Original Article

A three-year review of antimicrobial resistance of Salmonella enterica

serovars Typhi and Paratyphi A in Pakistan
Farah Naz Qamar1, Asma Azmatullah1, Abdul Momin Kazi1, Erum Khan2, Anita Kaniz Mehdi Zaidi1
1
2

Department of Pediatrics and Child Health, Aga Khan University Hospital, Karachi, Pakistan
Department of Pathology and Microbiology, Aga Khan University Hospital, Karachi, Pakistan

Abstract
Introduction: Enteric fever is among the most common bacteraemic illnesses in South Asia. Multidrug resistance as well as fluoroquinolone
resistance has severely limited therapeutic options in high disease burden countries such as Pakistan. This review was conducted to determine
the frequency of drug-resistant Salmonella enterica serovar Typhi (S.Typhi) and Salmonella enterica serovar Paratyphi A (S. Paratyphi A)
between2009 and 2011.
Methodology: This study was a review of laboratory data. The antibiotic susceptibility of typhoidal Salmonellae isolated from blood cultures
submitted to the Aga Khan University Hospital's laboratory from all over Pakistan between January 2009 and December 2011 were reviewed.
Results: The sensitivity data of 4,323 positive isolates of S. Typhi and S. Paratyphi A isolated during the three-year period were reviewed.
The majority of isolates were S. Typhi (59.6%).Over three years, the incidence of multidrug-resistant (MDR) S.Typhi remained high, ranging
from 64.8%66.0%, while MDR S. Paratyphi A decreased from 4.2% to 0.6%.Fluoroquinolone resistance increased for S. Typhi from 84.7%
to 91.7%.Cefixime- and ceftriaxone-resistant S. Typhi were isolated in two children.
Conclusions: Our results show high rates of multidrug and fluoroquinolone resistance among S. Typhi and S. Paratyphi. The occurrence of
two cases of ceftriaxone resistance is alarming.

Key words: typhoid fever; Salmonella typhi; paratyphi; resistance.

J Infect Dev Ctries 2014; 8(8):981-986. doi:10.3855/jidc.3817
(Received 22 May 2013 Accepted 22 January 2014)
Copyright 2014 Qamar et al. This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction
Enteric fever, caused by Salmonella enterica
serovars Typhi and Paratyphi A, continues to be a
major health problem in developing countries,
particularly in South Asia and Pakistan [1,2]. In the
year 2000, there were an estimated 21.6 million cases
of typhoid fever globally, with 210,000 deaths and 5.4
million cases of paratyphoid fever [3,4]. Untreated, the
disease carries a mortality rate of up to a 30% [5,6],
and up to 90% of deaths due to enteric fever occur in
Asia alone [4]. Definitive diagnosis is made by
isolation of causative organisms from blood, bone
marrow, or other body fluids; however, the yield of
blood culture is 60% to 80% [7].
Multidrug resistance, defined as resistance to the
three first-line classes of antimicrobial agents
(chloramphenicol, ampicillin, and trimethoprim /
sulphamethoxazole) has become prevalent in most of
South Asia, with a frequency ranging from 50% to
80% of all S. Typhi isolates [7-10]. MDR S. Paratyphi
has been reported globally at rates of up to 25% [11]

and is a significant problem in South Asia, ranging

from 13% in India [12] to 44% in Pakistan [13].
Fluoroquinolones became the first-line drug for
treatment after the emergence of MDR strains.
However, from 2000 onwards, there has been a
dramatic rise in fluoroquinolone-resistant S. Typhi
isolates [14-18]. There are reports from parts of South
Asia of isolates that are MDR and have reduced
sensitivity to fluoroquinolones [19]. Recently,
cephalosporins (ceftriaxone and cefixime) and
azithromycin have been suggested as alternatives for
treating MDR infections [6,7,20,21]. High levels of
multidrug and fluoroquinolone resistance have made
cephalosporins the drug of choice for empiric therapy
in SouthAsia [20,22].
An increasing trend of fluoroquinolone resistance
in S. Typhi and S. Paratyphi has been reported earlier
from Pakistan [23]. Shortfalls in diagnosis due to lack
of laboratory facilities, easy availability of
antimicrobial agents, and cheap substandard
formulations of fluoroquinolones are the underlying
risk factors for high antimicrobial resistance in

Qamar et al. Resistance patterns of typhoidal Salmonellae in Pakistan

J Infect Dev Ctries 2014; 8(8):981-986.

