Clinical Infectious Diseases Advance Access published August 28, 2013

Trends of etiology and drug resistance in enteric fever in the last two decades in

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Nepal: a systematic review and meta-analysis

Surendra Karki1, Prabin Shakya2, Allen C Cheng1, Shyam Prakash Dumre3, Karin
Leder1
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Infectious Disease Epidemiology Unit, Department of Epidemiology and Preventive

Microbiological Research Organization Nepal (MiRON), Kathmandu, Nepal

National Public Health Laboratory, Kathmandu, Nepal

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Corresponding author: Surendra Karki, Department of Epidemiology and Preventive

Medicine, Monash University, 99 Commercial Road, Melbourne VIC 3004. tel: +61 3
99030118 Email: surendra.karki@monash.edu

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Alternate author for contact: Allen C Cheng, Department of Epidemiology and Preventive
Medicine, Monash University. 2nd floor, Burnet Centre, Alfred Hospital, Commercial Road,
Melbourne VIC 3004. tel: +61 3 9076 3009, fax: +61 3 9076 2431, email:
allen.cheng@monash.edu

40 word summary

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Over the last two decades in Nepal, there has been a significant trend towards reduced
susceptibility or non-susceptibility to fluoroquinolones. In contrast, decreasing resistance to

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traditional first-line antibiotics, such as chloramphenicol, and co-trimoxazole, whereas

decreased multi-drug resistance have been observed.

TheAuthor2013.PublishedbyOxfordUniversityPressonbehalfoftheInfectiousDiseasesSocietyof
America.Allrightsreserved.ForPermissions,pleaseemail:journals.permissions@oup.com

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Medicine, Monash University, Melbourne, Australia

Abstract
Prospective time-trend analyses on shifting etiology, and trends of drug-resistance in enteric

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fever are scarce. We performed a systematic review and meta-analysis to understand the
trends in etiology, and resistance to antimicrobials since 1993, using published and

unpublished datasets from Nepal. Thirty-two studies involving 21,067 Salmonella enterica
serotype Typhi (ST) and Salmonella enterica serotype Paratyphi A (SPA) isolates were

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included. There was an increasing trend in enteric fever caused by SPA during the last two

decades (p<0.01). We observed sharply increasing trends in resistance to nalidixic acid, and

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chloramphenicol, and co-trimoxazole have significantly decreased for both organisms. The
resistance to ceftriaxone has remained low, suggesting it is likely to remain useful as a

reserve antibiotic for treatment. Decreasing resistance to traditional first-line antibiotics and

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decreasing MDR trend provides an opportunity to reconsider these drugs in therapy.

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ciprofloxacin for both ST and SPA. In contrast, multi-drug resistance (MDR), resistance to

Introduction
The term enteric fever includes Typhoid fever and Paratyphoid fever, caused by

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Salmonella enterica serotype Typhi (ST), and Salmonella enterica serotype Paratyphi A

(SPA), B and C respectively. Global estimates in 2000 suggested 21 million illnesses and
>210,000 deaths due to typhoid fever, plus 5.4 million cases of paratyphoid fever, with

similar figures also estimated for 2010 [1,2]. Enteric fever is endemic in Nepal with seasonal

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outbreaks; however studies suggest that sustained higher incidence of SPA cases is being

observed in recent years [3-5]. It is among the commonest causes for adults to visit health

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and SPA have been reported to cause indistinguishable clinical syndromes and disease
severity [7]. Moderately effective vaccines against ST are available, but vaccine uptake was

negligible in Nepal before 2011 [8]. Previously, a randomized controlled trial of Vi-based
vaccine in Nepal was shown to be 75% effective against ST, but it does not confer protection

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against SPA [9].

