REVIEWS OF INFECTIOUS DISEASES. VOL. 3, NO.3.

MAY-JUNE 1981
© 1981 by The University of Chicago. 0162-0886/81/0303-0005$02.00

Chloramphenicol: A Review of Its Use in Clinical Practice

Henry M. Feder, Jr., Carl Osier, From the Department of Family Medicine, University of
and Eufronio G. Maderazo Connecticut Health Center, Farmington, Connecticut; and
the Department of Pediatrics, and the Medical Research
Laboratory and Infectious Disease Division, Department of
Medicine, Hartford Hospital, Hartford, Connecticut

Chloramphenicol has certain notable characteristics: it penetrates reliably into the cen-
tral nervous system; it is usually bacteriostatic, but is bactericidal for Hemophilus in-
fluenzae, Streptococcus pneumoniae, and Neisseria meningitidis; it is metabolized in
the liver, and levelsof drug in serum need to be monitored in patients with liver disease
and in neonates. Potential toxicity limits the use of this drug. It has been estimated that
death from aplastic anemia occurs in one of 24,500-40,800 courses of treatment. The in-
cidence of aplastic anemia after parenteral therapy is unknown; however, only a few
cases have been reported. The gray baby syndrome occurred in premature and newborn
infants receiving high or unmodified doses of chloramphenicol. This condition can be
avoided by reduction of dosage and by monitoring levels of drug in the serum of these
infants. The most common toxicity is a reversible, dose-related bone marrow suppres-
sion, which is identified by serial monitoring of reticulocyte and complete blood cell
counts. Many of the indications for use of this drug are still controversial because
studies comparing the toxicity and efficacy of chloramphenicol and of alternative an-
tibiotics have not been done.

Introduced in 1949, chloramphenicol, the first chloramphenicol has reemerged as an important

broad-spectrum antibiotic, quickly gained accep-
tance. It could be given orally or parenterally; it
was easily synthesized and inexpensive; and it was
thought to have no significant toxicity. In 1950,
however, Rich et al. [1] reported aplastic anemia,
and Volini et al. [2] described a dose-related bone
marrow suppression; both conditions were associ-
ated with the use of chloramphenicol. In 1959,
Sutherland [3] reported the gray baby syndrome in
premature and newborn infants who had received
high-dose chloramphenicol therapy. As a result of
the toxicity of this drug and the development of
safer alternative antibiotics, the indications for use
of chloramphenicol narrowed and its use declined.
Recently, with the appearance of ampicillin-resis-
tant Hemophilus influenzae and the increased
knowledge of the pathogenicity of Bacteroides
fragilis in pelvic and intraabdominal infections,
Received for publication July 16, 1980, and in revised form
December 10, 1980.
We wish to thank Drs. Paul Lietman and James C.
McLaughlin for reviewing this manuscript, Dr. Raymond Bart-
lett for assistance in preparing table 1, and Mrs. Eleanor Pro-
copio for preparation of the manuscript.
Please address requests for reprints to Dr. Henry M. Feder,
Department of Family Medicine, University of Connecticut
Health Center, Farmington, Connecticut 06032.
antibiotic. Our purpose is to present a review of
the pharmacology, spectrum of activity, toxicity,
and clinical usages of this drug.
Pharmacology
As the parent compound, chloramphenicol is
available in capsules for oral administration. Un-
modified chloramphenicol cannot be given easily
as a suspension because it is extremely bitter; it
cannot be given parenterally because it is in-
soluble. These problems can be circumvented by
use of the two esters of chloramphenicol. Chlor-
amphenicol palmitate is tasteless in suspension
and can be taken by patients who cannot swallow
capsules. Chloramphenicol succinate is a water-
soluble ester suitable for iv use. These esters have
no antimicrobial activity [4-6], but, after oral or
iv administration, they are hydrolyzed at variable
but usually rapid rates [4-6] and circulate as unes-
terified chloramphenicol. Chloramphenicol suc-
cinate is hydrolyzed by the liver, lungs, and kid-
neys. In infants, 1 hr after iv administration, 170/0
of the drug in the serum remains as chlorampheni-
col succinate whereas 83% is unesterified [7].
Chloramphenicol palmitate is hydrolyzed to chlor-
amphenicol prior to gastrointestinal absorption. A

479
480
25-mg/kg dose of chloramphenicol palmitate
gives mean peak levels of drug in serum of 1"\.119
lig/ml at 2 hr after ingestion, whereas a 25-mg/kg
dose of iv chloramphenicol succinate gives levels
of 28 ug/rnl at 30 min after administration [8].
