Eur J Clin Microbiol Infect Dis (2009) 28:963–970
DOI 10.1007/s10096-009-0732-6
ARTICLE
Increasing rates and clinical consequences of nalidixic
acid-resistant isolates causing enteric fever in returned
travellers: an 18-year experience
S. Hume & T. Schulz & P. Vinton & T. Korman & J. Torresi
Received: 5 November 2008 / Accepted: 18 March 2009 / Published online: 9 April 2009
# Springer-Verlag 2009
Abstract The purpose of this study was to examine the rate
and clinical consequences of nalidixic acid-resistant (NAR)
isolates in travellers with enteric fever presenting to a hospital
in a developed country. We retrospectively examined micro-
biologically confirmed cases of enteric fever in adult returned
travellers over an 18-year period presenting to two tertiary
referral hospitals in Melbourne, Australia. There were 59
cases of Salmonella typhi infection, 43 cases of S. paratyphi
A infection and two cases of S. paratyphi B infection. Most
patients reported recent travel to India (36%) or Indonesia
(29%). NAR isolates were commonly encountered (41% of
all isolates), particularly from India (75%), Pakistan (80%)
and Bangladesh (60%). The number of NAR isolates
increased progressively after 2003. Patients with NAR
isolates had prolonged mean fever clearance time (5.6 vs.
3.3 days, P=0.03) and prolonged hospital stay (7.9 vs.
S. Hume (*) : T. Schulz : J. Torresi (*)
Victorian Infectious Diseases Service, Royal Melbourne Hospital,
Grattan Street,
Parkville, VIC 3050, Australia
e-mail: sam.hume@mh.org.au
P. Vinton : T. Korman
Department of Infectious Diseases, Monash Medical Centre,
Melbourne, VIC, Australia
J. Torresi
Department of Medicine, University of Melbourne,
Melbourne, VIC, Australia
J. Torresi (*)
Department of Infectious Diseases, Austin Hospital,
The University of Melbourne,
145 Studley Road,
Heidelberg, VIC 3084, Australia
e-mail: josepht@unimelb.edu.au
5.7 days, P=0.02) compared to non-resistant isolates. This
represents the largest report of NAR enteric fever in returned
travellers. NAR isolates predominate in cases of enteric fever
from South Asia and result in prolonged fever clearance time
and hospital stay. Empiric therapy with alternative antibiotics
such as ceftriaxone or azithromycin should be considered in
patients with suspected enteric fever from this region.
Introduction
Enteric fever caused by nalidixic acid-resistant (NAR)
isolates have reduced susceptibility to fluoroquinolones,
and in endemic countries, this is associated with higher
rates of morbidity and mortality, particularly prolonged
fever clearance time and increased need for retreatment
[1–4]. While a differential outcome in fever clearance time
for NAR compared to sensitive organisms has been
demonstrated in endemic countries, this finding has only
been reported from a developed country in a 3-year
retrospective series concluding in 2002 and a small case
series of just five patients [5, 6]. Treatment responses in
local populations may be affected by both pre-existing
immunity and comorbid illness, and, therefore, may not be
accurately extrapolated to travellers. As such, and given the
only limited data in returned travellers over a relatively
short time period, we primarily sought to assess the rate and
clinical consequence of infection with NAR isolates in
travellers presenting to two tertiary referral hospitals in
Melbourne, Australia, over an 18-year period.
Recently, an increasing proportion of cases of enteric
fever are due to Salmonella paratyphi [7–10]. Rather than
causing a less severe illness, it is increasingly recognised
that this organism is also capable of producing severe
disease [10, 11]. Therefore, we additionally sought to
964
compare the relative frequency, clinical features and illness
severity produced by infection with S. paratyphi compared
to S. typhi.
Materials and methods
Cases of enteric fever from 1 January 1990 to 31 December
2007 were identified retrospectively from microbiological
records, patient discharge summaries and hospital coding
data. A standard case report form was utilised to collect the
relevant data from each patient file. Some of the informa-
tion on patients from one institution was collected
prospectively and stored in a travel medicine database,