Discovery of chloramphenicol in 1948, and its use in treatment for enteric fever decreased
case-fatality due to infection from 20% to <1% [10]. Antimicrobials such as chloramphenicol,
ampicillin and co-trimoxazole were the drugs of choice for treatment of typhoid until the late

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1980s. Since then, the increasing incidence of multidrug-resistant (MDR) ST strains (i.e.
resistant to chloramphenicol, ampicillin and co-trimoxazole) led to the use of
fluoroquinolones (FQs), particularly ciprofloxacin for empiric treatment of enteric fever

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[11,12]. However, resistance to fluroquinolones quickly emerged, as has been reported from
South Asia and elsewhere since early 1990s [13-15].
Understanding the evolving epidemiology and drug resistance can guide policy makers
regarding appropriate interventions and optimal empiric treatment. Previously, there have

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facilities, with estimated incidence of >100 cases per 100,000 population [1,6]. In Nepal, ST

been prevalence studies at different time points; however a sufficiently long-term prospective
surveillance or time-trend analysis, particularly describing ST and SPA separately, has not

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been published. Thus, we conducted a systematic review and meta-analysis to understand the
trends in etiology, and antimicrobial resistance to ST, and SPA in Nepal from 19932011using available evidence.
METHODS

We included only studies conducted in Nepal, as in a restricted geographical setting

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antimicrobial use and policy is likely to be relatively homogeneous. The Kathmandu Valley,
divided into three major districts, is densely populated (2.5 million), where most enteric fever

cases are reported [16,17] and where most studies included in this review were conducted.
Provision of clean water and sanitation remain huge problems, with faecal coliform

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contamination in 100% of surface water and 60% of piped water at distribution points [18].
The majority of drug sales (~90%) occurs through private pharmacy retailers, who are often
untrained [19]. This has led to indiscriminate and unnecessary use of antimicrobials for a
range of illnesses [20]. Although antimicrobials are legislatively mandated as prescription

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drugs, this has been poorly enforced [19,20].

Literature search

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We searched in PubMed, MEDLINE, EMBASE, Google Scholar and the thesis directory of
Tribhuvan University of Nepal for relevant literature published/reported prior to December
2012. An electronic search was conducted using the following terms: enteric fever,
salmonella, typhoid, paratyphoid, nepal, kathmandu. A manual search was
conducted on all relevant references listed within articles identified after an initial screen. We

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Settings

included data from unpublished thesis works submitted to Tribhuvan University, and relevant
topics were identified from the thesis directory. We also performed individual searches in all

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peer reviewed medical journals published from Nepal (A detailed search strategy is listed in
Appendix 1).

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Eligibility criteria

The review included all identified hospital-based studies or publications from the national

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cases of enteric fever. Studies were included if antimicrobial resistance was measured by
standard disk-diffusion method according to guidelines from the Clinical and Laboratory

Standard Institute (CLSI; formerly NCCLS). Data from submitted theses to Tribhuvan
University, which are peer reviewed, were included if sufficient details were reported to meet

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eligibility criteria.

Studies were excluded if the majority of cases were from single source outbreaks, as they can
disproportionally distort trends. Studies with combined reporting of ST and SPA
antimicrobial susceptibility data were excluded, as were studies reporting antimicrobial

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susceptibility on isolates from stool culture. The study selection process is shown in Figure 1.
Quality of studies and publication bias

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We measured the quality of studies using a context-modified version of a tool generated for
assessing study quality on prevalence [21]. According to this tool, studies with a minimal risk
of bias have a maximum total quality score (TQS) of 19. The criteria for assessment of
quality are based on sampling, measurement and analysis. The outcome measurements in our
study involved laboratory methods rather than survey questionnaire, thus the assessment tool

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surveillance system reporting proportions of ST and SPA among all blood culture-confirmed

was adapted accordingly by replacing the term survey questionnaire with laboratory
methods. As blood culture and antimicrobial susceptibility testing are relatively standard

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procedures in hospital laboratories, most studies attained good scores. However all studies
were based on convenience sampling and thus scored poorly on sampling criteria. We

categorized studies in low (TQS, 17-19), moderate (TQS, 14-16) and high risk of bias (TQS,
11-13), arbitrarily. Studies with a TQS of <11 were excluded.

