A multi-center randomised controlled trial of gatifloxacin versus azithromycin for the treatment of uncomplicated typhoid fever in children and adults in Vietnam.

Abstract

Drug resistant typhoid fever is a major clinical problem globally. Many of the first line antibiotics, including the older generation fluoroquinolones, ciprofloxacin and ofloxacin, are failing.
We performed a randomised controlled trial to compare the efficacy and safety of gatifloxacin (10 mg/kg/day) versus azithromycin (20 mg/kg/day) as a once daily oral dose for 7 days for the treatment of uncomplicated typhoid fever in children and adults in Vietnam.
An open-label multi-centre randomised trial with pre-specified per protocol analysis and intention to treat analysis was conducted. The primary outcome was fever clearance time, the secondary outcome was overall treatment failure (clinical or microbiological failure, development of typhoid fever-related complications, relapse or faecal carriage of S. typhi).
We enrolled 358 children and adults with suspected typhoid fever. There was no death in the study. 287 patients had blood culture confirmed typhoid fever, 145 patients received gatifloxacin and 142 patients received azithromycin. The median FCT was 106 hours in both treatment arms (95% Confidence Interval [CI]; 94-118 hours for gatifloxacin versus 88-112 hours for azithromycin), (logrank test p = 0.984, HR [95% CI] = 1.0 [0.80-1.26]). Overall treatment failure occurred in 13/145 (9%) patients in the gatifloxacin group and 13/140 (9.3%) patients in the azithromycin group, (logrank test p = 0.854, HR [95% CI] = 0.93 [0.43-2.0]). 96% (254/263) of the Salmonella enterica serovar Typhi isolates were resistant to nalidixic acid and 58% (153/263) were multidrug resistant.
Both antibiotics showed an excellent efficacy and safety profile. Both gatifloxacin and azithromycin can be recommended for the treatment of typhoid fever particularly in regions with high rates of multidrug and nalidixic acid resistance. The cost of a 7-day treatment course of gatifloxacin is approximately one third of the cost of azithromycin in Vietnam.
Controlled-Trials.com ISRCTN67946944.

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A Multi-Center Randomised Controlled Trial of
Gatifloxacin versus Azithromycin for the Treatment of
Uncomplicated Typhoid Fever in Children and Adults in
Vietnam
Christiane Dolecek1,5,6*, Tran Thi Phi La3, Nguyen Ngoc Rang3, Le Thi Phuong4, Ha Vinh2, Phung Quoc
Tuan1, Doan Cong Du3, Nguyen Thi Be Bay3, Duong Thanh Long3, Luong Bich Ha3, Nguyen Trung Binh3,
Nguyen Thi Anh Hong3, Pham Ngoc Dung3, Mai Ngoc Lanh4, Phan Van Be Bay4, Vo Anh Ho4, Nguyen
Van Minh Hoang2, Tran Thu Thi Nga1,2, Tran Thuy Chau2, Constance Schultsz1,5, Sarah J. Dunstan1,5,
Kasia Stepniewska1,5, James Ian Campbell1,5, To Song Diep2, Buddha Basnyat7, Nguyen Van Vinh Chau2,
Nguyen Van Sach3, Nguyen Tran Chinh2, Tran Tinh Hien2, Jeremy Farrar1,5,6
1Oxford University Clinical Research Unit, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, 2The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam,
3An Giang Provincial Hospital, Long Xuyen, Vietnam, 4Dong Thap Provincial Hospital, Cao Lanh, Dong Thap, Vietnam, 5Nuffield Department of Clinical Medicine, John
Radcliffe Hospital, Oxford, United Kingdom, 6The London School of Hygiene and Tropical Medicine, London School of Hygiene and Tropical Medicine, London, United
Kingdom, 7Patan Hospital, Lagankhel, Lalitpur, Nepal
Abstract
Background: Drug resistant typhoid fever is a major clinical problem globally. Many of the first line antibiotics, including the
older generation fluoroquinolones, ciprofloxacin and ofloxacin, are failing.
Objectives: We performed a randomised controlled trial to compare the efficacy and safety of gatifloxacin (10 mg/kg/day)
versus azithromycin (20 mg/kg/day) as a once daily oral dose for 7 days for the treatment of uncomplicated typhoid fever in
children and adults in Vietnam.
Methods: An open-label multi-centre randomised trial with pre-specified per protocol analysis and intention to treat analysis
was conducted. The primary outcome was fever clearance time, the secondary outcome was overall treatment failure (clinical
or microbiological failure, development of typhoid fever-related complications, relapse or faecal carriage of S. typhi).
Principal Findings: We enrolled 358 children and adults with suspected typhoid fever. There was no death in the study. 287
patients had blood culture confirmed typhoid fever, 145 patients received gatifloxacin and 142 patients received
azithromycin. The median FCT was 106 hours in both treatment arms (95% Confidence Interval [CI]; 94–118 hours for
gatifloxacin versus 88–112 hours for azithromycin), (logrank test p=0.984, HR [95% CI]=1.0 [0.80–1.26]).
failure occurred in 13/145 (9%) patients in the gatifloxacin group and 13/140 (9.3%) patients in the azithromycin group,
(logrank test p=0.854, HR [95% CI]=0.93 [0.43–2.0]). 96% (254/263) of the Salmonella enterica serovar Typhi isolates were
resistant to nalidixic acid and 58% (153/263) were multidrug resistant.
Overall treatment
Conclusions: Both antibiotics showed an excellent efficacy and safety profile. Both gatifloxacin and azithromycin can be
recommended for the treatment of typhoid fever particularly in regions with highratesof multidrug and nalidixic acid resistance.
The cost of a 7-day treatment course of gatifloxacin is approximately one third of the cost of azithromycin in Vietnam.
