Journal of Antimicrobial Chemotherapy (1999) 44, 243250

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, chloram-
phenicol 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 cexime,
48
are useful
against MDR typhoid fever, but the required intravenous
route of administration renders them impractical for some
patients.
Azithromycin is the rst of a new class of broad-
spectrum antibiotics called azalides, which contain a
nitrogen atom in the macrolide aglycone ring.
9,10
Azithro-
mycin has an MIC of 416 mg/L against isolates of
S. typhi.
11
Rapid movement of azithromycin from blood
into tissue results in signicantly 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 azithro-
mycin in cells is advantageous in the treatment of experi-
mental Salmonella spp. infection in mice, which is
243
Treatment of typhoid fever with azithromycin versus chloramphenicol
in a randomized multicentre trial in India
Thomas Butler
a
*, C. B. Sridhar
b
, M. K. Daga
c
, Kamal Pathak
d
, R. B. Pandit
e
, Rasik Khakhria
f
,
Chandrashekhar N. Potkar
g
, Michael T. Zelasky
h
and Raymond B. Johnson
h
a
Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA;
b
Saint Johns Medical College and Hospital, Bangalore;
c
Maulana Azad Medical College, New Delhi;
d
Baroda Hospital, Baroda;
e
Central Railway Hospital, Bombay, India;
f
Bureau of Microbiology, Ottawa,
Ontario, Canada;
g
Pzer Limited, Bombay, India and
h
Central Research Division, Pzer Inc.,
Groton, CT, USA
To compare the clinical and bacteriological efcacies 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 ran-
domized 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 chloram-
phenicol 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.
*Corresponding author. Tel: 1-806-743-3155; Fax: 1-806-743-3148.
1999 The British Society for Antimicrobial Chemotherapy
JAC
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 level of 0.05, to show equiv-
alence in bacterial eradication from blood cultures at day 8,
using the 94% eradication rate observed in the chloram-
phenicol group, at a (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, abdo-
minal 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 con-
taining 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, pro-
thrombin 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 con-
rmed by slide agglutination using specic antisera (Difco
Laboratories, Detroit, MI, USA). Antimicrobial suscepti-
bilities at the investigative sites were determined by disc
diffusion. Isolates were considered resistant when zone
diameters for azithromycin discs containing 15 g were
13 mm and for chloramphenicol discs containing 30 g
were 12 mm. Isolates were sent to a reference laboratory
at Texas Tech University Health Sciences Center for deter-
mination 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 dened 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
dened 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 nal assessment on day 35.
Clinical relapse was dened as return of fever after day 14,
and bacteriological recurrence was dened 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
dened as a stool culture showing S. typhi or S. paratyphi
on day 21 or 35 after start of therapy. Clinical and bacterio-
logical response rates were calculated for each treatment
group and 95% CI were calculated for the difference in
population response rates between the two treatments.
Proportions of patients reporting adverse experiences and
showing abnormal laboratory values after start of therapy
were compared between treatment groups. Equivalence of
response rates was dened as a 95% CI of the two response
rates that covered zero, with the lower value being greater
than 10%. A P value of 0.05 indicated a signicant
difference between the two groups.
Results
Bacteriological identication and antimicrobial
susceptibilities
Ninety-two patients with blood cultures showing growth of
S. typhi or S. paratyphi A were enrolled. Isolates were
conrmed by biochemical reactions and agglutination by
antisera as S. typhi in 82 cases and S. paratyphi A in 10
cases. The most predominant Vi phage type of S. typhi was
E1 (Table I). Using zone diameters 13 mm for azithro-
mycin, resistance to azithromycin was reported in 11 of the
92 isolates (12%) by the Indian laboratories. Using zone
diameters of 12 mm, resistance to chloramphenicol was
reported also in 11 isolates (12%). Only one isolate of
S. typhi was resistant to both azithromycin and chloram-
phenicol. Chloramphenicol resistance occurred only
among S. typhi isolates, whereas azithromycin resistance
occurred in both S. typhi and S. paratyphi A (Table I).
Fifty-seven isolates that had been stored and were viable at
the end of the study were sent to Texas for further sus-
ceptibility testing. Five of these isolates had been reported
by the Indian laboratories as resistant to azithromycin and
seven resistant to chloramphenicol. All were susceptible
to azithromycin by disc diffusion method and 46 (81%)
isolates were susceptible to chloramphenicol. Ten of the
11 chloramphenicol-resistant isolates were also resistant
to ampicillin and co-trimoxazole, whereas one isolate
was resistant only to chloramphenicol. All isolates were
susceptible to ciprooxacin.
Azithromycin MICs were in the range of 432 mg/L for
all the tested isolates (Table I). The isolates of S. typhi
had lower MICs than the isolates of S. paratyphi A, with
most S. typhi inhibited by azithromycin 4 mg/L and most
S. paratyphi A inhibited by azithromycin 16 mg/L. The
assays using two-fold dilution series frequently showed a
trailing effect of azithromycin against S. typhi, with a clear
tube adjacent to a tube with light growth, which was
adjacent to a tube with heavy growth. One isolate of S. typhi
was more resistant in repeated testing than others, with an
MIC of 32 mg/L.
Patient enrolment, randomization and treatment
At the four sites in India, 109 patients met inclusion
criteria, signed consent and were randomized to therapies.
The distribution by site was 50 patients at Bangalore, 29
patients at New Delhi, 21 patients at Baroda and nine
patients at Bombay. Fifty-six patients were randomized to
receive azithromycin and 53 to receive chloramphenicol.
