1134

Azithromycin versus Ceftriaxone for the Treatment of Uncomplicated Typhoid

Fever in Children
Robert W. Frenck, Jr.,1 Isabelle Nakhla,1 Yehia Sultan,2
Samir B. Bassily,1 Youssef F. Girgis,1 John David,1
Thomas C. Butler,4 Nabil I. Girgis,1 and Mosaad Morsy3
1
US Naval Medical Research Unit #3, 2Abbassia Fever Hospital,
and 3Pfizer Pharmaceuticals, Cairo, Egypt; and 4Texas Tech
University School of Medicine, Lubbock

A total of 108 children aged 4–17 years were randomized to receive 7 days of azithromycin
(10 mg/kg/day; maximum, 500 mg/day) or ceftriaxone (75 mg/kg/day; maximum, 2.5 g/day),
to assess the efficacy of the agents for the treatment of uncomplicated typhoid fever. Salmonella
typhi was isolated from the initial cultures of blood samples from 64 patients. A total of 31
(91%) of the 34 patients treated with azithromycin and 29 (97%) of the 30 patients treated
with ceftriaxone were cured (P 1 .05). All 64 isolates were susceptible to azithromycin and

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ceftriaxone. Of the patients treated with ceftriaxone, 4 subsequently had relapse of their
infection. No serious side effects occurred in any study subject. Oral azithromycin administered
once daily appears to be effective for the treatment of uncomplicated typhoid fever in children.
If these results are confirmed, the agent could be a convenient alternative for the treatment
of typhoid fever, especially in individuals in developing countries where medical resources are
scarce.