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To examine whether there was evidence for publication or reporting biases, particularly
whether studies reporting higher resistance rates were more likely to be published, we

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addition, we carefully assessed for the duplication of cases between studies by an approach
similar to that suggested by Wood [22] where studies were examined to check if they were

published by the same authors, from the same hospital/institution, or where data was
collected during the same time period. The corresponding author was contacted if further

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clarification was needed.

Data extraction

Two authors (S.K and P.S) extracted data independently using a standard data collection form.
Information was compiled on total culture-confirmed enteric fever, exact year and location of

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sampling, number of ST and SPA isolates, number of MDR ST and SPA isolates, total
number of isolates tested for individual antimicrobials and number susceptible, intermediate

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or resistant to each antimicrobial. MDR was defined as resistance to three or more drugs
(chloramphenicol, co-trimoxazole, ampicillin or amoxicillin). All studies used Kirby-Bauer
disc diffusion method to measure susceptibility and a few additionally used minimum
inhibitory concentrations for further analyses; however proportion of resistance was
determined from results of disc diffusion. Resistance to nalidixic acid, chloramphenicol, co-

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performed visual analysis with funnel plot and statistical analysis with Eggers test. In

trimoxazole, amoxicillin and ampicillin was defined as isolates having a zone of inhibition
within the category of resistant according to CLSI guidelines. However, for public health

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purposes, CLSI emphasizes the importance of reporting both intermediate and resistant
isolates of Salmonella for fluroquinolones and third generation cephalosporins [23]. Thus, we
included intermediate and resistant strains in one non-susceptible category for

ciprofloxacin and ceftriaxone. Two large studies reported data from multiple years with

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antimicrobial resistance patterns and etiology of enteric fever broken down by year, thus we
included the annual data of these studies as different data-sets. Where studies reported

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Statistical analysis

We conducted meta-regression analyses using sample size weighted generalized linear

regression model. The outcome of meta-regression model was the odds ratio. Firstly, the
proportion (p) (proportion of etiology (ST or SPA), and proportion of resistance to individual

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antimicrobials) values were transformed to logit (log of the odds). A linear regression of
logit transformed values over time (year) was performed giving the following relationship
between the proportion , and time .

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The analytical weight was proportional to sample size, and we expressed the result of
regression as odds ratio (exponentiation of coefficient () gives odds ratio). The odds ratio

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from our model can be interpreted as the relative change in odds (i.e odds of ST, odds of SPA,
or odds of resistance to specific antimicrobials) per year.
Additionally, if the relative change in odds of etiology or resistance was not significant, we
calculated the overall pooled proportion. The reported proportion of resistance to individual

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summary data from multiple years we used the mid-interval year as the study time point.

antimicrobials in most studies was often either near 0 or near 1, and some studies reported no
resistant cases. To stabilize the variance in such studies, we used Freeman-Tukey type double

isolates tested) with variance of

(where

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arcsine transformation of the raw proportion (number of resistant bacterial isolates/total

is the number of Salmonella isolates

tested) [24]. In studies where resistance was not detected in any isolate, the proportion was
estimated as

. We pooled the transformed resistance proportion in a random effect

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analysis using DerSimonian-Laird weighting. The inferential values were back transformed
from the pooled estimate of transformed values [25]. Preliminary meta-regression showed

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pooled proportion of ST and SPA as well as individual antimicrobials in blocks of 5 years

from 1993 using random effect meta-analysis. We used STATA 12.1 (StataCorp, College

RESULTS

station, Texas) for all statistical analyses.

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Study characteristics

Out of the total 32 studies involving investigation of 21,067 ST and SPA isolates, only 5 were
reported from outside of the Kathmandu Valley and only 6 were conducted in children under
age 15 years. The pooled proportion of Salmonella isolation among all blood cultures from

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1993-2011 was 9.2% (95% CI 7.4, 11.0), with no significant trend over time (p=0.07). The
sample size, year of sampling, and proportions of SPA isolates among Salmonella isolates are

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shown in Figure 2.