However, there is no significant difference in the
total mean levels of drug in serum (area under the
curve) between oral chloramphenicol palmitate
and iv chloramphenicol succinate [8]. Unesterified
chloramphenicol in the serum is responsible for
both antimicrobial activity [4-6] and dose-related
toxicity [3, 9]. Chloramphenicol is metabolized
primarily in the liver to chloramphenicol glucuro-
nide [10]. Chloramphenicol glucuronide has no
antimicrobial activity [10] and is not known to
cause toxicity [9]. About 5070-10070 of the chloram-
phenicol is not metabolized but is excreted un-
changed in the urine [10, 11]; 0.14070 is excreted
unchanged in the bile [10]. Chloramphenicol glu-
curonide is excreted mainly by renal tubular secre-
tion, whereas active unesterified chloramphenicol
is excreted by glomerular filtration [10]. There-
fore, the administration of probenecid will result
in increased levels of inactive chloramphenicol
glucuronide in serum while not affecting levels of
active chloramphenicol. Levels of chlorampheni-
col in serum can be measured by use of biologic
[12, 13], enzymatic [14-16], and chromatographic
[17] assays. These assays measure the active parent
compound and not its ester precursors or its inac-
tive metabolites.
Absorption of oral chloramphenicol prepara-
tions is complete [3, 18] and does not decrease in
patients with diarrhea [6]. Because of this reliable
absorption, it has been recommended in the pack-
age insert that oral chloramphenicol be used
whenever possible. Unlike the reliable absorption
of the two oral preparations, the poor and unre-
liable absorption [19, 20] of chloramphenicol suc-
cinate administered im may result in clinical
failures (19].
The half-life of chloramphenicol is 1.6-3.3 hr in
adults [21], whereas in infants and children the
range is 0.87-17.8 hr, with a mean of 5.94 hr [22].
In anuric adults the half-life increases only slightly
to between 3.2 and 4.2 hr [21], and the nontoxic
metabolite, chloramphenicol glucuronide, accum-
ulates. In patients with liver disease or immature
liver function (premature infants and neonates),
the rate of metabolism of chloramphenicol may be
decreased [23, 24]. In patients with advanced cir-
Feder, Osier, and Maderazo
rhosis, the half-life of this drug may increase to
between 3 and 12 hr [21]. This longer half-life may
correlate with the increased level of bilirubin and
the decreased level of albumin in serum [23, 24].
In patients with immature liver function or liver
disease, levels of chloramphenicol in serum cannot
be predicted reliably, and these levels must be
monitored to avoid dose-related toxicity. Toxicity
can usually be avoided by maintenance of serum
concentrations of <25 lig of chloramphenicol/ml
[25]. Both chloramphenicol and bilirubin are
metabolized in the liver; however, they do not
compete and, therefore, this drug does not in-
crease levels of bilirubin in serum [26].
Chloramphenicol has been shown to inhibit the
metabolism of tolbutamide, diphenylhydantoin,
and dicumarol [27, 28]. As a result, it may be nec-
essary to decrease the dosage of these drugs when
they are used simultaneously with chlorampheni-
col. In animals, phenobarbital can increase the
rate of metabolism of chloramphenicol [29]. Black
et al. [30] speculated that this interaction was the
cause for decreased levels of chloramphenicol in
the serum of a neonate treated simultaneously
with both of these drugs. However, Koup et al.
[28] reported that chloramphenicol decreased the
rate of metabolism of phenobarbital. When these
two drugs were used together, this decrease re-
sulted in unexpectedly high levels of phenobarbital
in serum. Unfortunately, the interaction between
these two drugs has not been adequately defined,
and, at the present time, it is advisable to monitor
levels of both chloramphenicol and phenobarbital
in serum when these drugs are used simultaneously.
Chloramphenicol penetrates well into most tis-
sues [31] and tissue fluids such as synovial fluid
[32], pleural fluid [5], ascites fluid [33], aqueous
humor [34], sputum [35], breast milk [36], and the
cerebrospinal fluid in both inflamed and unin-
flamed meninges [5, 37-39]. Levels of chloram-
phenicol in the cerebrospinal fluid of adults are
1"\.150070 of levels achieved in serum [5, 39]. In new-
borns and young infants, penetration is better;
levels of drug in cerebrospinal fluid are 50070-99070
of levels in serum [7, 22].