Typhoid fever, a systemic infection caused by Salmonella ty-
phi and Salmonella paratyphi, is a common and sometimes fatal
infection among children living in developing countries, espe-
cially such countries in Asia and Africa [1]. For decades, chlo-
ramphenicol has been highly effective against S. typhi and S.
paratyphi, and it often remains the antibiotic of choice for the
treatment of typhoid fever [2, 3]. However, the widespread
emergence of multidrug-resistant S. typhi has necessitated the
Received 17 September 1999; revised 28 February 2000; electronically
published 6 November 2000.
Some of the authors of this manuscript are military service members or
employees of the US Government. This work was prepared as part of their
official duties. Title 17 U.S.C. 105 provides that “Copyright protection under
this title is not available for any work of the United States Government.”
Title 18 U.S.C. 101 defines a US Government work as “a work prepared
by a military service member or employee of the United States Government
as part of that person’s official duties.”
The study was reviewed and approved by the Egyptian Ministry of Health
as well as the US Navy Bureau of Medicine and Surgery Committee for
the Protection of Human Subjects.
This research was conducted in compliance with all US Federal Regu-
lations governing the protection of human subjects in research. The opinions
and assertions contained herein are the private ones of the authors and are
not to be construed as official or as reflecting the views of the US Navy
Department, US Department of Defense, US Government, or Egyptian
Ministry of Health.
Financial support: This work was supported by Pfizer Pharmaceuticals
(Cairo, Egypt) and the US Naval Medical Research and Development Com-
mand, Naval Medical Center, National Capitol Region (Bethesda, MD).
Correspondence: Dr. Robert W. Frenck, Jr., Commanding Officer, Head,
Clinical Investigations, US Naval Medical Research Unit #3, PSC 452, Box
121 (Attention Code 101C), FPO AE 09835-0007 (FrenckR@namru3
.med.navy.mil). Reprints: Research Publication Branch, US Naval Medical
Research Unit #3, PSC 452, Box 5000, FPO AE 09835-0007.
Clinical Infectious Diseases 2000; 31:1134–8
q 2000 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2000/3105-0004$03.00
search for other therapeutic options [4]. Fluoroquinolones have
proven to be effective; however, to date, they are restricted from
routine use in children, and quinolone-resistant strains of S.
typhi have begun to be reported [5, 6]. Ceftriaxone, a third-
generation cephalosporin, is highly effective against S. typhi
and has become the standard of care for the treatment of ty-
phoid fever in many parts of the world [7]. However, because
parenteral administration of ceftriaxone is required, the anti-
biotic is a less-than-ideal treatment alternative.
The recent availability of the azalide class of antibiotics has
provided another potential option for the treatment of typhoid
fever. Azithromycin, the first azalide evaluated, has in vitro
activity against many enteric intracellular pathogens, including
S. typhi [8–10]. Animal models have demonstrated that azith-
romycin is highly effective against both Salmonella enteritidis
and Salmonella typhimurium, with drug efficacy related to the
tissue concentration, rather than the serum concentration, of
the antibiotic [11, 12]. Studies of human volunteers have shown
that neutrophil concentrations of azithromycin are 1100 times
the serum concentration of the antibiotic [13]. Five days after
a 3-day course of azithromycin was completed, neutrophil con-
centrations of the drug still exceeded the typical MIC for S.
typhi by 120 times, whereas the drug was unmeasurable in the
serum [13].
These encouraging results led us to initiate a trial of azith-
romycin treatment in humans. Initially, azithromycin was dem-
onstrated, in an open-labeled, nonrandomized trial, to be ef-
fective in the treatment of adults with uncomplicated typhoid
fever [14]. A subsequent randomized trial demonstrated that
azithromycin was as effective as ciprofloxacin for the treatment
of uncomplicated typhoid fever in adults [15]. The results of
CID 2000;31 (November) Azithromycin vs. Ceftriaxone for Typhoid Fever
these studies prompted the present study of azithromycin sus-
pension versus ceftriaxone for the treatment of uncomplicated
typhoid fever in children.
Patients and Methods
Study site. The Abbassia Fever Hospital is a 1500-bed infec-
tious disease hospital that serves as both the primary infectious
disease hospital in Cairo and a referral center for patients with
infectious diseases from throughout Egypt.
Study population. Patients coming to the hospital were initially
screened in the reception department. During the study period, all
children of 4–17 years of age who, according to the reception de-
partment physician, had a clinical diagnosis of typhoid fever were
admitted to a single ward in the hospital. After admission to the
ward, a study physician reevaluated the patients to determine
whether they were eligible for enrollment in the study. Eligibility
for enrollment required that a subject have a documented fever
(temperature, >38.57C) and a history of fever for at least 4 days
plus at least 2 of the following criteria: abdominal tenderness, he-
patomegaly, splenomegaly, and/or rose spots. Subjects with the
following conditions were excluded from the study: allergy to cef-
triaxone or erythromycin (or to other macrolides), major compli-
cations of typhoid fever (e.g., pneumonia, intestinal hemorrhage
or perforation, shock, or coma), inability to swallow oral medi-
cation, significant underlying illness (e.g., heart disease, asthma
requiring chronic medications, or immunodeficiencies), or treat-
ment within the past 4 days with either study medication or chlo-
ramphenicol, trimethoprim-sulfamethoxazole (TMP-SMZ), or am-
picillin. Subjects who might be pregnant or who were lactating
were also excluded from the study. Parents of children meeting
eligibility requirements were asked to have their child enroll in the
study, and if they agreed, informed consent was obtained before
randomization of the study drug.
Sample size requirements. The study was designed to detect a
50% difference in clinical cure rates between the 2 treatment groups,
under the assumption that 80% of the subjects treated with cef-
triaxone would respond to therapy, with “response” defined as the
patient becoming afebrile within 5 days of starting treatment. Using
a type I error rate of 0.05 and a type II error rate of 0.2, it was
projected that 30 evaluable subjects (those with positive blood cul-
tures) would be needed in each treatment arm [16]. Historically,
∼50% of patients who are thought, as a result of findings of clinical
examination, to have typhoid fever have S. typhi or S. paratyphi
isolated from their blood or stool. Thus, enrollment of 60 subjects
in each treatment arm was planned for the trial.
Randomization and treatment. To control for age bias, patients
were stratified into 3 age groups (4–7 years, 8–12 years, and 13–17
years) before randomization. After study eligibility was determined
and informed consent was obtained, patients were randomized to
1 of the 2 treatment groups. Before randomization, sequentially
numbered sealed envelopes containing the name of the study agent
to be used were created by block randomization that was based
on a random list of numbers. At the time of randomization, neither
the subject nor the study physician was aware of which study agent
would be administered. Treatment assignments were made at en-
1135
rollment by opening the lowest numbered envelope that had yet to
be used for the age group of the child.
After assignment, subjects were treated, in an open-label format,
with either oral azithromycin suspension (10 mg/kg/day; maximum
dose, 500 mg/day) administered once daily for 7 days or im cef-
triaxone (75 mg/kg/day; maximum dose, 2.5 g/day) administered
once daily for 7 days. Azithromycin powder was reconstituted with
sterile water (according to package guidelines) in a bottle, and the
bottle was labeled with the unique identification number of the
study subject. After reconstitution, azithromycin was stored at
room temperature until it was administered to the study subject.
Ceftriaxone powder, which was mixed with 1% lidocaine solution
provided by the manufacturer, was administered immediately after
reconstitution by means of deep im injection. All medications were
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administered in the hospital by the nursing staff.
Procedures. Patients enrolled in the study were hospitalized
for the entire treatment period and for 3 days after therapy was
completed. Before initiation of antibiotic therapy, samples of blood,
stool, and urine were cultured. Repeated blood cultures were per-
formed for all subjects 4 and 10 days after treatment was initiated.
Repeated stool and urine cultures were performed on day 10 if the
initial culture result was positive. All subjects had a stool culture
performed 1 month after completion of therapy. A blood sample
was obtained for determination of the complete blood cell count
and for serum chemistry analysis at baseline and on day 10.
Cultures of blood and stool were processed by means of standard
clinical methods. All blood cultures were blindly subcultured after
1, 7, and 14 days of incubation. Subcultures were performed at
other times if the broth appeared cloudy. Identification of Sal-
monella isolates was performed by use of standard methods [17].
Stool specimens were plated on MacConkey agar and Salmonella-
Shigella agar, and colonies suggestive of Salmonella species were
further evaluated by means of standard methods to determine exact
identification [17]. All isolates of S. typhi or S. paratyphi were tested
for susceptibility to azithromycin, ceftriaxone, ciprofloxacin, chlo-
ramphenicol, ampicillin, and TMP-SMZ by means of agar disk
diffusion analysis done according to the method of Bauer et al.
[18].
During the period of hospitalization, vital signs (including body
temperature) were measured every 8 h, and clinical examination
was performed daily. During clinical examination, the general con-
dition of the patient as well as the presence of coated tongue,
abdominal tenderness, splenomegaly, hepatomegaly, or rash were
specifically noted. In addition, a structured questionnaire was ad-
ministered daily during hospitalization to record symptomatology
(including fever, headache, rash, abdominal pain, constipation, di-
arrhea, and/or anorexia) and possible adverse events. Subjects were
routinely checked at 2 and 4 weeks after completion of treatment
and were asked to return immediately if they became sick before
a scheduled follow-up visit.
Data analysis. Responses to treatment were classified as clin-
ical cure or failure and as microbiological cure or failure. “Clinical
cure” was defined as resolution of all typhoid-related symptoms or
signs by the end of 7 days of therapy. For response to therapy,
“fever” was defined as >1 rectal temperature 138.47C during a 24-
h period. “Clinical failure” was defined either as persistence of >1
typhoid-related symptoms or signs present at study entry, or as
1136 Frenck et al. CID 2000;31 (November)

