA to acceptor site of the ribosomal—mRNA complex. • The binding of tRNA to its codon is not affected, but failure of aminoacyl-tRNA to associate properly with the acceptor site prevents the subsequent transpeptidation reaction catalysed by peptidyl transferase.
  • 12. Source :Pharmacology by Rang and Dale
  • 13. • Although host ribosomes do not bind as effectively as do bacterial ribosomes, some host ribosomal protein synthesis is impaired. • At high doses, it can inhibit mammalian mitochondrial protein synthesis as well. • Bone marrow cell are especially susceptible.
  • 14. Antimicrobial spectrum • It is a broad spectrum antibiotic effective against both Gram positive and Gram negative bacteria and several anerobes (Bacteroidesfragilis), as well as Rickettsia, Chlamidia and Mycoplasma like tetracycline. • It has special efficacy against Salmonella including S. typthi, but less action on Gram positive cocci.
  • 15. • Like tetracycline it is inactive against Mycobacteria, Pseudomonas, many Proteus spp, viruses and fungi. • Florfenicol also has broad antimicrobial spectrum. • Bacterial resistance is due to synthesis of chloramphenicol acetyltransferase (plasmid mediated).
  • 16. Therapeutic uses • The use of chloramphenicol should be reserved for serious infections in which the benefit of the drug is greater than the risk of toxicity. • It is used for both local and systemic infections in animals: Drug of choice in Salmonella and Bacteroides septicaemia. • Also used in Bacterial meningoencephalitis, Brain abscess, Ophthalmitis, Mastitis (Intramammarily and/or parenterally), Intraocular infections, Equine dermatophilus infections (haematogenus delivery), Superficial skin and eye infections and Otitis externa (as 1% topical preparation).
  • 17. • In human it is effective in typhoid and paratyphoid fever but ciprofloxacin or amoxicillin and cotrimoxazole (in adult) or cefixime/cefoperazone/ceftriaxone (in children) are similarly effective and less toxic drugs.
  • 18. Toxicity Chloramphenicol in man (but not florfenicol) produces two types syndrome related to bone marrow depression. Non regenerative anaemia Reversible aplastic anaemia
  • 19. Non regenerative anaemia: • Such blood dyscrsias may also be seen in susceptible neonatal animals treated with adult doses of chloramphenicol. • This is the direct toxic effect of drug related to the interference with mRNA and protein synthesis in rapidly multiplying bone marrow cells.
  • 20. Reversible aplastic anaemia: • It is sometimes seen in dogs and cats, much more serious and related to idiosyncratic reaction. • Thiamphencol and florfenicol, without the nitro group, do not produce aplastic anaemia.
  • 21. Gray baby syndrome: • Chloramphenicol should be used with great care in newborns because inadequate inactivation and execration of the drug result in such toxic syndrome – vomiting flaccidity, hypothermia, and an ashen grey cyanosis followed by CV collapse and death.
  • 22. • GI disturbances : Oral administration of chlormphenicol in monogastric animals causes GI disturbances. • Hypersensitivity reactions to the antibiotic are uncommon. • The antibiotic causes immunosuppression so animal should not be vaccinated while being treated with chloramphenicol. • In large animal rapid IV injection of preparations containing propylene glycol may result in haemolysis, collaspse and death.
  • 23. Drug interactions • Chloramphenicol (a potent microsomal enzyme inhibitor) inhibits the metabolism of many other drugs like phenytoin, barbiturates, primidone, local anaesthetics and thereby either prolong their action or precipitate toxicity. • Phenobarbitone and phenytoin enhance chloramphenicol metabolism, reduce therapeutic concentration and cause failure of chemotherapy. • It should not be combined with bactericidal drugs and drugs that bind to 50S ribosomal subunit (macrolides and lincosamides).
  • 24. Dosage and withdrawal • Chloramphenicol: Oral administration (as capsule or as palmitate suspension): Calves & foals: 0.5g 2-3 times daily. • Chloramphenicol –Not approved in food animal • Chloramphenicol-withdrawal period 14 days • Florfenicol -withdrawal period 28 days
  • 25. Summary • Chloramphenicol was reported by Ehrlich, Burkholder and coworkers in the year 1947. • Once inside the bacterial cell, it binds reversibly to the 50 S ribosomal subunit and prevents the activity of peptidyl transferase enzyme. • Chloramphenicol