The recommended dose of chloramphenicol for
adults and children older than four weeks of age is
50-100 mg/kg per day. This dose will usually give
levels of drug in serum in the therapeutic range [9,
40] of 10-20 lig/ml. For premature infants and in-
fants less than two weeks old, the recommended
Chloramphenicol 481

dose is 25 mg/kg per day; for infants two to four
weeks old, the recommended dose is 50 mg/kg per
day. However, the levels of chloramphenicol in
serum are unpredictable in infants less than four
weeks of age [30, 41]; therefore, to avoid toxic ac-
cumulation (levels of >25 ug/ml) [25] of this drug
and to assure levels in the therapeutic range, se-
rum levels must be monitored.
Spectrum of Activity
Table 1 shows the spectrum of activity of chloram-
phenicol. This drug is also active against orga-
nisms not listed in the table, such as streptococci,
Neisseria species, corynebacteria, Listeria, and
anaerobes. It is frequently active against Salmo-
nella and Shigella and is also active against less
frequently recovered pathogens, such as Rickettsia
[42-44], Chlamydia [44], Mycoplasma [45],
Treponema pallidum [46, 47], Borrelia [44], Lep-
tospira [47], Pseudomonas pseudomallei [48], and
Actinomyces [44]. It is not active against Pseudo-
monas aeruginosa, mycobacteria, fungi, and para-
sites.
Chloramphenicol is generally bacteriostatic,
blocking bacterial protein synthesis by reversible
inhibition of the peptidyl transferase reaction at
the 50S subunit of the bacterial ribosomes [49].
However, this drug is usually bactericidal for H.
influenzae [50-52], Streptococcus pneumoniae [50,
52], and Neisseria meningitidis [50, 52]. Overturf
et al. [51] tested 297 isolates of H. influenzae type
b and found, with chloramphenicol, a median
MIC of 0.4 ug/ml and a median MBC of 0.8
IJg/ mi.
In 1951, Jawetz et al. [53] demonstrated in vitro
antagonism between chloramphenicol and penicil-
lin by showing that chloramphenicol could inhibit
the early rapid killing effect of penicillin. In this
study [53] and in others [54-56], chloramphenicol
had to be administered before the penicillin in
order to demonstrate antagonism. Antagonism
caused by chloramphenicol can be explained by
the recent observation [57] that this drug can in-
hibit bacterial autolytic enzymes that contribute to
rapid bacterial killing in the presence of penicillin.
In contrast to the studies demonstrating in vitro
antagonism between these two drugs [53-55],
other studies showed synergism [58-60] or an ad-
ditive effect [55]. The clinical relevance of possible
antagonism, synergism, or additive effect is still
open to question. Two clinical studies [61, 62]

Table 1. Sensitivities to chloramphenicol of bacterial isolates obtained from patients at Hartford Hospital (Hart-
ford, Conn.), 1980.
Percentage susceptible
Organism Total no. of isolates tested to chloramphenicol

Hemophilus influenzae type b 25 100

Hemophilus influenzae, nontypeable 25 100
Citrobacter 25 88
Enterobacter 100 93
Escherichia coli 100 98
Acinetobacter 50 6
Klebsiella 100 93
Proteus mirabilis 100 99
Proteus morganii (Morganella morganii) 25 100
Proteus rettgeri" 25 80
Proteus vulgaris 25 68
Providencia" 25 72
Serratia 50 88
Enterococcus 25 70
Staphylococcus aureus 100 96
Staphylococcus epidermidis 100 74
Bacteroides fragilis group 90 100
Bacteroides melaninogenicus 19 100
Bacteroides species 110 100
Fusobacterium 14 100
NOTE. Sensitivities were determined by the microdilution method; MIC for aerobes was ~8 "'8/ml (exception: MIC for
Hemophilus influenzae was ~4 ",g/ml); for anaerobes, the Wilkins-Chalgren broth microdilution method was used.
* Isolates of Proteus rettgeri and Providencia were gathered in 1979 and tested by disk diffusion method.
482
have reported possible antagonism between a
penicillin and chloramphenicol for treatment of
meningitis. In a prospective study of meningitis,
Mathies et al. [61] reported the deaths of six
(4.1070) of 145 patients treated with ampicillin
alone and 14 (11.4%) of 123 patients treated with
ampicillin, chloramphenicol, and streptomycin
(the latter used for only the first two days of ther-
apy). However, these studies were not repeated
and the results have not been duplicated. Lindberg
et al. [62] reported that children with meningitis
due to H. influenzae had more eighth-nerve se-
quelae when treated with ampicillin and chloram-
phenicol than when treated with ampicillin alone,
whereas the mortality of both groups was equal.
