Broad spectrum antibiotics chloramphenicol

Broad spectrum antibiotics chloramphenicol, anaerobic,soil bacteria. Description includes Physicochemical Properties,Mechanism of action-50S ribosome ,Inhibits Bacterial protein synthesis,Resistance,Interactions,Indications of chloramphenicol-Pyogenic meningitis.
Anaerobic infections.
Intraocular infections.
Enteric fever
Drug of choice in some conditions.
Urinary tract infections
Topically In conjunctivitis & external ear Infections. Snehal chakorkar

1. Broad Spectrum Antibiotic:
Chloramphenicol
Miss Snehal S. Chakorkar (M.pharm)
Dept Of Pharmacology
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•Chloramphenicolisanantibiotic
producedbyStreptomyces venezuelae
•andothersoilbacteria.
•Chloramphenicolwasfirstdiscovered
in1947.
•Nowproducedsynthetically.
Streptomycesvenezuelae
Introduction:
Chloramphenicol
•broad spectrum of activity against
both aerobic and anaerobic
Gram-positive and Gram-negative
bacteria and rickettsia.

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Physicochemical Properties:
It is a yellowish white crystalline solid but
aqueous solution is quite stable.
It stands boiling,butneeds protection from light.
The nitrobenzene moiety of chloramphenicolis
probably responsible for the antibacterial activity which
produces intensely bitter taste.

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Mechanism of action: Chloramphenicol
Transfer’ of the elongating peptide chain
to the newly attached aminoacyl-tRNAat the
ribosome-mRNA complex
50S ribosome (near the acceptor (A) site) and prevents
peptide bond formation between the newly attached
aminoacidand the nascent peptide chain
Bacterial protein synthesis
Chloramphenicol
By attach to
Interfering with
inhibits
At high doses, it can inhibit mammalian mitochondrial protein
synthesis as well. Bone marrow cells are especially susceptible.

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Antimicrobial spectrum
Chloramphenicolis primarily bacteriostatic, at high concentrations
have been shown to exert cidaleffect on some bacteria, e.g. H.
influenzaeand N. meningitidis.
It is a broad-spectrum antibiotic, gram-positive and negative cocci
and bacilli, rickettsiae, mycoplasma.
Activity Species
Highly active Salmonella S. Typhi(but easily form resistance.)
More active than
tetracyclines
H. influenzae,B. pertussis, Klebsiella, N. meningitidis
and anaerobes including Bact. fragilis.
Less active against gram-positive cocci, spirochetes, certain
Enterobacteriaceaeand Chlamydia.
Ineffective againstEntamoebaand Plasmodia Mycobacteria, Pseudomonas,
many Proteus,
viruses and fungi.

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Resistance
Being orally active, broad spectrum and relatively cheap,
chloramphenicolwas mostly prefer.
Resistance caused due to;
Chloramphenicol
Causes
Formation of an acetyl
transferase(Enzyme) which
inactivates chloramphenicol.
acquisition of R plasmid
Interfering with
ButAcetyl-chloramphenicol does
not bind to the bacterial ribosome

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Chloramphenicol
Transport occurs by passive
diffusion as well as by facilitated
transport
Decreased permeability
in bacterial cell wall
Interfering with
lowered affinity of
bacterial ribosome
Resistance
Resistance cause 2

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Absorption : oral . It is 50–60% bound to plasma proteins
Distribution: very widely distributed:Vd1 L/kg.
It freely penetrates serous cavities and blood-brain barrier
& placenta, secreted in bile and milk.
Metabolism: Conjugated with glucuronicacid in the liver
Excretion: Urine.
Pharmacokinetics

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1. Bone marrow depression: chloramphenicolcauses
of aplasticanaemia, agranulocytosis, thrombocytopenia
or pancytopenia.
(a)Non-dose related idiosyncratic reaction.
(b)Dose and duration of therapy related
myelosuppression:
Adverse effects

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(a) Non-dose related idiosyncratic reaction:
Rare (1 in 40,000), unpredictable, but serious, often
fatal, & has a genetic basis occurs after repeated
courses.
Aplasticanaemia is the most common with higher
mortality.
Many victims after some times develop leukaemia's.
(b) Dose and duration of therapy related
myelosuppression: a direct toxic effect, predictable and
probably due to inhibition of mitochondrial enzyme
synthesis in the erythropoieticcells.
Reversible without long-term sequelae. Liver and kidney
disease predisposes to such toxicity.