which was subsequently extracted for analysis. We evalu-
ated the travel history, patient demographics, clinical
presentation, investigation results, change in antibiotic
susceptibilities over time, treatment and outcomes of
microbiologically confirmed cases of enteric fever caused
by S. typhi and S. paratyphi A and B. Due to the
retrospective nature of the study, we only included patients
in the denominator if a documented reference was made to
the presence or absence of specific findings.
Enteric fever was defined as the occurrence of a systemic
febrile illness in conjunction with a positive blood and/or
stool culture for S. typhi or S. paratyphi A or B. Fever was
defined as a maximum recorded temperature of >37.5°C.
Patients were excluded from analysis if they were less than
15 years old at the time of presentation, reported no
overseas travel in the previous 2 months or had stool
carriage of S. typhi or S. paratyphi without a systemic
illness (i.e. carrier state).
The strict classification of patients as visiting friends and
relatives (VFRs) was not consistently performed over the
study period; however, we were interested in this sub-group
as they have a higher risk of acquiring travel-related illness
[12]. Therefore, we chose to examine patients who were
born overseas and returned to their country of birth on the
assumption that they were likely to have a similar risk of
travel-related illness as VFRs.
Isolates were identified at each hospital according to the
Clinical Laboratory Standards Institute (CLSI) or predeces-
sor guidelines current at the time of culture positivity and
were then sent to the state reference laboratory (Microbi-
ologic Diagnostic Unit) for sensitivity testing (95 of 104
isolates) [13]. Introduced in November 2004, agar dilution
with a breakpoint concentration of 16 µg/ml was used for
nalidixic acid susceptibility testing. Prior to this time, the
disc diffusion method with nalidixic acid disc concentration
of 30 µg/ml was employed.
Analyses were performed using Microsoft Office Excel
2003 (Microsoft) and Stata/SE Version 9.0 (StataCorp, Texas,
USA). The Chi-square test and Fisher’s exact test were used as
Eur J Clin Microbiol Infect Dis (2009) 28:963–970
appropriate. Due to skewing in the data, sample median values
and ranges are presented, and for statistical comparisons, the
Wilcoxon rank-sum test was used.
Results
One hundred and four microbiologically confirmed cases of
enteric fever were identified with 59 cases (56.7%) of S.
typhi infection, 43 cases (41.3%) of S. paratyphi A
infection and two cases (1.9%) of S. paratyphi B infection.
Between 1990 and 2001, there were 31 S. typhi isolates
(67.4%) and 15 S. paratyphi isolates (32.6%), while
between 2002 and 2007, there were 25 S. typhi isolates
(45.5%) and 30 S. paratyphi isolates (54.5%) (Fig. 1).
Sixty-four patients (61.5%) were male and 80/99 patients
(80.8%) were born outside Australia. The median age was
24.7 years (range 15.4–66.5 years), and there was no
difference between the mean age of patients with S. typhi
infection or S. paratyphi infection (27.1 years vs. 28.9 years,
P=0.39).
Asia (99/104 patients, 95.2%) was the most common
continent from which patients reported recent travel, with
India (36 patients, 35.6%), Indonesia (30 patients, 28.8%)
and Cambodia (9 patients, 8.7%) being the most common
countries visited, followed by Bangladesh and Pakistan (5
patients each, 4.8%). Sixty-one patients (59%) travelled
from their country of birth.
Fourteen patients (13.5%) reported pre-travel typhoid
vaccination, and, of these, only one patient was returning
from their country of birth. Of the vaccinated patients, four
patients developed S. typhi infection and ten patients
developed S. paratyphi infection.
Patients arrived in Australia a mean of 17.0 days
(median 14.0 days, range 1–54 days) before hospital
attendance and the mean duration of symptoms was 9.9 days
(median 7.0 days, range 1–34 days). There was no
16
Paratyphi
14
Typhi
12
10
Frequency
8
6
4
2
0
1990 1992 1994 1996 1998 2000 2002 2004 2006
Fig. 1 Proportion of Salmonella typhi and S. paratyphi isolates by
year from 1990 to 2007
Eur J Clin Microbiol Infect Dis (2009) 28:963–970 965