The score for quality of studies varied from 13 to 17 on the assessment scale. Out of 32
studies, 4 were categorized as having low risk of bias, 24 as moderate risk and 4 as high risk.
Since there were few studies with low or high risk of bias, sensitivity analyses were not
performed based on study quality. In the funnel plot analysis, we observed considerable

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that resistance varied with time but not with geographical location, thus we calculated the

scattering of studies regarding prevalence of resistance to antimicrobials, likely related to

inter-study heterogeneity over time. However, testing for asymmetry of the funnel plot for

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reported prevalence of resistance to antimicrobials among ST or SPA was not significant

(Egger test, p>0.05, for all). In addition, there was no evidence of duplication of cases
between the studies included in final meta-analyses.
Trends in etiology of enteric fever

confirmed enteric fever cases [4-7,26-49]. The pooled proportion of enteric fever due to SPA

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increased from 25.0% in years 1993-1997 to 41.0% in years 2008-2011 (Figure 2). The
relative change in odds of SPA as an etiology of enteric fever increased significantly over
time [Odds ratio (OR) = 1.04, 95% CI 1.02, 1.06]. The visual illustration of the decreasing

proportion of ST as an etiology of enteric fever is shown in Figure 3.A.

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Trends in multi-drug resistant ST and SPA

Fourteen studies reported the prevalence of MDR ST [6,27-29,32,34-36,39,42,43,47,49,50]

and twelve studies reported the prevalence of MDR SPA [6,27-29,32,34,35,39,42,43,47,49].
The relative change in odds of multi-drug resistance decreased significantly over time for
both ST and SPA (p<0.01), however prevalence of MDR SPA was lower at each time blocks

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compared to ST (Table 1) (Figure 3.B). The pooled prevalence of MDR ST was 3.0% (95%
CI 0.3, 8.1) and MDR SPA was 0.5% (95% CI 0.01, 1.7) for 2008-2011 (Table 1).

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Trends in resistance to fluroquinolones and third generation cephalosporin

Eighteen studies reported nalidixic acid (NA) resistance for ST [5-7,34,35,37,39-43,4648,50-53] and fourteen studies for SPA [5-7,34,35,37,39-43,46-48]. The odds of NA
resistance in ST was stable over time with a pooled prevalence of 63.4% (95% CI 56.2, 70.7);

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Twenty-eight studies reported the proportion of ST and SPA isolates among all blood-culture

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however the relative change in odds of NA in SPA sharply increased over time (OR= 1.24,
95% CI 1.08, 1.41) (p<0.001), and the pooled prevalence was 90.5% (95% CI 85.6, 95.4) in

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years 2008-2011 (Table 1) (Figure 4.A and 4.B).

Twenty-two studies reported the prevalence of ciprofloxacin resistance for ST [5-7,2629,32,34,35,39,40,42-47,50-53] and eighteen studies reported this for SPA [5-7,26-

29,32,34,35,39,40,42-47]. The relative change in odds of ciprofloxacin resistance (including

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intermediate resistance) significantly increased over time for both ST (p<0.01) and SPA

(p<0.05). In the years 2008-2011, the pooled prevalence of ciprofloxacin resistance in ST and

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(Figure 4.C and 4.D).

Fifteen studies reported ceftriaxone resistance in ST [5,7,29,32,34,35,39,43,44,46,47,50-

52,54] and eleven in SPA [5,7,29,32,34,35,39,43,44,46,47]. There was no significant change

in odds of ceftriaxone resistance over time in both ST and SPA. The overall pooled

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prevalence of ceftriaxone was 1.5% in ST and 0.7% in SPA (Table 1) (Figure 4.E and 4.F).
Trends in resistance to chloramphenicol, and co-trimoxazole
Nineteen studies reported chloramphenicol resistance [5,7,26-28,32,34,35,39,42-44,46,47,4952,54], and eighteen studies reported co-trimoxazole resistance [5-7,26-28,32,34,35,39,42-

