Chloramphenicol
An antimicrobial substance produced by the growth of certain
strains of Streptomyces venezuelae , but now mainly prepared
synthetically.
A white to greyish-white or yellowish-white, fine crystalline
powder or hne crystals, needles, or elongated plates. Soluble
1 in 400 of water: freely soluble in alcohol, in propylene gly-
col. in acetone, and in ethyl acetate: slightly soluble in ether.
A 2:5% suspension in water has a pH of 4.5 to 7.5. Store in
airtight containers. Protect from light.
Solubility. Both urea and benzalkonium chloride have been
reported to improve the solubility of chloramphenicol in
water: the latter combination reportedly showed synergistic
activity in vitro against Pseudomonas
Stability : Chloramphenicol is reported to be stable inaque-
ous solution over a wide pH range , although stability can be
improved with suitable buffering: one study reported a loss of
about 50% from unbuffered aqueous solutions on storage for
290 days at 20° lo 22°. whereas the loss from solutions buff-
ered to pH 7.4 with borax was only 14%. Loss of chloram-
phenicol (by hydrolysis) is increased by heating: about 4% ii
lost from aqueous solution on heating at 100° for 30 minutes,
and 10% at 115°for abut 30 minutes. Heating at 98°to 100°
for 30 minutes has been suggested for sterilisation of eye
drops and it was calculated that no more than 10~ potency
would be lost in drops sterilised in this manner and stored for
4 months at 20° or 2 years at 4°. However aqueous solutions
must be protected from light since photochemical decompo-
sition occurs. with yellowing of the solution and develop-
ment of an acid pH.
The stability of chloremphenicol in ointment bases has also
been investigated , it was found to be more stable in oil-in-
water emulsion bases than water-in-oil bases, and stability
was better in bases containing wool fat than those with cetyl
alcohol .
Chloramphenicol Sodium Succinate
A white or yellowish-white hygroscopic powder. 1.4 g of
monograph substance is approximately equivalent to I g of
chloramphenicol. Each g of monograph substance represents
about 2.2 mmol of sodium.
Very soluble in water: freely soluble in alcohol: practically
insoluble in ether. A 25% solution in water has a pH of 6.4 to
7.0. Store in airtight containers. Protect from light.
Incompatibilities. Incompatibility or loss of activity has
been reported between chloramphenicol and a wide variety of
other substances. Other factors, especially, drug concentra-
tion. may play a part and many interactions are chiefly seen
with concentrated solutions.
Adverse Effects
Chloramphenicol may cause serious and sometimes
fatal adverse effects. Some of its toxicity is thought
to be due to effects on mitochondrial protein synthe-
sis. The most serious adverse effect of chloramphen-
icol is its depression of the bone marrow, which can
take 2 different forms. The first is a fairly common
dose-related reversible depression occurring usually
when plasma-chloramphenicol concentrations ex-
ceed 25 ng per mL and is characterised by morpho-
logical changes in the bone marrow, decreased iron
utilisation, reticulocytopenia. anaemia, leucopenia.
and thrombocytopenia. This effect may be due to in-
hibition of protein synthesis in the mitochondria of
bone marrow cells.
The second and apparently unrelated form of bone-
marrow toxicity is severe irreversible aplastic anae-
mia. This is fairly rare, with a suggested incidence
of about 1:20000 to 1:50000, although the inci-
dence varies throughout the world, and is not con-
sidered to be dose-related. The aplasia usually
develops after a latent period of weeks or even
months and has been suggested to be the result of a
nitrated benzene radical produced in vivo. It is con-
sidered that victims may have some genetic or bio-
chemical predisposition but there is no way of
identifying susceptible patients. Although the ma-
jority of cases have followed oral administration
aplasia has also occurred after intravenous and topi-
cal (eye drops) dosage of chloramphenicol. Survival
is most likely in those with early onset aplasia but
they may subsequently develop acute non-lympho-
blastic leukaemia.
A toxic manifestation—'the grey syndrome' char-
acterised by abdominal distension, vomiting, ashen -
colour, hypothermia, progressive pallid cyanosis,
irregular respiration, and circulatory collapse fol-
lowed by death in a few hours or days , has occurred
in premature and other newborn infants receiving
large doses of chloramphenicol. The syndrome is as-
sociated with high plasma concentrations of chlo-
ramphenicol. due to reduced capacity for
glucuronidation and decreased glomerular filtration
in children of this age. leading to drug accumula-
tion. Recovery is usually complete if the drug is
withdrawn early enough after onset, but up to 40%
of infants with the full-blown syndrome may die.
The syndrome has also been reported in infants born
to mothers given chloramphenicol in late pregnancy.
