Review

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Typhoid fever: issues in laboratory detection,

treatment options & concerns in
management in developing countries
Balaji Veeraraghavan*,1 , Agila K Pragasam1 , Yamuna D Bakthavatchalam1 & Ravikar Ralph2
1
Department of Clinical Microbiology, Christian Medical College, Vellore 632004, Tamil Nadu, India
2
Department of Medicine, Christian Medical College, Vellore 632004, Tamil Nadu, India
*Author for correspondence: Tel.: +91 9442 210 555; [email protected]

Multidrug-resistant Salmonella enterica subsp. enterica serovar Typhi (resistant to ampicillin, chloram-
phenicol and cotrimoxazole), was significantly reduced with the increased usage of fluoroquinolones
and azithromycin. This has led to declining multidrug resistance rates in India with increasing ciprofloxacin
nonsusceptibility rates and clinical failures due to azithromycin. However, for the available agents such as
ceftriaxone, azithromycin and fluoroquinolones, the dose and duration for treatment is undefined. The
ongoing clinical trials for typhoid management are expected to recommend the defined dose and dura-
tion for better clinical outcome. We made an attempt to summarize the issues in laboratory detection,
treatment options and responses, and the concerns in clinical practice seen in the developing countries.

Lay abstract: Typhoid fever is an important cause of mortality in developing countries and is a major public
health concern. Cephalosporins or azithromycin are the drugs of choice for treating infection caused by
the reduced fluoroquinolone susceptibility of S. Typhi. Emergence of cephalosporin resistance in S. Typhi
and azithromycin-associated clinical and microbiological failure is of significant concern in developing
countries. An approach of cephalosporin–azithromycin combination therapy has been suggested, which
could be a potential alternative in treating uncomplicated S. Typhi infection in endemic areas. This review
summarizes the field so far.

First draft submitted: 10 January 2018; Accepted for publication: 26 April 2018; Published online:
26 June 2018

Keywords: azithromycin • cefixime • ceftriaxone • Salmonella Typhi

Typhoid fever is caused by the bacterium Salmonella enterica subsp. enterica serovar Typhi. It is mainly due to the
inadequate access to safe water and sanitation, which is a major problem in developing countries. The global burden
of typhoid fever was estimated to be 12 million cases and 130,000 deaths in the year 2010. It exceeded 100 cases
per 100,000 people/year in South East Asian countries, and has especially high burden rates in India. A recent
systematic review and meta-analysis estimated the prevalence of laboratory confirmed typhoid and paratyphoid
cases in India to be 9.7 and 0.9%, respectively [1].
In endemic areas, patients with typhoid are considered as outpatients and treated with oral antibiotics, with
hospital admission required only for complicated cases. Important concerns about typhoidal cases include relapse,
which may complicate the illness; and fecal carriage, which can become chronic and may lead to continued
transmission [2]. In late 1980s, 2–3 weeks of chloramphenicol was the treatment of choice for typhoid fever [3]. Sub-
sequently, an increased number of strains with plasmid-mediated multidrug resistance (MDR) to chloramphenicol,
ampicillin and cotrimoxazole are reported. Fluoroquinolone (ciprofloxacin and ofloxacin) has become the favored
drug following the emergence of strains with MDR [4]. Although fluoroquinolones are superior to cephalosporins,
the spread of strains with decreased susceptibility to ciprofloxacin has limited their effectiveness, particularly in
Asia [5]. Extended spectrum cephalosporins (ceftriaxone and cefixime) and azithromycin are suitable alternatives
for reduced fluoroquinolone susceptible S. Typhi [2,6]. The combinations of cephalosporin and azithromycin are
quite frequently used to treat the patients who failed to respond promptly. The general rationale for their use is for

10.4155/fsoa-2018-0003 
C 2018 Dr Balaji Veeraghavan Future Sci. OA (2018) 04(06), FSO312 eISSN 2056-5623
Review Veeraraghavan, Pragasam, Bakthavatchalam & Ralph

broadening the spectrum of antimicrobial activity, to exploit the potential synergy between the drugs and reduce
the probability of resistance development during course of treatment [7,8].
Although typhoid continues to be seen in large numbers, documented typhoid cases are reducing in recent years.
The definitive diagnosis of typhoid fever requires a confirmed diagnosis based on the blood or bone marrow culture.
However, blood culture has several limitations including amount of blood required (2–4 ml from toddlers and
10–15 ml from adolescents and adults) due to low levels of bacteremia and prior antibiotic use [9]. Furthermore,
such laboratory facilities are limited or nonexistent in many Asian countries. An accurate and rapid diagnosis of
typhoid fever improves the management of patients with appropriate antibiotic therapy. The sensitivity of blood
culture is estimated to be between 40 and 60% [10]. Partly, this could be due to increased use of oral antibiotics
prescribed in the communities without laboratory investigations.
This review summarizes the challenges in the laboratory diagnosis of typhoid fever and the current situation of
MDR S. Typhi, and further explores the problem of antimicrobial resistance in these infections, management issues
in clinical practice and combination treatment options for typhoidal Salmonella.

Challenges in detection of typhoidal Salmonella

Although there is a decline in the incidence of S. Typhi, the true isolation of S. Typhi from blood cultures is still
challenging [11]. Patients who are suspected of typhoid fever are given antimicrobials in the community and later
referred to the tertiary care hospital for blood cultures. In India, ofloxacin-based combinations such as ofloxacin plus
cefixime or ofloxacin plus azithromycin are most abundantly used and are available over the counter. According to
the Center for Disease Dynamics, Economics & Policy, the consumption rate of cephalosporin has increased from
1887 to 7269 standard units/1000 people from 2000 to 2014, respectively. Similarly, macrolide usage has increased
from 1166 to 1862 standard units/1000 people from 2000 to 2014, respectively. Meanwhile, fluoroquinolone
usage ranged about 2608 to 2661 standard units/1000 population from 2000 to 2014, respectively [12]. This
indicates the abundant usage of cephalosporins, fluoroquinolones and macrolides in the Indian setting. Owing to
this, patients who have taken a cephalosporin-based combination (cefixime plus ofloxacin) are likely to exhibit a
false-negative blood culture. It is, therefore, imperative to obtain a blood culture before initiating the antimicrobial
therapy as the presence of antimicrobials could reduce the yield of S. Typhi in the blood cultures. To counteract
this, commercial blood culture systems have incorporated synthetic resin molecules in the bottles to neutralize
the antimicrobials present. Previous studies have demonstrated the neutralization of antimicrobials by the use of
resin-based culture bottles [13–15]. However, certain antimicrobials have not been neutralized by the resins, hence
this remains a limitation. This includes the fluoroquinolones and cephalosporins, which are the commonly used
drugs in the community for suspected typhoid fever. Importantly, no published studies on the recovery of S. Typhi
in blood cultures collected from patients with prior antibiotics were found.
Diagnosis of typhoid fever by conventional blood culture is challenging and time consuming as it takes about
24–48 h, after which the culture bottle flags positive. Although it is the gold standard method for detection of S.
Typhi in the blood, turnaround time plays a significant role in the management. WIDAL slide agglutination test
is the second most commonly prescribed test. Yet, poor sensitivity and specificity is a limitation [16]. Due to this,
commercial rapid diagnostic tests (RDTs) are of great interest. However, owing to the poor sensitivity and specificity
rates, definite detection is still limited. Typhidot-M, TUBEX-TM and Test-it are the three serological-based tests
that have been evaluated. Performance of these tests have been shown to be poor and variable due to the high rates
of disease burden in Asia, which is endemic for typhoid. In contrast, evaluation done in the Philippines has shown
high sensitivity and specificity rates [17]. Among the three tests, TUBEX performance was found better with 78%
of sensitivity and 87% specificity [18]. Due to these limitations, the WHO has issued no recommendations on the
use of commercial RDTs [16]. Although RDT uses serum and urine samples, other than blood, isolation of S. Typhi
from blood culture and bone marrow still remains the gold standard, as the susceptibility profile of the infected
organisms cannot be inferred from serologic-based tests.