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44,46,49,50,52,54] in ST isolates. Similarly, fifteen studies reported chloramphenicol

resistance [5,7,26-28,32,34,35,39,42-44,46,47,49], and fifteen studies reported co-

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trimoxazole resistance [5-7,26-28,32,34,35,39,42-44,46,49] in SPA isolates. The relative

odds of resistance to both antibiotics significantly decreased for both ST and SPA (Table 1)
(Figure 5). In the years 2008-2011, the pooled prevalence of resistance to chloramphenicol,
and co-trimoxazole for ST was 4.2% (95% CI 1.9, 7.2), and 6.9% (95% CI 3.4, 11.6)
respectively (Table 1). Similarly, for the same time period, the pooled prevalence of

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SPA was 10.65% (95% CI 6.3, 15.8) and 14.3% (95% CI 5.2, 26.9), respectively (Table 1)

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resistance to chloramphenicol, and co-trimoxazole for SPA was 3.2% (95% CI 2.0, 4.6) and
2.0% (95% CI 1.1, 3.2), respectively (Table 1).

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DISCUSSION

We observed significant changes in epidemiology of enteric fever in Nepal. Our review

suggests that the proportion of enteric fever cases due to Salmonella enterica serotype
Paratyphi A (SPA) is significantly increasing. The prevalence of resistance to NA is

intermediate resistance) is significantly increasing for ST and SPA, but ceftriaxone resistance

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has remained relatively low for both. Conversely, the prevalence of resistance to traditional
first line antibiotics like, chloramphenicol, and co-trimoxazole is significantly decreasing.
The prevalence of MDR ST and MDR SPA is also decreasing, reflecting the decreasing

chloramphenicol, and co-trimoxazole resistance in the past decade.

The selective pressures behind the shifting etiology of enteric fever are not well understood.

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A decrease in the incidence of ST but an unchanged or increased incidence of SPA could

occur due to the impact of vaccines against ST. However, although Vi-based vaccines are
currently available in Nepal, they were used uncommonly during the study years. Another
possible explanation may be due to changes in faecal carriage of these organisms. In context

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of higher prevalence of reduced susceptibility to NA and higher minimum inhibitory

concentration towards all commonly used fluroquinolones among SPA [5,7,55],

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indiscriminate empiric fluoroquinolones may be having a differential effect on long-term

carriage of SPA versus ST cases. Alternatively, there may be distinctive risk factors for ST
and SPA, as a study from Indonesia reported that consumption of food from street vendors
was predominantly a risk factor for SPA, not for ST [56]. Moreover, SPA cases are incident

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increasing sharply in SPA, but has remained stable in ST. Ciprofloxacin resistance (including

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equally throughout the year whereas ST cases peak in July and August, the months with
highest annual precipitation, again possibly reflecting differential exposure risks [4,5].

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The fact that SPA is increasingly being common simultaneously with steep increases in NA
and ciprofloxacin resistance raises serious concerns about empirical treatment of suspected

enteric fever cases with fluroquinolones. Detection of resistance to NA is a good marker of

reduced susceptibility to ciprofloxacin, but isolates with reduced susceptibility to

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ciprofloxacin without resistance to NA have been reported in South-east Asia [57,58].

Reasons for higher prevalence of NA resistance in SPA compared to ST are unclear. In

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isolates, a novel mutation in quinolone resistance determining region has been reported from
Nepal [59]. A linear increasing trend in the MIC of ciprofloxacin over time has also been

described for ST from India [60].

As has been reported from other countries in South-Asia [60], we observed a low and

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relatively stable prevalence of resistance towards ceftriaxone. Ceftriaxone requires parenteral

administration and has higher cost, so ceftriaxone is generally reserved for treatment of
complicated and hospitalized cases.