Trial Registration: Controlled-Trials.com ISRCTN67946944
Citation: Dolecek C, Phi La TT, Rang NN, Phuong LT, Vinh H, et al. (2008) A Multi-Center Randomised Controlled Trial of Gatifloxacin versus Azithromycin for the
Treatment of Uncomplicated Typhoid Fever in Children and Adults in Vietnam. PLoS ONE 3(5): e2188. doi:10.1371/journal.pone.0002188
Editor: Robert Frenck, Cincinnati Children’s Hospital Medical Center, United States of America
Received July 23, 2007; Accepted March 27, 2008; Published May 21, 2008
Copyright: ? 2008 Dolecek et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was funded by the Wellcome Trust, UK. The funding source did not play any role in the design, conduct, analysis or publication of the study.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: cdolecek@oucru.org
Introduction
There are approximately 21 million cases of typhoid fever
annually, with more than 210 000 deaths [1]. The emergence of
antimicrobial drug resistance in Salmonella enterica serovar Typhi (S.
typhi) is a major problem particularly in South East Asia and the
Indian sub-continent and challenges our current treatment options
[2–4]. There is a need for an efficacious, safe and affordable oral
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treatment, particularly in regions with a high proportion of both
multidrug and nalidixic acid resistant S. typhi.
In Vietnam, multidrug resistant (MDR) isolates of S. typhi
(resistant to ampicillin, chloramphenicol and trimethoprim-
sulfamethoxazol) first appeared in 1993 [5]. From this time the
fluoroquinolones became the treatment of choice for typhoid fever
[4], and were simultaneously sold widely over the counter to treat
fever of various aetiologies. The extensive antibiotic pressure lead
to the selection of single point mutations in the DNA Gyrase A of S.
typhi, causing resistance to nalidixic acid (the prototype quinolone)
and reduced susceptibility to the fluoroquinolones (but formally
these isolates are still within the Clinical Laboratory Standard
Institute (CLSI) breakpoints for susceptibility) [6]. This resulted in
a poor clinical response to treatment with the older generation
fluoroquinolones, ofloxacin or ciprofloxacin [7,8].
The World Health Organisation recommends the fluoroquin-
olones or cefixime for the treatment of MDR typhoid fever and
azithromycin, the third-generation cephalosporins, or a 10–14 day
course of high-dose older generation fluoroquinolones (e.g.
ofloxacin or ciprofloxacin) for the treatment of nalidixic acid
resistant typhoid fever [9].
Azithromycin, an azalid antibiotics, has achieved excellent
clinical results in the treatment of MDR and nalidixic acid
resistant typhoid fever [7,8]. However azithromycin is expensive.
Cefixime has recently failed in the treatment of nalidixic acid
resistant typhoid fever in Nepal (these data were not available at
the start of this trial) [10].
A recent trial from southern Vietnam used ofloxacin at the
maximum recommended dose of 20 mg/kg/day for 7 days for the
treatment of MDR and nalidixic acid resistant typhoid fever and
showed high clinical failure rates (36%), high immediate post-
treatment faecal carriage (19%), which may lead to transmission in
the community after discharge from hospital, and prolonged mean
fever clearance times of 8.2 days (95% CI, 7.2–9.2 days) [8].
These results underline that the older generation fluoroquino-
lones are clearly failing in the treatment of nalidixic acid resistant
typhoid fever.
Of the newer fluoroquinolones, gatifloxacin is available and
affordable in South and South East Asia including Vietnam [10].
Of all the fluoroquinolones, gatifloxacin showed the lowest
minimum inhibitory concentrations (MICs) for nalidixic acid
resistant S. typhi from Nepal [11] and Vietnam and a rapid
bactericidal effect in time-kill experiments involving S. typhi isolates
with single and double mutations in the GyrA of S. typhi [6].
We conducted a randomised controlled trial comparing the
efficacy of gatifloxacin to azithromycin in southern Vietnam, an
area characterised by a very high proportion of MDR (88%) and
nalidixic acid resistant (93%) S. typhi isolates [8].
Methods
The protocol for this trial and supporting CONSORT checklist
are available as supporting information; see Checklist S1 and
Protocol S1.
Study design and objectives
The study was designed as a multicenter, open-label rando-
mised controlled trial to compare the efficacy and safety of
gatifloxacin versus azithromycin for the treatment of uncompli-
cated typhoid fever in children and adult in-patients in southern
Vietnam.
The overall objective of the study was to identify an efficacious,
safe, available and affordable oral treatment for MDR and
nalidixic acid resistant typhoid fever.
Participants
Patients were eligible to be included in the study if they had
clinically suspected or culture confirmed uncomplicated typhoid
fever and if fully informed written consent had been obtained. For
children, consent was obtained from the parent. Exclusion criteria
were pregnancy, age under 6 months, history of hypersensitivity to
either of the trial drugs, any signs of severe typhoid fever (shock,
deep jaundice, encephalopathy, convulsions, bleeding, suspicion or
evidence of gut perforation), or previous reported treatment with a
fluoroquinolone antibiotics, a third generation cephalosporine or
macrolide antibiotics within one week prior to hospital admission.
The study sites and ethical approval
The study was conducted at three hospitals in the south of
Vietnam.
Adult and paediatric patients were recruited at the Hospital for
Tropical Diseases in Ho Chi Minh City, at the Dong Thap
Provincial hospital in Cao Lanh, Dong Thap province and at the
An Giang Provincial hospital in Long Xuyen, An Giang province.
The study was approved by the Ethical and Scientific
Committee of the Hospital for Tropical Diseases in Ho Chi Minh
City and the Oxford University Tropical Research Ethics
Committee (OXTREC), UK for all three study sites. The clinical
and microbiological data from the first 40 patients recruited to
each arm of the study were sent to the independent Data Safety
and Monitoring Committee for their advice regarding the
continuation of the study. The study was not stopped.
