JAC

Journal of Antimicrobial Chemotherapy (1999) 44, 243250

Treatment of typhoid fever with azithromycin versus chloramphenicol

in a randomized multicentre trial in India
Thomas Butlera*, C. B. Sridharb, M. K. Dagac, Kamal Pathakd, R. B. Pandite, Rasik Khakhria f,
Chandrashekhar N. Potkarg, Michael T. Zelaskyh and Raymond B. Johnsonh
a

Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA;
b
Saint Johns Medical College and Hospital, Bangalore; cMaulana Azad Medical College, New Delhi;
d
Baroda Hospital, Baroda; eCentral Railway Hospital, Bombay, India; fBureau of Microbiology, Ottawa,
Ontario, Canada; gPfizer Limited, Bombay, India and hCentral Research Division, Pfizer Inc.,
Groton, CT, USA
To compare the clinical and bacteriological efficacies of azithromycin and chloramphenicol for
treatment of typhoid fever, 77 bacteriologically evaluable adults, with blood cultures positive
for Salmonella typhi or Salmonella paratyphi A susceptible to their assigned drugs, were
entered into a randomized open trial at four hospitals in India. Forty-two patients were randomized to receive azithromycin 500 mg po od for 7 days and 35 to receive chloramphenicol
23 g po od in four divided doses for 14 days. Thirty-seven patients (88%) in the azithromycin
group responded with clinical cure or improvement within 8 days and 30 patients (86%) in the
chloramphenicol group responded with cure or improvement. By day 14 after the start of
treatment, all patients treated with azithromycin and all except two of the patients treated with
chloramphenicol (94%) were cured or improved. Blood cultures repeated on day 8 after start of
therapy showed eradication of organisms in 100% of patients in the azithromycin group and
94% of patients in the chloramphenicol group. By day 14 the eradication rate in the chloramphenicol group had increased to 97%. Stool cultures on days 21 and 35 after start of treatment
showed no prolonged faecal carriage of Salmonella spp. in either group. These results indicate
that azithromycin given once daily for 7 days was effective therapy for typhoid fever in a region
endemic with chloramphenicol-resistant S. typhi infection and was equivalent in effectiveness
to chloramphenicol given to patients with chloramphenicol-susceptible infections.

Introduction
Chloramphenicol has been the drug of choice for typhoid
fever for more than 40 years in regions of the world where
Salmonellatyphi remains susceptible to the drug. However,
multiple drug resistance (MDR) to ampicillin, chloramphenicol and trimethoprimsulphamethoxazole in S. typhi
has emerged in many countries of Asia and Africa and
limits the usefulness of these traditional drugs.13 The
cephalosporins, ceftriaxone and cefixime,48 are useful
against MDR typhoid fever, but the required intravenous
route of administration renders them impractical for some
patients.
Azithromycin is the first of a new class of broadspectrum antibiotics called azalides, which contain a

nitrogen atom in the macrolide aglycone ring.9,10 Azithromycin has an MIC of 416 mg/L against isolates of
S. typhi.11 Rapid movement of azithromycin from blood
into tissue results in significantly higher azithromycin
concentrations in tissue than in plasma (up to 50100 times
the maximum observed concentration in plasma). After
oral administration, serum concentrations of azithromycin
decline in a polyphasic pattern, resulting in an average
terminal half-life of 68 h. The high values for apparent
steady-state volume of distribution (31.1 L/kg) and plasma
clearance (630 mL/min) suggest that the prolonged half-life
is due to extensive uptake and subsequent release of drug
from tissues. 10,12 The prolonged concentration of azithromycin in cells is advantageous in the treatment of experimental Salmonella spp. infection in mice, which is

*Corresponding author. Tel: 11-806-743-3155; Fax: 11-806-743-3148.

