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 associ-ation of
peptidyltransferase with the amino acid sub-strate. Resistance due to changes
in the ribosome-binding site results in a decreased affinity for the drug,
decreased permeability, and plasmids that code for en-zymes that degrade the
The drug-induced inhibition
of mitochondrial pro-tein synthesis is probably responsible for the associated
Chloramphenicol is a
broad-spectrum antibiotic that is effective against gram-positive and
gram-negative bac-teria, including Rickettsia,
Mycoplasma, and Chlamydia spp.
Chloramphenicol is also effective against most anaerobic bacteria, including Bacteroides fragilis.
Metabolism, and Excretion
Chloramphenicol is rapidly
and completely absorbed from the gastrointestinal tract and is not affected by
food ingestion or metal ions. Parenteral administration is generally reserved
for situations in which oral therapy is contraindicated, as in the treatment of
meningitis and septicemia or when vomiting prohibits oral administra-tion. The
biological half-life of chloramphenicol is 1.5 to 3.5 hours. Although up to 60%
of the drug is bound to serum albumin, it penetrates the brain and CSF and
crosses the placental barrier.
inactivated in the liver by glu-curonosyltransferase and is rapidly excreted
(80–90% of dose) in the urine. About 5 to 10% of the administered drug is
excreted unchanged. Renal elimination is by tu-bular secretion and glomerular
filtration. Other degra-dation pathways are known to exist and may account for
some of the toxicity seen in neonates and children.
The potentially fatal nature
of chloramphenicol-induced bone marrow suppression restricts its use to a few
life-threatening infections in which the benefits out-weigh the risks. There is no justification for its use in
treating minor infections.
Chloramphenicol is no longer
recognized as the treatment of choice for any bacterial infection. In almost
all instances, other effective antimicrobial agents are available. Since
effective CSF levels are obtained, it used to be a choice for treatment of
specific bacterial causes of meningitis: Haemophilus
influenzae, Neisseria menin-gitidis, and
S. pneumoniae. Additionally, it was effective against H. influenzae–related
arthritis, osteomyelitis, and epiglottitis. The development of β-lactamase-producing
strains of H. influenzae increased
the use of chloram-phenicol. However, with the advent of third-generation
cephalosporins such as ceftriaxone and cefotaxime, chlo-ramphenicol use has
significantly decreased. If the pa-tient is hypersensitive to β-lactams,
chloramphenicol administration is appropriate therapy for meningitis caused by N. meningitidis and S. pneumoniae.
Chloramphenicol remains a
major treatment of ty-phoid and paratyphoid fever in developing countries.
However, with increasing resistance to ampicillin,
tri-methoprim-sulfamethoxazole and, to some extent, chlo-ramphenicol,
fluoroquinolones and some third-generation cephalosporins (e.g., ceftriaxone)
have become the drugs of choice. Salmonella infections, such as osteomyelitis,
meningitis and septicemia, have also been indications for chloramphenicol use.
Nevertheless, antibiotic resistance patterns can be a problem. As noted
previously, nonty-phoidal salmonella enteritis is not benefited by treatment
with chloramphenicol or other antibiotics.
Chloramphenicol also is
widely used for the topical treatment of eye infections. It is a very effective
agent because of its extremely broad spectrum of activity and its ability to
penetrate ocular tissue. The availability of safer, less irritating instilled
ophthalmic antibiotics and the increase in fatal aplastic anemia associated
with the use of this dosage form suggest that this agent might best be
Chloramphenicol is an
alternative to tetracycline for rickettsial diseases, especially in children
younger than 8 years, and alone or in combination with other antibi-otics, it
has been used to treat vancomycin-resistant en-terococci. Another indication
for chloramphenicol is in the treatment of serious anaerobic infections caused
by penicillin-resistant bacteria, such as B.
fragilis. Clinda-mycin and metronidazole are now preferred for treat-ment
of anaerobic infections. Chloramphenicol, in com-bination with surgical
drainage, is useful in treating cerebral abscesses caused by anaerobic
bacteria, partic-ularly those that are resistant to penicillin.
Newborn infants, especially
those born prematurely, cannot adequately conjugate chloramphenicol to form the
glucuronide; they also have depressed rates of glomerular and tubular
secretion. Because of these metabolic deficiencies, high levels of free
chloram-phenicol may accumulate and cause a potentially fatal toxic reaction,
the gray baby syndrome. This syndrome
is characterized by abdominal distention, vomiting, pro-gressive cyanosis,
irregular respiration, hypothermia, and vasomotor collapse. The mortality rate
is high. The syndrome also has been observed in older children and is
associated with high serum levels of chloramphenicol.
The presence of multiple
metabolites in the serum of neonates treated with chloramphenicol suggests that
the biotransformation of chloramphenicol takes place by multiple routes to
include oxidation, reduction, and conjugation. The presence of particular
metabolites does not appear to correlate with toxicity.
The most publicized adverse
affects are those in-volving the hematopoietic system; they are manifested by
toxic bone marrow depression or idiosyncratic aplas-tic anemia. The bone marrow
depression is dose related and is seen most frequently when daily doses exceed
4 g and plasma concentrations exceed 25 μg/mL. The bone marrow depression is
characterized by anemia, sometimes with leukopenia or thrombocytopenia, but it
is reversible on discontinuation of chloramphenicol.
Aplastic anemia occurs in
only about 1 in 24,000 to 40,000 cases of treatment. It is not a dose-related
re-sponse and can occur either while the patient is taking chloramphenicol for
days to months after completion of therapy. The aplastic or hypoplastic response
involves all cellular elements of the marrow and is usually fatal. The
mechanism is not known, but it occurs most fre-quently with oral or ocular