A similar syndrome has been reported in adults and
older children given very high doses.
Prolonged oral administration of chloramphenicol
may induce bleeding, either by bone-marrow de-
pression or by reducing the intestinal flora with con-
sequent inhibition of vitamin K synthesis.
Haemolytic anaemia has occurred in some patients
with the Mediterranean form of glucose 6-phos-
phate dehydrogenase deficiency, but is rare in pa-
tients with milder forms of the deficiency.
Peripheral as well as optic neuritis has been reported
in patients receiving chloramphenicol, usually over
prolonged periods. Although ocular symptoms are
often reversible if treatment is withdrawn early, per-
manent visual impairment or blindness has oc-
curred.
Other neurological symptoms have included en-
cephalopathy with confusion and delirium-, mental
depression, and headache. Ototoxicity has also oc-
curred. especially after the use of ear drops.
Hypersensitivity reactions including rashes, fever,
and angioedema may occur especially after topical
use: anaphylaxis has occurred but is rare. Jarisch-
Herxheimer-like reactions may also occur. Gastro-
intestinal symptoms including nausea, vomiting,
and diarrhoea can follow oral administration. Dis-
turbances of the oral and intestinal flora may cause
stomatitis, glossitis, and rectal irritation. Patients
may experience an intensely bitter taste following
rapid intravenous administration of chlorampheni-
col sodium succinate.
A review of the toxicity of chloramphenicol. including the
potential role of the p-nitro group in producing aplastic anae-
mia. Derivatives such as thiamphenicol. which lack this
grouping are not associated with increased incidence ofaplas-
lic anaemia.
Overdosage. Charcoal haemoperfusion was found to be far
superior to exchange transfusion in the removal of chloram-
phenicol from blood, although it did not prevent death in a 7-
week-old infant with the grey baby syndrome following a
dosage error.
Precautions
Chloramphenicol is contra-indicated in patients
with a history of hypersensitivity or toxic reaction to
the drug. It should never be given systemically for
minor infections or for prophylaxis. Repeated
courses and prolonged treatment should be avoided
and it should not be used in patients with pre-exist-
ing bone-marrow depression or blood dyscrasias.
Routine periodic blood examinations are advisable
in all patients, but will not warn of aplastic anaemia.
Concomitant administration of chloramphenicol
with other drugs liable to depress bone-marrow
function should be avoided.
Reduced doses should be given to patients with im-
paired liver function. Excessive blood concentra-
tions may also OCCUT following administration of
usual doses to patients with severe renal impairment
and in premature and full-term neonates who have
immature metabolic processes. Monitoring of
plasma-chloramphenicol concentrations may be de-
sirable in patients with risk factors. A suggested
range for peak plasma concentrations is 10 to 25 ng
per mL and 5 to 15 ng per mL for trough concentra-
tions.
Because of the risk of the 'grey syndrome' newborn
infants should never be given chloramphenicol sys-
temically, unless it may be life-saving and there is
no alternative treatment. The use of chlorampheni-
col is probably best avoided during pregnancy, par-
ticularly in the last trimester, and in nursing mothers
since chloramphenicol given to the mother is dis-
tributed into breast milk.
Chloramphenicol may interfere with the develop-
ment of immunity and it should not be given during
active immunisation.
Ocular use. Ocular chloramphenicol is widely used in Brit-
ain for the treatment of superficial eye infections. In view of
the potential for serious toxicity, such as aplastic anaemia.
following systemic absorption some. particularly in the USA.
have advised that its ocular use should be restricted to situa-
tions where there is no alternative treatment.' However, apart
from patients with a personal or family history of blood dys-
crasias. the use. particularly of short courses, was defended
by several specialists in the UK and the arguments have
been the subject of several reviews. Prospective case-con-
trol studies should help to clarify the risk. and one such in-
volving 145 patients with aplastic anaemia and 1226 controls
found that only 3 of the patients had been exposed to ocular
chloramphenicol and calculated that the absolute risk was no
more than 0.5 cases per million treatment courses.
PORPHYRIA :
Chloramphenicol has been associated with acute attacks of
porphyria and is considered unsafe in patients with porphyria.
Interactions
Chloramphenicol is inactivated in the liver and may.
therefore, interact with drugs that are metabolised
by hepatic microsomal enzymes. For example, chlo-
ramphenicol enhances the effects of coumarin anti-
coagulants such as dicoumarol and warfarin sodium.
some hypoglycaemics such as chlorpropamide and
tolbutamide, and antiepileptics such as phenytoin,
and may reduce the metabolism of cyclophospha-
mide to its active form. Conversely the metabolism
of chloramphenicol may be increased by inducers of
hepatic enzymes such as phenobarbitone or ri-
fampicin. Contradictory results have been reported
with paracetamol and phenytoin.