243
1999 The British Society for Antimicrobial Chemotherapy

T. Butler et al.
intracellular,13 and may explain the good results obtained
with azithromycin in patients with typhoid fever in Chile 14
and Egypt.15

Materials and methods

Sample size and patient selection
Eighty patients with blood cultures showing Salmonella
spp. were selected for randomization of approximately
40 patients each to azithromycin and chloramphenicol
treatment groups. This sample size was large enough, with
a power of 80% and with an a level of 0.05, to show equivalence in bacterial eradication from blood cultures at day 8,
using the 94% eradication rate observed in the chloramphenicol group, at a d (lower boundary of the 95% CI on
the difference in eradication rates) of 14.9.16 Males or
females of at least 18 years of age with suspected typhoid
fever on the basis of histories of fever for 415 days were
considered and examined for the presence of two or more
of the following features: oral temperature .38.5C, abdominal tenderness, hepatomegaly, splenomegaly, rose spots,
coated tongue with sparing of margins, toxic physical
appearance or relative bradycardia. Written consent was
obtained from each patient before inclusion. Patients were
excluded if they were pregnant or lactating; had allergies
to chloramphenicol, erythromycin or other macrolide
antibiotics; had major complications of typhoid fever
(pneumonia, gastrointestinal haemorrhage, intestinal
perforation, shock or coma); were unable to swallow
medication; had been treated with antimicrobial drugs
within 7 days unless blood cultures remained positive for
Salmonella spp.; or had serious underlying disease affecting
bone marrow, kidneys, liver, heart, lung or nervous system.
To eliminate selection bias, patients were screened for
entry criteria and asked for signed consent without the
knowledge by the patient or physician of their assigned
treatments. Randomized treatments were assigned after
entry, by the physicians opening a sealed envelope containing the coded treatment choice that was made from a
table of random numbers. Patients and physicians were
unblinded to the treatment after patients were entered.

Clinical and laboratory testing

The admission evaluation included history and physical
examination; two blood cultures; a stool culture; blood for
white blood cell count, haemoglobin, platelet count, prothrombin time, creatinine, blood urea nitrogen, bilirubin,
alkaline phosphatase, AST, and ALT and urinalysis. After
entry, symptoms and changes in physical examination
were recorded daily during treatment, and blood cultures
were obtained on days 4, 8 and 14 after start of treatment.
Isolates of S. typhi and Salmonella paratyphi were confirmed by slide agglutination using specific antisera (Difco

Laboratories, Detroit, MI, USA). Antimicrobial susceptibilities at the investigative sites were determined by disc
diffusion. Isolates were considered resistant when zone
diameters for azithromycin discs containing 15 mg were
<13 mm and for chloramphenicol discs containing 30 mg
were <12 mm. Isolates were sent to a reference laboratory
at Texas Tech University Health Sciences Center for determination of MICs and to a reference laboratory in Ottawa,
Canada, for Vi phage typing.17 MICs of azithromycin were
measured by the tube dilution method in cation-adjusted
MuellerHinton broth (Difco Laboratories).

Treatment and follow-up visits

Azithromycin was administered as 500 mg po (two capsules
of 250 mg) od for 7 days. Doses were given 1 h before or 2 h
after eating food. Chloramphenicol was administered po as
23 g daily in four divided doses for 14 days, with the dose
determined by the patients weight (with those ,60 kg
receiving the lower dose). After clinical improvement in
the hospital, patients were discharged home to complete
their therapies. If discharged before 14 days after start of
therapy, they were asked to return daily until 14 days had
elapsed. Follow-up visits were scheduled on days 21 and 35
for physical examination, cultures of stool and for the same
blood tests that were performed at the time of admission.
Blood cultures were repeated on days 21 and 35 if fever
(.38C) had returned at these times. Physicians and other
caregivers were unblinded about patients treatments
during follow-up.