development of a typhoid-related complication (including pneu-
monia, intestinal hemorrhage or perforation, shock, or coma) after
at least 4 days of therapy. “Microbiological cure” was defined as
a sterile blood culture on days 4 and 10 of therapy. “Relapse” was
defined as recurrence of fever with signs or symptoms of typhoid
fever within 4 weeks of completion of therapy along with isolation
of S. typhi or S. paratyphi from the blood. The x2 test was used
to determine significant differences in cure rates between groups.
For groups with !5 events in a cell, Fisher’s exact test was used.
Results
A total of 108 patients (53 males and 55 females; mean
tients treated with ceftriaxone (P p NS ). Of the 3 patients with
clinical failure in the azithromycin group, 2 had failure as a
result of slow resolution of fever without other symptoms. All
3 subjects received ceftriaxone for an additional 5–7 days after
they had received azithromycin for 7 days; all 3 had complete
cures without any significant consequences.
Microbiological cure occurred in 33 (97%) of 34 patients
treated with azithromycin versus 29 (97%) of 30 patients treated
with ceftriaxone (P p NS). The patient with microbiological
failure in the azithromycin group had S. typhi isolated from
blood on both day 4 and day 10, whereas the patient with
microbiological failure in the ceftriaxone group had S. typhi
isolated from blood on day 10. Both patients with microbio-