However, this study was neither randomized nor
controlled, and the number of infants studied was
too small to make meaningful conclusions.
Toxicity
The use of chloramphenicol is limited by its toxici-
ty. Two types of toxicity induced by this drug are
potentially fatal: aplastic anemia, which is idio-
syncratic, and the gray baby syndrome, which is
dose-related. A third type of toxicity is a dose-
related bone marrow suppression.
In 1950, Rich et al. [1] reported the first case of
aplastic anemia associated with chloramphenicol;
this condition occurred in a 63-year-old man with
pyuria who had received this drug intermittently
for three months. Since this report, there have
been "-'700 cases [63-68] of chloramphenicol-
related blood dyscrasias in the United States. Most
of these were cases of aplastic anemia. Unfor-
tunately, chloramphenicol-associated aplastic
anemia cannot be predicted by the monitoring of
blood cell counts and, when it occurs, it frequently
does so weeks or months after use of the drug. The
mortality for patients who develop aplastic
anemia associated with chloramphenicol is "-'50%;
however, the prognosis is poorest if aplastic ane-
mia develops two months or more after adminis-
tration of the drug [69].
In 1952, reports of aplastic anemia associated
with chloramphenicol prompted the U.S. Food
and Drug Administration (FDA) to conduct a na-
tional survey of blood dyscrasias [63]. Of 296
cases of aplastic anemia reported, 139 involved
patients who had received chloramphenicol before
developing this condition, and 68% of this latter
Feder, Osier, and Maderazo
group had had intermittent or prolonged therapy
with chloramphenicol. After this survey, labels
were required warning that blood dyscrasias may
be associated with intermittent or prolonged use
of chloramphenicol and that the drug should not
be used for minor infections or indiscriminately.
In a 1954 survey of 349 cases of aplastic anemia,
only 80 cases were associated with chlorampheni-
col, and in most of these the patient had received
the drug prior to the 1952 warning [64]. There-
fore, from 1952-1954, there was a reduction in the
number of cases of aplastic anemia associated
with chloramphenicol; this reduction was perhaps
due to a reduction in usage of the drug.
In 1953, the American Medical Association es-
tablished the Registry on Blood Dyscrasias, which
accumulated data on drugs associated with aplas-
tic anemia. Best [66] reviewed 408 cases of blood
dyscrasias associated with chloramphenicol that
occurred from 1953-1964. He found that this drug
had been prescribed for inappropriate or trivial in-
fections such as the common cold, bronchitis, ton-
sillitis, and acne. In 39070 of the cases, patients had
received chloramphenicol intermittently. Not sur-
prisingly, since this drug was more frequently
prescribed for women than for men, 62070 of those
cases reviewed by Best affected women. Finally,
Best [66] reported a mortality of "-'50070, and non-
white patients had a better prognosis than did
whites. In 1970, the Registry on Blood Dyscrasias
was discontinued but not without argument in
favor of continuing it [70].
Most surveys of blood dyscrasias associated
with chloramphenicol lacked information on the
use of this drug. However, in 1969 Wallerstein et
al. [67] studied the relationship between the use of
chloramphenicol and fatal aplastic anemia in
California from 1963-1964. They estimated that
fatal aplastic anemia associated with this drug oc-
curred in one of 24,500-40,800 courses of treat-
ment and found that fatal aplastic anemia was 13
times more common in patients treated with chlor-
amphenicol than in those who had no exposure to
chloramphenicol during that year. They also
noted that the incidence of idiopathic aplastic
anemia (unassociated with chloramphenicol) in-
creased with age (figure 1). Unfortunately, no in-
formation about chloramphenicol usage by age
groups was available, and, therefore, no correc-
tion for age was made. Consequently, no definite
conclusions can be made regarding the apparent
Chloramphenicol 483

tered chloramphenicol is hard to prove because of

z:
8 20 other variables, such as old age and exposure to
~
:5 other drugs, which are associated with aplastic
ir 18
0
Q..
anemia.