Analysis of data
Patients were considered evaluable if their admission
blood cultures grew S. typhi or S. paratyphi susceptible to
the assigned antibiotic and they took azithromycin for at
least 4 days or chloramphenicol for at least 4 days for the
day 8 analysis and at least 7 days for the day 14 analysis.
Patients with negative cultures or with other infections
requiring additional antibiotics were removed from the
study. Patients were considered clinically cured if fever
disappeared and all signs and symptoms of typhoid
fever resolved, and were considered improved if fever
disappeared and signs and symptoms of typhoid fever had
partially resolved. Clinical failure was defined as lack of
improvement or worsening of signs and symptoms or need
to change antibiotic therapy. Patients were considered
afebrile when the daily maximum temperature was ,38C
for 2 days or longer. Bacteriological eradication was
defined as negative blood cultures for S. typhi and S. para typhi on day 8 after start of therapy, with all cultures
remaining negative to the final assessment on day 35.
Clinical relapse was defined as return of fever after day 14,
and bacteriological recurrence was defined as a blood
culture positive for S. typhi or S. paratyphi on day 21 or

244

Treatment of typhoid fever

35 after start of therapy. Prolonged faecal carriage was
Table I. In-vitro susceptibilities of 92 isolates of
defined as a stool culture showing S. typhi or S. paratyphi
Salmonella typhi and S. paratyphi A and distribution
on day 21 or 35 after start of therapy. Clinical and bacterioof Vi phage types of S. typhi
logical response rates were calculated for each treatment
group and 95% CI were calculated for the difference in Disc diffusiona
No. of isolates
population response rates between the two treatments.
Proportions of patients reporting adverse experiences and
Salmonella typhi (n 5 82)
showing abnormal laboratory values after start of therapy
azithromycin susceptible or intermediate
73
were compared between treatment groups. Equivalence of
azithromycin resistant
9
response rates was defined as a 95% CI of the two response
chloramphenicol susceptible or intermediate
71
rates that covered zero, with the lower value being greater
chloramphenicol resistant
11
than 10%. A P value of ,0.05 indicated a significant
resistant to both azithromycin and
difference between the two groups.
chloramphenicol
1
Salmonella paratyphi A (n 5 10)
azithromycin susceptible or intermediate
8
Results
azithromycin resistant
2
chloramphenicol susceptible or intermediate
10
Bacteriological identification and antimicrobial
chloramphenicol resistant
0

susceptibilities
Azithromycin MIC (mg/L)b
No. of isolates
Ninety-two patients with blood cultures showing growth of
S. typhi or S. paratyphi A were enrolled. Isolates were
confirmed by biochemical reactions and agglutination by S. typhi
4
30
antisera as S. typhi in 82 cases and S. paratyphi A in 10
8
16
cases. The most predominant Vi phage type of S. typhi was
16
0
E1 (Table I). Using zone diameters <13 mm for azithro>32
1
mycin, resistance to azithromycin was reported in 11 of the
S.
paratyphi
A
92 isolates (12%) by the Indian laboratories. Using zone
4
0
diameters of <12 mm, resistance to chloramphenicol was
8
3
reported also in 11 isolates (12%). Only one isolate of
16
7
S. typhi was resistant to both azithromycin and chloram>32
0
phenicol. Chloramphenicol resistance occurred only
c
S.
typhi
Vi
phage
type
among S. typhi isolates, whereas azithromycin resistance
E1
24
occurred in both S. typhi and S. paratyphi A (Table I).
Untypable
7
Fifty-seven isolates that had been stored and were viable at
A
6
the end of the study were sent to Texas for further sus3
ceptibility testing. Five of these isolates had been reported E7
0
2
by the Indian laboratories as resistant to azithromycin and
B1
degraded
2
seven resistant to chloramphenicol. All were susceptible
DVS
1
to azithromycin by disc diffusion method and 46 (81%)
B3
1
isolates were susceptible to chloramphenicol. Ten of the
11 chloramphenicol-resistant isolates were also resistant aCarried out at investigative sites in India.
to ampicillin and co-trimoxazole, whereas one isolate bCarried out at reference laboratory in Texas, USA.
was resistant only to chloramphenicol. All isolates were cCarried out at reference laboratory in Ottawa, Canada.
susceptible to ciprofloxacin.
Azithromycin MICs were in the range of 432 mg/L for
Patient enrolment, randomization and treatment
all the tested isolates (Table I). The isolates of S. typhi
had lower MICs than the isolates of S. paratyphi A, with At the four sites in India, 109 patients met inclusion
most S. typhi inhibited by azithromycin 4 mg/L and most criteria, signed consent and were randomized to therapies.
S. paratyphi A inhibited by azithromycin 16 mg/L. The The distribution by site was 50 patients at Bangalore, 29
assays using two-fold dilution series frequently showed a patients at New Delhi, 21 patients at Baroda and nine
trailing effect of azithromycin against S. typhi, with a clear patients at Bombay. Fifty-six patients were randomized to
tube adjacent to a tube with light growth, which was receive azithromycin and 53 to receive chloramphenicol.
adjacent to a tube with heavy growth. One isolate of S. typhi Study drug was actually received initially by 106 patients.
was more resistant in repeated testing than others, with an
Patients with negative blood cultures were removed
MIC of >32 mg/L.
from the study and offered other appropriate therapies.
245

