Journal of Antimicrobial Chemotherapy (1997) 40, 91–98

JAC
Factors affecting the pharmacokinetics of parenteral chloramphenicol
in enteric fever

G. P. Acharyaa, T. M. E. Davisb*, M. Hoc, S. Harrisd, C. Chatauta, S. Acharyaa, N. Tuhladara,

K. E. Kaflea, B. Pokhrela, F. Nostenb, D. A. B. Danceb, A. Smithe, A. Webere and N. J. Whiteb
a
Tribhuvan University Teaching Hospital, Kathmandu, Nepal; bNuffield Department of Clinical Medicine,
Oxford University, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK; cDepartment of
Microbiology and Infectious Diseases, University of Calgary, Calgary, Canada; dUniversity of Calgary Health
Development Project, Tribhuvan University Teaching Hospital, Kathmandu, Nepal; eDepartment of
Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, USA

Chloramphenicol pharmacokinetics were studied in 29 Nepalese adults diagnosed with

uncomplicated enteric fever and randomized to receive succinate ester 30 mg/kg iv or im.
Serial plasma concentrations of chloramphenicol, and iothalamate (to estimate glomerular
filtration rate), antipyrine (hepatocellular function) and Indocyanine Green (liver blood flow)
were measured by HPLC and kinetic parameters estimated by non-compartmental analysis.
In culture-positive patients (n = 16), mean residence times (MRTs) and steady-state volumes
of distribution (Vdss) for iv chloramphenicol (mean ± S.D.; 4.9 ± 0.9 h and 1.9 ± 0.8 L/kg; n = 7)
were less than after im chloramphenicol (12.3 ± 7.3 h and 3.7 ± 2.5 L/kg; n = 9; P < 0.05), with
a higher peak plasma concentration after iv (16.2 ± 9.1 versus 7.8 ± 3.6 mg/L; P < 0.05);
plasma clearance (Clp) was similar in the two groups (368 ± 172 and 310 ± 224 mL/kg/min
after iv and im respectively). In 17 patients examined during convalescence, MRT and Vdss
were less than in acute illness regardless of route chloramphenicol administration. There
were similar changes in chloramphenicol kinetic parameters in culture-negative patients.
Antipyrine Clp and liver blood flow correlated weakly with chloramphenicol Clp in culture-
positive patients (P ≤ 0.1) and were higher in convalescence; no such associations were seen
for iothalamate Clp. These data indicate that iv chloramphenicol produces peak plasma
concentrations which are on average twice those after im injection of the same dose, due
principally to a smaller Vdss. Clp is uninfluenced by route of administration and is determined
more by hepatic metabolism than renal excretion. Intramuscular treatment may result in
sub-therapeutic chloramphenicol concentrations initially, but continued regular iv dosing is
more likely to produce levels at which bone marrow toxicity occurs.

Introduction vomiting and/or altered consciousness. Venous access

Chloramphenicol is a widely available and inexpensive
antibiotic. Despite the emergence of resistant strains of
Salmonella typhi, chloramphenicol is still used as first-line
treatment for enteric fever in many parts of the world.1 It
can be given by mouth or parenterally but the bioavailability
of oral formulations is better than that achieved after im or
iv injection of the succinate ester pro-drug.2 Nevertheless,
parenteral dosing is indicated in patients with nausea,
cannot always be obtained where health-care facilities are
basic and, even when high quality care is available, patient
discomfort and inconvenience, staff time, and risks such as
overhydration and thrombophlebitis may make iv injection
less attractive than im administration. Early data relating
to the relative magnitude of plasma concentrations follow-
ing im and iv injection were conflicting.3,4 Although an
inadequate therapeutic response has been reported after
im administration,5,6 more recent studies in enteric fever

*Corresponding author: Professor T. M. E. Davis, University of Western Australia, Department of Medicine, Fremantle Hospital, PO
Box 480, Fremantle, Western Australia 6160, Australia.
Tel: 61-619-431-3229; Fax: 61-619-431-2977;E-mail: tdavis uniwa.uwa.edu.au