Intervention
According to their randomisation number patients were
assigned to oral treatment with either 20 mg/kg azithromycin
(ZithromaxH suspension, Pfizer, USA; 200 mg/5 mL or Zithro-
maxH tablets, Pfizer, USA; 500 mg/tablet) or 10 mg/kg gatiflox-
acin (TequinH, Bristol-Myers Squibb, USA; 400 mg/tablet) once
daily for 7 days. Tablets were cut to obtain the appropriate study
dosage and administered with water. Inevitably, the dose
administered was an estimate of 10 mg/kg/day of gatifloxacin
or 20 mg/kg/day of azithromycin (number of tablets or
proportions of tablets were documented in the CRFs). Gatifloxacin
was only available as tablets, which were cut to obtain the
appropriate dosage and crushed if necessary for children.
The maximum dose of azithromycin was 1 g per day. All drugs
were purchased commercially.
Procedures
In-patient procedures.
patient’s full history was taken, a standard clinical examination
was performed and axillary temperature, weight and height were
measured. Before treatment, full blood counts including white
blood differential counts, serum aspartate transaminase (AST),
serum alanine transaminase (ALT) and bilirubin were checked and
blood cultures were obtained. For adult patients, creatinine, blood
urea nitrogen (BUN) and glucose levels were additionally
measured. In some patients bone marrow cultures were
obtained. Urines were checked with dipstick and pre-treatment
stool cultures were obtained. Chest X-ray and abdominal
ultrasound were performed and repeated as clinically indicated.
Randomisation and initiation of therapy took place either
immediately on admission to hospital or patients were observed
until results of blood tests including blood cultures were available
and then randomised. Vital signs including measurement of
axillary temperatures were measured and recorded every 6 hours
(at 6, 12, 18 and 24 hours) until discharge. Patients were examined
On admission to the hospital the
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daily until discharge from hospital, with particular reference to
clinical symptoms, FCT, side effects of the drug and any
complication of the disease. Additionally laboratory tests were
scheduled if clinically indicated. All adverse events were recorded.
On day 7 to 9 after the start of treatment full blood counts, liver
function tests, blood and stool cultures were checked. In case of
insufficient response to therapy, development of complications or
drug-associatedadverseevents,
suspended and parenteral ceftriaxone (2 g per day) in two
divided doses was used as rescue treatment for 10 days.
Follow-up procedures.
Out-patient follow-up appointments
were scheduled at 1 month, 3 months and 6 months after
discharge from hospital to seek evidence for relapse (1 month visit)
and check for chronic typhoid carriage (all visits). At these
appointments a full history was taken, relevant examinations
performed and stool cultures obtained. Blood or bone marrow
cultures were only obtained if clinical symptoms were indicative of
acute infection. If patients did not attend their follow up
appointment, they were reminded by letter or a member of the
study team visited their home. If stool samples were not available,
a rectal swab was obtained.
Patients with convalescent stool carriage of S. typhi or S. paratyphi
A were retreated according to the sensitivity of the isolate and were
further followed up. Ultrasound was performed to exclude biliary
or kidney stones if carriage was persistent.
the initialtreatment was
Microbiology
Five to 8 mL of blood was collected from adults and inoculated
into Bactec Plus Aerobic Blood bottles, and 3 to 5 mL of blood
from children was inoculated into Bactec Peds Plus culture bottles
(Becton Dickinson, New Jersey, USA). The bottles were incubated
at 37uC in the BACTEC 9050 automated analyser for 7 days and
sub-cultured according to standard methods when the machine
indicated a positive signal, or incubated at 37uC in a standard
laboratory incubator (An Giang hospital) and examined daily.
Stool samples or rectal swabs were inoculated onto MacConkey
agar and Xylose Lysine Decarboxylase (XLD) agar plates, and in
10 mL of selenite F broth. Plates and broth were incubated at
37uC overnight and the broth was sub-cultured on MacConkey
and XLD agar plates the next morning.
Isolates were screened using standard biochemical tests and S.
typhi and S. paratyphi A were identified using API20E (bioMerieux,
Paris, France) and slide agglutination with specific antisera
(Murex, Dartford, UK).
Antimicrobial susceptibility testing was performed by disc
diffusion according to Clinical Laboratory Standards Institute
(CLSI) guidelines [12], using CLSI breakpoints [13]. Antimicro-
bial agents tested were: ampicillin, chloramphenicol, trimetho-
prim-sulfamethoxazol, nalidixic acid, ofloxacin, ciprofloxacin and
ceftriaxone (Oxoid, Basingstoke, UK). Minimum Inhibitory
Concentrations (MICs) for amoxicillin, chloramphenicol, nalidixic
acid, ofloxacin, ciprofloxacin, gatifloxacin, ceftriaxon and azith-
romycin were determined by E-test (AB Biodisk, Solna, Sweden).
Multidrug resistance (MDR) of isolates was defined as resistance to
chloramphenicol (MIC$32 mg/mL), ampicillin (MIC$32 mg/
mL) and trimethoprim-sulfamethoxazole (MIC$8/152 mg/mL).
Nalidixic acid resistance was defined as an MIC$32 mg/mL. The
CLSI breakpoints for ofloxacin and gatifloxacin were #2 mg/mL
susceptible and $8 mg/mL resistant, for ciprofloxacin #1 mg/mL
susceptible and $4 mg/mL resistant and for ceftriaxone #8 mg/
mL susceptible and $64 mg/mL resistant. There were no CLSI
MIC breakpoints for azithromycin [13]. The control strains used
for all susceptibility tests were E. coli ATCC 25922, Pseudomonas
aeruginosa ATCC 27853, Staphylococcus aureus ATCC 29213.