significant difference in mean duration following arrival in
Australia (17.5 days vs. 16.2 days, P=0.98) and mean
duration of symptoms (11.3 days vs. 9.5 days, P=0.61)
between S. typhi and S. paratyphi groups. The rate of
hospitalisation was similar between cases of S. typhi
infection and cases of S. paratyphi (54/59 patients, 92%
vs. 38/44 patients, 86%, P=0.4), as was the mean duration
of hospital stay (6.7 days vs. 5.8 days, P=0.5).
Presenting symptoms and signs are shown in Table 1.
Patients with diarrhoea were investigated for other gastro-
intestinal pathogens. Only two patients with diarrhoea had
another pathogen identified; one patient had Campylobacter
jejuni isolated and another had Blastocystis hominis
identified. One patient without diarrhoea had B. hominis
identified. Patients with hepatomegaly and splenomegaly
presented a mean of 11.0 and 12.3 days after symptom
onset, respectively. There was no difference in the
frequency of symptoms or signs between infection with S.
typhi or S. paratyphi. The presenting full-blood examina-
tion, biochemistry and liver function tests are summarised
in Table 2.
In the S. typhi group, blood cultures were positive in 53/
59 patients (90%), while five patients had negative blood
but positive stool cultures. One patient had a positive urine
culture for S. typhi. Blood and stool cultures were positive
in 28 patients with S. typhi. In the S. paratyphi group, blood
cultures were positive in 40/45 patients (89%), while five
patients had negative blood but positive stool cultures. In
the S. paratyphi group, 23 patients were positive for both
blood and stool cultures. Only 10/104 patients (9.6%) had
negative blood but positive stool cultures and excluding
them from the analysis did not alter the duration of fever or
hospital stay.
Five percent of isolates were resistant to ampicillin and
9% were resistant to chloramphenicol (Fig. 2). One hundred
and two isolates had a ciprofloxacin minimum inhibitory
concentration (MIC) performed. Twenty-three (22.5%) had
intermediate ciprofloxacin susceptibility and all of these
isolates were resistant to nalidixic acid. A further 16 NAR
isolates were reported as fully susceptible to ciprofloxacin.
There were no isolates resistant to ciprofloxacin or
ceftriaxone. Of the 39 isolates (41%) resistant to nalidixic
acid, the majority were from India (72%), Pakistan (11%)
and Bangladesh (8%) (Table 3). Despite 30 patients
reporting recent travel to Indonesia, no NAR isolates were
identified from these patients. The first NAR isolate was
identified in July 1997 from Pakistan, and there has been a
dramatic increase in the overall number of NAR isolates
since 2003 (Fig. 3). The majority of isolates from India
since 1999 have been NAR (28/32 isolates, 88%) (Fig. 4).
The mean fever clearance time following the commence-
ment of antibiotics was 4.1 days for the 88 patients for
whom this information was available (median 3.0 days,
range 0–21 days). Patients infected with S. typhi had a trend
towards longer mean fever clearance time than those
infected with S. paratyphi (4.7 vs. 3.1 days, P=0.05).
Patients with NAR isolates had a prolonged mean fever
clearance time (5.6 vs. 3.3 days, P=0.03) and longer length