91
© 1997 The British Society for Antimicrobial Chemotherapy
 G. P. Acharya et al.
have suggested that peak plasma chloramphenicol concen-
trations are not influenced significantly by the route of par-
enteral administration.2,7
After iv or im chloramphenicol succinate injection,
approximately one-third of the dose is excreted unchanged
in the urine while the remainder is hydrolysed to free drug
and either excreted in the urine or conjugated in the liver.8
Renal chloramphenicol clearance correlates with indices
of renal function including creatinine clearance9 and an
association between hepatic function and plasma chloram-
phenicol concentrations has been reported.10,11 However,
creatinine clearance is an imprecise measure of glomerular
filtration rate (GFR) and conventional biochemical tests of
liver function reflect more than hepatocellular injury.
Iothalamate, a widely used radiological contrast medium, is
excreted exclusively by the kidney and its clearance from
plasma can provide a valid index of GFR.12 Antipyrine and
Indocyanine Green (ICG) clearance can act as surrogate
markers of hepatocellular function and liver blood flow
respectively.13
In order to characterize the factors affecting chlor-
amphenicol pharmacokinetics after its parenteral adminis-
tration as treatment for enteric fever, we studied the
disposition of chloramphenicol after iv or im injection of
the succinate ester, together with simultaneous estimates
GFR (iothalamate clearance), hepatocellular function
(antipyrine clearance) and liver blood flow (ICG clear-
ance).
Patients and methods
Patients
Twenty-nine Nepalese adults (20 males and nine non-
pregnant females) aged 14–56 years were recruited. Most
were farmers or rural labourers living in the Kathmandu
valley. All had been admitted to Tribhuvan University
Teaching Hospital, Kathmandu, with symptoms of enteric
fever including fever for more than 3 days, headache,
cough, abdominal pain and distension, and constipation or
diarrhoea. Those who had received recent chlorampheni-
col treatment or had a history of chloramphenicol allergy
were excluded. All patients gave informed consent to study
procedures which were approved by the Nepalese Ministry
of Health, Kathmandu.
Methods
Clinical procedures. After clinical assessment, a suitable
forearm vein was cannulated and blood drawn for full blood
count, plasma electrolyte, urea and creatinine
concentrations and liver function tests. Three separate 5
mL volumes of blood were drawn at 15 min intervals for
culture. A bone marrow aspirate was taken for preparation
of a smear and culture, and rectal swab and urine collection
for culture were also performed. Patients were randomized
92
to 30 mg/kg body weight chloramphenicol succinate
(Chloromycetin, Parke Davis Medical, Eastleigh, UK),
equivalent to 21.8 mg/kg chloramphenicol base, to be given
either iv or im. Intramuscular injection was into the ante-
rior thigh. Immediately afterwards, antipyrine (10 mg/kg),
iothalamate (10 mg/kg) and ICG (0.3 mg/kg) were given by
rapid injection into the side-arm of a rapid iv infusion of
sterile normal saline solution. Heparinized blood samples
were taken at time 0 and 4, 5, 6, 8, 10, 12, 14, 16, 20, 25, 30,
45, 60, 90 and 120 min, and at 3, 4, 6 and 8 h. All samples
were kept on ice and centrifuged promptly, and separated
plasma was either assayed within 24 h for ICG concentra-
tion or stored and transported at below 20°C before assay
for chloramphenicol, antipyrine and iothalamate. After the
8 h sample, patients able to tolerate oral medication were
given chloramphenicol 600 mg qds by mouth. Further blood
samples were taken each morning immediately before and
30 min after the first chloramphenicol dose of the day. A
full blood count was also performed on day 3 of treatment
and at discharge (between days 5 and 7). All patients were
asked to complete a 14 day course of chloramphenicol and
to attend for re-examination the day after their last dose.
At this 15 day visit, a second pharmacokinetic study was
performed using an identical protocol to that up to the 8 h
sample in the acute study. A final follow-up visit 28 days
post-admission was scheduled for a repeat full blood count
and biochemical profile, in addition to clinical reassessment
and repeat stool culture.
Microbiological techniques. Blood and bone marrow
cultures were performed in 50 mL Columbia broth incu-
bated at 37°C and routinely subcultured at 12–24 h, 36–48 h
and after 7 days of incubation, on to chocolate and
MacConkey agars. Urine and rectal swabs were cultured
routinely, including selective culture on desoxycholate
citrate agar (DCA) and in selenite broth. Isolates were
identified as S. typhi or Salmonella paratyphi using conven-
tional biochemical tests14 and serological testing for O, H
and Vi antigens. Biochemical results were subsequently
confirmed using the API20E system (bio-Mérieux,
Basingstoke, UK). Antibiotic susceptibility to chlor-
amphenicol, ampicillin, trimethoprim, sulphafurazole,
cefotaxime and ciprofloxacin was tested initially by disc