All cultures, identification of S. typhi and S. paratyphi A and disc
diffusion were performed at the three study sites. All isolates were
sent to the Hospital for Tropical Diseases, Ho Chi Minh City, for
confirmation of identity, susceptibility testing and MIC testing.
Outcomes of the study
The primary endpoint of the study was the resolution of fever
(fever clearance time, FCT), which was defined as the time from
the start of the antibiotic treatment to when the axillary
temperature first fell #37.5uC and remained there for at least
48 hours. Secondary endpoints were the overall failure to
treatment, which was defined a priori as any of the following:
clinical failure (persistence of fever and symptoms two days after
the end of treatment, i.e. on day 10) or need for re-treatment due
to insufficient treatment response as judged by the treating
physician; microbiological failure (positive blood culture on day 7
to 9 after the start of treatment); the development of typhoid fever-
related complications during hospital-stay; the occurrence of
relapse (symptoms and signs suggestive of typhoid fever) within 1
month after completion of treatment or the detection of faecal
carriage of S. typhi at the follow-up visits at 1, 3 and 6 months (to
exclude faecal carriage a minimum of two consecutive follow-up
visits had to be attended).
Sample Size
The primary outcome measure for the study was the fever
clearance time (FCT).
Previous studies that used azithromycin to treat typhoid fever
patients, reported a mean fever clearance time of 130 hours [7]
and 139 hours [8]. For gatifloxacin, clinical observations from a
small number of typhoid fever patients were available and
indicated a mean FCT of 76 hours. We calculated that 139
patients with culture-confirmed typhoid fever would be needed in
each treatment arm to detect a Hazard Ratio of 1.40 with two-
sided alpha of 0.05 and power of 0.80 [14]. Therefore, assuming a
median fever clearance time of 130 hours for azithromycin, the
sample size of 140 patients with culture-confirmed typhoid fever in
each arm would give power of at least 0.80 to detect a difference
between treatments if the fever clearance time in the gatifloxacin
group was 92 hours or less.
Randomization procedures and assignment of
intervention (sequence generation, allocation
concealment, implementation)
An administrator independent from the study generated the
random number sequence in Excel using RAND function. These
randomised codes were blocked in a size of 50. Treatment
assignments were folded and kept in opaque, sealed, sequentially
numbered envelopes at all three study sites. Due to logistic reasons
randomisation was not stratified by centre.
After all inclusion and exclusion criteria were checked, and
informed consent given, the study doctor opened the envelope to
determine which treatment the subject would receive. The sealed
envelopes were opened in strict numeric sequence.
Blinding
This study was conducted as an open study.
Statistical methods
Binary outcomes (clinical failure, microbiological failure,
typhoid fever-related complications) were compared between the
two treatment groups using Fisher’s exact test, assuming the worst
case scenario (all lost to follow up treated as failures). The un-
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adjusted Odds Ratio (OR) and Cornfield’s 95% confidence
interval [15] were calculated to show the relative risk of developing
individual secondary outcomes (clinical, microbiological failure,
typhoid fever-related complications) in the gatifloxacin group
compared to the azithromycin group.
Fever clearance time, time to relapse and time to overall failure
were analysed using survival methods. The time to overall failure
equaled the earliest time individual failure was recorded. Kaplan-
Meier estimates of probabilities of each event were calculated at
any time-point, and they were compared between the two
treatment groups using the log-rank test. Data of patients who
were lost to follow-up were censored at the time of the last
recorded outcome. The Hazard Ratio was derived from Cox
proportional hazard model [16].
All patients with positive blood or bone marrow culture for S.
typhi and S. paratyphi A (per protocol analysis) and separately all
randomised patients (intention to treat analysis) were analysed.
All data were recorded prospectively into individual Case
Record Forms (CRF) and entered into an electronic database (Epi
Info 2003, CDC, Atlanta, USA) and double-checked.
Analysis was performed using STATA version 8.0 (Stata
Corporation, Texas, USA) statistical software program.
Results
Participant flow and recruitment
During the study period, 460 patients were assessed for
eligibility (Figure 1). One hundred and two patients were non-
eligible, the main reason was the reported previous use of
fluoroquinolone, macrolid or third generation cephalosporin
antibiotics (41 patients) in the week before hospitalisation.
Between April 2004 and August 2005, 358 patients with
suspected typhoid fever were randomised to receive either
gatifloxacin or azithromycin. Two hundred eighty-eight of these
patients had blood or bone marrow confirmed typhoid fever and
70 patients were culture negative for S. typhi. One culture positive
patients was excluded from the per protocol analysis (PP), because
he had received ciprofloxacin before entry to the trial. The PP
group consisted of 287 patients, 145 in the gatifloxacin group and
142 in the azithromycin group. All PP patients, except two in the
azithromycin group, finished the full course of treatment.
The total number patients visiting the follow-up at 1 month was
275 out of 287 (96%), at 3 months 268 out of 287 (93%), at 6
months 128 out of 287 (44%) patients.
Numbers analysed
All 358 randomised patients were analysed in the intention to
treat (ITT) analysis. Two hundred and eighty-seven patients with
culture confirmed typhoid fever, 145 treated with gatifloxacin and
142 with azithromycin, were analysed in the pre-specified PP
analysis.
Baseline Data
The median age of patients recruited in this trial was 11 years
(range 1–41) in the PP group.
The baseline characteristics of the patients were similar in the
two treatment groups and in the culture negative patients (Table 1).