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2. Hypersensitivity reactions Rashes, fever, atrophic
glossitis, angioedemaare infrequent.
3. Irritativeeffects Nausea, vomiting, diarrhoea,
pain on injection.
4. Superinfections.
5. Gray baby syndrome It occurred when high doses
(~100 mg/kg) were given prophylacticallyto neonates,
especially premature..

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Chloramphenicolinhibits metabolism of tolbutamide,
chlorpropamide, warfarin, cyclophosphamideand
phenytoin.
If dose adjustments are not done toxicity can occur .
Phenobarbitone, phenytoin, rifampinenhance
chloramphenicolmetabolism → reduce its concentration
→ failure of therapy may occur.
Being bacteriostatic, chloramphenicolcan antagonize
the cidalaction of β-lactams/aminoglycosides.
Interactions

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Clinical use of chloramphenicolfor systemic infections
is highly restricted due to fear of fatal toxicity due to
risk of bone marrow aplasia.
Never use chloramphenicolin;
(a) Minor infections.
(b) Infections treatable by other safer antimicrobials.
(c) Avoid repeated courses.
(d) Daily dose not to exceed 2–3 g; duration of therapy
to be < 2 weeks, total dose in a course < 28 g.
(e) Regular blood counts (especially reticulocyte
count) may detect dose-related bone marrow toxicity
but not the idiosyncratic type.
(f) Combined formulation of chloramphenicol
with any drug meant for internal use.
Restrict Uses ofchloramphenicol

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Indications of chloramphenicolare:
1.Pyogenicmeningitis.
2.Anaerobic infections.
3.Intraocular infections.
4.Enteric fever
5.Drug of choice in some conditions.
6.Urinary tract infections
7.Topically In conjunctivitis& external ear Infections.
Uses

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1. Pyogenicmeningitis:
Third generation cephalosporins(±vancomycin) are
presently the first line drugs for bacterial meningitis
Chloramphenicolin a dose of 50–75 mg/kg/day may be
used as a second line drug for H. influenzaeand
meningococcal meningitis, in young children and
cephalosporin allergic patients, because it has
excellent penetration into CSF.
2. Anaerobic infections : Bact. fragilisand others
(wound infections, intraabdominalinfections, pelvic
abscess, and brain abscess, etc.) respond well to
chloramphenicol.

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3. Intraocular infections: Chloramphenicol
given systemically to attains high concentration in
ocular fluid in condition of endophthalmitiscaused by
sensitive bacteria.
4. Enteric fever: Chloramphenicolwas the first
antibiotic and the drug of choice for typhoid fever till the
1980s
when resistant S. typhiemerged then it became clinically
unreliable; 50–80% isolates showed in vitro resistance.
Being orally active and inexpensive, it may be used only
if the local strain is known to be sensitive and responsive
clinically. 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.

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5. As second choice drug
Brucellosis and rickettsialinfections, in whom
tetracyclinesare contraindicated.
In whooping cough.
6. Urinary tract infections:It should be used only
when the organism is found to be sensitive only to
choramphenicol.
7. Topically In conjunctivitis& external ear
Infections: chloramphenicol0.5–5.0% is highly
effective.

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Reference:
Rang H.P. and Dale M.M.: Pharmacology, Churchill
Livingstone, Edinbergh.
KatzungB.G.: Basic and Clinical Pharmacology,
Lange Medical Publications, California.
Craig C.R. and StitzelR.E.: Modern Pharmacology,
Little Brown and Co., Boston.
Bowman W.C. and Rand M.J.: Textbook of
Pharmacology, Blackwell Scientific Publications,
Oxford.
P.N Bennett & M J Brown: Clinical Pharmacology,
Churchill Livingstone, Edinburgh.
TripathiK.D.: Essentials of Medical Pharmacology,
JaypeeBrothers, Medical Publishers, New Delhi.

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