T. Butler et al.
Blood cultures positive for S. typhi or S. paratyphi A were
present in 92 patients (48 assigned to azithromycin, 44 to
chloramphenicol). Four patients in each group were
excluded because their isolates showed resistance to the
study drug. Seven patients treated with azithromycin had
isolates resistant to chloramphenicol and six patients
treated with chloramphenicol had isolates resistant to
azithromycin. Additionally, one patient assigned to
azithromycin never took it, and five patients assigned to
chloramphenicol stopped therapy early or never took it
because of choices of individual physicians and their
patients and not because of adverse events. Finally, one
azithromycin patient was excluded from the analysis

because of insufficient follow-up data. The remaining 77

patients were clinically and bacteriologically evaluable.
Demographic characteristics, clinical findings and laboratory features of patients in the two treatment groups were
comparable (Table II).

Response to therapy
In the patients treated with azithromycin, blood cultures on
day 4 of treatment showed no growth in 83% of patients,
and on days 8 and 14 after start of treatment showed no
growth in all patients (Table III). In patients treated with
chloramphenicol, blood cultures showed no growth in 94%

Table II. Characteristics of blood culture positive patients before treatmenta

Azithromycin (n 5 42)
Age (years)
mean
range
Gender
No. males
No. females
Weight (kg)
mean
range
Days of fever before admission
mean
Temperature, C, oral
mean
No. of patients with:
abdominal tenderness
hepatomegaly
splenomegaly
rose spots
coated tongue
toxic appearance
lethargy
Blood cultures yielded
S. typhi
S. paratyphi A
Mean laboratory values (normal range)
haematocrit, % (3954)
white blood cells/mm3 ((4.410.7) x 103)
platelets/mm3 ((130394) x 103)
creatinine, mg/100 mL (0.81.6)
AST, IU/mL (1136)
ALT, IU/mL (643)
alkaline phosphatase, IU/mL (31110)
prothrombin time, s (1016)

26.2
1753

28.5
1760

34
8

25
10

52.2
4074

53.1
3575

11.9

10.4

39.1

38.9

21
10
29
3
12
3
3

10
11
22
0
13
4
2

38
4

29
6

43.2
6.2
189
1.24
61b
41
88.6
14.8

Chloramphenicol (n 5 35)

44.9
6.6
179
1.32
35
36
94.6
15.2

Patients were included if blood cultures showed S. typhi or S. paratyphi A susceptible to assigned study drug and patients took
sufficient doses of drug to be evaluated for efficacy.
b
One patient in the azithromycin group had a baseline AST value of 638 IU/mL, attributed by the investigator to hepatitis
caused by the primary disease.

246

Treatment of typhoid fever

Table III. Number (percentage) of patients with blood culture-positive typhoid fever; bacterial and clinical
responses
Azithromycin
(n 5 42)

Chloramphenicol
(n 5 35)