MDR Salmonella Typhi

Approximately 65% MDR rates were seen during 1990–1992 in India, with 71% MDR rates in central India and
55% in southern parts of India [19]. Due to the high rates of MDR strains, the use of ampicillin, chloramphenicol and
cotrimoxazole has declined, resulting in the increased use of fluoroquinolones (ofloxacin and ciprofloxacin) [20,21].
This has resulted in the phenomenon of decreased ciprofloxacin susceptibility (DCS) while cephalosporin resistance
has begun to rise. Recently, MDR rates have drastically declined and the rates have fallen down from 26% in 2004

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Table 1. Burden of antimicrobial resistance rates reported in typhoidal Salmonella from Indian studies of past 15 years.
Antibiotic Salmonella Typhi Salmonella Paratyphi A
Ampicillin† 5–72% 0–74%
Chloramphenicol† 3–27% 0–23%
†
Cotrimoxazole 2.3–35% 0–36%
Nalidixic acid 78–100% 63–100%
Ciprofloxacin‡ 0–97% 0–100%
Ceftriaxone 0–4% 0–6%
†
MDR S. Typhi classified based in resistance to ampicillin, chloramphenicol and cotrimoxazole is coming down in the recent years.
‡ High rates of ciprofloxacin resistance is due to the revised breakpoints in the CLSI guideline.
Refs: [23–29]
CLSI: Clinical and Laboratory Standards Institute; MDR: Multidrug-resistant.

Table 2. Antimicrobial resistance mechanisms reported in typhoidal Salmonella.

Antibiotic class Resistance mechanism AMR genes responsible Ref.
ß-lactams (ampicillin) Enzymatic hydrolysis bla TEM , bla CTX-M , bla SHV [30]
Chloramphenicol Enzymatic hydrolysis cat [30]
Sulfonamides Enzymatic hydrolysis dfrA, sul1 and sul2 [30]
(trimethoprim/sulfamethoxazole)
Quinolones (nalidixic acid, Drug target alterations (QRDR) gyrA, gyrB, parC,parE [31]
ciprofloxacin,pefloxacin)
Enzymatic hydrolysis (PMQR) qnrA, qnrB, qnrS, aac(6 )-Ib-cr, qepA [32]
Cephalosporins (ceftriaxone, cefixime) AmpC ß-lactamases ESBLs bla CMY , bla FOX bla CTX-M-15 –
Macrolides (azithromycin) Enzymatic hydrolysis overexpression of efflux ereA, ereB, ermB, mefA, mphA, mphB and [32–35]
pumps mphD
ESBL: Extended spectrum beta-lactamase; PMQR: Plasmid-mediated quinolone resistance; QRDR: Quinolone-resistance determining region.

to 1% at present [20]. A similar picture is noted in Christian Medical College (CMC), Vellore, India, with less than
1% MDR rates (V. Balaji, Unpublished Data) and at New Delhi [10] and all over India. Furthermore, the Indian
Network for Surveillance of Antimicrobial Resistance conducted between 2008 and 2010 has reported less than
5% of MDR S. Typhi across India [22]. In addition, the burden of antimicrobial resistance reported in the Indian
studies are summarized in Table 1. The antimicrobial resistance mechanisms seen in S. Typhi and reported in the
literature are mentioned in Table 2.

Fluoroquinolones
Fluoroquinolones are a class of broad-spectrum antibiotic and are the direct inhibitors of bacterial DNA synthesis.
Ciprofloxacin and ofloxacin are currently the drugs of choice for most cases of typhoid fever. These fluoroquinolones
have become affordable for use in many resource-limited areas. Ofloxacin was an excellent choice of antibiotic used
for treating typhoidal Salmonella, as it has excellent plasma and intracellular penetrations with more bactericidal
activity [36]. However, the phenomenon of reduced susceptibility to fluoroquinolones has also been implicated in
ofloxacin treatment. For the isolates with an MIC of ≥0.25 μg/ml, despite prolonged duration and increased dose
of therapy, clinical failure has been seen [37]. This was observed with a randomized control trial (RCT) carried out
between 1992 and 2001. The study provided evidence for the clinical failure cases of S. Typhi when the isolates
ofloxacin MIC was ≥0.25 μg/ml. However, for isolates with an MIC of ≤0.125 μg/ml, 96% clinical success was
observed [37]. Due to the inconsistencies in the cutoffs, the Clinical and Laboratory Standards Institute (CLSI,
M100-S23) has removed the disc diffusion breakpoint criteria and recommended MIC testing for determining
susceptibility, and revised the susceptible range interpretation from ≤2 μg/ml in 2012 to ≤0.12 μg/ml in 2013
for ofloxacin and levofloxacin as well [38].
For ciprofloxacin, the CLSI has revised the breakpoints for categorizing the clinical isolates ≤0.06 μg/ml as
susceptible in 2012 [39]. Clinically, DCS is associated with clinical failure when ciprofloxacin MIC was ranging from
0.12 to 1 μg/ml, which is commonly seen in India [23,40]. MDR isolates with decreased ciprofloxacin susceptibility
strains in India are on the increase, and this needs continuous monitoring [41]. Earlier, this was missed as the

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Review Veeraraghavan, Pragasam, Bakthavatchalam & Ralph

dependence was on nalidixic acid resistance (NAR) using disc diffusion testing. Moreover, monitoring NAR was
not carried out with ciprofloxacin MIC.
However, in recent times, rising DCS with the sustained decrease in the MDR typhoidal Salmonella has been
seen [20]. Similarly, Singhal et al. reported the declining MDR rates with the increased incidence of nalidixic acid-
resistant, DCS isolates in Northern India [23]. There has been a reported decline in MDR with a parallel increase
in DCS among S. Typhi. Ampicillin, chloramphenicol or cotrimoxazole are less likely preferred because of longer
duration of therapy, threat of re-emergence of resistance, side effects and higher relapse rates.
Quinolone resistance is due to mutations in the quinolone-resistance determining regions of chromosomal
genes such as gyrA, gyrB, parC and parE and plasmid-mediated qnr, qepA and aacs(6 )-Ib-cr genes [42]. Studies
have reported that plasmid-mediated resistance showed reduced susceptibility to ciprofloxacin (MIC of 0.125–
1.0 μg/ml), which could not be picked up by the nalidixic acid test [43]. Therefore, the CLSI and EUCAST
recommend a new screening surrogate marker of pefloxacin (5 μg) disc diffusion for detecting both chromosomal-
and plasmid-mediated resistance. This observation was evidenced by testing of pefloxacin, wherein 80% of the
NAR and ciprofloxacin moderately susceptible isolates were resistant to pefloxacin [44,45]. Therefore, pefloxacin
testing would ultimately help in the accurate identification of quinolone susceptibility for a better therapeutic
success rate.
Gatifloxacin is an inexpensive fluroquinolone antibiotic with an excellent in vitro activity against S. Typhi.
Gatifloxacin has the lowest MIC with the MIC50 of 0.19 μg/ml against S. Typhi, compared with ciprofloxacin and
ofloxacin (MIC50, 0.75 μg/ml) [46]. Strikingly, gatifloxacin showed activity against isolates with DCS phenomenon.
This is due to the ability of gatifloxacin to evade the point mutations in gyrA (Ser 83 Phe, Asp 87 Gly) contributing
for DCS. For isolates included from India, the MIC range was observed to be 0.006–0.25 and 0.012–0.19 μg/ml
for ciprofloxacin and gatifloxacin, respectively [47]. Furthermore, two trials have reported that good clinical response
was noted with 7 days of therapy (10 mg/kg per day) and suggested gatifloxacin to be more effective than other
agents. More importantly, fever clearance time was 92 h for gatifloxacin, while it was 138 h for patients who received
cefixime, with 3.5 and 37.6% treatment failure in gatifloxacin and cefixime groups, respectively [46,48]. Dysglycemia
is a major concern, for which sugar monitoring is essential [49]. Although gatifloxacin has an advantage over other
quinolones, its use is banned in India.