~ 16 The association of aplastic anemia with the use
:J
...J
E 14
of oral preparations of chloramphenicol [71, 72]
a:
UJ
has led some clinicians to administer this drug ex-
Q..
ca:
12 clusively by the iv route, which now appears to be
s:f 10
the preferred route for inpatients. Thus, in a uni-
u versity study of 100 inpatients who received chlor-
;:: 8
CI) amphenicol [77], only four patients received an
:5
Q..
ca: 6
oral preparation. Also, in a study of 202 inpatients
~ at a community hospital who received this drug,
LL
4 only four patients received oral chloramphenicol
:::z:
~ [78]. The association of aplastic anemia with the
UJ
Q 2
0
oral preparation may be due in part to the fact
0-9 20-29 40-49 60-69 80-ABOVE
that a larger number of patients received oral
AGE IN YEARS preparations of this drug. Unfortunately, data are
not available comparing the incidence of aplastic
Figure 1. Frequency of death from idiopathic aplastic
anemia (unassociated with chloramphenicol) by age. anemia after administration of oral vs. parenteral
chloramphenicol and, therefore, firm conclusions
cannot be drawn concerning their relative safety.
clustering of chloramphenicol-associated aplastic A recent editorial [79] discussing the advantages
anemia in the elderly. Also, in contrast to prior of oral chloramphenicol for the treatment of
observations by Best [66], Wallerstein et al. [67] meningitis caused by H. influenzae stated that in
found that all their cases of aplastic anemia countries where oral chloramphenicol is available
associated with chloramphenicol occurred in black without a prescription the incidence of aplastic
patients. anemia is not increased and implied that the asso-
Most cases of aplastic anemia associated with ciation between the oral preparation and aplastic
chloramphenicol have occurred after oral admin- anemia is lacking. It is important to emphasize
istration of the drug [71, 72]. In fact, to our that the association of oral chloramphenicol with
knowledge, there are only six cases in the literature aplastic anemia is firm, and that what is not
where chloramphenicol-associated aplastic anemia known is whether parenteral exposure alone also
occurred after parenteral exposure [67, 68, 73-76]. increases the incidence of aplastic anemia. In
Since 1971, 41 cases of aplastic anemia associated countries where oral chloramphenicol may be used
with this drug have been reported to the FDA (per- indiscriminately, the lack of cases of aplastic
sonal communication; M. Dreis, U.S. Food and anemia most likely reflects a failure of detection
Drug Administration, Drug Experience Division, or of reporting. Until better data are available, the
Rockville, Md.). Three of these cases were asso- best estimate of risk of fatal aplastic anemia fol-
ciated with parenteral administration only. In one lowing the use of chloramphenicol is one for every
of these three cases, a complete record was sent to 24,500-40,800 courses of treatment [67], while the
the FDA. This case involved a 66-year-old man risk may be less with parenteral therapy. This esti-
who was treated prophylactically with iv chloram- mate of risk of fatal aplastic anemia associated
phenicol succinate for coronary artery bypass sur- with the use of chloramphenicol can be put into
gery. Approximately 10 days after the drug had better perspective when it is realized that paren-
been stopped, the patient developed aplastic teral penicillin G is associated with fatal ana-
anemia. Two weeks later the patient died from phylaxis in one of 50,000-67,000 (11 of 800,000 to
sepsis, and an autopsy confirmed the diagnosis of four of 200,000) treated patients [80]. In a smaller
aplastic anemia. In this patient, as in all previously study involving 94,655 patients treated with peni-
reported isolated cases; the definite association be- cillin, one death from anaphylaxis was recorded
tween aplastic anemia and parenterally adminis- [81].
484
In addition to reports of aplastic anemia associ-
ated with orally and parenterally administered
chloramphenicol, cases of aplastic anemia after
prolonged use of chloramphenicol ophthalmic
preparations have been reported [82-84]. The first
reported case involved a patient [82] who devel-
oped aplastic anemia after using 10 ml of a 0.5070
chloramphenicol suspension each month for 23
months. Another patient [84] developed aplastic
anemia after using 6.5 ml of a 0.5% chloramphen-
icol suspension over the course of a year. Finally,
a fatal case of aplastic anemia was reported in a
33-year-old man who used chloramphenicol-poly-
myxin B ophthalmic ointment intermittently for
four months [84]. With only these case reports as
evidence, the causal association of aplastic anemia
with chloramphenicol ophthalmic preparations is
not definite.
Theories regarding the pathogenesis of chlor-
amphenicol-associated aplastic anemia have pro-
liferated. A 1960 communication to the Registry
on Blood Dyscrasias [66] reported aplastic anemia
in a twin exposed to chloramphenicol while the
other twin developed thrombocytopenia after ad-
ministration of this drug. Then, in 1969, Nagao
and Mauer [85] reported aplastic anemia in iden-
tical twins exposed to chloramphenicol. Although
common environmental exposures could not be
ruled out, these findings led to speculation about a
genetic predisposition. It was theorized [86] that a
genetic metabolic defect induced by chloramphen-
icol resulted in damage to undifferentiated mar-
row stem cells [87].