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age 5 SD, 9.8 5 2.8 years) were enrolled in the study and as-
signed to a treatment arm. Cultures of blood specimens ob-
tained from 64 children (34 azithromycin recipients and 30 cef-
triaxone recipients) were positive for S. typhi; these subjects
were included in the analysis.
Demographic and pretreatment laboratory evaluation of the
subjects demonstrated that there were no significant differences
between the treatment groups (table 1). Antimicrobial suscep-
tibility testing showed that all 64 blood culture isolates of S.
typhi were susceptible to azithromycin, ceftriaxone, and cipro-
floxacin.
Responses to treatment were excellent in both groups (table
2). Patients responded quickly to therapy; the mean time to
defervescence 5 SD was 4.1 5 1.1 days and 3.9 5 1.0 days for
azithromycin recipients and ceftriaxone recipients, respectively
(P p NS). Clinical cure occurred in 31 (91%) of 34 patients
treated with azithromycin, compared with 29 (97%) of 30 pa-
logical failure also had clinical failure. Another course of an-
tibiotics (ceftriaxone for the subject who initially received azith-
romycin and chloramphenicol for the subject who initially
received ceftriaxone) was administered to both subjects after
they had received initial therapy for 7 days. For both subjects,
the second course of antibiotics was clinically successful.
After discharge from the hospital, 58 subjects (30 of 34 azith-
romycin recipients and 28 of 30 ceftriaxone recipients) who had
S. typhi initially isolated from their blood returned for post-
treatment follow-up evaluation. Six of the 30 subjects treated
with ceftriaxone returned before the scheduled 1-month follow-
up evaluation because of recurrence of typhoid-related symp-
toms; S. typhi was isolated from blood specimens from 4 of
these patients. All 6 subjects were treated with a second course
of antibiotics that resulted in resolution of their symptoms and
sterile posttreatment blood cultures. No relapses occurred in

Table 1. Admission characteristics of azithromycin and ceftriaxone recipients

who had typhoid fever and for whom blood cultures were positive.
Azithromycin Ceftriaxone
recipients recipients
Characteristic (n p 34) (n p 30)
Age, mean y (range) 9.7 (5–17) 10.1 (5–14)
Sex, male 20 17
Duration of fever before admission,
mean d (range) 9.7 (3–30) 9.2 (3–15)
Blood culture result
Salmonella typhi 34 30
Salmonella paratyphi 0 0
Blood culture that yielded MDR S. typhi 5 6
Stool culture result
S. typhi 7 3
S. paratyphi 0 0
Laboratory test result, mean 5 SD
(normal range)
Hemoglobin level, g/dL (11–18) 10.4 5 1.2 10.8 5 1.3
WBC count, cells/mm3 (4.5–10.5 3 103) 6.2 5 2.3 6.3 5 1.6
Platelet count, cells/mm3 (150,000–350,000) 212,000 5 75,000 211,000 5 96,000
Total bilirubin level, mg/dL (0.2–1.0) 0.4 5 0.1 0.5 5 0.1
AST level, U/L (0–33) 87 5 48 83 5 70
Blood urea nitrogen level, mg/dL (7–18) 10.3 5 3.1 11.4 5 6
Serum creatinine level, mg/dL (0.7–1.5) 0.7 5 0.1 0.6 5 0.2
NOTE. Data are no. of patients, unless otherwise indicated. AST, aspartate amino-
transferase; MDR, multidrug resistant.
CID 2000;31 (November) Azithromycin vs. Ceftriaxone for Typhoid Fever 1137

Table 2. Responses to treatment with azithromycin or ceftriaxone among patients

who had typhoid fever and for whom blood cultures were positive.
Azithromycin Ceftriaxone
recipients recipients
Finding (n p 34) (n p 30)
Clinical cure by day 7, no. (%) 31 (91) 29 (97)
Duration of fever after starting therapy,
mean d 5 SD 4.1 5 1.1 3.9 5 1.0
Microbiological cure, no. (%) 33 (97) 29 (97)
Blood culture that yielded Salmonella on
a
Day 4 1 0
a
Day 10 1 1
Stool culture that yielded Salmonella on day 10 0 0
Relapse 0 4
Laboratory test result on day 10, mean 5 SD
(normal ranges)