Patients with suspected and blood culture confirmed typhoid
fever were eligible for this trial. In the PP group, the median delay
in time between hospital admission and randomisation was 3 days
(interquartile range 1–4) in the gatifloxacin group and 3 days
(interquartile range 2–4) in the azithromycin group. In the ITT
group, the median delay in time between hospital admission and
randomisation was 2 days (interquartile range 0–4) in the
gatifloxacin group and 3 days (interquartile range 1–4) in the
azithromycin group.
Protocol deviations and modifications
At one study site, the An Giang Provincial Hospital, the follow-
up visit at 6 months was not possible for logistic reasons. It was
therefore agreed to carry out two follow-up visits at 1 and 3
months and to schedule additional (cross-sectional) follow-up dates
to invite as many patients as possible to a third follow-up visit.
From the PP population, 22 out of 91 patients in the gatifloxacin
arm and 17 out of 87 patients in the azithromycin arm attended
the third visit.
Outcomes and estimation
Primary outcomes.
the resolution of fever (FCT) between the two treatment groups
(Table 2).
By PP analysis, the median FCT was 106 hours in both
treatment arms (95% Confidence Interval [CI]; 94–118 hours for
gatifloxacin versus 88–112 hours for azithromycin), (logrank test
p=0.984, HR [95% CI]=1.0 [0.80–1.26]). The Kaplan-Meier
survival curve for the fever clearance time is shown in Figure 2. At
day 7, fever clearance rate was 82.8% (95% CI; 76.2%–88.4%) in
the gatifloxacin group and 80.5% (95% CI; 73.6 %–86.6 %) in the
azithromycin group.
In the ITT population, the median FCT was 100 hours in both
treatment arms (95% CI; 92–106 hours for gatifloxacin versus 88–
112 hours for azithromycin), (logrank test p=0.914, HR [95%
CI]=1.01 [0.82–1.25]). At day 7, fever clearance rate was 84.2%
(95% CI; 78.5%–89%) in the gatifloxacin group and 82.6% (95%
CI; 76.5%–87.9%) in the azithromycin group (Figure 3).
Secondary outcomes.
There was no death in the study.
There was no significant difference in overall failure to
treatment between the two groups (Table 2).
By PP analysis, the number of patients that showed overall
failure to treatment was 13/145 (9%) in the gatifloxacin group and
13/140 (9.3%) in the azithromycin group (logrank test p=0.854,
HR [95% CI]=0.93 [0.43–2.0]), or when assuming the worst case
scenario, that all dropped-out patients were failures, 15/142
(10.6%) failures in the azithromycin group (logrank test p=0.570,
HR [95% CI]=0.81 [0.38–1.7]). Figure 4 shows the proportion of
patients failing through time after the start of treatment.
In the azithromycin arm, more than one failure event occurred
in individual patients (Table 2). Clinical failure occurred in 6/145
(4.3%) patients in the gatifloxacin group and in 6/140 (4.2%) in
the azithromycin group (p=1.000, OR [95% CI]=0.96 [0.25–
3.7]). Three patients in each study arm were re-treated with
ceftriaxone, the other patients resolved their symptoms within
24 hours.
Microbiological failure was seen in 2 out of 145 patients in the
gatifloxacin arm (1.4%) and in 3 out of 140 (2.2%) in the
azithromycin arm (p=0.680, OR [95% CI]=0.64 [0.05–5.7]).
Two of the azithromycin recipients showed additionally signs of
clinical failure.
There were no typhoid fever-related complications in the 145
gatifloxacin patients compared to 8 out of 140 (5.7%) patients in
the azithromycin arm (p=0.003, OR [95% CI]=0 [0–0.4]). Two
azithromycin recipients developed signs of liver dysfunction
(elevated AST and ALT, deepening of jaundice) in addition to
signs of clinical failure. Study treatment was continued and
symptoms resolved by the time of discharge. Four patients, three
children and one adult, suffered from gastrointestinal bleeding on
day 3, day 5 (2 cases) and day 7 of treatment respectively, three
patients received blood transfusions. One of these patients
There was no significant difference in
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developed shock but responded to intravenous fluids and
supportive treatment. Treatment was discontinued immediately
in all the patients and re-treatment with ceftriaxone was initiated.
Two adult patients developed pneumonia during treatment.
Relapse was evaluated only in patients that were initially
categorised as successfully treated, patients with clinical failure,
microbiological failure or complications were not evaluated. Four
patients out of 137 (2.9%) relapsed in the gatifloxacin group
compared to 0/127 in the azithromycin group (logrank test
p=0.052, HR [95% CI]=not estimable due to zero observations
in one group), (Figure 5). These relapses with symptoms suggestive
of typhoid fever occurred on day 7, 11, 13 and 15 respectively,
after completion of treatment, three patients were confirmed
culture positive for S. typhi. One patient developed acute
respiratory distress syndrome (ARDS) and needed ventilation.
The patient was treated with ceftriaxone and perfloxacine and
subsequently made a complete recovery.
Chronic faecal carriage was evaluated in patients who attended
at least two follow-up appointments, 137 in the gatifloxacin group
and 131 in the azithromycin group. Only one patient with chronic
Figure 1. Profile of the Trial.
doi:10.1371/journal.pone.0002188.g001
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Table 1. Baseline characteristics of culture confirmed patients (PP analysis) and culture negative patients.
