LESSON 16
CHLORAMPHENICOL AND ITS
DERIVATIVES
CHLORAMPHENICOL is produced by Streptomyces venezuelae, a soil organism first
isolated in 1947 from a soil sample from Venezuela. Chloramphenicol use in animals
intended for food is now banned in the Philippines because chloramphenicol is known
to cause humans aplastic anemia.
CHEMISTRY
Chloramphenicol is a derivative of dichloroacetic acid
and contains a nitrobenzene moiety which makes it
fairly unique among natural antibiotics.
Thiamphenicol is a derivative of chloramphenicol
wherein one pf the hydroxyl groups in the benzene
ring is replaced by a methylsulfonyl group.
Florfenicol is a derivative of thiamphenicol wherein
one of the hydroxyl group os replaced by a flourine
atom.
MECHANISM OF ACTION
Chloramphenicol and its derivatives which are primarily bacteriostatic, inhibit protein
synthesis by binding to 50S ribosomal subunit.
They can also inhibit mitochondrial protein synthesis in mammalian cells. The mammalian
erythropoietic cells seem to be particularly sensitive to these drugs.
ANTIMICROBIAL SPECTRUM AND CLINICAL USE
Chloramphenicol has a broad spectrum pf activity similar to that
of tetracyclines, with a good gram-negative spectrum including:
Haemophilus, Salmonella, E. coli, Enterobacteria, Klebsiella,
Proteus, and Pasteurella. Pseudomonas aeruginosa is resistant.
Anaerobic bacteria, rickettsia, chlamydia, and mycoplasma are
also affected.
It is very useful for:
•Salmonella infections
•Brain abscesses
•Bacterial meningitis
•Intra-ocular infections
In humans, its use is restricted to typhoid fever, or other
severe infections against which no other antibacterial
agents are effective. In general, chloramphenicol should
probably be used as a second choice antibacterial but
may be a first choice for some deep infections of the eye.
The rapid elimination of chloramphenicol in the horse and
frequent dosing needed to maintain therapeutic level
throws some doubt on its usefulness in the horse.
Thiamphenicol and Florfenicol have very similar antibacterial spectrum as
chloramphenicol. In general, thiamphenicol is less potent than chloramphenicol about
half as active as chloramphenicol but with equal activity against Haemophilus,
Bacteroides fragilis, and streptococci. Florfenicol is more potent than thiamphenicol and
is active against some strains resistant to chloramphenicol.
MECHANISM OF RESISTANCE
Resistance to chloramphenicol has increased since the drug was first
introduced. Plasmid – mediated resistance is very important in Gram –
negative bacteria. A specific acetyltransferase acetylates chloramphenicol to
an inactive compound. In Staphylococcus aureus, an inducible form of
chloramphenicol acetyltransferase has been demonstrated.
PHARMACOKINETICS
Absorptio
Absorption
of chloramphenicol after oral administration in monogastric
n
animals is rapid with good bioavailability but absorption after IM or SC is
unpredictable. In adult ruminants, orally administered chloramphenicol is
inactivated by rumen microorganisms.
Distribution
Chloramphenicol has a very wide distribution in the body due to high lipid
solubility. It penetrates intracellular as well as extracellular fluid. Highest
concentrations are attained in the liver, bile, and kidney. Therapeutic
concentration is attained in the brain, CSF, eye, prostate, and milk.
Chloramphenicol crosses the placenta and may affect the fetus. It may penetrate
the eye following topical or subconjunctival administration.
Elimination
Hepatic metabolism is the principal process of elimination of
chloramphenicol. Chloramphenicol glucoronide is the main metabolite
excreted (90%); others are de – acylated or dehalogenated metabolites
(2%), and unchanged drug (8%). There are species variations in the rate
of glucuronidation and his corresponds with variations in elimination half
– life.
For example:
-in the horse, the half – life is about 1 hour, and
-in cat, about 5 hours
-neonates cannot conjugate chloramphenicol as rapidly as
adults and this results in elimination half – life considerably
longer than in adults
Adverse Reactions and Toxicity
Chloramphenicol may:
•reduce appetite
•cause vomiting
•weight loss
•dehydration
•CNS depression
The effects are seen more frequently in cats than in dogs. Bone marrow suppression
(hypoplasia) occurs in most species given high levels of the drug, and is dose –
dependent and reversible.
It is characterized by:
•anemia
•leukopenia, and
•thrombocytopenia
HYPERSENSITIVITY REACTION OCCURS RARELY
Chloramphenicol inhibits hepatic drug metabolism specifically
oxidation and glucuronidation. Consequently, it prolongs the effects
of drugs that are dependent on hepatic microsomal enzymes for
their elimination (e.g. phenobarbital, phenytoin, lidocaine). Like other
broad spectrum antibacterials, chloramphenicol may cause
superinfection.
“Grey Syndrome” occurs in neonatal humans, and in young and adult
cats. This syndrome is characterized by cardiovascular collapse and
cyanosis, and is associated with deficient glucoronide conjugation in
neonates and in cats.
FORMULATIONS
01.
02.
03.
Chloramphenicol is
Chloramphenicol free
Chloramphenicol
available in capsules and
base is exceedingly bitter
palmitate – tasteless; for
liquid suspension for oral
so that formulations are
oral use; inactive as is,
administration, and as
in the form of esters
but hydrolyzed to active
ophthalmic ointment
drug in the circulation.
THANK YOU
VERY MUCH!