diffusion15 and MICs were determined subsequently. Sero-
logical tests were not included as these have been shown to
be unreliable for the diagnosis of enteric fever in adults.16
Assay techniques. Plasma chloramphenicol assay was
performed on samples at 0, 14, 30, 60 and 120 min, at 3, 4, 6
and 8 h, and on all pre- and post-dose daily samples, using
HPLC as described previously.17 Indocyanine Green was
assayed within 24 h in plasma from all samples taken
between 0 and 120 min using the method of Grainger et al.18
Plasma antipyrine and iothalamate concentrations were
also determined on these samples by HPLC techniques
which ensure no interference between analytes.19
 Parenteral chloramphenicol in enteric fever
Pharmacokinetic analysis. Pharmacokinetic analysis of
plasma chloramphenicol, iothalamate and antipyrine
concentrations was by model-independent methods. The
Lagrange algorithm was used to calculate area under the
concentration–time curve (AUC) and the product–
moment curve (AUMC). Mean residence time (MRT) is
the ratio AUMC/AUC, the volume of distribution at steady
state (Vdss) is given by the formula (dose AUMC)/
(AUC2), and the plasma clearance (Clp) by dose/AUC. For
both iv and im administration, Vdss and Clp are given as
divided by the fraction of drug absorbed or available (f).
Liver blood flow was estimated using rate constants derived
from a two-compartment pharmacokinetic model with
elimination from the peripheral (liver) compartment.18
Statistical analysis. Data were analysed using parametric
tests (SPSS for Windows, SPSS Inc., Chicago, IL, USA)
and are, unless otherwise stated, reported as mean
standard deviation (S.D.). Two-sample comparisons were
performed by Student’s t-test, multiple comparisons by
analysis of variance, and associations between variables
by Pearson’s product–moment correlation coefficient.
Results
Clinical course
In 16 patients (55%), Salmonella spp. were isolated from
blood and/or bone marrow cultures. Details of culture-
positive patients are summarized in Table I. Of these
patients, 13 were positive for S. typhi and three for S.
paratyphi A. All cultured organisms were fully antibiotic-
sensitive. None of the patients was obtunded or shocked or
had evidence of gastrointestinal bleeding or perforation or
other manifestations of severe infection. All 16 responded
to treatment with a median fever clearance time of 5 days
(range 2–9 days). None of the 14 culture-positive patients
who attended the 28 day review had new symptoms of
enteric fever.
In the other 13 patients (see Table I), no pathogen was
Table I. Details of the 16 patients who were culture-positive for S. typhi (n 13) or
S. paratyphi and 13 who were culture-negative. Data are expressed as mean S.D.
Culture-positive
Age (years)
Number of males
Route (iv/im)
Haemoglobin (g/dL)
White cell count ( 109/L)
Serum creatinine ( mol/L)
Serum bilirubin ( mol/L)
Serum aspartate transaminase (iU/L)
Serum albumin (g/L)
93
isolated from cultures, but all were given a standard course
of chloramphenicol with a satisfactory clinical response.
Five of these culture-negative patients had received anti-
biotics active against local strains of S. typhi (ampicillin,
amoxycillin or co-trimoxazole before presentation. Eleven
of the 16 culture-positive and six of the 13 culture-negative
patients were restudied on day 15.
Haematological indices
None of the 29 patients was anaemic at presentation
(haemoglobin 13.1 3.0 g/dL) and there was only a minor
fall in the mean haemoglobin concentration, with the
lowest point being 12.1 1.4 g/dL immediately after the 14
day chloramphenicol course. There was a similar small fall
in the mean total white cell count from 6.1 2.6 to 5.3 1.5
109/L on day 15, but no patient developed significant
leucopaenia or neutropaenia during treatment. The platelet
count remained stable throughout (172,100 76,000 and
176,000 86,500 109/L on days 1 and 15 respectively). In
the 14 patients who attended for review on day 28, the
mean haemoglobin concentration (13.3 1.5 g/dL), and
white cell (7.6 1.2 109/L) and platelet (261,400 85,000
109/L) counts were all within normal limits.
Chloramphenicol pharmacokinetics
Seven patients randomized to iv treatment proved culture-
positive and seven were culture-negative. The equivalent
patient numbers for im treatment were nine and six,
respectively. Mean S.D. plasma chloramphenicol concen-
trations for culture-positive patients are shown in Figure 1;
the plasma concentration profiles after iv and im adminis-
tration for culture-negative patients were similar (data not
shown). Derived pharmacokinetic parameters by culture
result and route of administration are summarized in Table
II. There was a significantly greater peak concentration
after iv compared with im administration (P 0.012), and
this peak was attained earlier (P 0.015) regardless of the
culture result. The MRT was significantly shorter after iv
Culture-negative
21 4 28 13
13 7
7/9 7/6
14.3 1.6 11.8 3.9
5.6 1.3 6.8 3.5
98 14 91 14
7 3 10 5
32 9 28 8
37 6 37 4
G. P. Acharya et al.