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Hemoglobin level, g/dL (11–18) 9.9 5 1.4 10.4 5 1.0
WBC count, cells/mm3 (4.5–10.5 3 103) 6.3 5 1.6 7.4 5 2.2
Platelet count, cells/mm3 (150,000–350,000) 434,000 5 122,000 431,000 5 164,000
Total bilirubin level, mg/dL (0.2–1.0) 0.3 5 0.1 0.4 5 0.2
AST level, U/L (0–33) 50 5 30 62 5 34
Blood urea nitrogen level, mg/dL (7–18) 8.9 5 3.5 9.5 52.4
Serum creatinine level, mg/dL (0.7–1.5) 0.7 5 0.1 0.6 5 0.2
NOTE. Data are no. of patients, unless otherwise indicated. AST, aspartate amino-
transferase.
a
Same patient.

the group treated with azithromycin. With the exception of the
6 subjects described above, all patients were clinically well when
they returned for evaluation 1 month after completion of ther-
apy. Antimicrobial susceptibility testing demonstrated that all
8 of the S. typhi isolates from children who had relapses or for
whom treatment failed remained susceptible to all antibiotics
tested.
No subject had a serious adverse event. Gastrointestinal
symptoms were commonly reported by both groups. Vomiting
occurred more frequently in subjects treated with azithromycin
than in those treated with ceftriaxone; however, the symptom
was mild and transient, resolving, in most cases, within 1 day
of initiation of treatment with azithromycin. In no case was
the symptom severe enough to require treatment or alteration
of antibiotic therapy. Pain at the site of injection, the most
common adverse event in the ceftriaxone group, was typically
mild; however, 6 subjects complained of pain up to 24 hours
after injection, despite both the mixture of lidocaine with cef-
triaxone before injection and the rotation of injection sites. With
the exception of 1 patient from each group who had a mild,
residual elevation of alanine aminotransferase concentration,
all subjects with abnormal results of pretreatment laboratory
analysis had normal values at the end of therapy. Blood eval-
uation on day 10 revealed that 4 patients in the azithromycin
group and 3 patients in the ceftriaxone group had thrombo-
cytosis (platelet count, 1500,000 cells/mm3), but all subjects
were asymptomatic. In addition, 4 subjects treated with cef-
triaxone and 2 subjects treated with azithromycin developed
mild, asymptomatic elevations in aspartate aminotransferase
concentrations (range, 110–170 U/L) during the course of
therapy.
Discussion
In a comparative, randomized trial, we demonstrated that
azithromycin is highly effective for the treatment of uncom-
plicated typhoid fever in children. In the present study, findings
of clinical cure rates 190% and microbiological cure rates 195%
for subjects receiving either azithromycin or ceftriaxone com-
pare favorably with findings from past trials of standard an-
tibiotics for the treatment of typhoid fever [2, 6, 19–21]. It is
interesting that, in the present study, 14% of subjects with bac-
teremia who were treated with ceftriaxone had relapses of in-
fection within 1 month of completion of therapy. These data
are consistent with relapse rates of 5%–15% in other trials of
ceftriaxone for the treatment of typhoid fever [2, 7, 19, 22].
Although our sample size was small, no subject who was treated
with azithromycin had a relapse; this finding may be attrib-
utable to the long half-life of azithromycin within the intra-
cellular compartment, with eradication of residual organisms
after completion of therapy, as well as to its elevated concen-
tration within the biliary system. The extremely long half-life
of azithromycin in tissue, in conjunction with the success of
the drug in the present trial, may warrant trials in which shorter
courses of this agent are used for the treatment of typhoid fever,
as have been successfully tried for quinolone antibiotics [6, 19,
23].
Clinical differences between the 2 treatment groups were few.
1138 Frenck et al.
Patients treated with ceftriaxone had a slightly shorter time to
defervescence than did those treated with azithromycin (3.9 vs.
4.1 days, respectively); however, the difference was not signif-
icant, and both results were within time frames reported in
previous typhoid treatment trials [3, 19, 23–25]. Mild and tran-
sient gastrointestinal symptoms occurred in both treatment
groups, but no adverse event was severe enough to require
alteration in therapy.
In conclusion, azithromycin given for 7 days at a dosage of
10 mg/kg/day (maximum dose, 500 mg/day) appears to be
highly effective for the treatment of uncomplicated typhoid
fever in children, with clinical cure rates comparable to those
for ceftriaxone. Once-daily administration of oral azithromycin
may offer a simple treatment regimen for typhoid fever caused
by either susceptible or drug-resistant strains of S. typhi and
may be suitable for use in areas where medical resources are
limited.
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