Chloramphenicol may decrease the effects of iron
and vitamin B); in anaemic patients and impair the
action of oral contraceptives.
For the effects of chloramphenicol on the activity of
other antibacterials, see under Antimicrobial Ac-
tion, below.
Antlepiteptics. For reference to the effects of chloramphen-
icol on phenobarbitone and phenytoin, see their records
respectively. While serum concentrations of chloramphenicol
are usually reduced by the hepatic enzyme induction that oc-
curs with phenobarbitone , when given with phenytoin ele-
vated and potentially toxic serum-chloramphenicol
concentrations have resulted, apparently due to competition
for binding sites, although increased metabolism may alterna-
tively lead to decreased serum-chloramphenicol concentra-
tions.
Cimetidine. Fatal aplastic anaemia of rapid onset has oc-
curred in 2 patients who received intravenous chlorampheni-
col and cimetidine concomitantly. As there is usually a
latent period of 2 weeks to 12 months before aplastic anaemia
develops following chloramphenicol therapy it is plausible
that an additive or synergistic effect may have occurred be-
tween the 2 drugs to cause bone-marrow toxicity.
Cyclophosphamide. For the effect of chloramphenicol on
Cyclophosphamide , see cyclophosphamide.
Oral contraceptives. For the suggestion that chloramphen-
icol may reduce the efficacy of oral contraceptives, see Hor-
monal Contraceptives.
Paracetamol. Contradictory results have been reported in
patients receiving both chloramphenicol and paracetamol.
Buchanan and Moodley' reported an increase in chloram-
phenicol half-life from 3.25 to 15 hours when intravenous pa-
racetamol was given to 6 patients in intensive care 2 hours
after intravenous chloramphenicol. In contrast. Spika and col-
leagues' in a study in 5 children found that the half-life of
intravenous chloramphenicol was reduced from 3 to 1.2
hours, concomitant with an increase in clearance, when oral
paracetamol was given 30 minutes beforehand. Furthermore,
Keams and colleagues' in a study in 26 children found no
evidence of altered disposition when oral paracetamol was
given to patients receiving intravenous chloramphenicol. and
Stein and colleagues' found no significant change in chloram-
phenicol phannacokinetics in 5 patients given oral chloram-
phenicol and paracetamol.
Antimicroblal Action
Chloramphenicol is a bacteriostatic antibiotic with a
broad spectrum of action against both Gram-posi-
tive and Gram-negative bacteria, as well as some
other organisms.
Mechanism of action. Chloramphenicol is thought
to enter sensitive cells by an active transport proc-
ess. Within the cell it binds to the 50S subunit of the
bacterial ribosome at a site adjacent to the site of ac-
tion of the macrolides and clindamycin, and inhibits
bacterial protein synthesis by preventing attachment
of aminoacyl transfer RNA to its acceptor site on the
ribosome. thus preventing peptide bond formation
by peptidyl transferase. The block in protein synthe-
sis results in a primarily bacteriostatic action, al-
though it may be bactericidal to some organisms.
including Haemophilus influenzae, Neisseria men-
ingitidis, and Streptococcus pneumoniae, at concen-
trations about 2 to 4 times the inhibitory
concentration.
Spectrum of activity. Chloramphenicol has activity
against many types of bacteria although in most
cases there are less toxic alternatives available. The
following pathogens are usually susceptible (but see
also Resistance, below).
Gram-positive cocci including staphylococci such
as Staph. epidermidis and some strains of Staph. au-
reus, and streptococci such as Str. pneumoniae, Str.
pyogenes, and the viridans streptococci. Methicillin-
resistant staphylococci and Enterococcus faecalis
are considered to be resistant.
Other Gram-positive species including Bacillus an-
thracis, Corynebacterium diphtheriae, and anaer-
obes such as Peptococcus and Peptostreptococcus
spp.
Gram-negative cocci such as Neisseria meningitidis
and N. gonorrhoeae are usually highly sensitive, as
are Haemophilus influenzae and a variety of other
Gram-negative bacteria including Brucella abortus,
Campylobacter spp.. Legionella pneumophila, Pas-
teurella, and Vibrio spp. The Enterobacteriaceae
vary in their susceptibility, and many strains have
shown acquired resistance, but Escherichia coli, and
strains of Klebsiella spp., Proteus mirabilis, Salmo-
nella, Shigella, and Yersinia spp. have been reported
to be susceptible. Many strains of Enterobacter, in-
dole positive Proteus, and Serratia spp. are resistant.
or at best moderately susceptible. Pseudomonas
aeruginosa is invariably resistant although Burkhol-
deria (formerly Pseudomonas) spp. may be suscep-
tible.