Table 1 Presenting symptoms and signs of returned travellers with Salmonella typhi and S. paratyphi enteric fever

All cases S. typhi S. paratyphi A/B

Symptoms n Positive % n Positive % n Positive % P-value*

Fever 104 103 99% 58 58 100% 45 44 98% 0.43

Rigors 72 43 60% 37 21 57% 35 22 63% 0.64
Headache 103 58 56% 58 31 53% 45 27 60% 0.55
Diarrhoea 103 57 55% 58 31 53% 45 26 58% 0.69
Abdominal pain 103 51 50% 58 31 53% 45 20 44% 0.43
Fatigue 103 36 35% 58 18 31% 45 18 40% 0.41
Vomiting 103 31 30% 58 21 36% 45 10 22% 0.14
Cough 103 23 22% 58 13 22% 45 10 22% 1.00
Myalgia 103 20 19% 58 12 21% 45 8 18% 0.80
Rash 103 4 4% 58 2 3% 45 2 4% 1.00
Signs
Fever (T>37.5°C) 99 94 95% 59 55 93% 40 39 98% 0.65
Abdominal tenderness 102 46 45% 58 25 43% 44 21 48% 0.83
Hepatomegaly 102 10 10% 58 5 9% 44 5 11% 0.74
Splenomegaly 102 8 8% 58 6 10% 44 2 5% 0.46
Rash 102 6 6% 58 4 7% 44 2 5% 0.70

*P-value for S. typhi vs. S. paratyphi using Fisher’s exact test

966 Eur J Clin Microbiol Infect Dis (2009) 28:963–970

Table 2 Presenting symptoms

and signs of returned travellers Units Normal range n Mean Median Inter-quartile range
with S. typhi and S. paratyphi
enteric fever White cell count ×109/L 4.0–11.0 102 6.3 6.0 4.6–8.1
Neutrophils ×109/L 2.0–8.0 98 3.6 3.4 2.3–4.8
Lymphocytes ×109/L 1.2–4.0 31 1.3 1.1 0.8–1.6
Platelets ×109/L 150–400 103 215 201 148–275
ALP IU/L <120 97 120 99 76–149
ALT IU/L <55 98 154 98 46–183
Bilirubin μmol/L <19 64 19 13 9–21
C-reactive protein mg/L <8 79 85 70 43–107

of hospital stay (7.9 vs. 5.7 days, P=0.02) compared to
non-resistant isolates.
Information on antibiotic use was available for 99
patients. Forty-one patients (41%) were treated with
ciprofloxacin alone, three patients (3%) were treated with
intravenous ceftriaxone alone, one patient (1%) was treated
with oral azithromycin alone and one patient (1%) was
treated with intravenous ampicillin alone. Fifty-three
patients (54%) were treated with a combination of anti-
biotics, most commonly intravenous ceftriaxone followed
by oral ciprofloxacin.
Thirty-two of the 41 patients (78%) treated with
ciprofloxacin alone had the fever clearance time recorded.
Of these, 27/32 patients (84%) had nalidixic acid-sensitive
isolates and their mean fever clearance time was shorter
than the 5/32 patients (16%) with NAR isolates (2.6 vs.
5.4 days, P=0.02).
A number of complications were identified, all in
patients infected with NAR isolates. One patient with S.
typhi in blood and stool cultures developed a splenic
abscess. He was febrile for 21 days and required percuta-
neous aspiration, together with a 6-week course of cipro-
floxacin and ceftriaxone. Another patient with S. typhi
infection presented with a febrile diarrhoeal illness and
spontaneous abortion at 6 weeks gestation. She required
intensive care support for acute respiratory distress syn-
Ceftriaxone 97
102
Ciprofloxacin
Nalidixic acid 57 39
Chloramphenicol 90
Ampicillin 98
0 20 40 60 80
Number of isolates
Sensitive Resistant
Fig. 2 Distribution of antibiotic sensitivities of S. typhi and S.
paratyphi isolates
drome, persistent hypotension and acute renal failure. She
developed pancytopaenia and had evidence of haemopha-
gocytosis on bone marrow aspirate. Fevers persisted for
19 days on ceftriaxone, but no metastatic focus was
identified on imaging, trans-oesophageal echocardiogram
or positron emission tomography.
Three patients with S. typhi and one with S. paratyphi,
all NAR, had prolonged fever requiring a change in
antibiotics. One patient treated with ciprofloxacin required
readmission to hospital and then home-based intravenous
ceftriaxone. Four patients with a mean age of 26.8 years
developed delirium. They presented a mean of 6.8 days
after symptom onset and had a mean hospital stay of
7.0 days. Two patients had prolonged faecal carriage of S.
paratyphi, which resolved without further antibiotic
courses. One patient developed pancytopaenia on ceftriax-
one, which resolved following a change to ciprofloxacin.
Discussion
This study evaluates microbiologically confirmed cases of
enteric fever acquired overseas presenting to two tertiary
referral centres over an 18-year period and represents the
largest report of NAR isolates of S. typhi and S. paratyphi
in returned travellers. We detected a high rate of nalidixic
acid resistance in travellers from India and Pakistan
compared with South East Asia. A sharp rise in the
0 frequency of S. typhi and S. paratyphi NAR isolates was
0
noted from 2003, especially from these two countries. The
consequences of infection with NAR isolates included a
prolongation of mean fever clearance time and hospital
9 stay. A complicated clinical course was only observed in
patients infected with NAR isolates.
5
Enteric fever is the eighth most common cause of fever
100 120 reported in returned travellers, immigrants or refugees seen
in a specialist clinic or requiring admission under an
infectious diseases unit [14]. The disease, however, is
relatively uncommon in developed countries and is mainly
seen in returned travellers [15–17]. In the state of Victoria,
Australia, approximately 20–40 confirmed cases of enteric
Eur J Clin Microbiol Infect Dis (2009) 28:963–970 967