Cephalosporins
The cephalosporins are a class of ß-lactam antibiotics. Cephalosporins bind to the penicillin-binding proteins
on bacteria and inhibit synthesis of the bacterial cell wall leading to cell lysis and death. With the rising DCS
phenomenon, third-generation cephalosporins such as cefixime and ceftriaxone are preferred for the treatment of
MDR and nalidixic acid-resistant isolates, to avoid clinical failures. As there is an increased use of cephalosporins,
emergence of resistance is being observed [50–52]. Subsequently, 113 blood cultures confirmed that ceftriaxone-
resistant S. Typhi cases have been reported from Karachi, Pakistan [53]. The mechanism of resistance is due to the
production of ESBLs such as blaSHV and bla CTX-M-15 . Prospective clinical trials assessment in Asia showed that
the resistance prevalence to ceftriaxone was 0%, with cure rate of 72–97% with 3–14 days of therapy. However,
the relapse rate was about 0–17%, which occurred in patients treated for 7 days or less, while treatment for 8–14
days did not show any relapses [54]. Although the route of administration of ceftriaxone is parental, it requires
hospitalization and increase in healthcare costs. Cefixime is the preferred choice in developing countries due to the
availability of an oral form for uncomplicated typhoid fever.

Azithromycin
Azithromycin, a member of the macrolide class of antibiotic, is an effective and convenient alternative for treating
mild-to-moderate enteric fever. Clearly defined MIC breakpoints for azithromycin susceptibility have not been
established, but data suggest that isolates with an MIC ≤16 μg/ml generally respond well to azithromycin and
can be considered susceptible. The available clinical or pharmacokinetic/pharmacodynamic (PK/PD) data on
azithromycin are limited. Notably, azithromycin nonsusceptibility rate was lower than the other agents. In Asia,
analysis of 20 prospective clinical trials has proven that the relapse rate was 0% with azithromycin treatment, while
the cure rate was about 81–100% with 5–7 days of therapy [55]. A study from New Delhi reported the MIC90 for
S. Typhi and S. Paratyphi to be 24 μg/ml [40]. Following this, 34 and 38% resistance to azithromycin was reported
in S. Typhi and S. Paratyphi A, respectively [55]. Recently, a case of azithromycin clinical and microbiological failure
with the MIC of 4 μg/ml was reported from a patient with S. Typhi infection, from India [56]. Similarly, S. Paratyphi

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Table 3. Preferred therapy for management of typhoid fever.

Antimicrobial agents Route of administration Children Adult
Ceftriaxone IM/IV 50 mg/kg per day IV; for 7–10 days 1–2 g per day IV; for 7–10 days
Ciprofloxacin, levofloxacin or other FQ† Oral/IV – FQ given in full doses as recommended;
for 7–10 days
Azithromycin Oral Used in complicated cases 500 mg twice a day for 5 days
Cefixime–ofloxacin Oral – 200–200 mg; for 7–14 days
†
High-dose therapy is based on antimicrobial susceptibility profile of the infected typhoidal Salmonella strain, as majorities are nonsusceptible to quinolones. Least preferred as majority
of the isolates show intermediate resistance to quinolones.
FQ: Fluoroquinolone; IM: Intramuscular; IV: Intravenous.

A with azithromycin clinical failure case with MIC of 12 μg/ml was reported in Australia [57]. Azithromycin is a
valuable therapeutic alternative, due to higher intracellular concentrations (100-fold higher than in serum), early
fever clearance rate (4–5 days), lower rates of relapse or reinfection and 5–7 days of therapy for complete cure [58].
However, azithromycin is not preferred as a monotherapy in severe typhoid, as it results in poor clinical response.
Moreover, determination of MIC for azithromycin and monitoring clinical success is essential.

Typhoid fever therapy: challenges in clinical practice

For the clinical management of typhoid fever, an early initiation of effective antimicrobial therapy shortens the
duration of illness, and reduces the complications and mortality. The emergence and sustained circulation of
reduced fluoroquinolone susceptible S. Typhi, the steady rise in nalidixic acid-resistant S. Typhi (NARST) and
cases of azithromycin treatment failure are of concern [37,56]. Typically, in these cases, a slow resolution of fever and
increased risk of clinical and microbiological failure were described [59–62]. Fluoroquinolones are commonly used
for treating of MDR S. Typhi causing uncomplicated enteric fever. The widespread use of fluoroquinolones in
primary healthcare settings contributes to emergence of strains with elevated MIC to ciprofloxacin and ofloxacin
across Asia and parts of Africa [63,64]. The preferred therapy for management of typhoid fever is mentioned in
Table 3.
In addition to preventing weight-based dose titrations, most of these formulations also contain subtherapeutic
doses of azithromycin. A review of 22 different Indian brands of fixed-dose combinations (FDCs) containing
azithromycin with ofloxacin or cefixime revealed that while formulations contained an adequate fluoroquinolone
or cephalosporin dose, the dose of azithromycin was 250 mg/tablet. This quantity is one fifth of the WHO
recommended dose for a 60 kg individual (1200 mg; 10 mg/kg per day). Administering five tablets of the above
FDC to a 60 kg individual would not only result in a high pill burden and poor adherence rates but also in toxic
doses of the accompanying drug.
Despite Association of Physicians of India expert advisory panel for typhoid and WHO recommendations on
weight-based antimicrobial dose titration, it is possible that typhoid patients continue to be prescribed antibiotics
at standard doses. For azithromycin, while dose recommendations vary between 10 and 20 mg/kg per day for 5–7
days, specific weight-based dose and therapy-duration guidelines are yet to be determined. A randomized controlled
trial by Parry et al. comparing ofloxacin (20 mg/kg body weight per day for 7 days), azithromycin (10 mg/kg per
day for 7 days) and ofloxacin (15 mg/kg per day for 7 days) combined with azithromycin (10 mg/kg per day for
the first 3 days) in MDR and NARST typhoid showed that defervescence time for azithromycin-treated patients
was significantly shorter than that for patients treated with ofloxacin–azithromycin and ofloxacin alone. Table 4
summarizes the studies on monotherapy and combination therapy carried out for typhoid fever management.
Fluoroquinolones and azithromycin attain better tissue penetration and kill bacteria within
monocytes/macrophages more efficiently compared with third-generation cephalosporins, which primarily achieve
blood stream bacterial clearance. This fact has resulted in the exploration of the possibility of combination regimens
in typhoid treatment. Studies demonstrating combination therapy superiority compared with monotherapy are,
however, limited. A study of 37 individuals with NARST S. paratyphi A bacteremia demonstrated that the time to
fever defervescence was shorter in patients treated with ceftriaxone–azithromycin combination therapy compared
with those treated with ceftriaxone monotherapy [78]. However, the significance of this finding should be confirmed
with large clinical trials for its safety and efficacy. In contrast, a comparative Indian study of 62 typhoid fever patients
failed to reveal a significant difference in time to defervescence between the single drug (fluoroquinolone or third-
generation cephalosporin) and combination drug group (fluoroquinolone with third-generation cephalosporin) [79].