developing countries [24]. Also of concern is the

sporadic occurrence of resistance to third-generation
cephalosporins observed among typhoidal Salmonellae
[25-27].
Keeping surveillance of resistance trends among
strains, monitoring rational use of antimicrobial
agents, and developing clinical management
guidelines to standardize therapy can be useful
strategies in curtailing the development of resistance
against the remaining mainstay of therapy thirdgeneration cephalosporins. We reviewed antibiotic
susceptibility data of S. Typhi and S. Paratyphi A
isolated from blood cultures at the Aga Khan
Universitys Clinical Microbiology Laboratory
between 2009 and 2011.
Methodology
Antimicrobial susceptibility data of Salmonella
enterica serovars Typhi and Paratyphi A isolated from
blood cultures submitted to the Aga Khan University
Hospitals (AKUH) Clinical Microbiology Laboratory
were reviewed.Thelaboratory receives samples from
more than 190 collection units located in all major
cities and towns across the country. The AKUH
laboratory operates according to laboratory guidelines
of international standards (certified by ISO and Joint
Commission International Accreditation).
Laboratory methods
A venous blood sample was collected from all
patients referred to the lab for blood culture. Blood
was inoculated into enriched soybean-casein digest
broth with resins in BACTEC (Becton-Dickinson,
New Jersey, USA) bottles. For patients less than five
years of age, BACTEC PEDS Plus bottles were used.
Upon growth as indicated by the BACTEC machine,
blood culture bottles were sub-cultured onto a
MacConkey agar plate. Colonies giving biochemical
reactions suggestive of Salmonellae were confirmed
serologically with specific O and H antisera (BD

Laboratories). Salmonella isolates were tested for

antimicrobial susceptibility by the Kirby-Bauerdisk
diffusion method [28] on Muller-Hinton agar with
standard antimicrobial disks (Clinical Laboratory
Standards
Institute
2009)
[29].Antimicrobial
susceptibility for seven antimicrobial agents
ampicillin,
chloramphenicol,
trimethoprim
/
sulphamethoxazole,
cefixime,
ceftriaxone,
ciprofloxacin, and/or ofloxacin was performed.
From January 2009 to December 2011, a total of
116,690 blood culture specimens from patients
belonging to all age groups were submitted to the
clinical laboratory. Laboratory data pertaining to
isolate species, age of patient, year of collection, and
area of collection were collected.
Multidrug resistance was considered if isolates
were resistant to three antimicrobial classes
(ampicillin, chloramphenicol, and trimethoprim /
sulphamethoxazole), while isolates were considered
fluoroquinolone resistant if they were resistant to
ofloxacin. Sequencing for the quinolone resistancedetermining regions was not performed. Due to the
very low number of S. Paratyphi B and C (n = 21),
they were omitted from the analysis.
Results were tabulated and analyzed using
Microsoft Excel 2007.
Results
A total of 4,323 isolates of Salmonella enterica
serovars Typhi and Paratyphi A, B, and C strains were
isolated from 116,690 blood cultures submitted
between 2009 and 2011. The majority of blood
cultures (93.3%; n = 4,035) were from subjects seen in
Karachi at the inpatient and outpatient departments of
AKUH. Most of the isolates were from adults 15
30years of age (27.5%, with a 6%culture positivity
rate), followed by children 510 years of age and
children under 5 years of age (Table 1).
Isolates were predominantly S. Typhi (59.6%; n =
2,576) and S. Paratyphi A (39.9%; n = 1,726).

Table 1. Breakdown of total blood cultures, percentage culture positivity and distribution of S. Typhi and S. Paratyphi A
isolates by age groups
Age
Ages < 5
Ages 5 10 years
Ages 10 15 years
Ages 15 30 years
Ages 30 50 years
Ages > 50 years
All ages

S. Typhi
n (%)
718 (79.2%)
688 (68.3%)
400 (58.2%)
553 (46.5%)
164 (39.6%)
53 (44.2%)
2,576 (59.6%)

S. Paratyphi A
n (%)
174 (19.2%)
319 (31.6%)
285 (41.5%)
634 (53.4%)
248 (59.9%)
66 (55.0%)
1,726 (39.9%)

Positive for typhoidal

Salmonellae n*/N** (%)
906/35,297 (2.6%)
1,008/9,263 (10.9%)
687/6,645 (10.3%)
1,188/19,805 (6.0%)
414/18,683 (2.2%)
120/26,997 (0.4%)
4323/116690 (3.7%)

% of total positive
samples
21.0%
23.3%
15.9%
27.5%
9.6%
2.8%
100.0%

* total number of positive blood cultures; ** total blood cultures in that age group; S. Paratyphi B and C are omitted from table as only 21 isolates were
identified.