than im injection in both culture-positive and negative

groups (P 0.015) and estimates of Vdss were lower (P
0.045). There was no difference in systemic clearance
between the two routes of administration (P 0.125).
Plasma chloramphenicol concentrations before and after
the first dose of oral therapy from the second to the fourth
day of treatment inclusive in culture-positive patients are
shown in Figure 2. There were no significant differences
between concentrations in those patients who were given
initial iv chloramphenicol and those allocated to the im
route. This was also evident in culture-negative patients (P
0.08; data not shown). Almost all plasma chlorampheni-
col concentrations (trough and peak) were 10 mg/L from
day 2 onwards.
Seventeen patients consented to re-study on day 15 (see
Table II). Overall, peak plasma chloramphenicol concen-
trations were higher at this time than on admission (P
0.025), but times to peak concentration were similar (P
0.4). When the convalescent data were analysed by culture
result and route of injection, only those who received im
antibiotic had significantly higher peak plasma concentra-
tions in convalescence compared with acute illness (P
0.04). However, differences between acute and convales-
cent mean peak concentrations were 3 mg/L (see Table
II). In the culture-positive patients, convalescent values for
both MRT and Vdss were generally lower than those in
acute illness with both iv and im injection (P 0.07; see
Figure 2). No significant differences were found in the case
of culture-negative patients (P 0.4).

Antipyrine clearance
Antipyrine clearance on admission in culture-positive
patients was not significantly different from that in culture-
negative individuals (P 0.17; see Table III). In the series
as a whole, antipyrine clearance during the acute study did
not correlate significantly with chloramphenicol clearance
(r 0.09, n 28, P 0.33). However, when culture-
positive patients were considered as a separate group, a
weak positive association between antipyrine and chlor-
amphenicol clearance was observed (r 0.35, n 15, P
0.10). There was a highly significant reduction in antipyrine
clearance in acute illness compared with that in convales-
cence, both in the series as a whole (P 0.005; n 15) and
in culture-positive patients (P 0.001; see Table III).