Characteristics
Culture confirmed patients treated with
Blood culture negative
patients, n=70
Gatifloxacin, n=145Azithromycin, n=142
Median age in years (range)11 (2–30)11 (1–41) 9 (2–42)
Number of children defined as age under 15 (%) 109 (75.2)101 (71.1) 56 (80)
Number of males (%) 71 (49) 76 (53.5)29 (41)
Median weight in kilograms (range)25 (8.5–55) 24.5 (9.5–57)19.5 (10.5–53)
Median duration of fever before admission in days (range)7 (2–30) 7 (2–30)7 (3–30)
Number of patients who received pretreatment (%)*21 (14.5) 18 (12.7)16 (22.9)
Median temperature at admission in uC (range) 39 (37–40.5)39 (37.3–41) 38.75 (37–40)
Hepatomegaly, number of patients (%)69 (47.6)63 (44.4) 36 (51.4)
Splenomegaly, number of patients (%) 17 (11.7)14 (9.8) 2 (2.9)
Abdominal pain, number of patients (%) 82 (56.5)76 (53.5) 43 (61.4)
Weight loss, number of patients (%) 69 (47.6)71 (50) 21 (30)
Vomiting, number of patients (%)47 (32.4) 54 (38)19 (27.1)
Diarrhoea, number of patients (%)95 (65.5) 82 (57.7) 49 (70)
Mild jaundice, number of patients (%)12 (8.3)20 (14.1) 1 (1.4)
Median haematocrit in % (range)34.3 (19.2–54.3) 34.6 (20.7–60.5)34.2 (24.6–46.7)
Median white cell count, 109/L (range)6.9 (2–17.2) 7.05 (2.4–16.8)7.25 (2.8–11.7)
Median platelet count, 109/L (95% CI, range)172 (34–500) 172.5 (45–578)208 (51–496)
Median AST, U/L(range) 85 (16.9–773) 72 (17.6–1190)50.1 (11–533)
Median ALT, U/L (range) 67.4 (10.3–276)59.4 (10.2–734)44.1 (10–375)
Numbers of S.typhi/S.paratyphi A isolated from blood cultures 144/1 138/40
Positive pretreatment faecal cultures, numbers (%)11/124 (8.9) 6/118 (5.1)0
AST, Serum Aspartate Aminotransferase AST (normal range, 12–30 U/L).
ALT, Serum Alanine Aminotransferase ALT (normal range, 13–40 U/L).
*Treatment with amoxicilline or cotrimoxazole prior to hospital admission.
doi:10.1371/journal.pone.0002188.t001
Table 2.
Outcome Type Outcomes Sub-Categories
Treatment group (n=287)
Gatifloxacin n=145Azithromycin n=142
p-Value
PrimaryFever Clearance Time in hours (95% CI)106 (94–118)106 (88–112)0.984ˆ
SecondaryOverall treatment failure, numbers of patients (%)13/145 (9)13/140 (9.3)"
0.854ˆ
Did not complete full treatment course, n (%)02
*Clinical failure, n (%) 6/145 (4.3)6/140 (4.2) 1.000#
*Microbiological failure, n (%)2/145 (1.4)3/140 (2.2)0.680#
*Typhoid-fever related complications, n (%)0/145 (0)8/140 (5.7)0.003#
Gastrointestinal bleeding04
Pneumonia02
Liver dysfunction02
Relapse after discharge from hospital, n (%)4/137 (2.9)0/127 (0) 0.052ˆ
1Number of patients with faecal carriage at follow-up, n (%)1/137 (0.7)0/131 (0)
*Patients can fail in more than one subcategory.
"In the worst case scenario: 15/142 (10.6%) showed overall treatment failure in the azithromycin group, log rank test p=0.570.
ˆThe p value is based on the log rank test.
#The p value is based on Fisher’s exact test.
1Evaluated in patients who attended at least two follow-up visits.
doi:10.1371/journal.pone.0002188.t002
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faecal carriage was detected after 6 months (An Giang study site),
the patient had received gatifloxacin.
In the ITT analysis (all 358 randomised patients), overall
treatment failure was reported in 13 out of 185 (7%) in the
gatifloxacin group compared to 14 out of 168 (8.4%) in the
azithromycin group (logrank test p=0.615, HR [95% CI]=0.82
[0.39–1.76]). One culture negative patient in the azithromycin
group had a positive blood culture on day 7 after start of
treatment. There were no clinical failures or typhoid fever-related
complications in the culture negative patients.
Figure 2. Proportion of culture confirmed patients still febrile. Kaplan-Meier survival curve showing the proportion of culture confirmed
patients (PP analysis) still febrile through time by treatment group.
doi:10.1371/journal.pone.0002188.g002
Figure 3. Proportion of all randomised patients still febrile. Kaplan-Meier survival curve showing the proportion of all randomised patients
(ITT analysis) still febrile through time by treatment group.
doi:10.1371/journal.pone.0002188.g003
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Adverse events
Both treatments were well tolerated. One adverse event related
to azithromycin was reported, a maculopapular rash that occurred
after the first dose of treatment. Azithromycin was discontinued
immediately and the patient was treated with ceftriaxone.
Gastrointestinal side-effects (change in consistency and frequen-
cy of stools) that were probably typhoid fever related were
relatively frequent in both treatment arms at the start of treatment.
In the gatifloxacin group, one patient experienced vomiting on day
2 and day 3 and one patient diarrhoea (4 episodes/day) on day 4
and day 5 of treatment. These episodes were self-limiting and did
not require the interruption of therapy.
The median levels of serum AST and ALT fell in both groups
after 7 days of therapy. In the PP group, the median post-
treatment AST was 46.35 U/L (range 12.8–217.5) in the
gatifloxacin arm and 45 U/L (range 5–358) in the azithromycin
arm. The median post-treatment ALT fell to 46.8 U/L (range
7.4–278) and 49.9 (1.1–494), respectively. In the culture-negative
patients, the median post-treatment AST was 44.8 U/L (range
12–654) and ALT was 40 U/L (range 10–424.4).
Antimicrobial susceptibilities of S. typhi and S. paratyphi
A isolates
From the PP population, 282 (98%) S. typhi and 5 (2%) S.
paratyphi A strains were isolated. Two hundred and sixty three S.
typhi and 5 S. paratyphi A were received at the Hospital for Tropical
Diseases for antimicrobial susceptibility testing.