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Review Veeraraghavan, Pragasam, Bakthavatchalam & Ralph

Table 4. Controlled and noncontrolled trials on monotherapy and combination therapy for typhoid fever.
Antibiotics No. of Study type Dose/duration of Fever Clinical/ Relapse (%) Fecal Ref.
patients (n) (duration of the therapy (days) defervescence microbiological failure carriage (%)
study)/location (days) (%)
Azithromycin vs 108 Prospective Azithromycin Azithromycin – Clinical failure: Azithromycin – 0 NA [65]
ceftriaxone (IV; (children) study 10 mg/kg per day for 7 4.1 Ceftriaxone Azithromycin – 0 Ceftriaxone – 13
short course (2000)/Egypt days – 3.9 Ceftriaxone – 19
therapy) 2.5 g per day for 7 days Microbiological failure:
Azithromycin – 0
Ceftriaxone – 3
Azithromycin vs 149 Prospective Azithromycin Azithromycin – Clinical failure: Azithromycin – 0 NA [66]
ceftriaxone (IV; study 20 mg/kg per day for 5 4.5 Ceftriaxone Azithromycin – 6 Ceftriaxone – 17
short course (2004)/Egypt days – 3.6 Ceftriaxone – 3
therapy) 2.5 g per day for 5 days Microbiological failure:
Azithromycin – 3
Ceftriaxone – 3
Azithromycin 117 Open-labeled Azithromycin – 3.45 Clinical failure: NA NA [67]
(children) noncomparative 20 mg/kg per day for 6 Azithromycin – 6
study days Microbiological failure:
(2011)/India Azithromycin – 15.5
Azithromycin vs 40 (adult) Prospective Ofloxacin – 200 mg Ofloxain – 3.68 Clinical failure: No relapse 0 [68]
ofloxacin (2012)/India orally twice daily for 7 Azithromycin – Ofloxacin–10
days 3.65 Azithromycin – 0
Azithromycin – 1 g on
day 1 and then 500 mg
daily from days 2–6
Ofloxacin vs 82 (children) Randomized Ofloxacin – 10 mg/kg Ofloxacin – 4.4 Clinical failure: Ofloxacin – 0 Ofloxacin – 0 [69]
cefixime open trial per day for 5 days Cefixime – 8.5 Ofloxacin – 3 Cefixime – 3 Cefixime – 3
(1995– Cefixime – 20 mg/kg Cefixime – 25
1996)/Vietnam per day for 7 days
Ofloxacin 235 Randomized Ofloxacin (10 mg/kg 2-day group: 3.8 Clinical failure: 2-day group: 2 NA [70]
open per day) – 2 days 3-day group: 4.2 2-day group: 13.5 3-day group: 2
study/Vietnam Ofloxacin (10 mg/kg 3-day group: 7.5
per day) – 3 days Microbiological failure:
2-day group: 4
3-day group: 1
50 Randomized Chloramphenicol Clinical failure: NA NA [71]
Chloramphenicol open study/Laos (50 mg/kg per day) for Chloramphenicol Chloramphenicol – 1%
vs ofloxacin 14 days – 3.7
Ofloxacin (15 mg/kg Ofloxacin – 2.2
per day) – 3 days
Ofloxacin vs 88 Randomized Azithromycin Ofloxacin – 7 Clinical failure: Ofloxacin – 4.5 Ofloxacin – [72]
azithromycin control (20 mg/kg per day) for Azithromycin – 5 Ofloxacin – 13.6 Azithromycin – 0 41
study/Nepal 5 days Azithromycin – 4.5 Azithromycin
Ofloxacin – (8 mg/kg Microbiological failure: –0
per day) for 5 days Ofloxacin – 4.5
Azithromycin – 0
Ofloxacin, 187 Randomized Ofloxacin – 20 mg/kg Ofloxacin – 8.2 Clinical failure: Relapse was not Ofloxacin – [73]
azithromycin, control study per day for 7 days Azithromycin – Ofloxacin – 12.3 seen in patients 19.4
ofloxacin (1998– Azithromycin – 5.8 Azithromycin – 18.8 treated with Azithromycin
/azithromycin 2002)/Vietnam 10 mg/kg per day for 7 Ofloxacin/ Ofloxacin/azithromycin ofloxacin or – 1.6
days azithromycin – – 6.4 azithromycin or Ofloxacin/
Ofloxacin (15 mg/kg 7.1 Microbiological failure: ofloxacin/ azithromycin
per day)/azithromycin Ofloxacin – 1.6 azithromycin – 6.5
(10 mg/kg per day) Azithromycin – 0
Ofloxacin/azithromycin
- 1.6 (patient
experienced
microbiologcal failure)
Gatifloxacin vs 287 RCT/Vietnam Gatifloxacin (10 mg/kg Gatifloxacin – Clinical failure: Gatifloxacin – Gatifloxacin [46]
azithromycin per day) for 7 days 4.4 Gatifloxacin – 4.3 2.9 – 0.7
Azithromycin Azithromycin – Azithromycin – 4.2 Azithromycin – 0 Azithromycin
(20 mg/kg per day) for 4.4 Microbiological failure: –0
7 days Gatifloxacin – 1.4
Azithromycin – 2.2
Gatifloxacin vs 390 RCT/Nepal Gatifloxacin (10 mg/kg Gatifloxacin – Clinical failure: Gatifloxacin – NA [48]
cefixime per day) for 7 days 3.8 Cefixime – Gatifloxacin – 1 0.9 Cefixime – 3
Cefixime (20 mg/kg 5.7 Cefixime – 27
per day) for 7 days
IV: Intravenous; NA: Not available; RCT: Randomized clinical trial.

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Table 4. Controlled and noncontrolled trials on monotherapy and combination therapy for typhoid fever (cont.).
Antibiotics No. of Study type Dose/duration of Fever Clinical/ Relapse (%) Fecal Ref.
patients (n) (duration of the therapy (days) defervescence microbiological failure carriage (%)
study)/location (days) (%)
Gatifloxacin vs 844 RCT/Nepal Gatifloxacin (10 mg/kg Clinical failure: Gatifloxacin – 2 NA [74]
chloramphenicol per day) for 7 days Gatifloxacin – 7 Chlorampheni-
Chloramphenicol Chloramphenicol – 8 col –
(75 mg/kg per day) for Microbiological failure: 4
14 days Gatifloxacin – 1
Chloramphenicol – 0
Gatifloxacin vs 627 RCT/Nepal Gatifloxacin (10 mg/kg Gatifloxacin – Clinical failure: Gatifloxacin – 5 NA [75]
ofloxacin per day) for 7 days 3.3 Ofloxacin – Gatifloxacin – 5 Ofloxacin – 6
Ofloxacin (10 mg/kg 4.7 Ofloxacin – 7
per day) for 7 days Microbiological failure:
None
Gatifloxacin vs 239 RCT/Nepal Gatifloxacin (10 mg/kg Gatifloxacin – Gatifloxacin – 15 NA NA [76]
ceftriaxone per day) for 7 days 2.43 Ceftriaxone – 16
Ceftriaxone (2 g per Ceftriaxone –
day) for 7 days 2.93
Azithromycin– 25 Prospective Ceftriaxone (IV) – 2 g 4.8 Clinical and No relapse NA [77]
ceftriaxone study (2014– daily for 14 days microbiological failure:
combination 2015)/India Azithromycin – 500 mg 4
daily for the first 7 days
IV: Intravenous; NA: Not available; RCT: Randomized clinical trial.