Blood cultures that showed no growth of Salmonella spp. at times after start of treatment:
day 4
35 (83)
33 (94)
day 8
42 (100)
33 (94)
day 14
42 (100)
34 (97)
Stool cultures that showed no growth of Salmonella spp. at times after start of treatment:
day 21
42 (100)
35 (100)
day 35
42 (100)
35 (100)
Clinical success within 8 days:
cure or improvement
37 (88)
30 (86)
cure
25 (60)
17 (49)
improvement
12 (29)
13 (37)
Clinical failure within 8 days
5 (12)
5 (14)
Clinical success at 14 days:
cure or improvement
42 (100)
33 (94)
cure
32 (76)
24 (69)
improvement
10 (24)
9 (26)
Clinical failure at 14 days:
0 (0)
2 (6)
duration (days) of fever after start of treatment,
(mean 6 S.D.)
4.162.4
4.363.1
Adverse events, total
5 (12)
0 (0)
gastrointestinal
2 (5)
0 (0)

P values (95% CI)

0.14 (24.6, 2.7)
0.12 (2.0, 13.4)
0.27 (2.7, 8.4)

0.76 (12.8,17.6)

0.12 (2.0, 13.4)

CI, confidence interval.

of patients on days 4 and 8 after start of treatment, and in

97% of patients on day 14. Stool cultures on days 21 and 35
after start of treatment showed no growth of Salmonella
spp. in all patients in both treatment groups.
Clinical responses were cures or improvements within 8
days of starting treatment in 88% of patients treated with
azithromycin and 86% of patients treated with chloramphenicol (Table III). There were five patients in each group
who were judged as treatment failures because they had
continuing fever or other symptoms. At 14 days after start
of treatment, the five patients treated with azithromycin
who were failures at day 8 all responded to become cured
or improved, whereas two (6%) of the patients treated with
chloramphenicol remained treatment failures. The mean
number of days of fever after start of treatment was 4.1 for
azithromycin and 4.3 for chloramphenicol. There were
no relapses after the end of treatment. Adverse events
occurred in five patients treated with azithromycin and
none of the patients treated with chloramphenicol; in two
of the patients the adverse events were gastrointestinal in
nature. The adverse events were not severe and did not
result in change of study medication. There was no significant difference in laboratory abnormalities between the
two treatment groups.

The 10 patients infected with S. paratyphi A responded

in ways comparable with the patients infected with S. typhi.
Four of the patients infected with S. paratyphi A were
treated with azithromycin, and all showed bacteriological
eradication after treatment and all were clinically cured.
The six patients treated with chloramphenicol all showed
bacteriological eradication and were clinically cured.

Discussion
The results of this comparative randomized trial of azithromycin and chloramphenicol for typhoid fever indicated
that the two treatments were effective and equivalent, by
giving clinical cures or improvements in 8688% of patients
within 8 days, and producing bacteriological eradication
of Salmonella spp. from blood cultures in 97100% of
patients. The mean durations of fever after the start of
treatment in the two treatment groups of 4.14.3 days indicate that most patients responded promptly to therapy.
These results compare favourably with other antimicrobial
agents tested recently in typhoid fever, including ceftriaxone, cefixime and fluoroquinolones,5,1826 and confirm the
findings of trials in Chile and Egypt that azithromycin is

