CHLORAMPHENICOL

1. CHLORAMPHENICOL

2. Introduction
•Chloramphenicol is a broad-spectrum
antibiotic.
•Chloramphenicol is a bacteriostatic antimicrobial
•With the drug's wide use, it became evident
that chloramphenicol could cause serious and
fatal blood dyscrasias. For this reason,
chloramphenicol is now reserved for treatment
of life-threatening infections (e.g., meningitis,
rickettsial infections) in patients who cannot take
safer alternatives because of resistance or
allergies

3. Source
• Originally derived from the bacterium
called Streptomyces Venezuelae,
isolated by David Gottlieb,in 1947.
• But nowa days it is produced
synthetically.

4. Description:
Chloramphenicol is a white crystalline compound
that is soluble in alcohal but slightly soluble in
water and it is bitter in taste. So sometimes we need to
increase its solubility when it is intended to be
administered by IV route and sometimes we need to
mask its taste when it administered in the form of
suspension. Thus chloramphenicol palmitate is
Tasteless but insoluble in water and is used in
suspension while chloramphenicol succinate is soluble
in water but bitter in taste and is used for injections.

7. PK
The usual dosage of chloramphenicol is 50-100
mg/kg/d. Chloramphenicol palmitate is a prodrug that
is hydrolyzed in the intestine to yield free
chloramphenicol. The parenteral formulation is a
prodrug, chloramphenicol succinate, which hydrolyzes
to yield free chloramphenicol, giving blood levels
somewhat lower than those achieved with orally
administered drug. Chloramphenicol is widely
distributed to virtually all tissues and body fluids,
including the central nervous system and cerebrospinal
fluid, such that the concentration of chloramphenicol
in brain tissue may be equal to that in serum.

8. PARAMETER VALUE
Route of
administration
Oral, IV
Metabolism In Liver by conjugation
Excretion Kidney, breast milk
Half Life 1.5 – 3.5 hours
Protein binding
capacity
60%

9. The drug penetrates cell membranes readily.
Most of the drug is inactivated either by conjugation
with glucuronic acid (principally in the liver) or by
reduction to inactive aryl amines. Active
chloramphenicol (about 10% of the total dose
administered) and its inactive degradation products
(about 90% of the total) are eliminated in the urine. A
small amount of active drug is excreted into bile and
feces. The systemic dosage of chloramphenicol need
not be altered in renal insufficiency, but it must be
reduced markedly in hepatic failure. Newborns less
than a week old and premature infants also clear

10. chloramphenicol less well, and the dosage should be
reduced to 25 mg/kg/d.
N)
Parenteral administration of Chloramphenicol is
generally reserved for situations in which oral therapy
is contraindicated, as in the treatment of meningitis
and septicemia or when vomiting prohibits oral
administration.

11. Antimicrobial Spectrum:
Chloramphenicol is a bacteriostatic broad-spectrum
antibiotic that is active against both aerobic and
anaerobic gram-positive and gram-negative organisms.
It is active also against rickettsiae but not chlamydiae.
H influenzae, S. Typhi, N meningitidis, and some
strains of bacteroides are highly susceptible.
It is not active against Pseudomonas aeruginosa or
Enterobacter species.

12. Antibacterial activity
H. Influenzae S. typhi
N. Meningitidis E. coli
S. Pneumoniae V.cholera
Ricketsiae
Anaerobes- clostridium &

13. Therapeutic Uses
 Therapy with chloramphenicol must be
limited to infections for which the benefits of
the drug outweigh the risks of the potential
toxicities. When other antimicrobial drugs
are available that are equally effective and
potentially less toxic than chloramphenicol,
they should be used

14. Chloramphenicol has a wide range
activity that includes gram+, gram-
, aerobic and anaerobic bacteria
Typhoid Fever
Bacterial Meningitis
Anaerobic Infections
Rickettsial Diseases
Brucellosis

15. Chloramphenicol
Clinical uses
Limited because of potential toxicities
(a plastic anaemia &)
1. Typhoid fever- s. typhi ( quinolones are
preffered)
2. Meningitis –
H.influenzae,N.meningitidis,S.pneumoniae
( Ceftriaxone is preffered )
3. Anaerobic infections- B. fragilis
(Metronidazole is the drug
of choice)
4. Rickettsial infections – Doxycycline is preffered
5. Bacterial conjunctivitis ( topical )