Study drug was actually received initially by 106 patients.
Patients with negative blood cultures were removed
from the study and offered other appropriate therapies.
245
Table I. In-vitro susceptibilities of 92 isolates of
Salmonella typhi and S. paratyphi A and distribution
of Vi phage types of S. typhi
Disc diffusion
a
No. of isolates
Salmonella typhi (n 82)
azithromycin susceptible or intermediate 73
azithromycin resistant 9
chloramphenicol susceptible or intermediate 71
chloramphenicol resistant 11
resistant to both azithromycin and
chloramphenicol 1
Salmonella paratyphi A (n 10)
azithromycin susceptible or intermediate 8
azithromycin resistant 2
chloramphenicol susceptible or intermediate 10
chloramphenicol resistant 0
Azithromycin MIC (mg/L)
b
No. of isolates
S. typhi
4 30
8 16
16 0
32 1
S. paratyphi A
4 0
8 3
16 7
32 0
S. typhi Vi phage type
c
E1 24
Untypable 7
A 6
E7 3
0 2
B1 degraded 2
DVS 1
B3 1
a
Carried out at investigative sites in India.
b
Carried out at reference laboratory in Texas, USA.
c
Carried out at reference laboratory in Ottawa, Canada.
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 ve 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 insufcient follow-up data. The remaining 77
patients were clinically and bacteriologically evaluable.
Demographic characteristics, clinical ndings and labora-
tory 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%
246
Table II. Characteristics of blood culture positive patients before treatment
a
Azithromycin (n 42) Chloramphenicol (n 35)
Age (years)
mean 26.2 28.5
range 1753 1760
Gender
No. males 34 25
No. females 8 10
Weight (kg)
mean 52.2 53.1
range 4074 3575
Days of fever before admission
mean 11.9 10.4
Temperature, C, oral
mean 39.1 38.9
No. of patients with:
abdominal tenderness 21 10
hepatomegaly 10 11
splenomegaly 29 22
rose spots 3 0
coated tongue 12 13
toxic appearance 3 4
lethargy 3 2
Blood cultures yielded
S. typhi 38 29
S. paratyphi A 4 6
Mean laboratory values (normal range)
haematocrit, % (3954) 43.2 44.9
white blood cells/mm
3
((4.410.7) x 10
3
) 6.2 6.6
platelets/mm
3
((130394) x 10
3
) 189 179
creatinine, mg/100 mL (0.81.6) 1.24 1.32
AST, IU/mL (1136) 61
b
35
ALT, IU/mL (643) 41 36
alkaline phosphatase, IU/mL (31110) 88.6 94.6
prothrombin time, s (1016) 14.8 15.2
a
Patients were included if blood cultures showed S. typhi or S. paratyphi A susceptible to assigned study drug and patients took
sufcient doses of drug to be evaluated for efcacy.
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.
Treatment of typhoid fever
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 chloram-
phenicol (Table III). There were ve 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 ve 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 ve 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 signi-
cant 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 azithro-
mycin 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 indi-
cate that most patients responded promptly to therapy.
These results compare favourably with other antimicrobial
agents tested recently in typhoid fever, including ceftriax-
one, cexime and uoroquinolones,
5,1826
and conrm the
ndings of trials in Chile and Egypt that azithromycin is
247
Table III. Number (percentage) of patients with blood culture-positive typhoid fever; bacterial and clinical
responses
Azithromycin Chloramphenicol
(n 42) (n 35) P values (95% CI)
Blood cultures that showed no growth of Salmonella spp. at times after start of treatment:
day 4 35 (83) 33 (94) 0.14 (24.6, 2.7)
day 8 42 (100) 33 (94) 0.12 (2.0, 13.4)
day 14 42 (100) 34 (97) 0.27 (2.7, 8.4)
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) 0.76 (12.8,17.6)
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) 0.12 (2.0, 13.4)
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 S.D.) 4.12.4 4.33.1
Adverse events, total 5 (12) 0 (0)
gastrointestinal 2 (5) 0 (0)
CI, condence interval.
T. Butler et al.
effective against infections caused by S. typhi and S. para -
typhi A.
14,15
Although ve 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 reso-
lution of physical signs, such as splenomegaly and hepato-
megaly, 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 prin-
ciples 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 thera-
peutic activity against the predominantly intracellular
pathogen S. typhi. On the other hand, serum concen-
trations of azithromycin reported to be in the range of
0.040.4 mg/L during treatment
12,27
are less than the MIC of
azithromycin against S. typhi and are less than the serum
concentrations of 5.557 mg/L reported for chlorampheni-
col during treatment of typhoid fever.
4
The ability of
azithromycin to achieve intracellular concentrations in
monocytes 231 times greater than the serum concentra-
tions 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 ve 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 (ve 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 investi-
gator 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 treat-
ment with chloramphenicol.
Emergence of antimicrobial drug resistance in S. typhi is
a global problem
13
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 resis-
tance 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 difculty 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 rst 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 dened 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 uoroquinolones ciprooxacin and
ooxacin have been tested in adults in geographical areas
with multidrug resistance and gave good results.
5,18,19
However, the uoroquinolones 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,
cexime and aztreonam.
3335
The availability of a paedi-
atric suspension of azithromycin provides an opportunity
to examine the efcacy 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 Pzer
Central Research, Groton, CT. These results were pre-
sented 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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