A second hypothesis suggests that certain en-
teric bacteria can produce a specific enzyme that
degrades chloramphenicol to a toxic product [71].
The rarity of these enzyme-producing enteric bac-
teria would explain the infrequency of aplastic
anemia. It is a tempting explanation of the ap-
parent association of aplastic anemia with the oral
forms of this drug.
A third theory was advanced by Yunis [88], who
speculated that the p-nitrosulfathiazole group is
responsible for aplastic anemia by inhibiting DNA
synthesis in marrow stem cells. His theory was
based on the observation that thiamphenicol, a
chloramphenicol derivative not possessing a
p-nitrosulfathiazole group (figure 2) and used in
Europe, has not been assoicated with aplastic
anemia.
A fourth theory [89] proposes that for chloram-
Feder, Osier, and Maderazo
o
HOCH
I
HC(NHCOCHCI 2
6
HOCH
I
2CH3
H9NHCOCHCI2
CH20H CH 20H
Figure 2. Chemical structures of chloramphenicol
(left) and its derivative, thiamphenicol (right).
phenicol to cause aplastic anemia, there must be
some preexisting marrow damage. This theory is
based on studies of mice in which pretreatment
with busulfan to induce marrow damage resulted
in marrow stem cell loss upon subsequent chal-
lenge with chloramphenicol.
The monitoring of blood cell counts cannot be
relied upon to predict aplastic anemia, since the ir-
reversible stage of this disease occurs before
changes are seen. However, periodic monitoring is
valuable for detection of dose-related marrow
suppression. The first signs of chloramphenicol-
induced marrow suppression are increased levels
of iron in serum and vacuolation of marrow eryth-
roblasts [25], a process which is associated with
electron microscopic changes in mitochondrial ul-
trastructure of bone marrow cells [90]. Reticulocy-
topenia, which can be seen three to five days after
initiation of treatment with chloramphenicol, oc-
curs either at the same time as [9] or after the in-
crease in concentration of iron in serum [25]. A
fall in hemoglobin and platelet counts [25, 91] can
occur after reticulocytopenia. Neutropenia, a rare
manifestation of suppression by chloramphenicol,
can occur after the fall in concentration of hemo-
globin [25, 91]. Unfortunately, this sequence of
suppression is not always apparent, and suppres-
sion of one blood element alone can occur. Bone
marrow suppression occurred in 18 of 21 adults
treated with 6 g of chloramphenicol per day, a
dose that was associated with trough levels of drug
in serum of >25 t-tg/ml [25]. Suppression occurred
in two of 20 adult patients receiving 2 g of chlor-
amphenicol per day, a dose that was associated
with trough levels of drug in serum of <10 t-tg/ml
[22].
Vacuolation of marrow erythroid and myeloid
precursors is not specific for marrow suppression
induced by chloramphenicol since it also occurs in
alcoholism, DiGuglielmo syndrome, riboflavin
deficiency, and phenylketonuria [92]. By the ad-
Chloramphenicol
ministration of phenylalanine, Ingall et al. [93] re-
versed the marrow vacuolation associated with
chloramphenicol therapy. They proposed that
chloramphenicol inhibited the incorporation of
phenylalanine into proteins (since chlorampheni-
col is similar in structure to uridine phosphate)
and that a uridine triplet is the genetic code for
phenylalanine. In a subsequent study [94], how-
ever, the protective effect of phenylalanine was
not duplicated.
In a recent controlled study [95], a regimen of
chloramphenicol plus gentamicin was compared
to a regimen of clindamycin plus gentamicin or ti-
carcillin plus gentamicin for treatment of abdom-
inal or pelvic sepsis. The rates of development of
anemia (2%-4.5070) and leukopenia (0-1.5%) were
similar among the three treatment groups; how-
ever, the group receiving chloramphenicol plus
gentamicin had higher rates of reticulocytopenia
(14070 vs. 2% in the other groups) and thrombocy-
topenia (9.5% vs. 2070 in the other groups). It is in-
teresting to note that in this study [95] the rates of
occurrence of anemia were similar among the
three groups.
For patients receiving chloramphenicol, it is
recommended that a hemoglobin determination
and reticulocyte, platelet, and white blood cell
counts be done initially and then every three to
four days. If marrow suppression develops, it may
be reversed by discontinuation of the drug or by
reduction of the dose until trough levels measure
<25 ug/rnl.