Table 3 Nalidixic acid-resistant

(NAR) isolates by country of Country NAR isolates % of all isolates, by country, that express NAR
acquisition. Proportion of all
isolates, by country, that express India 28 (71.7%) 75%
nalidixic acid resistance Pakistan 4 (10.5%) 80%
Bangladesh 3 (7.9%) 60%
Cambodia 1 (2.6%) 11%
Malaysia 1 (2.6%) 100%
China 1 (2.6%) 50%
Sri Lanka 1 (2.6%) 100%
Total 39 (100%)

fever are notified each year, and almost all are acquired
overseas [18]. The patterns of NAR isolates in returned
travellers are, however, poorly described.
NAR isolates have increased substantially in endemic
countries in recent years, and this is reflected in an increase
in the number of imported cases in developed countries [3–
5, 16, 19–23]. The United States Centers for Disease
Control and Prevention (CDC) data for notified isolates of
S. typhi demonstrates that the nalidixic acid resistance rate
more than doubled from 19% in 1999 to 42% in 2004 [24].
In the United Kingdom, the rate of NAR S. typhi increased
from 35% to 47% across 2001 to 2004, while resistance
rates for S. paratyphi increased from 23% to 70% over the
same time period [25]. Our study of returned travellers
corroborates this global trend of escalating rates of nalidixic
acid resistance, particularly from India, where 75% of
isolates demonstrated nalidixic acid resistance.
Increased fever clearance times in patients with NAR
isolates have been noted prospectively in endemic
countries, but to the best of our knowledge, only two
studies have reported this finding in a developed country
[1–3]. A small Canadian series of 21 patients provided
clinical information on five patients with a suboptimal
response to fluoroquinolones [6]. In a recently published
United States-based retrospective study of S. typhi infection
between 1999 and 2002, median fever clearance times were
prolonged by 20 h for 23 patients with decreased
ciprofloxacin-susceptible isolates (MIC 0.12–1 µg/ml)
18
NA sensitive NA resistant
16
14
compared to 44 patients with fully sensitive isolates (MIC
<0.12 µg/ml) [5]. Our study, which was marginally larger,
additionally examined S. paratyphi isolates, and not only
corroborates the finding of prolonged mean fever clearance
time (by>2 days) but, moreover, provides evidence for a
striking increase in NAR isolates since the conclusion of
the previous paper’s study period.
The high rate of NAR isolates from India, Pakistan and
Bangladesh presents a strong case for initiating non-
fluoroquinolone-based therapy for suspected enteric fever
in patients returning from these countries. This is appropri-
ately reflected in local guidelines where oral azithromycin
or intravenous ceftriaxone are first-line recommendations in
this group [26]. Azithromycin is more efficacious than the
older fluoroquinolones ofloxacin and ciprofloxacin for the
treatment of NAR isolates. In one study in which 93% of
isolates were NAR, higher clinical cure rates (82% vs.
64%), shorter mean fever clearance times (5.8 vs. 8.2 days)
and lower rates of post-treatment stool carriage (1.6% vs.
19.4%) were observed with azithromycin compared to
ofloxacin [27]. Azithromycin is comparable to ceftriaxone,
with similar cure rates for the treatment of uncomplicated
typhoid fever in children and adolescents [28]. Relapses
only occurred in the ceftriaxone group. An ongoing
potential for resistance to these two agents exists; although
there are no current azithromycin CLSI breakpoints,
9
Naladixic acid sensitive Nalidixic acid resistant
8
7
6
Frequency