Concern in management in developing countries

In South East Asia (SEA) and Africa, a rise in the MIC of fluoroquinolones against S. Typhi has shown a significant
increase and is associated with longer duration of fever defervescence [37,64,80]. This reiterates that fluoroquinolone
should not be recommended for empirical treatment of typhoid fever. Azithromycin treatment failure and emergence
of cephalosporin resistance are of concern [52,56,81]. However, antimicrobial resistance to ceftriaxone/cefixime and
azithromycin remains rare. In the areas where fluoroquinolone resistance is uncommon, the quinolones are the
treatment of choice for all the age groups. Treatment at the maximal recommended doses (20 mg/kg per day) for
7–10 days has been successful in 90–95% of patients [82]. Remarkably, quinolone-resistant S. Typhi strains are on
rise and therefore the drug of choice is limited to azithromycin or cephalosporins, which are expensive.
Randomized control trials (RCTs) of third-generation cephalosporins, primarily ceftriaxone/cefixime, in treating
typhoid fever have reported an average fever clearance of 7 days, with a treatment failure rate between 5 and 10%,
relapse rates of 3–6% and fecal carriage of less than 3% [48,65,69,76]. Similarly, RCTs on treating uncomplicated
with azithromycin for 5–7 days resulted in 95% cure rate and fever defervescence of 4–6 days [46,66–68,72]. Notably,
relapse rate and fecal carriage are less than 3%. However, treatment with cephalosporin exhibits a slow response
with a mean time of 5–7 days or an even longer duration of fever defervescence [83]. This could be attributed to
poor penetration capability of the drug into cells, and thus difficulty to eradicate the bacteria from the intracellular
niche. An approach of cephalosporin–azithromycin combination therapy has been suggested based on the indi-
vidual pharmacokinetics [77]. The complimentary action of cephalosporins on the extracellular compartment and
azithromycin on the intracellular compartment could be beneficial in treating S. Typhi infection.
Fixed dose combinations (FDCs) of cefixime–ofloxacin (200–200 mg) are widely used across India. With the
biggest market sale of approximately $46 million, they are increasingly available as over-the-counter prescrip-
tion. An in vitro study has reported that none of the tested S. Typhi isolates demonstrated antagonism against
this combination [84]. Some FDCs are banned for clinical use in India; these include cefixime–azithromycin,
cefpodoxime–azithromycin and ofloxacin–azithromycin. Azithromycin is known to reduce cefpodoxime efficacy
by PD antagonism [85]. The expert committee of the Chief Drug Advisory body of India has deemed that
these FDCs are irrational. Currently, two clinical trials (clinicaltrial.gov: NCT02224040, NCT02708992) using
cefixime–azithromycin and ceftriaxone–azithromycin for various indication are in progress. In the differential di-
agnosis of febrile illness, doxycycline plus cefixime–azithromycin is prescribed as empiric therapy, especially in SEA
where rickettsial infection is common. However, drug–drug interactions showed that doxycycline decreases effects
of ceftriaxone by PD antagonism [85]. There is a huge market available for these combinations in SEA and they
are frequently prescribed for pelvic inflammatory infection. Greater misuse is expected with availability of this
cephalosporin–azithromycin combination, which is worrisome.

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Review Veeraraghavan, Pragasam, Bakthavatchalam & Ralph

Collectively, this reiterates that in the context of reduced fluoroquinolone susceptibility, third-generation
cephalosporins, such as ceftriaxone/cefixime or azithromycin, are the treatment of choice for treating S. Typhi
in developing countries. In addition, evidence from the progressing clinical trials (clinicaltrial.gov: NCT02224040,
NCT02708992), on cefixime–azithromycin and ceftriaxone–azithromycin FDCs could prove them to be be an
effective alternative therapy for the management of quinolone-resistant S. Typhi.

Natural products in treating typhoid fever

The use of medicinal plants to treat disease is almost universal and is more affordable than purchasing expensive
conventional drugs. Natural plants contain phytoconstituents containing chemical properties similar to synthetic
antibiotics. Since the issues with antibiotic efficacy of monotherapy have been reported, it has become essential to
evaluate biological properties of plants. Tulsi (Ocimum sanctum) has potent antibacterial activity against S. Typhi
[FL1] [86]. An in vitro study has demonstrated significant synergy of chloramphenicol and trimethoprim with O.
sanctum leaf extract against S. Typhi [86]. Similarly, acetone mango leaf extract was demonstrated with the inhibitory
effect at the concentration of 10–50 μg/ml against MDR S. Typhi [87]. Nkuo-Akenji et al. have reported the lowest
MIC of 0.02–0.06 μg/ml against S. Typhi with the formulation of the methanol leaf extract of Cymbogogon citratus,
Carica papaya and Zea mays silk [88,89]. Overall, studies have reported potent in vitro activity of various leaf extracts
against S. Typhi. However, in vivo studies on the bioavailability, PK/PD, antibacterial interaction or safety profile
of these natural products are limited [90]. Consequentially, defined dosage and its significant activity in treating
complicated typhoid fever remain uncertain.

Conclusion
Given the emergence of fluoroquinolone and azithromycin nonsusceptible S. Typhi strains, it is interesting to note
that there has been a recent sustained decrease in MDR typhoidal Salmonella isolates in India. This observation
suggests the possible reintroduction of ampicillin, chloramphenicol and cotrimoxazole as first-line options. While
these agents are inexpensive and easily available, disadvantages associated with their use include a longer duration
of therapy to prevent relapses, higher relapse rates and serious adverse effects. The rate and likelihood of resistance
to an antimicrobial is a function of the frequency of its use, due to the excessive selective pressure generated. It,
therefore, appears likely that the decline in MDR rates would not be sustained if the abovementioned traditional
first-line drugs were to be recruited into routine first-line use.
In severe cases of typhoid fever, ceftriaxone IV (2 g per day) for 10–14 days is given followed by azithromycin
(20 mg/kg per day) for 7 days. For DCS S. Typhi causing uncomplicated typhoid fever, fluoroquinolone therapy is
to be avoided. If necessary, higher dose of ciprofloxacin (20 mg/kg per day) may be more effective in treating typical
cases of mild typhoid fever. However, with fluoroquinolone therapy, delay in fever defervescence, relapse and faecal
carriage can be expected. Therefore, treatment with azithromycin (20 mg/kg per day) for 7 days is recommended
for treating uncomplicated cases.

Future perspective
Increased use of cephalosporin or azithromycin in treating fluoroquinolone nonsusceptible S. Typhi may lead to a rise
in cephalosporin resistance or azithromycin treatment failure. In the era of MDR, combination therapy could be an
alternative for treating S. Typhi infection. The goal of this article is to inspire more research into the FDCs available
for treatment of S. Typhi. In vitro combination testing of cefixime–azithromycin and ceftriaxone–azithromycin
will provide detailed insights into the antimicrobial effect and drug–drug interaction of these combinations. The
result of on-going clinical trials is welcomed and this could be an added value for research output. Furthermore, the
extensive studies on the bioavailability, dosing, antibacterial effect, PK/PD and safety profile of natural products
could reveal an alternative for antibiotics in treating S. Typhi infection.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or finan-
cial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria,
stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

Future Sci. OA (2018) 04(06) future science group

 Typhoid fever management Review

Summary points
• Reduced fluoroquinolones susceptibility of Salmonella enterica subsp. enterica serovar Typhi (S. Typhi) is on the
rise and of significant concern in developing countries.
• Third-generation cephalosporins (cefixime, ceftriaxone) or azithromycin are the alternative for treating S. Typhi
infection with decreased susceptibility to ciprofloxacin.
• An approach of cephalosporin plus azithromycin can address the shortcomings of cephalosporins including poor
response and longer duration for fever defervescence.
• Cefixime–ofloxacin combination is the hugely marketed fixed-dose combination in India, for the treating S. Typhi
infection.
• Evidence from the on-going clinical trials (clinicaltrial.gov: NCT02224040, NCT02708992) could be value-added
information for using fixed-dose combinations, as a standard practice in treating S. Typhi, especially in Asia and
parts of Africa.