Iothalamate clearance
Iothalamate clearance was similar in both culture-positive
and culture-negative patients during the acute study (P
0.4; see Table III). Admission and convalescent values
were also similar (P 0.16). In the total series of patients,
iothalamate clearance in acute illness did not correlate with
chloramphenicol clearance (r 0.24, n 29, P 0.11),
though a weak inverse association was evident in culture-
positive patients (r 0.35, n 16, P 0.10).

94
 Parenteral chloramphenicol in enteric fever

Figure 1. Mean S.D. plasma chloramphenicol concentrations in culture-positive patients who received either an iv ( ) or im ( )
injection at time 0.

Figure 2. Mean S.D. plasma chloramphenicol concentrations before and 30 min after the first dose of oral antibiotic on the second to
the fourth days of treatment in culture-positive patients who received either an iv ( ) or im ( ) injection on the first day of treatment.

chloramphenicol clearance at presentation which was of

Liver blood flow
Estimates of liver blood flow were available for 18 patients
in acute illness (14 of whom were culture-positive) and for
seven in convalescence (see Table III). There was a posi-
tive association between estimates of liver blood flow and
borderline statistical significance (r 0.39, n 14, P
0.08). Hepatic blood flow also tended to parallel antipyrine
clearance in the acute study (r 0.37, n 13, P 0.10).
Although liver blood flow estimates in convalescence were
generally higher than in acute illness (see Table III), no