A significant decrease in resistance to chloramphenicol, and co-trimoxazole as well as in

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MDR isolates was observed, probably due to reduced use of these antibiotics over recent
decades. Similar results have been reported from India [61,62]. We speculate that the

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restoration of susceptibility may have a genetic basis with resistance residing in plasmids.
These findings suggest that there is an opportunity to re-consider antibiotics which were
rendered non-effective by resistance 20 years previously. Alternatively, there are a few other
drugs like gatifloxacin and azithromycin whose efficacy for the treatment of enteric fever has
been tested recently in clinical trials [63,64]. However, clinicians involved in treating patients

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addition to increasing prevalence of resistance to ciprofloxacin among both ST and SPA

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with enteric fever should consider various factors like cost, availability, dose requirements,
and patient co-morbidities in relation to side effects, before making specific antimicrobial

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choices.
Our study has several limitations. Although we calculated the predicted relative change in

odds of etiology/drug-resistance patterns, findings are solely for understanding trends over
time and should not be used for prediction beyond the time period of study or to predict

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clinical efficacy. Additionally, the current CLSI recommended zone of inhibition for

fluoroquinolone susceptibility is controversial and may not correlate with true in vivo

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of resistance to NA, and/or preferably on the basis of MICs for individual fluroquinolones.
Further, we do not have information about the extent of clustering of cases of enteric fever in

the studies included in the meta-analysis, as most of the primary studies did not explore for
such an observation. However, it should be noted that when the cases are clustered in

biased.

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outbreaks, they do not supply independent information and the estimate of prevalence may be

In conclusion, Salmonella enterica serotype Paratyphi A is emerging as an increasingly

important etiology of enteric fever, with high rates of increase in nalidixic acid resistance.

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Resistance to ceftriaxone has remained low, suggesting it is likely to remain useful as a

reserve antibiotic for treatment. Decreasing resistance to chloramphenicol, and cotrimoxazole presumably associated with declining use of these antibiotics, has resulted in the

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restoration of these agents as therapeutic options.

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effectiveness. The functional susceptibility for fluroquinolones should be judged on the basis

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NOTES
Acknowledgements

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We thank Professor John Crump, University of Otago, New Zealand for comments on a draft
of this manuscript, and Associate Professor Rory Wolfe, Monash University, Australia for

Contributors

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SK and AC designed the study. SK and PS extracted the data, assessed the quality of studies,
and independently decided for inclusion or exclusion, and in events of disagreement, SD
helped to resolve. SD contacted corresponding authors of potentially eligible studies, if

needed. SK performed all the statistical analyses with help from AC, and KL. SK prepared
manuscript with the help from AC, and KL. All authors contributed to the draft of this report

Funding
None

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and interpreted the findings.

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Conflict of interests

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We declare that we have no conflict of interests.

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statistical advice.

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Figure 1: Flow diagram for study selection process (ST= Salmonella enterica serotype Typhi,

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SPA=Salmonella enterica serotype Paratyphi A, MDR= Multi-drug resistance).

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23

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Figure 2: Forest plot showing pooled proportion of enteric fever due to Salmonella enterica

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serotype Paratyphi A (SPA). CI=confidence interval, ST= Salmonella enterica serotype

Typhi, n=number of isolates. [Note: The dotted line in middle represents the overall pooled

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proportion during the year 1993-2011]

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Figure 3: (A) Proportion of Salmonella enterica serotype Typhi (ST) among total Salmonella

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enterica isolates (p<0.01, for trend). (B) Proportion of multi-drug resistant ST among total
ST isolates. Each grey circle indicates an individual study, and area of circle size is
proportional to the sample size. The sizes of circles are comparable within individual graphs

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only. The trend line (dashed) is the predicted prevalence from the regression model.

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Figure 4: Trends of resistance to different antimicrobials- (A) Nalidixic acid resistance in

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Salmonella enterica serotype Typhi (ST). (B) Nalidixic acid resistance in Salmonella enterica
serotype Paratyphi A (SPA). (C) Ciprofloxacin resistance in ST. (D) Ciprofloxacin resistance
in SPA. (E) Ceftriaxone resistance in ST. (F) Ceftriaxone resistance in SPA. Each grey circle
indicates an individual study, and the area of circle size is proportional to the sample size.