Fifty-eight percent of the S. typhi isolates were MDR and 96%
were nalidixic acid resistant and showed reduced susceptibility to
the older generation fluoroquinolones (Table 3). However
technically, using current CLSI breakpoints, all isolates remained
susceptible in vitro to ciprofloxacin and ofloxacin. The MIC90of
gatifloxacin was the lowest of all the fluoroquinolones tested at
0.19 mg/mL (range 0.004–0.5). All isolates were susceptible to
ceftriaxone.
The 5 S. paratyphi A strains were fully susceptible to all the
antimicrobials tested.
Discussion
Interpretation
The results of this trial show that both antibiotics worked well
for the treatment of MDR and nalidixic acid resistant typhoid
fever in Vietnam. A seven day oral course of gatifloxacin had
similar efficacy and safety as a seven day course of azithromycin,
which is recommended for the treatment of MDR and nalidixic
acid resistant typhoid fever [7,9].
However, azithromycin is not available throughout much of the
developing world and it is expensive. The costs of a 7-day
treatment course of gatifloxacin (at 10 mg/kg/day) for an adult
patient in Vietnam are approximately 25 US$, the costs of
azithromycin (at 20 mg/kg/day) are more than 90 US$.
The results for gatifloxacin in this trial are comparable to the
excellent clinical outcomes achieved with ofloxacin in Vietnam in
the early 1990s, when S. typhi isolates were still susceptible to
nalidixic acid [17–19].
Gatifloxacin has a higher affinity to GyrA and is less inhibited
by the common mutations in the GyrA gene [20]. The gatifloxacin
MIC50of the study isolates was 0.19 mg/mL compared to the
oxfloxacin MIC50of 0.75 mg/mL. We would not recommend the
continued use of the older generation fluoroquinolones (ofloxacin
and ciprofloxacin) in regions with high rates of nalidixic acid
resistant typhoid fever for fear of selecting further mutations in
gyrA [21]. This could put at risk the potential clinical benefit of the
newer fluoroquinolones, including gatifloxacin.
There have been several case reports of gatifloxacin-associated
dysglycemia in patients with type II diabetes mellitus, overweight
Figure 4. Proportion of patients with overall failure in the culture confirmed population. Kaplan-Meier survival curve showing the
proportion of patients with overall failure in the culture confirmed population (PP analysis) by treatment group.
doi:10.1371/journal.pone.0002188.g004
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or with other comorbidity [22–24]. Recently there have been
concerns about the use of gatifloxacin, after a retrospective case-
control study in 1.4 million individuals over the age of 66 years
(mean age 77 years) in Canada was published [25].
As our trial was completed before publication of this report, we
did not systematically monitor for hypo- and hyperglycemia.
Blood glucose levels taken as part of the routine care were normal.
All patients were managed as in-patients and potential symptoms
of hypo- and hyperglycemia would have been noted by the study
physicians. No dysglycemia events were reported during the in-
patient period or during the follow up period of 3 to 6 months.
The patients in our trial were healthy, young and non-obese
individuals. A trial in 867 children with otitis media with glucose
monitoring and a one year follow-up [26], as well as a recent
enteric (typhoid and paratyphoid) fever trial in Nepal used
gatifloxacin and did not report any dysglycemia [10]. In our
setting and in our patient population gatifloxacin was highly
effective despite very high rates of drug resistance and was well
tolerated.
Other newer generation fluoroquinolones, i.e. gemifloxacin and
moxifloxacin have shown low MICs for nalidixic acid resistant S.
typhi and S. paratyphi A [11], unfortunately these drugs are not
available in Vietnam and they are considerably more expensive.
The in vitro results seen with these other newer generation
fluoroquinolones should be evaluated in clinical trials.
Generalizability
The emergence of nalidixic acid resistant S. typhi and S. paratyphi
A with reduced susceptibility to the fluoroquinolones is a
widespread problem throughout Asia and therefore our study is
relevant to the whole region [2,6]. Many case reports and some
randomised controlled trials have described the worsening clinical
response to ciprofloxacin and ofloxacin [8,27,28].
The search for effective antibiotics to treat typhoid fever is
imperative.
Typically trials in typhoid fever are limited by small sample
sizes, a recent Cochrane Report has stressed the need for large
well-designed trials in enteric fever [29]. The evidence from our
trial is strengthened by a sample size of 287 patients with culture
confirmed typhoid fever (358 patients randomised), which we
believe is so far the largest RCT performed in typhoid fever.
Both antibiotics also worked well for the patients with negative
blood cultures. This is an important finding because the sensitivity
of blood culture for the diagnosis of typhoid fever is only
approximately 50 to 80% [9].
Limitations of the study
The randomisation sequence was generated with a large block
size of 50, which resulted in uneven numbers in the two treatment
groups (186 versus 172 patients in the ITT population).
One possible limitation was the low rate of stool cultures positive
for S. typhi. Faecal carriage is usually characterised by intermittent
shedding and the stool culture for S. typhi is not very sensitive.
When comparing our data with other studies that demonstrate
that azithromycin is highly efficacious for the treatment of typhoid
fever, we find similar low rates of faecal carriage at follow-up
[7,30]. It could be hypothesized that antibiotics that show high
intracellular concentrations and good tissue penetration like
azithromycin and the fluoroquinolones, achieve rapid bacterial
killing and elimination throughout the body, which reduces faecal
carriage.
The dose of gatifloxacin and azithromycin tablets was prepared
by careful cutting of the tablets (proportions of the tablets
administered were recorded in the CRFs). Inevitably, it was
therefore an estimation of the exact dose, hence we cannot
guarantee that each patient received exactly 10 mg/kg/day of
gatifloxacin or 20 mg/kg/day of azithromycin.