The gray baby syndrome was described by
Weiss et al. [96] in 1960 as "abdominal distention,
with or without emesis; progressive pallid
cyanosis, vasomotor collapse, frequently accom-
panied by irregular respiration; and sometimes
death within a few hours of onset of these symp-
toms." It occurred [97] in premature and full-term
infants who received >100 mg of chlorampheni-
col/kg per day for three to five days. It is theo-
rized that chloramphenicol at high levels inhibits
electron transport within mitochondria [98] and
that this inhibition causes circulatory collapse.
The gray baby syndrome is avoided by use of the
recommended reduced dosage of chloramphenicol
for premature infants and neonates. Inadvertent
overdosage of this drug can also cause an adult
form of the gray baby syndrome, as was seen in a
man who was mistakenly given 20 g of chloram-
phenicol by rapid infusion (with a resulting level
485
of drug in serum of 201 ug/rnl) and who went into
shock characterized by circulatory collapse,
cyanosis, and coma [99]. Overdosage of chloram-
phenicol has been successfully treated with ex-
change transfusion [100] or charcoal-column
hemoperfusion [101].
With the exception of gross overdosage, the
gray baby syndrome has been well documented
only in infants younger than 30 days of age and in
premature infants. A six-week-old infant with
bacterial meningitis was reported to have de-
veloped the gray baby syndrome 12 hr after ther-
apy with im chloramphenicol succinate had been
initiated [102]; however, in this case, shock seems
likely to have been due to inadequate treatment of
the meningitis with im chloramphenicol. Craft et
al. [103] noted the occurrence of the gray toddler
syndrome in three infants six to 25 months old
who had received chloramphenicol. However,
these infants also had received iv sulfadimidine.
Allergic reactions associated with the adminis-
tration of chloramphenicol are rare. This drug has
not caused anaphylaxis, and only once has it been
convincingly reported to have caused drug fever
[104]. Two infrequent adverse effects associated
with this drug include optic neuritis [105-107] (re-
lated to chronic use) and hemolytic anemia in pa-
tients with the glucose-6-phosphate dehydrogenase
deficiency of the Mediterranean variant who were
treated with chloramphenicol for typhoid fever
[108, 109]. Additional adverse effects include such
gastrointestinal reactions as nausea, unpleasant
metallic aftertaste, stomatitis, and diarrhea [110].
Dermatologic reactions include vesicular and
maculopapular eruptions [110], but these reac-
tions are rare.
Chloramphenicol has been shown to be an im-
mune suppressant [111, 112]. When compared
with controls, adults treated with this drug have
shown a decreased anamnestic response to tetanus
toxoid; however, the clinical significance of this
effect is not known [111]. Also, chloramphenicol
has been shown to suppress cell-mediated immuni-
ty in vitro [112].
Clinical Indications
Chloramphenicol is the drug of choice for few in-
fections. It is indicated for initial treatment of
serious infections caused by ampicillin-resistant
H. influenzae [113]. For patients allergic to peni-
486
cillins, chloramphenicol is the drug of choice for
meningitis caused by H. influenzae, S. pneu-
moniae, or N. meningitidis [114].
A combination of chloramphenicol and ampi-
cillin has been recommended as initial therapy
[115] for pediatric patients with meningitis pos-
sibly due to H. influenzae; then, if the organism is
determined to be ampicillin-sensitive, chloramphen-
icol can be discontinued. Although chlorampheni-
col alone is effective initial therapy for meningitis
[116] caused by H. influenzae, S. pneumoniae, or
N. meningitidis, the addition of ampicillin is
recommended for infants and children because of
the rare occurrence of resistance of H. influenzae
to chloramphenicol [117-119] . However, the
futility of such an approach (attempting to cover
for all possibilities of drug resistance) was brought
into clearer focus recently when meningitis due to
H. influenzae type b that was resistant to both
chloramphenicol and ampicillin was reported
[120]. A recent report [121] of 1,885 cases of men-
ingitis due to H. influenzae stated that 180/0 of the
isolates were resistant to ampicillin and none were
resistant to chloramphenicol. Because resistance
of H. influenzae to chloramphenicol is very rare
[117-119] and, if present, can be determined
rapidly [122], we recommend an alternate ap-
proach to management of bacterial meningitis in
infants and children. In order to avoid potential
antagonism between chloramphenicol and ampi-
cillin, we would advise initial therapy with chlor-
amphenicol alone and then a continuation of this
drug or a change to ampicillin (if the organism is
sensitive). Studies comparing different therapeutic
approaches are necessary to define optimal man-
agement of meningitis due to H. influenzae.