95
 G. P. Acharya et al.
Table III. Model-independent estimates of antipyrine and iothalamate clearance, and liver blood flow from
Indocyanine Green plasma concentration profiles, on admission and at follow-up in culture-positive and
culture-negative patients randomized to either iv or im chloramphenicol
Acute illnessa
culture-positive culture-negative
Antipyrine Clp (mL/kg/min) 0.43 0.15 0.52
Iothalamate Clp (mL/kg/min) 2.3 0.5 2.2
Liver blood flow (mL/kg/min) 19.3 6.50 17.6
a
For patient numbers see text.
b
P 0.05 versus acute illness.
significant differences were observed in the series as a
whole or in culture-positive patients (P 0.22).
Discussion
Plasma chloramphenicol profiles in both salmonella
culture-positive and culture-negative patients in our series
indicated that peak concentrations were significantly lower
and occurred significantly later after im than iv injection.
This pattern was also found in convalescent studies
performed in a sub-group of the patients. There has been
debate in the literature over several decades as to whether
the route of parenteral administration of chloramphenicol
succinate is an important determinant of plasma chloram-
phenicol per se .8 Our data suggest that im administration
could lead to subtherapeutic concentrations of chloram-
phenicol, at least during initial therapy, in a significant
proportion of patients with enteric fever.
After im injection in our culture-positive patients, mean
plasma chloramphenicol concentrations were 6.7 and 5.4
mg/L at 2 and 5 h, respectively. These values are, allowing
for dose and age, generally low compared with those
in previous studies. McCrumb et al.3 and Ciocatto &
Marchiaro,20 reported mean concentrations of 4–6 mg/L at
these times after 15 mg/kg body weight chloramphenicol
succinate (half the dose used in the present study) given by
im injection to adult patients with acute infections. Ross et
al.21 and Shann et al.7 have reported higher concentrations
(14–17 mg/L) in children at equivalent times after doses of
50 mg/kg and 25 mg/kg respectively. Consistent with
concentration profiles after iv and im injection which did
not differ significantly in the latter study,7 Glazko et al.2
reported plasma chloramphenicol levels at least as high
after im as after iv injection of the succinate ester in small
numbers of healthy adults. These results indicate that
factors such as age and severity of illness make it difficult to
come to firm conclusions regarding the adequacy of im
administration.
Changes in assay methodology over time and the
anatomical site of im injection are also important consider-
ations when reviewing available data. HPLC assays have
96
Convalescencea
culture-positive culture-negative
b
0.33 0.68 0.20b 0.31 0.20
0.9 2.4 0.9 2.3 1.2
6.40 24.4 7.20 23.4 9.60
been used since the 1970s, replacing microbiological,
colorimetric and other methods.8 Our patients had im
injections into the anterior thigh which would reduce the
risk of inadvertent intralipomatous administration as com-
pared with when given into the buttock,22 but mean
concentrations were still lower than those after iv adminis-
tration. Although all our patients recovered, the spread of
resistant S. typhi may mean that the chance of therapeutic
failure after repeated im administration increases, as
reported previously by other authors.5,6
Therapeutic plasma concentrations of chloramphenicol
are considered to range from a trough of 5–10 mg/L to a
peak of 10–20 mg/L.23,24 The majority of our patients
treated initially by im injection were well below these
values during the first 8 h of the study. Institution of oral
therapy after this time and its greater bioavailability
resulted in satisfactory plasma chloramphenicol concentra-
tions the next day regardless of initial route of parenteral
administration. However, none of our patients had
infections severe enough to warrant prolonged parenteral
treatment.
Pharmacokinetic analyses of chloramphenicol concen-
trations after injection of the succinate ester are com-
plicated by the rate of hydrolysis and the associated renal
losses of the succinate pro-drug. Nevertheless, Clp
estimates in our patients were consistent with those
reported previously for patients with essentially normal
hepatic and renal function.8 The significant differences in
MRT are likely to reflect differences in rates of absorption
from the two administration sites.25 Although no statistic-
ally significant differences were found in AUC, estimates
were generally greater after im compared with following iv
injection, suggesting greater bioavailability after im
administration. This could result, at least in part, from
greater renal excretion and/or hepatic metabolism of
chloramphenicol at the higher concentrations achieved
after iv injection.
The majority of our patients had normal hepatorenal
function as judged by conventional biochemical tests.
Nevertheless, sequential determination of antipyrine and
iothalamate clearance revealed that hepatocellular but not
renal function was significantly altered during typhoid
 Parenteral chloramphenicol in enteric fever
fever. Weak associations between chloramphenicol clear-
ance, antipyrine clearance and liver blood flow are consis-
tent with previously published preliminary data relating
serum transaminase and chloramphenicol concentrations
in children with enteric fever.10 A similar relationship in
cirrhosis has been debated,8 but serum chloramphenicol
levels in patients with a variety of liver diseases appear
to be highest in those with the most severe hepatocellular
dysfunction.26
Our patients exhibited no evidence of bone marrow
toxicity during a standard course of chloramphenicol and
no other significant side-effects were observed. Although
adequate patient follow-up in developing countries is often
difficult to achieve, we are not aware of recurrent infec-
tions in any of the patients studied, regardless of their
culture status. A proportion of the culture-negative
patients, especially those who received antimicrobial treat-
ment before admission, may have had typhoid or para-
typhoid fever. The results from culture-positive and
-negative groups were generally similar, especially in the
comparisons between plasma chloramphenicol concentra-
tions after iv and im injection.
We found chloramphenicol to be safe and effective for
the treatment of clinically suspected enteric fever in adult
Nepalese patients. However, im administration resulted in
relatively low plasma chloramphenicol concentrations
which may have remained subtherapeutic for several doses
had this route of administration been maintained. Although
our cases were not severe, there was some evidence of an
association between chloramphenicol metabolism and
both hepatocellular function and liver blood flow, which
could have clinical consequences in patients with more
severe and complicated infections. As susceptibility of S.
typhi to chloramphenicol declines, this will become of
increasing relevance. Bone marrow toxicity is most marked
when the plasma chloramphenicol concentration is 25
mg/L.27 Although such concentrations were not achieved
in most of our patients in the first few days of treatment,
jaundiced patients and those with significantly raised
transaminase concentrations should be assessed haemato-
logically at regular intervals in order to minimize the risk of
toxicity occurring.
Acknowledgements
We are grateful to clinical, nursing and laboratory staff
at Tribhuvan University Teaching Hospital for their co-
operation during the study. This study was supported by
the Wellcome Trust of Great Britain and the Heritage
Foundation of Medical Research, Alberta, Canada.
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Received 28 August 1996; accepted 4 December 1996
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