Figure 5. Proportion of patients with relapse in the culture confirmed population. Kaplan-Meier survival curve showing the proportion of
patients with relapse in the culture confirmed population (PP analysis) by treatment group.
doi:10.1371/journal.pone.0002188.g005
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Overall evidence.
‘‘azithromycin, clinical trial, typhoid/enteric fever’’ and used the
recent enteric fever Cochrane report [29] to identify 6 clinical
trials in the literature. In total, 251 typhoid fever patients were
treated with azithromycin.
Four trials, three from Egypt and one from India, used
azithromycin to treat MDR typhoid fever [30–33]. Azithromycin
achieved cure rates between 88% and 100%, the mean FCT
ranged from 3.8 to 4.5 days. Two trials performed in Vietnam
used azithromycin at 20 mg/kg/day [7] and at 10 mg/kg/day [8]
for the treatment of MDR and nalidixic acid resistant typhoid
fever. In total, 107 patients with culture confirmed typhoid fever
were enrolled. The cure rate was 93% and 82% and the FCT was
5.6 and 5.8 days, respectively. Our results concur with these
excellent data .
A recent trial conducted in Kathmandu, Nepal used gatifloxacin
at the same dose and duration for the treatment of nalidixic acid
resistant typhoid fever [10]. Successful treatment was achieved in
96.5% (85 out of 88) patients and the median FCT (95% CI) was
92 hours (84–114 hours). The trial in Nepal was stopped early by
We performed a MEDLINE search for
the independent Data and Safety Monitoring Committee as a
result of the poor clinical response in the patients randomised to
cefixime.
We believe on the basis of this and other recently published
trials, that gatifloxacin or azithromycin are now the treatments of
choice for enteric fever in areas of MDR and nalidixic acid
resistance [7,8,10]. However it is important to use these
antimicrobial agents cautiously because indiscriminate use would
inevitably induce further resistance.
Supporting Information
Protocol S1
Found at: doi:10.1371/journal.pone.0002188.s001 (0.07 MB
DOC)
Trial Protocol
Checklist S1
Found at: doi:10.1371/journal.pone.0002188.s002 (0.06 MB
DOC)
CONSORT Checklist
Table 3. Antimicrobial susceptibilities and minimum inhibitory concentrations (MIC) of 263 S. typhi isolate.
Treatment with
All isolatesGatifloxacinAzithromycin
n=263n=137n=126
Multidrug resistant, numbers (%)153 (58)87 (63.5) 66 (52.3)
Nalidixic acid resistant, numbers (%)254 (96.5) 132 (96.3)121 (96)
MIC 50 (mg/ml)
MIC 90 (mg/ml)
range (mg/ml)
MIC 50 (mg/ml)
MIC 90 (mg/ml)
range (mg/ml)
MIC 50 (mg/ml)
MIC 90 (mg/ml)
range (mg/ml)
MIC 50 (mg/ml)
MIC 90 (mg/ml)
range (mg/ml)
MIC 50 (mg/ml)
MIC 90 (mg/ml)
range (mg/ml)
MIC 50 (mg/ml)
MIC 90 (mg/ml)
range (mg/ml)
MIC 50 (mg/ml)
MIC 90 (mg/ml)
range (mg/ml)
MIC 50 (mg/ml)
MIC 90 (mg/ml)
range (mg/ml)
.256
.256
.256
Amoxicillin
.256
.256
.256
0.125 to .256 0.5 to .2560.125 to .256
.256
.256
.256
Chloramphenicol
.256
.256
.256
0.38 to .2562 to .2560.38 to .256
.256
.256
.256
Nalidixic acid
.256
.256
.256
1.5 to .2561.5 to .256 1.5 to .256
0.750.751
Ofloxacin 1.51.5 1.5
0.023–20.032–20.023–2
0.380.380.38
Ciprofloxacin 0.50.5 0.5
0.004–0.750.006–0.750.004–0.38
0.1250.1250.125
Gatifloxacin 0.190.19 0.19
0.004–0.5 0.006–0.250.004–0.5
0.1250.125 0.125
Ceftriaxone 0.1250.125 0.19
0.064–0.250.064–0.19 0.064–0.25
888
Azithromycin121212
1.5–16 1.5–164–16
MIC50/90, concentration at which 50% and 90% of the organisms respectively are inhibited. MDR is defined as resistance to chloramphenicol, ampicillin and
trimethoprim-sulfamethoxazole. CLSI MIC breakpoints are as follows: for chloramphenicol, ampicillin and nalidixic acid resistance $32 mg/mL; ofloxacin and gatifloxacin
#2 mg/mL susceptible and $8 mg/mL resistant; ciprofloxacin #1 mg/mL susceptible and $4 mg/mL resistant; ceftriaxone #8 mg/mL susceptible and $64 mg/mL
resistant; there are none for azithromycin.
doi:10.1371/journal.pone.0002188.t003
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Acknowledgments
We are grateful to all the doctors and nurses who cared for the patients in
this study and to all the patients and their relatives. We wish to thank the
members of the Data and Safety Monitoring Board, Dr. Christopher M.
Parry, Liverpool University, UK and Professor Nicholas J. White, Mahidol
University, Bangkok, Thailand.
Author Contributions
Conceived and designed the experiments: TH JF SD PT NS NC KS CD
BB JC TS NV TP NR LP HV DD NB ML PB VH CS. Performed the
experiments: TH JF SD NS NC CD JC TS NV TP NR LP HV DD NB
DL LH NB NH PD ML PB VH NH TN TC CS. Analyzed the data: TH
JF PT NS NC KS CD NV TP NR LP HV. Wrote the paper: TH JF PT
NS NC KS CD NV TP NR LP HV.
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