12 5
Frequency

10
4
8
3
6
2
4
2 1
0 0
1990 1992 1994 1996 1998 2000 2002 2004 2006 1991 1993 1995 1997 1999 2001 2003 2005 2007

Fig. 3 Frequency of nalidixic acid-sensitive and -resistant S. typhi and Fig. 4 Frequency of nalidixic acid-sensitive and -resistant S. typhi and
S. paratyphi isolates by year from 1990 to 2007 S. paratyphi isolates from India by year from 1990 to 2007
968
isolates with higher azithromycin MICs have been reported
in India, and there have been sporadic reports of ceftriaxone
resistance [13, 21, 29–32].
Especially high rates of enteric fever have been observed
in India and Indonesia, with >1,000 incident cases per
100,000 population annually [16]. In the present study, and
statewide, patients with enteric fever commonly reported
recent travel to India and Indonesia [18]. Indeed, travel to
the Indian subcontinent incurs a higher risk of developing
enteric fever. Swedish estimates based on notification data
define the risk of enteric fever as 39.6 cases per 100,000
travellers to the Indian subcontinent compared to 4.8 and
2.8 cases per 100,000 travellers to the Middle East and East
Africa, respectively [33]. Conversely, highly successful
school-based mass vaccination campaigns and improve-
ments in sanitation in Thailand during the 1970s and 1980s
markedly reduced the incidence of typhoid fever [34, 35].
In the 5 years to August 2006, 4.6% of Australian travellers
went to Thailand compared with 1.9% who went to either
India or Pakistan [36]. Despite being a popular tourist
destination for Australian travellers, we report only a single
case of enteric fever acquired in Thailand during the 18-
year study period. The recognition of highly endemic
countries and the corresponding increased risk to travellers
reinforces the importance of targeted traveller education
and vaccination.
The relative rate of S. paratyphi to S. typhi infection has
been increasing in Asia, even in areas without community-
based typhoid vaccination campaigns [7–10, 19, 20, 33,
37]. Consistent with this trend, we noted an increasing
relative frequency of S. paratyphi to S. typhi over the study
period (Fig. 3). The severity of illness produced by S. typhi
and S. paratyphi A/B is similar, as exemplified by the
comparable time to presentation, need for hospitalisation,
duration of hospital stay and symptom frequency, although
there was a trend towards longer fever clearance time for
infection with S. typhi.
Ten vaccinated patients developed S. paratyphi infection,
an organism for which neither injectable Vi polysaccharide
nor oral Ty21a vaccines provide any cross-protection. This
lack of cross-protection is likely to become an increasingly
important issue in endemic Asian countries and for travellers
to them as the relative frequency of S. paratyphi increases.
Additionally, we noted a low rate of pre-travel medical
consultation and vaccination (13.5%), an important risk
factor for acquiring enteric fever abroad [17]. While the
efficacy of typhoid vaccination has been variously reported
as 50–70%, these figures are derived from studies of local
populations in endemic areas with, presumably, some pre-
existing immunity to typhoid [16]. The extrapolation of
similar efficacy rates to travellers may not be accurate. Four
patients received vaccination and subsequently developed
infection with S. typhi. As we only reported on patients
Eur J Clin Microbiol Infect Dis (2009) 28:963–970
where a specific reference to vaccination was made, we
cannot comment on the efficacy of vaccination but, rather,
note the low rate of documented vaccination and the fact that
some cases occurred despite vaccination.
Patients returning to a developed country after visiting
friends and relatives (VFRs) are at higher risk of develop-
ing a number of infectious diseases [38–40]. This increased