17. Exp
Cloramphenicol is not DOC b/c of its adverse effects,
bacterial resistance and availability of better agents.
1.Chloramphenicol is very effective against
H.influenzae meningitis. It is an alternative to a β
lactam antibiotic for treatment of meningococcal
meningitis occurring in patients who have major
hypersensitivity reactions to penicillin or bacterial
meningitis caused by penicillin resistant strains of
pneumococci. The dosage is 50-100 mg/kg/d in four
divided doses.
2. Severe rickettsial infections

18. 3. As drops or ointment, it is used for eye or ear
infections.
4. Chloramphenicol was the DOC for enteric fever but
now it is on reserve list due to availability of safer
drugs (Ciprofloxacin).
5. Since effective CSF levels are obtained, it used
to be a choice for treatment of specific bacterial causes
of meningitis: Haemophilus influenzae, Neisseria
meningitidis, and Strepcoccus pneumoniae.

19. Mechanism of Action
 Chloramphenicol inhibits protein synthesis in
bacteria and, to a lesser extent, in eukaryotic cells.
The drug readily penetrates bacterial cells, probably
by facilitated diffusion.

20. Chloramphenicol is a potent inhibitor of microbial
protein synthesis. It binds reversibly to the 50S subunit
of the bacterial ribosome and inhibits the peptidyl
transferase thus inhibiting the peptide bond formation
b/w peptide chain at P site and amino acid at site A
(protein synthesis)

21. Fig.
Steps in bacterial protein synthesis and targets of
several antibiotics. Amino acids are shown as
numbered circles. The 70S ribosomal mRNA complex
is shown with its 50S and 30S subunits. In step 1, the
charged tRNA unit carrying amino acid 8 binds to the
acceptor site A on the 70S ribosome. The peptidyl
tRNA at the donor site, with amino acids 1 through 7,
then binds the growing amino acid chain to amino acid
8 (transpeptidation, step 2). The uncharged tRNA left
at the donor site is released (step 3), and the new

22. 8-amino acid chain with its tRNA shifts to
the peptidyl site (translocation, step 4). The antibiotic
binding sites are shown schematically as triangles.
Chloramphenicol (C) and macrolides (M) bind to the
50S subunit and block transpeptidation (step 2). The
tetracyclines (T) bind to the 30S subunit and prevent
binding of the incoming charged tRNA unit (step 1).
Note
Chloramphenicol and the macrolide class of
antibiotics both interact with the 50S ribosomal
subunit, chloramphenicol is not a macrolide.
Furthermore, their mechanisms are slightly different.
While chloramphenicol directly interferes with
substrate binding, macrolides sterically block the progression of the growing
peptide

23. MOA (S) (I)
It acts by inhibiting protein synthesis in bacteria by
binding reversibly to 50 S subunit and preventing the
binding of amino aceyl tRNA to the acceptor site on
the 50 S subunit. It interferes with the interaction b/w
peptidyl transferase and amino acid, thereby
preventing peptide bond formation.

24. MOA (L) (i)
Chloramphenicol (Chloromycetin) is a nitrobenzene
derivative that affects protein synthesis by binding to
the 50S ribosomal subunit and preventing peptide
Bond formation. It prevents the attachment of the
amino acid end of aminoacyl-tRNA to the A site,
hence the association of peptidyltransferase with the
amino acid substrate.

25. Resistance:
Bacterial ribosome develops resistance to
chloramphenicol either
1.Decreasing its permeability into the bacterial cell.
2.Inactivation of the drug by acetyl transferase enzyme
produced by resistant organisms which causes
acetylation at 1 and 3 positions.

26. Interaction with other drugs
Chloramphenicol inhibits hepatic microsomal
enzymes that metabolize several drugs. Half-lives are
prolonged, and the serum concentrations of phenytoin,
tolbutamide, chlorpropamide, Cyclophosphamide and
warfarin are increased. Some drugs like chronic administration of
phenobarbitone or acute administration of rifampicin
may increase the elimination of chloramphenicol by
enzyme induction. Like other bacteriostatic inhibitors
of microbial protein synthesis, chloramphenicol can antagonize
bactericidal drugs such as penicillins or aminoglycosides.