Authors’ contributions
AK Pragasam, YD Bakthavatchalam collected details and wrote the manuscript. B Veeraraghavan and R Ralph gave critical revision
on the manuscript. All authors read and approved the final manuscript.

Open access
This work is licensed under the Creative Commons Attribution 4.0 License. To view a copy of this license, visit http://creativecomm
ons.org/licenses/by/4.0/

References
Papers of special note have been highlighted as: • of interest; •• of considerable interest
1. John J, Van Aart CJC, Grassly NC. The burden of typhoid and paratyphoid in India: systematic review and meta-analysis. PLoS Negl.
Trop. Dis. 10(4), e0004616 (2016).
2. Parry CM, Beeching NJ. Treatment of enteric fever. BMJ 338, b1159 (2009).
3. Kalra SP, Naithani N, Mehta SR et al. current trends in the management of typhoid fever. Med. J. ArMed. Forces India. 59(2), 130–135
(2003).
4. Divyashree S, Nabarro LE, Veeraraghavan B et al. Enteric fever in India: current scenario and future directions. Trop. Med. Int.
Health. 21(10), 1255–1262 (2016).
5. Rahman BA, Wasfy MO, Maksoud MA et al. Multi-drug resistance and reduced susceptibility to ciprofloxacin among Salmonella enterica
serovar Typhi isolates from the Middle East and Central Asia. New Microbes New Infect. 2(4), 88–92 (2014).
6. Bhutta ZA. Current concepts in the diagnosis and treatment of typhoid fever. BMJ 333(7558), 78–82 (2006).
7. Beeching NJ, Parry CM. Outpatient treatment of patients with enteric fever. Lancet Infect. Dis. 11(6), 419–421 (2011).
• Describes the management of typhoid fever with dose and duration.
8. Parry CM, Basnyat B, Crump JA. The management of antimicrobial-resistant enteric fever. Expert Rev. Anti. Infect. Ther. 11(12),
1259–1261 (2013).
9. World Health Organization, Department of Vaccines and Biologicals. Background document: the diagnosis, treatment and prevention of
typhoid fever. 19–23 (2003).www.who.int/rpc/TFGuideWHO.pdf
10. Wain J, Hosoglu S. The laboratory diagnosis of enteric fever. J. Infect. Dev. Ctries 2(6), 421–425 (2008).
11. Mogasale V, Ramani E, Mogasale VV et al. What proportion of Salmonella Typhi cases are detected by blood culture? A systematic
literature review. Ann. Clin. Microbiol. Antimicrob. 15(1), 32 (2016).
12. Center for Disease Dynamics, Economics & Policy, State of the World’s Antibiotics, 2015. CDDEP, Washington, DC (2015).
https://resistancemap.cddep.org/AntibioticUse.php
13. Flayhart D, Borek AP, Wakefield T et al. Comparison of BACTEC PLUS blood culture media to BacT/Alert FA blood culture media for
detection of bacterial pathogens in samples containing therapeutic levels of antibiotics. J. Clin. Microbiol. 45(3), 816–821 (2007).
14. Miller NS, Rogan D, Orr BL et al. Comparison of BD Bactec Plus blood culture media to VersaTREK Redox blood culture media for
detection of bacterial pathogens in simulated adult blood cultures containing therapeutic concentrations of antibiotics. J. Clin.
Microbiol. 49(4), 1624–1627 (2011).
• Describes the neutralization of antimicrobial substances, which improves blood culture positivity for isolation of S. Typhi.
15. Mitteregger D, Barousch W, Nehr M et al. Neutralization of antimicrobial substances in new BacT/Alert FA and FN Plus blood culture
bottles J. Clin. Microbiol. 51(5), 1534–1540 (2013).