risk relates to low rates of pre-travel medical consultation
and vaccination, longer duration of stay, more commonly
visiting a remote location and a lack of appropriate food
and water hygiene. VFRs are seven times as likely to
acquire typhoid fever compared to tourist travellers [12]. In
our study, we could not define the 61 patients who returned
to their country of birth as VFRs, as not all patients were
explicitly questioned on their reason for travel. It is likely,
however, that most of these 61 patients were VFRs and
were over-represented, as nearly 60% of the cases in this
study relate to this increased risk.
The clinical presentation of enteric fever in returned
travellers is relatively non-specific, with similar rates of
fever, headache, diarrhoea and abdominal pain as reported
previously [6, 10, 16, 17, 19, 20, 41]. Complication rates
were lower in our series, possibly because most patients
(81/104, 78%) presented within 14 days of symptom onset
and received treatment before entering the third week of
illness. The complication rate was higher in children
infected with NAR strains in an Indian study, and, recently,
a link between nalidixic acid resistance and increased
clinical virulence of S. typhi has been proposed [42, 43].
Of note, we only observed a complicated clinical course in
patients infected with NAR isolates.
One of the main limitations of our retrospective study
was assessing the appropriateness of initial therapy and the
relative contribution of different antibiotics to fever
duration and hospital stay. Many patients received initial
therapy with an intravenous antibiotic, most commonly
ceftriaxone, and were subsequently changed to an oral
antibiotic, most often ciprofloxacin, before fever resolution
and/or discharge, a reflection of the standard of inpatient
care for returned travellers with enteric fever in a developed
country. Notwithstanding, of almost one third of the study
population who used ciprofloxacin alone, the mean fever
duration was significantly longer for those with NAR
isolates when compared to nalidixic acid-sensitive isolates.
Many of the ongoing challenges in the prevention,
diagnosis and management of enteric fever in returned
travellers are evident in the present study. Of primary
importance, the widespread use of fluoroquinolones in
South Asia has increasingly limited the utility of an
effective, orally available class of antibiotics, as demon-
strated by the 41% rate of NAR strains in our study. We
have demonstrated prolonged fever clearance time and
prolonged hospital stay as a consequence of nalidixic acid
Eur J Clin Microbiol Infect Dis (2009) 28:963–970
resistance in a moderately sized population of returned
travellers seen in a tertiary hospital. As such, we suggest
non-fluoroquinolone-based therapy in the form of oral
azithromycin or intravenous ceftriaxone as initial therapy
for those presenting with enteric fever from India, Pakistan
and Bangladesh. Fluoroquinolones are appropriate initial
therapy for those from other regions. Additionally, our
study demonstrates recent increases in the relative rate of S.
paratyphi, mirroring reports across Asia, and provides
evidence that this organism produces a similar clinical
illness to S. typhi. Against this background, the develop-
ment of an effective vaccine against both S. typhi and S.
paratyphi, in addition to improving vaccine uptake and pre-
travel advice, may help limit the impact of escalating rates
of nalidixic acid resistance.
Acknowledgements We acknowledge Elizabeth Matchett, Royal
Microbiologic Hospital, Joan Pauling, Melbourne Diagnostic Unit,
and Despina Kotsanas, Southern Health, for their contribution to the
data collection.
Conflicts of interest All authors: no conflicts.
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