247

T. Butler et al.
effective against infections caused by S. typhi and S. para typhi A.14,15 Although five patients in each treatment group
were considered clinical failures after 8 days of treatment
because they persisted in showing fever and/or other
symptoms, they did not deteriorate clinically and most of
them subsequently improved or were cured by 14 days after
the start of treatment. The design of clinical trials of
typhoid fever should include an observation period of
about 14 days to allow complete defervescence and resolution of physical signs, such as splenomegaly and hepatomegaly, after shorter courses of antimicrobial agents of
7 days or less.
The two study drugs were very different in regard to
their administration, pharmacokinetics, therapeutic principles and side effects. Azithromycin was given once daily in
a dose of 500 mg a day for 7 days, whereas chloramphenicol
was given four times a day in doses of 23 g a day for 14
days. Both antibiotics penetrate into cells effectively, and
this intracellular penetration explains the effective therapeutic activity against the predominantly intracellular
pathogen S. typhi. On the other hand, serum concentrations of azithromycin reported to be in the range of
0.040.4 mg/L during treatment12,27 are less than the MIC of
azithromycin against S. typhi and are less than the serum
concentrations of 5.557 mg/L reported for chloramphenicol during treatment of typhoid fever.4 The ability of
azithromycin to achieve intracellular concentrations in
monocytes 231 times greater than the serum concentrations and in polymorphonuclear leucocytes 83 times the
serum concentrations, 28,29 as well as a long half-life of 23
days of the intracellular concentration,10 appears to be
essential for its therapeutic activity in typhoid fever.
Adverse events, including gastrointestinal symptoms,
were reported by five patients treated with azithromycin in
this trial, but these events were not serious and did not
require discontinuation of therapy. Although none of the
patients treated with chloramphenicol reported adverse
events, more patients randomized to chloramphenicol
therapy than to azithromycin refused therapy or stopped
therapy early (five versus one) and were excluded from
analysis. The reasons were that individual patients, after
reconsidering their decisions to enter the study, chose not
to take chloramphenicol because of concern about possible
adverse events. Additionally, in view of the fact that this
was an open study, there may have been less reporting of
adverse events with chloramphenicol because of investigator bias toward an older, more tried agent. The known
haematological side effects of chloramphenicol cause
physicians in some countries to select alternative therapies
routinely, and baseline leucopenia in one of the patients in
this trial was the reason his physician did not initiate treatment with chloramphenicol.
Emergence of antimicrobial drug resistance in S. typhi is
a global problem13 and was the compelling reason for us to
undertake this trial of a new antibiotic for typhoid fever.
In-vitro resistance was reported by the Indian laboratories

to chloramphenicol in 12% of isolates and to azithromycin

in 12% of isolates. Chloramphenicol resistance was
expected because of the high prevalence of multidrug resistance to ampicillin, chloramphenicol and co-trimoxazole
on the Indian subcontinent.2,30,31 Azithromycin resistance
was not expected because this drug has not been used
extensively yet in India. When 57 of the isolates of S. typhi
were tested in Texas for azithromycin MICs, all isolates
except one were susceptible, with MICs of 48 mg/L. This
discrepancy between results of susceptibility testing by disc
zone diameters and MICs suggests that there was less
azithromycin resistance in our isolates of S. typhi than was
reported initially from results of disc diffusion. A tendency
for zones around the azithromycin discs to show a trailing
of light growth rather than the sharp demarcation noted in
the Texas laboratory is a technical difficulty in obtaining
reproducible results by disc diffusion. Our results of
azithromycin MICs against 10 isolates of S. paratyphi A
showed that seven were relatively resistant, with MICs of
16 mg/L. This is the first report of azithromycin resistance
in S. paratyphi A. Although our patients with S. paratyphi
A infection all did well when treated with azithromycin,
this in-vitro resistance deserves attention in future studies
of typhoid fever.
The place of azithromycin in the treatment of typhoid
fever needs to be defined by further clinical studies in
adults and children. Once-daily oral treatment for 7 days
is convenient and should be favourable for out-patient
compliance. At the time of this study a parenteral form of
azithromycin was not available. Although parenteral
azithromycin is now available, it has not yet been tested in
typhoid fever. The fluoroquinolones ciprofloxacin and
ofloxacin have been tested in adults in geographical areas
with multidrug resistance and gave good results.5,18,19
However, the fluoroquinolones are generally not approved
for use in children because of the potential for these drugs
to damage cartilage in growing bones in animals. Children
are affected by typhoid fever more frequently than adults.32
Children with multidrug-resistant typhoid fever have
been treated successfully with furazolidone, ceftriaxone,
cefixime and aztreonam.3335 The availability of a paediatric suspension of azithromycin provides an opportunity
to examine the efficacy and safety of this drug in young
children with typhoid fever.

Acknowledgements
Assistance was provided by John Vincent, Krishna
Prakash, Madan M. Bahadur, Kishan Jani and Wendy
Johnson. This work was supported by a grant from Pfizer
Central Research, Groton, CT. These results were presented at the Fourth International Conference on the
Macrolides, Azalides, Streptogramins and Ketolides in
Barcelona in 1998.

248

Treatment of typhoid fever

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Received 23 November 1998; returned 9 February 1999; revised
3 March 1999; accepted 6 April 1999

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