Some Gram-negative anaerobes are susceptible, or
moderately so. including Bacteroides fragilis, Veil-
lonella. and Fusobacterium spp.
Other susceptible organisms include Actinomvces
spp.. Leptospira spp.. spirochaetes such as Trepone-
ma pallidum, chlamydias, mycoplasmas, and rick-
ettsias. Nocardia spp. are resistant.
Chloramphenicol is ineffective against fungi, proto-
zoa, and viruses.
Minimum inhibitory concentrations (MICs) for the
most sensitive organisms such as Haemophilus in-
fluenzae or Neisseria spp. range from about 0.25 to
2 ng per mL, but organisms with MICs of up to
about 12 ng per mL are generally considered sus-
ceptible.
Activity with other antimicrobials. As with other
bacteriostatic antimicrobials the possibility exists of
an antagonistic effect if chloramphenicol is given
with a bactericidal drug, and some antagonism has
been demonstrated in vitro between chlorampheni-
col and various beta lactams and aminoglycosides
but the clinical significance of most of these interac-
tions is usually held to be doubtful. Because of the
adjacency of their binding sites on the ribosome
chloramphenicol may competitively inhibit the ef-
fects of macrolides or lincosamides such as clin-
damycin.
Resistance. Acquired resistance has been widely re-
ported, although the prevalence of resistance has
tended to decline where use of the drug has become
less frequent. The most commonly seen form of re-
sistance has been the production of an acetyltrans-
ferase that inactivates the drug. Such resistance is
usually plasmid-mediated and may be associated
with resistance to other drugs such as the tetracy-
clines. Other mechanisms that may reduce sensitiv-
ity to chloramphenicol include reduced
permeability or uptake, and ribosomal mutation.
The actual incidence of resistance varies considera-
bly in different countries and different centres. Epi-
demics of chloramphenicol-resistant Salmonella
and Shigella spp. have occurred in the past, and al-
though the prevalence of resistance in Salmonella
spp. has been reported to be negligible except in
parts of South or South-east Asia. resistant saimo-
nellal infections acquired in these regions are in-
creasingly being seen elsewhere. Resistance among
Haemophilus and Neisseria spp. occurs, and the lat-
ter may be problematic in developing countries, al-
though it does not yet seem to be widespread.
However, resistant strains of enterococci and pneu-
mococci are reported to ,be relatively common in
some areas, and over 50% of staphylococcal strains
have been reported to show resistance in some hos-
pitals.
Pharmacokinetics
Chloramphenicol is readily absorbed when given by
mouth. Blood concentrations of 10 ).ig per mL or
more may be reached about I or 2 hours after a
single dose of I g by mouth and blood concentra-
tions of about 18.5 ng per mL have been reported
aftermultiple I-g doses. Chloramphenicol palmitate
is hydrolysed to chloramphenicol in the gastro-in-
testinal tract prior to absorption, and the sodium suc-
cinate. which is given parenterally. is probably
hydrolysed to free drug mainly in the liver, lungs.
and kidneys; such hydrolysis may be incomplete in
infants and neonates contributing to the variable
pharmacokinetics in this age group. Chlorampheni-
col sodium succinate is. even in adults, only partial-
ly and variably hydrolysed so that blood
concentrations of chloramphenicol obtained after
parenteral administration of the sodium succinate
are often lower than those obtained after administra-
tion of chloramphenicol by mouth, with up to 30%
of a dose excreted unchanged in the urine before hy-
drolysis can take place.
Chloramphenicol is widely distributed in body tis-
sues and fluids: it enters the CSF, giving concentra-
tions of about 50% of those existing in the blood
even in the absence of meningitis: it diffuses across
the placenta into the fetal circulation, into breast
milk. and into the aqueous and vitreous humours of
the eye. It also enters the aqueous humour following
topical application. Up to about 60% in the circula-
tion is bound to plasma protein. The half-life of
chloramphenicol has been reported to range from
1.5 to 4 hours: the half-life is prolonged in patients
with severe liver impairment and is also much long-
er in neonates. Renal impairment has relatively little
effect on the half-life of the active drug, due to its
extensive metabolism, but may lead to accumulation
of the inactive metabolites.
Chloramphenicol is excreted mainly in the urine but
only 5 to 10% of an oral dose appears unchanged:
the remainder is inactivated in the liver, mostly by
conjugation with glucuronic acid. About 3% is ex-
creted in the bile. However, most is reabsorbed and
only about 1%, mainly in the inactive form. is ex-
creted in the faeces.