Chloramphenicol is considered by some clini-
cians to be the drug of choice for typhoid [123,
124] and enteric [72, 123] fevers if these condi-
tions are caused by bacterial strains susceptible to
chloramphenicol [125]. Recent studies comparing
oral therapies have shown that either trimetho-
prim-sulfamethoxazole [126-128] or amoxicillin
[129] is as effective as chloramphenicol for
typhoid fever. However, no large studies have yet
been done comparing iv chloramphenicol with
other antibiotics by this route.
Because of its ability to penetrate the blood-
brain barrier and its activity against the organisms
usually causing brain abscess (especially B. fra-
gilis) , chloramphenicol is one of the drugs of
Feder, Osier, and Maderazo
choice for the treatment of brain abscess [124,
130-133] before the identification of the causative
organism or organisms. It is indicated for menin-
gitis and other infections of the central nervous
system caused by gram-negative bacilli that are re-
sistant either to ampicillin or to other antibiotics
that penetrate well into the central nervous
system. Resistance to chloramphenicol, however,
can develop during therapy [134, 135]. Aminogly-
cosides are an alternative to chloramphenicol but,
when given parenterally, they penetrate poorly in-
to the cerebrospinal fluid [136]. Unfortunately,
when given intrathecally [137] or intraventricular-
ly [138], aminoglycosides did not increase the rate
of survival of neonates with meningitis due to
gram-negative bacilli over the rate of survival for
those treated by the parenteral route only.
The use of chloramphenicol becomes controver-
sial when alternative antibiotics could be admin-
istered. It is frequently difficult to decide which
antibiotic is less toxic and clinically more effec-
tive. Both in vitro and clinical studies have shown
that either chloramphenicol or clindamycin is ef-
fective for anaerobic infections [139-141]. Be-
cause pelvic and abdominal sepsis are frequently
caused in part by anaerobes, including B. fragilis,
chloramphenicol or clindamycin is indicated in the
initial therapy. Carbenicillin, cefoxitin, and
metronidazole are also effective against the an-
aerobes, including most B. fragilis; however, there
are no large controlled clinical studies comparing
these antibiotics to chloramphenicol. In a more re-
cent controlled study [95] involving 175 patients
with serious abdominal or pelvic sepsis due to mixed
aerobic and anaerobic organisms, chlorampheni-
col, clindamycin, and ticarcillin given concomi-
tantly with gentamicin were equally effective.
Anaerobic pulmonary infections, even when B.
fragilis is present, usually respond to penicillin
alone [132], and thus the routine use of chloram-
phenicol is unnecessary for these infections.
Either chloramphenicol or tetracycline is effec-
tive for rickettsial infections [142-145]. In young
children or pregnant women, for whom tetra-
cycline is contraindicated, chloramphenicol should
be used. Although a few cases of successful
therapy with chloramphenicol have been reported
[146, 147], this drug is not indicated for treatment
of bacterial endocarditis because it is usually bac-
teriostatic. Clinical results of its use for such infec-
tions have been poor [146, 148, 149].
Chloramphenicol
Chloramphenicol has few indications for pa-
tients outside the hospital setting. Unfortunately,
it has been used for the treatment of trivial infec-
tions in some patients and, in a number of these,
aplastic anemia has developed [67, 69]. The mis-
use of chloramphenicol was emphasized in a
1973-1974 Tennessee study of outpatients [150]
which showed that, out of 1,061 prescriptions for
chloramphenicol, only one was deemed indicated.
In conclusion, chloramphenicol is a valuable
antibiotic with proven effectiveness and firm indi-
cations. The potential for development of fatal
aplastic anemia (one of 24,500-40,800 treatment
courses) must be considered whenever this drug is
used [67]; however, this toxicity is best put into
perspective when it is realized that parenteral peni-
cillin is associated with fatal anaphylaxis in about
one of every 67,000 treated patients [80]. The as-
sociation of aplastic anemia with oral forms of
chloramphenicol has been well established, where-
as the association of this disease with parenteral
administration needs further study. Reinstituting
a registry for chloramphenicol-associated blood
dyscrasias is one step in this direction. Finally,
controversy concerning the toxicity of and indica-
tions for chloramphenicol will continue until con-
trolled prospective studies comparing this drug
with alternate antibiotics are completed.
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