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The sizes of circles are comparable within individual graphs only. The trend line (dashed) is
the predicted prevalence from the regression model. [Please note the prevalence scales are

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unique to each figure]

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Figure 5: Trends of resistance to different antimicrobials- (A) Chloramphenicol resistance in

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Salmonella enterica serotype Typhi (ST). (B) Chloramphenicol resistance in Salmonella

enterica serotype Paratyphi A (SPA). (C) Co-trimoxazole resistance in ST. (D) Cotrimoxazole resistance in SPA. The trend line (dashed) is the predicted prevalence from the

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regression model. [Please note the prevalence scales are unique to each figure]

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28

Table 1: Trends in prevalence of antimicrobial resistance in Salmonella enterica serotype

Typhi and Salmonella enterica serotype Paratyphi A

MDR

SPA

ST

SPA

ST

Year (1998-

Year (2003-

Year (2008-

Overall

1997)

2002)

2007)

2011)

(1993-2011)

NA

10.3 (0.7,

6.5 (3.3,

3.0 (0.3,

28.5)

10.7)

8.1)

NA

2.2 (1.1,

0.5 (0.01,

3.6)

1.7)

NA

NA

NA

NA

NA

NA

NA

1.6 (0.04,

90.5 (85.6,

91.7)

95.4)

2.5 (0.6,

10.6 (6.3,

Ceftriaxone

NA

5.3)

5.8)

15.8)

3.9 (0.1,

2.9 (0.4,

14.3 (5.2,

pt
ed

SPA

ST

NA

ce

SPA

NA

Chloramphenicol

ST

Ac

SPA

Co-trimoxazole

ST

SPA

NA

NA

NA

83.9 (76.0,

Ciprofloxacin

Year (1993-

16.2)

7.5)

26.9)

NA

NA

NA

NA

NA

NA

(95% CI)

0.87 (0.78,

0.97)**

NA

0.87 (0.81,

0.95)**

63.4 (56.2,

0.97 (0.85,

70.7)

1.11)

NA

1.24 (1.08,
1.41)**

NA

1.14 (1.04,
1.26)**

NA

1.11 (1.01,
1.22)*

1.5 (0.5, 2.9)

1.22 (0.94,
1.58)

NA

0.7 (0.2, 1.5)

0.95 (0.88,
1.02)

13.6 (5.1,

4.7 (0.5,

4.2 (1.9,

25.2)

12.9)

7.2)

NA

1.2 (0.2,

3.2 (2.0,

2.8)

4.6)

19.1 (10.5,

12.5 (6.0,

2.4 (0.9,

6.9 (3.4,

29.6)

20.9)

4.6)

11.6)

4.9 (3.6,

1.7 (1.2,

1.2 (0.3,

2.0 (1.1,

6.4)

2.4)

2.8)

3.2)

NA

0.86 (0.82, 0.91)***

NA

0.89 (0.81,
0.99)*

NA

0.85 (0.82,
0.89)***

NA

0.85 (0.79, 0.91)***

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Nalidixic acid

Odds ratio

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ST

Pooled proportion expressed as percentage (95% CI)

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MDR

Isolate

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Antimicrobials

29

[Note: ***= p<0.001, ** = p<0.01, * = p<0.05, = p>0.05, NA=not appropriate,

CI=confidence interval, ST= Salmonella enterica serotype Typhi, SPA= Salmonella enterica

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serotype Paratyphi A. Pooled proportion in five-year time blocks is not shown if there were
less than 3 studies within that year block, and is noted as NA. Overall pooled proportion was
not shown if the relative change in odds is significant over time (1993-2011), and is noted as
NA. The odds ratio (OR) can be interpreted as relative change in odds per year. A

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significant OR <1 indicates a decreasing trend and vice-versa. ]