27. Adverse Reactions

28. Adverse Reactions----------------------------------
1. Gastrointestinal disturbances
These include Nausea, vomiting, and diarrhea. The
chances of intestinal superinfection (unlike
tetracycline) are rare b/c it is completely absorbed
from GIT.
2. Bone marrow depression (Aplastic anemia) when
used for 1-2 weeks or more.
3. Toxicity for newborn infants (Neonates)
Newborn infants lack an effective glucuronic acid
conjugation mechanism for the degradation and

29. detoxification of chloramphenicol. Consequently,
when infants are given dosages above 50 mg/kg/d, the
drug may accumulate, resulting in the gray baby
syndrome, with vomiting, flaccidity, hypothermia,
gray color, shock, and collapse. To avoid this toxic
effect, chloramphenicol should be used with caution in
infants and the dosage limited to 50 mg/kg/d or less
(during the first week of life) in full-term infants more
than 1 week old and 25 mg/kg/d in premature infants.

30. Toxicity in neonates;
If neonates, specially premature babies, are exposed to
75mg/kg/day or more more of chloramphenicol,
chloramphenicol toxicity, commonly called gray baby
syndrome may develop wihin two to three days of
administration of the drug.It starts with vomiting,
refusal to suck, irregular and rapid respiration,
abdominal distension, periods of cynosis, with loose
green stool. Within another twenty four hours they
become flaccid, develop hypothermia and turns ashes
gray. Metabolic acidosis may appear and death occurs
in 40% of the patients.

31. The mechanisms responsible for he gray syndrome are
1.Failure of the drug to be conjugated with glucuronic
acid due to in adequate activity of glucuronyl
transferase in the liver in the neonate period
2.Inadequate renal excretion of unconjugated drug in
neonate.

32. Preparations available:
1. Chloromax by Pharmedic
Inj. 1 gm chloramphenicol (As sodium succinate)
2. Chloromycetin by parke-Davis/Pfizer
Cap- 250 mg Chloramphenicol base
Susp: Per 5 mL: Chloramphenicol palmitate equiv. to
125 mg chloramphenicol base.
3. Neo-Phenicol by PDH
Susp: Per 5 mL: Chloramphenicol palmitate equiv. to
125 mg chloramphenicol base.

33. Dosage (I)
The usual dose is 50 mg/kg/day in four divided doses:
the usual dose in an adult male is therefore around
750 mg four times daily; this dose is doubled in severe
illness. Half the dose is used in premature babies or
neonates, because they do not metabolise the drug as
effectively.
chloramphenicol is sold as chloramphenicol palmitate
ester. Chloramphenicol palmitate ester is inactive, and
is hydrolysed to active chloramphenicol in the small
intestine. There is no difference in bioavailability
between chloramphenicol and chloramphenicol

34. palmitate.
The intravenous (IV) preparation of chloramphenicol
is the succinate ester, because pure chloramphenicol
does not dissolve in water. This creates a problem:
chloramphenicol succinate ester is an inactive prodrug
and must first be hydrolysed to chloramphenicol; the
hydrolysis process is incomplete and 30% of the dose
is lost unchanged in the urine, therefore serum
concentrations of chloramphenicol are only 70% of
those achieved when chloramphenicol is given orally.
For this reason, the chloramphenicol dose needs to be
increased to 75 mg/kg/day when administered IV in

35. order to achieve levels equivalent to the oral dose. The
oral route is therefore preferred to the intravenous
route.
Chloramphenicol and the liver
Chloramphenicol is metabolised by the liver to
chloramphenicol glucuronate (which is inactive). In
liver impairment, the dose of chloramphenicol must
therefore be reduced. There is no standard dose
reduction for chloramphenicol in liver impairment,
and the dose should be adjusted according to measured
plasma concentrations. Chloramphenicol is also noted
for its cause of "Gray Baby Syndrome" because of infants lack of the enzyme
glucoronyl transferase
which is the main pathway.

36. Clinical features
Toxic levels of chloramphenicol after 2–9 days result
in:
1.Vomiting
2. Ashen gray color of the skin
3. Limp body tone
4. Hypotension (low blood pressure)
5. Cyanosis blue discolouration of lips and skin.
5. Hypothermia
6. Cardiovascular collapse

37. Treatment
Chloramphenicol therapy is discontinued immediately;
exchange transfusion may be required to remove the
drug.
Prevention
The condition can be prevented by using
chloramphenicol at the recommended doses and
monitoring blood levels, or alternatively, third
generation cephalosporins can be effectively
substituted for the drug, without the associated toxicity

38. Cynosis:
Bluish coloration of the skin due to low level of
oxygen in blood.
Hemolytic anemia:
It is characterized by rupture of RBC’s.
Agranulocytosis:
Decrease in no. of granulocytes.
Pancytopenia
The decrease in the number of RBC’s , WBCs and
Platelets.