future science group www.future-science.com

Review Veeraraghavan, Pragasam, Bakthavatchalam & Ralph

16. Keddy KH, Sooka A, Letsoalo ME et al. Sensitivity and specificity of typhoid fever rapid antibody tests for laboratory diagnosis at two
sub-Saharan African sites. Bull. World Health Organ. 89(9), 640–647 (2011).
17. Kawano RL, Leano SA, Agdamag DM. Comparison of serological test kits for diagnosis of typhoid fever in the Philippines. J. Clin.
Microbiol. 45(1), 246–247 (2007).
18. Wijedoru L, Mallett S, Parry CM. Rapid diagnostic tests for typhoid and paratyphoid (enteric) fever. Cochrane Database Syst. Rev. 5,
CD008892 (2017).
19. Harish BN, Menezes GA. Antimicrobial resistance in typhoidal salmonellae. Indian J. Med. Microbiol. 29(3), 223–239 (2011).
20. Balaji V, Sharma A, Ranjan P et al. Revised ciprofloxacin breakpoints for Salmonella Typhi: its implications in India. Indian J. Med.
Microbiol. 32(2), 161–163 (2014).
21. Raveendran R, Wattal C, Sharma A et al. High level ciprofloxacin resistance in Salmonella enterica isolated from blood. Indian J. Med.
Microbiol. 26(1), 50–53 (2008).
22. Joshi S. Antibiogram of S. enterica serovar Typhi and S. enterica serovar Paratyphi A: a multi-centre study from India. WHO South East
Asia J. Public Health. 1(2), 182–188 (2012).
23. Singhal L, Gupta PK, Kale P et al. Trends in antimicrobial susceptibility of Salmonella Typhi from North India (2001–2012). Indian J.
Med. Microbiol. 32(2), 149–152 (2014).
24. Dutta S, Das S, Mitra U et al. Antimicrobial resistance, virulence profiles and molecular subtypes of Salmonella enterica serovars Typhi
and Paratyphi A blood isolates from Kolkata, India during 2009–2013. PLoS ONE 9(8), e101347 (2014).
25. Jain S, Chugh TD. Antimicrobial resistance among blood culture isolates of Salmonella enterica in New Delhi. J. Infect. Dev.
Ctries. 7(11), 788–795 (2013).
26. Shetty AK, Shetty IN, Furtado ZV et al. Antibiogram of Salmonella isolates from blood with an emphasis on nalidixic acid and
chloramphenicol susceptibility in a tertiary care hospital in coastal Karnataka: a prospective study. J. Lab. Physicians 4(2), 74 (2012).
27. Menezes GA, Harish BN, Khan MA et al. Antimicrobial resistance trends in blood culture positive Salmonella Typhi isolates from
Pondicherry, India, 2005–2009. Clin. Microbiol. Infect. 18(3), 239–245 (2012).
28. Muthu G, Suresh A, Sumathy G et al. Studies on antimicrobial susceptibility pattern of Salmonella isolates from Chennai, India. Int. J.
Pharma. Bio. Sci. 2(2), 435–442 (2011).
29. Bhattacharya SS, Das U, Choudhury BK. Occurrence & antibiogram of Salmonella typhi & S. paratyphi A isolated from Rourkela,
Orissa. Indian J. Med. Res. 133(4), 431 (2011).
30. Olarte J, Galindo E. Salmonella typhi resistant to chloramphenicol, ampicillin, and other antimicrobial agents: strains isolated during an
extensive typhoid fever epidemic in Mexico. Antimicrob. Agents Chemother. 4(6), 597–601 (1973).
31. Wong VK, Baker S, Pickard DJ et al. Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi
identifies inter- and intracontinental transmission events. Nat. Genet. 47(6), 632 (2015).
32. Rodrigues C, Kapil A, Sharma A et al. Whole-genome shotgun sequencing of cephalosporin-resistant Salmonella enterica Serovar Typhi.
Genome Announc. 5(10), e01639–e01616 (2017).
33. Akinyemi KO, Iwalokun BA, Oyefolu AO et al. Occurrence of extended-spectrum and AmpC β-lactamases in multiple drug resistant
Salmonella isolates from clinical samples in Lagos, Nigeria. Infect. Drug Resist. 10, 19 (2017).
34. Phoba MF, Barbé B, Lunguya O et al. Salmonella enterica serovar Typhi producing Ctx-m-15 extended spectrum β-lactamase in the
Democratic Republic of the Congo. Clin. Infect. Dis. 65(7), 1229–1231 (2017).
35. Sjölund-Karlsson M, Joyce K, Blickenstaff K et al. Antimicrobial susceptibility to azithromycin among Salmonella enterica isolates from
the United States. Antimicrob. Agents Chemother. 55(9), 3985–3989 (2011).
36. Bethell DB, Day NPJ, Nguyen MD. Pharmacokinetics of oral and intravenous ofloxacin in multidrug-resistant typhoid fever.
Antimicrob. Agents Chemother. 40, 2167–2172 (1996).
37. Parry CM, Vinh H, Chinh NT et al. The influence of reduced susceptibility to fluoroquinolones in Salmonella enterica serovar Typhi on
the clinical response to ofloxacin therapy. PLoS Negl. Trop. Dis. 5(6), e1163 (2011).
38. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; twenty-third informational
supplement. Clinical and Laboratory Standards Institute. CLSI document M100-S23. Wayne, PA, USA (2013).
39. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; twenty-second informational
supplement. Clinical and Laboratory Standards Institute. CLSI document M100-S22. Wayne, PA, USA (2012).
40. Capoor MR, Nair D, Aggarwal P et al. Salmonella enterica serovar typhi: molecular analysis of strains with decreased susceptibility and
resistant to ciprofloxacin in India from 2001–2003. Braz. J. Infect. Dis. 11(4), 423–425 (2007).
41. Dahiya S, Sharma P, Kumari B et al. A Characterisation of antimicrobial resistance in Salmonellae during 2014–2015 from four centres
across India: an ICMR antimicrobial resistance surveillance network report. Indian J. Med. Microbiol. 35(1), 61–68 (2017).
42. Hopkins KL, Day M, Threlfall EJ. Plasmid-mediated quinolone resistance in Salmonella enterica, United Kingdom. Emerg. Infect.
Dis. 14(2), 340–342 (2008).
•• Describes the plasmid-mediated quinolone-resistant gene distribution among reduced ciprofloxacin susceptible S. Typhi.

Future Sci. OA (2018) 04(06) future science group

 Typhoid fever management Review

43. Balaji V, Shalini A, Dhiviya Prabaa MS et al. Molecular characterization of intermediate susceptible Typhoidal Salmonella to
ciprofloxacin and its impact. Mol. Diagn. Ther. 20(3), 213–219 (2016).
• Describes the advantage of using pefloxacin for screening of reduced fluoroquinolone susceptible S. Typhi.
44. Balaji V, Shalini A, Dhiviya Prabaa MS et al. Pefloxacin as a surrogate marker for fluoroquinolone susceptibility for Salmonella Typhi:
problems and prospects. J. Clin. Diagn. Res. 10(8), DL01–DL02 (2016).
45. Sharma P, Dahiya S, Kumari B et al. Pefloxacin as a surrogate marker for quinolone susceptibility in Salmonella enterica serovars Typhi &
Paratyphi A in India. Indian J. Med. Res. 145(5), 687–692 (2017).
46. Dolecek C, Tran TPL, Nguyen NR et al. 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 (2008).
47. Chau TT, Campbell JI, Galindo CM et al. Antimicrobial drug resistance of Salmonella enterica serovar typhi in asia and molecular
mechanism of reduced susceptibility to the fluoroquinolones. Antimicrob. Agents Chemother. 51(12), 4315–4323 (2007).
48. Pandit A, Arjyal A, Day JN et al. An open randomized comparison of gatifloxacin versus cefixime for the treatment of uncomplicated
enteric fever. PLoS ONE 2(6), e542 (2007).
49. Zvonar R. Gatifloxacin-induced dysglycemia. Am. J. Health Syst. Pharm. 63(21), 2087–2092 (2006).
50. Naveen Kumar DR, Dhiviya Prabaa MS, Baby Abirami S et al. Draft genome sequence of blaTEM-1 mediated cephalosporin resistant
Salmonella Typhi from blood stream infection. J. Glob. Antimicrob. Resist. 7, 11–12 (2016).
51. Rodrigues Camilla, Kapil Arti, Sharma Anita et al. Whole-genome shotgun sequencing of cephalosporin resistant Salmonella enterica
Serovar Typhi. Genome Announc. 5(10), e01639–16 (2017).
• Describes the plasmid carrying both fluoroquinolones and third-generation cephalosporins-resistant genes.
52. Klemm EJ, Shakoor S, Page AJ. et al. Emergence of an extensively drug-resistant Salmonella enterica Serovar Typhi clone harboring a
promiscuous plasmid encoding resistance to fluoroquinolones and third-generation cephalosporins. MBio 9(1). pii: e00105–e00118
(2018).
53. Yousafzai MT et al. Outbreak investigation of cefriaxone resistant S. Typhi in Hyderabad, Pakistan. 10th International Conference on
Typhoid and Other Invasive Salmonellosis. Kampala, Uganda, 4–6 April 2017.
54. Butler T. Treatment of typhoid fever in the 21st century: promises and shortcomings. Clin. Microbiol. Infect. Dis. 17(7), 959–963 (2011).
55. Rai S, Jain S, Prasad KN et al. Rationale of azithromycin prescribing practices for enteric fever in India. Indian J. Med. Microbiol. 30(1),
30–33 (2012).
• Describes the case of azithromycin treatment failure.
56. Manesh A, Balaji V, Kumar DRN et al. A case of clinical and microbiological failure of azithromycin therapy in Salmonella enterica
serotype Typhi despite low azithromycin MIC. Int. J. Infect. Dis. 54, 62–63 (2017).
57. Fernando S, Molland JG, Gottlieb T. Failure of oral antibiotic therapy, including azithromycin, in the treatment of a recurrent breast
abscess caused by Salmonella enterica serotype Paratyphi A. Pathog. Glob. Health. 106(6), 366–369 (2012).
58. Parry CM, Thieu NT, Dolecek C et al. Clinically and microbiologically derived azithromycin susceptibility breakpoints for Salmonella
enterica serovars Typhi and Paratyphi A. Antimicrob. Agents Chemother. 59, 2756 (2015).
59. Chiou CS, Alam M, Kuo JC et al. Chromosome-mediated multidrug resistance in Salmonella enterica serovar Typhi. Antimicrob. Agents
Chemother. 59(1), 721–723 (2015).
60. Hassing RJ, Goessens WH, Mevius DJ et al. Decreased ciprofloxacin susceptibility in Salmonella Typhi and Paratyphi infections in
ill-returned travellers: the impact on clinical outcome and future treatment options. Eur. J. Clin. Microbiol. Infect. Dis. 32(10),
1295–1301 (2013).
61. Koirala S, Basnyat B, Arjyal A et al. Gatifloxacin versus ofloxacin for the treatment of uncomplicated enteric fever in Nepal: an
open-label, randomized, controlled trial. PLoS Negl. Trop. Dis. 7(10), e2523 (2013).
62. Parry CM, Thompson C, Vinh H et al. Risk factors for the development of severe typhoid fever in Vietnam. BMC Infect. Dis. 14, 73
(2014).
63. Smith AM, Govender N, Keddy KH. Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA).
Quinolone-resistant Salmonella typhi in South Africa, 2003–2007. Epidemiol. Infect. 138(1), 86–90 (2010).
64. Kariuki S, Revathi G, Kiiru J et al. Typhoid in Kenya is associated with a dominant multidrug-resistant Salmonella enterica serovar Typhi
haplotype that is also widespread in Southeast Asia. J. Clin. Microbiol. 48(6), 2171–2176 (2010).
65. Frenck RW, Nakhla I, Sultan Y et al. Azithromycin versus ceftriaxone for the treatment of uncomplicated typhoid fever in children. Clin.
Infect. Dis. 31(5), 1134–1138 (2000).
66. Frenck RW, Mansour A, Nakhla I et al. Short-course azithromycin for the treatment of uncomplicated typhoid fever in children and
adolescents. Clin. Infect. Dis. 38(7), 951–957 (2004).
67. Aggarwal A, Ghosh A, Gomber S et al. Efficacy and safety of azithromycin for uncomplicated typhoid fever: an open label
non-comparative study. Indian Pediatr. 48(7), 553–556 (2011).