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Qamar et al. Resistance patterns of typhoidal Salmonellae in Pakistan

J Infect Dev Ctries 2014; 8(8):981-986.

Figure 1. Antimicrobial resistance of S. Typhi and S. Paratyphi identified in blood cultures between 2009 and 2011.

Figure 2. Trends of antimicrobial resistance of S.Typhi and S. Paratyphi A over three years (2009-2011).

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Qamar et al. Resistance patterns of typhoidal Salmonellae in Pakistan

The remaining 0.48% (n = 21) were S. Paratyphi B and

C (Table 1).
The resistance to antimicrobial agents of all
isolates over the three years is shown in Figure
1.Almost identical resistance was seen to ampicillin
(66.1%), chloramphenicol (66.8%), and trimethoprim /
sulphamethoxazole (66.5%) for S. Typhi, from a total
of 2,576 positive isolates. Fluoroquinolone resistance
in S. Typhi was seen in 88.2%of the isolates. Lower
resistance rates for S. Paratyphi A species were
reported: 2.3% (ampicillin), 2.6% (chloramphenicol),
and 2.8% (trimethoprim / sulphamethoxazole). The
rate of fluoroquinolone resistance in S. Paratyphi was
83.9%.
From 2009 to 2011, MDR S. Typhi remained high,
ranging from 64.8% in 2009 to 66.0% in 2011 (Figure
2). However, fluoroquinolone resistance increased for
S. Typhi, from 84.7% in 2009to 91.7% in 2011.MDR
S. Paratyphi A decreased from 4.2% to 0.6% from
2009 to 2011; however, fluoroquinolone resistance for
S. Paratyphi increased, from 72.1% to 95% (Figure 2).
The pattern of antimicrobial resistance was
uniform across all ages except for two isolates (0.08%)
recovered from children three and four years of age,
respectively, with resistance to third-generation
cephalosporins (ceftriaxone and cefixime). Both were
residents of Karachi. Ceftriaxone minimum inhibitory
concentration was performed for both of these isolates
and was found to be >32 g/mL. No further
genotyping was performed.
Discussion
Since the 1980s, outbreaks caused by strains of S.
Typhi resistant to chloramphenicol, ampicillin, and
trimethoprim/sulphamethoxazole have been reported
to such an extent as to be considered endemic in many
developing countries and areas, especially Pakistan
and South Asia [3]. Such multidrug-resistant strains
most likely arise from unchecked use of antimicrobials
for every febrile illness in both adults and children,
which is especially true in South Asia [20,30]. More
recently, third-generation cephalosporins have
emerged as necessary agents against enteric fever. The
emergence of MDR Salmonella strains with resistance
to fluoroquinolones and now reports of resistance to
third-generation cephalosporins is alarming, resulting
in a shortage of therapeutic options against enteric
fever.
We report a very high rate of MDR S. Typhi over
the three-year period. This trend of multidrug
resistance over the last three years reflects the

J Infect Dev Ctries 2014; 8(8):981-986.