The absorption, metabolism, and excretion of chlo-
ramphenicol are subject to considerable interindi-
vidual variation, especially in infants and children.
making monitoring of plasma concentrations neces-
sary to determine pharmacokinetics in a given pa-
Uses and Administration
The liability of chloramphenicol to provoke life-
threatening adverse effects, particularly bone-mar-
row aplasia. has severely limited its clinical useful-
ness, although it is still widely used in some
countries. It should never be given systemically for
minor infections and regular blood counts are usual-
ly advisable during treatment. The third-generation
cephalosporins are now favoured for many of the
former indications of chloramphenicol. There are
consequently few unambiguous indications for the
use of chloramphenicol. It has been used in severe
typhoid and other salmonella infections, although it
does not eliminate the carrier state. Chlorampheni-
col is an alternative to a third-generation cepha-
losporin in the treatment of bacterial meningitis,
both empirically and against sensitive organisms
such as Haemophilus influenzae. It has been used in
the treatment of severe anaerobic infections, partic-
ularly in brain abscesses, and in infections below the
diaphragm where Bacteroides fragilis is often impli-
cated: however, other drugs are usually preferred.
Although the tetracyclines remain the treatment of
choice in rickettsial infections such as typhus and'"
the spotted fevers . Chloramphenicol is also used as
an alternative where the tetracyclines cannot be given.
Other bacterial infections in which chloramphenicol
may be used as an alternative to other drugs include
anthrax, severe systemic infections with Campylo-
bacter fetus, ehrlichiosis, severe gastro-enteritis, gas
gangrene, granuloma inguinale. severe Haemophil-
us influenzae infections other than meningitis (for
example in epiglottitis). listeriosis. severe melioido-
sis plague (especially if meningitis develops), psit-
tacosis , tularaemia (especially when meningitis is
suspected), and Whipple disease.
Chloramphenicol is extensively used in the topical
treatment of ear and. in particular, eye infections.
despite the fact that many of these are mild and self-
limiting. It is also used topically in the treatment of
skin infections.
When given by mouth, chloramphenicol is usually
administered in capsules or as a suspension of chlo-
ramphenicol palmilate. When oral administration is
not feasible water-soluble chloramphenicol sodium
succinate may be given intravenously, but oral ther-
apy should be substituted as soon as possible; an in-
travenous dose should be injected over at least one
minute. Administration by intramuscular injection
is controversial because of doubts whether absorp-
tion is adequate. In some countries chloramphenicol
has been given rectally as suppositories.
Doses are expressed in terms of chloramphenicol
base and are similar whether administered by mouth
or intravenously. For adults and children the usual
dose is 50 mg per kg body-weight daily in divided
doses every 6 hours: up to 100 mg per kg daily may
be given in meningitis or severe infections due to
moderately resistant organisms, although these
higher doses should be reduced as soon as possible.
To minimise the risk of relapse it has been recom-
but mended that treatment should be continued after the
patient's temperature has returned to normal for a
further 4 days in rickettsial diseases and for 8 to 10
days in typhoid fever.
Where there is no alternative to the use of chloram-
phenicol. premature and full-term neonates may be
given daily doses of 25 mg per Kg body weight and
full-term infants over the age of 2 weeks may be given up to 50
mg per kg daily, in 4 divided doses.
Monitoring of plasma concentrations is essential to
avoid toxicity.
In patients with impaired hepatic function or severe
renal impairment the dose of chloramphenicol may
need to be reduced because of decreased metabo-
lism or excretion.
In the treatment of eye infections chloramphenicol
is usually applied as a 0.5% solution or as a 1% oint-
ment.
Chloramphenicol has also been used in the form of
various other derivatives including the arginine suc-
cinate, the cinnamate. the glycinate. the glycinate
sulphate, the palmitoyiglycolate. the pantothenate.
the steaglate, the stearate. and the hydrogen succi-
nate-.
Administration. INTRAMUSCULAR ADMINISTRATION. When
parenteral administration of chloramphenicol is necessary the
intravenous route is generally preferred although the intra-
muscular route has been advocated. Shann and others' report-
ed adequate serum concentrations after intramuscular
injection, contrary to the widely held belief that chloram-
phenicol sodium sufccinate is poorly absorbed by this route.
and claimed that pain on injection was minimal. Following a
study in children with bacterial meningitis they suggested
treatment with intramuscular chloramphenicol for 2 or 3
days, followed by oral therapy. However. Coulthard and
Lamb found that children describe intramuscular chloram-
phenicol as amongst the worst treatments they ever receive,
and certainly much worse than the insertion of intravenous
cannulae.