future science group www.future-science.com

Review Veeraraghavan, Pragasam, Bakthavatchalam & Ralph

68. Chandey M, Multani AS. A comparative study of efficacy and safety of azithromycin and ofloxacin in uncomplicated typhoid fever: a
randomised, open labelled study. J. Clin. Diagn. Res. 6(10), 1736–1739 (2012).
69. Cao XT, Kneen R, Nguyen TA et al. A comparative study of ofloxacin and cefixime for treatment of typhoid fever in children. The Dong
Nai Pediatric Center Typhoid Study Group. Pediatr. Infect. Dis J. 18(3), 245–248 (1999).
70. Vinh H, Duong NM, Phuong LT et al. Comparative trial of short-course ofloxacin for uncomplicated typhoid fever in Vietnamese
children. Ann. Trop. Paediatr. 5(1), 17–22 (2005).
71. Phongmany S, Phetsouvanh R, Sisouphone S et al. A randomized comparison of oral chloramphenicol versus ofloxacin in the treatment
of uncomplicated typhoid fever in Laos. Trans. R. Soc. Trop. Med. Hyg. 99(6), 451–458 (2005).
72. Chinh NT, Parry CM, Ly NT et al. A randomized controlled comparison of azithromycin and ofloxacin for treatment of
multidrug-resistant or nalidixic acid-resistant enteric fever. Antimicrob. Agents Chemother. 44(7), 1855–1859 (2000).
73. Parry CM, Ho VA, Phuong LT et al. Randomized controlled comparison of ofloxacin, azithromycin, and an ofloxacin-azithromycin
combination for treatment of multidrug-resistant and nalidixic acid-resistant typhoid fever. Antimicrob. Agents Chemother. 51(3),
819–825 (2007).
74. Arjyal A, Basnyat B, Koirala S et al. Gatifloxacin versus chloramphenicol for uncomplicated enteric fever: an open-label, randomised,
controlled trial. Lancet Infect. Dis. 11(6), 445–454 (2011).
75. Koirala S, Basnyat B, Arjyal A et al. Gatifloxacin versus ofloxacin for the treatment of uncomplicated enteric fever in Nepal: an
open-label, randomized, controlled trial. PLoS Negl. Trop. Dis. 7(10), e2523 (2013).
76. Arjyal A, Basnyat B, Nhan HT et al. Gatifloxacin versus ceftriaxone for uncomplicated enteric fever in Nepal: an open-label, two-centre,
randomised controlled trial. Lancet Infect. Dis. 16(5), 535–545 (2016).
77. Giri VP, Giri OP, Srivastava A et al. A clinical trial of treatment of uncomplicated typhoid fever: efficacy of ceftriaxone-azithromycin
combination. Int. J. Basic Clin. Pharmacol. 4(4), 673–677 (2015).
78. Meltzer E, Stienlauf S, Leshem E et al. A large outbreak of Salmonella Paratyphi. A infection among Israeli travelers to Nepal. Clin.
Infect. Dis. 58(3), 359–364 (2014).
79. Balasubramanian S, Rajeswari, Sailakshmi, Shivbalan S. Single vs multidrugtherapy in enteric fever. Indian J. Pediatr. 73(1), 103 (2006).
80. Thompson CN, Karkey A, Dongol S et al. Treatment response in enteric fever in an era of increasing antimicrobial resistance: an
individual patient data analysis of 2092 participants enrolled into 4 randomized, controlled trials in Nepal. Clin. Infect. Dis. 64(11),
1522–1531 (2017).
81. Munir T, Lodhi M, Ansari JK et al. Extended spectrum beta lactamase producing cephalosporin resistant Salmonella Typhi, reported
from Rawalpindi, Pakistan. J. Pak. Med. Assoc. 66(8), 1035–1036 (2016).
82. Parry CM, Hien TT, Dougan G et al. Typhoid fever. N. Engl. J. Med. 347(22), 1770–1782 (2002).
83. Capoor MR, Nair D. Quinolone and cephalosporin resistance in enteric fever. J. Glob. Infect. Dis. 2(3), 258–262 (2010).
84. Bakthavatchalam YD, Kumar DT, Tayubi IA et al. In vitro efficacy and in silico analysis of cefixime-ofloxacin combination for Salmonella
Typhi from bloodstream infection. J. Appl. Microbiol. 123(3), 615–624 (2017).
85. Preston LC (Ed.). Stockley’s drug interactions. (2015). www.medicines-complete.com
86. Mandal S, Mandal MD, Pal NK. Enhancing chloramphenicol and trimethoprim in vitro activity by Ocimum sanctum Linn.
(Lamiaceae) leaf extract against Salmonella enterica serovar Typhi. Asian Pac. J. Trop. Med. 5, 220–224 (2012).
87. Hannan A, Asghar S, Naeem T et al. Antibacterial effect of mango (Mangifera indica Linn.) leaf extract against antibiotic sensitive and
multi-drug resistant Salmonella Typhi. Pak. J. Pharm. Sci. 26(4), 715–719 (2013).
88. Nkuo-Akenji T, Ndip R, McThomas A et al. Anti-Salmonella activity of medicinal plants from Cameroon. Cent. Afr. J. Med. 47,
155–158 (2001).
89. Efunwole O, Adetuberu I, Oladipupo A et al. Antibacterial effect of Carica papaya against Salmonella Typhi, causative agent of Typhoid
fever. IOSR-JESTFT 12(4), 1–6 (2018).
90. Chattopadhyay D, Ojha D, Mukherjee H et al. Validation of a traditional preparation against multi-drug resistant Salmonella Typhi and
its protective efficacy in S. Typhimurium infected mice. BioMed. Pharmacother. 99, 286–289 (2018).

Future Sci. OA (2018) 04(06) future science group