endemicity of such resistant strains in this region and

is much higher than that seen in eight countries of Asia
[31] and in a study by Hasan et al., which showed
multidrug resistance rates of 34.2% to 48.5% for S.
Typhi from 2001 to 2006 [23]. Our results, however,
are similar to those reported from Pakistan by Hazir et
al. in 2002, who reported a cumulative prevalence of
MDR S. Typhi of 67.2%, although this was from one
center only [10].We report low rates of MDR S.
Paratyphi A over the last three years, similar to results
reported by Hasan et al. (a decrease from 44.5% to
8.6%). This is in contradiction to an increasing rate of
MDR S. Paratyphi A, from 14% in 1996 to 44% in
2003, from other parts of Pakistan [13]. The
decreasing trend of multidrug resistance over time
[32,33] in other regions maybe due a change in choice
of therapy and a decrease in usage of these three
agents [27]. It may also represent isolated outbreaks of
susceptible strains [34]. However, no such decrease in
resistance of S. Typhi was seen in this study,
suggesting stable genomic changes in S. Typhi and
more unstable genomic mutations in S. Paratyphi in
this region. Although advocated by some [35], use of
these antimicrobial agents should not be advised for
empiric treatment of enteric fever in Pakistan.
The S.Typhi resistance to fluoroquinolones of
91.7%was observed in this review during 2011, much
higher
than
the
5%30%
resistance
to
fluoroquinolones seen in India [17,18,36], and higher
than the previously reported 54% resistance seen in
children in southern Pakistan in 20072008 [37].
Indiscriminate use of fluoroquinolones is seen in
Pakistan for many febrile illnesses [38], with
resistance to a number of organisms increasing as well
[39,40]. Weak health systems together with ready
availability of low-cost substandard formulations of
fluoroquinolones on the market aggravate the
development and spread of resistant strains [24]. Not
enough efforts on regional and international levels are
being made to curb the uncontrolled use of
antimicrobial agents, to promote culture confirmed
sensitivity-based therapy, and to spread awareness
among prescribing physicians and the public.
The two cases of resistance to third-generation
cephalosporins is the most worrisome finding in this
review, and the potential spread of such extensively
resistant S. Typhi isolates is an alarming situation.
Cephalosporin-resistant S. Typhi have been reported
from other regions in Asia [25-27]. The threat of a
regional spread of such resistance patterns, and even

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Qamar et al. Resistance patterns of typhoidal Salmonellae in Pakistan

sporadic occurrences of these cases, are major

concerns since both limit therapeutic options.
This review of lab data of blood cultures collected
from more than 190 laboratories throughout Pakistan
included strains from communities as well as hospital
inpatients. Our results are therefore reflective of the
resistance patterns of S .Typhi and S. Paratyphi
throughout the country. There was a similar trend of
antimicrobial susceptibility among strains from all
over the country.
The present study shows that the antimicrobial
resistance patterns among S. Typhi isolates can also
change significantly over relatively short periods, with
the prevalence of multidrug and fluoroquinolone
resistance S. Typhi isolates increasing substantially
within a six-year period. Therefore, routine
surveillance of antimicrobial resistance patterns is
critical.
Vaccination is a valuable tool for preventing
enteric fever in travelers from developed countries to
endemic countries, for preventing and controlling
epidemics, and for preventing illness in children in
endemic settings. Further development in this area is
warranted, and this is especially true in children
attending school, where the burden of S. Typhi
infection is highest, based on the distribution of
positive isolates identified in this study. Proposals for
the incorporation of typhoid vaccines into extended
programs of immunization are required, as is the
development of paratyphoid vaccines.
Our review has limitations. Being an extract of a
laboratory database, percent positivity does not reflect
prevalence figures. Furthermore, no clinical
information of the severity of illness in the subjects
with MDR strains is reported. Of note, further
characterization of cephalosporin-resistant isolates was
not possible since the isolates have not been archived.
Conclusion
We report a high rate of multidrug and
fluoroquinolone resistance; this can have implications
for empiric antimicrobial therapy in a country endemic
for typhoid. Vaccination against typhoid and measures
to reduce antimicrobial overuse and misuse of
antimicrobials should be developed and implemented
to limit the disease and spread of resistance.
Authors contribution
All authors listed have made substantial contributions to the
work reported in the manuscript. Individual role in the
manuscript is as detailed: Clinical lab data was reviewed by
E. Khan and F. Qamar as part of larger study design

J Infect Dev Ctries 2014; 8(8):981-986.

currently in process. F. Qamar helped in the conception and

design of the manuscript as well as analysis and
interpretation of the data and writing and review of the
manuscript; A. Azmatullah analyzed the data, contributed to
data interpretation, tabulation of results, and manuscript
writing. AM Kazi helped in retrieving the data and analysis
of data. E. Khan and A. Zaidi reviewed and revised the final
manuscript.
Acknowledgements
We are thankful to Dr. Sadia Shakoor, Senior Instructor
Research (Dept of Pediatrics) for her valuable input in the
manuscript and to the pediatric research officers Mr.
Shahzad Saleem and Mr. Murtaza Ali for data entry and
cleaning of data.
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Corresponding author
Dr. Farah Naz Qamar
Department of Pediatrics and Child Health, Aga Khan University
Hospital, Stadium Road, PO Box 3500, Karachi 74800, Pakistan
Phone: + 92 213 4865025
Email: [email protected]

Conflict of interests: No conflict of interests is declared.

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