Treatment and Prevention of Enteric (Typhoid and Paratyphoid) Fever - UpToDate

2/12/21 11:35 Treatment and prevention of enteric (typhoid and paratyphoid) fever - UpToDate
Official reprint from UpToDate®
www.uptodate.com
© 2021 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Treatment and prevention of enteric (typhoid and

paratyphoid) fever
Authors: Edward T Ryan, MD, DTMH, Jason Andrews, MD, Jacob John, MD
Section Editor: Stephen B Calderwood, MD
Deputy Editor: Elinor L Baron, MD, DTMH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2021. | This topic last updated: Sep 22, 2021.
INTRODUCTION
Enteric fever is characterized by severe systemic illness with fever and abdominal pain [1].
The organism classically responsible for the enteric fever syndrome is Salmonella enterica
serotype Typhi (formerly S. typhi). Other Salmonella serotypes, particularly S. enterica
serotypes Paratyphi A, B, or C, can cause a similar syndrome; however, it is usually not
clinically useful or possible to reliably predict the causative organism based on clinical
findings [2]. The term "enteric fever" is a collective term that refers to both typhoid and
paratyphoid fever, and "typhoid" and "enteric fever" are often used interchangeably.
The treatment and prevention of enteric fever will be reviewed here. The epidemiology,
pathogenesis, clinical manifestations, and diagnosis of enteric fever are discussed
separately. (See "Pathogenesis of enteric (typhoid and paratyphoid) fever" and
"Epidemiology, microbiology, clinical manifestations, and diagnosis of enteric (typhoid and
paratyphoid) fever".)
ANTIMICROBIAL RESISTANCE
Treatment of enteric fever has been complicated by the development and rapid global
spread of typhoidal organisms resistant to ampicillin, trimethoprim-sulfamethoxazole, and
chloramphenicol. Additionally, development of increasing resistance to fluoroquinolones is a
growing challenge.
Multidrug resistance — Multidrug-resistant (MDR) strains (ie, those resistant to ampicillin,

trimethoprim-sulfamethoxazole, and chloramphenicol) are prevalent worldwide, though
https://www.uptodate.com/contents/treatment-and-prevention-of-enteric-typhoid-and-paratyphoid-fever/print?search=fiebre tifoidea&source=sear… 1/27

they have been in decline as other antibiotics have been more widely used for treatment of
enteric fever.
MDR strains of S. Typhi and S. Paratyphi have caused numerous outbreaks in endemic
regions, including South and Southeast Asia, China, and Africa [3-5]. Because of this,
ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol fell out of favor as first-line
agents for treatment of enteric fever.
Prevalence of MDR strains varies, throughout Africa, the Middle East, and Central Asia, from
10 to 80 percent, depending on the country [6-9]. Genome sequencing and analysis of
international isolates has identified a predominant MDR S. Typhi strain, H58, that has
disseminated throughout Asia and Africa, displacing more susceptible strains and driving
ongoing MDR epidemics [10]. As of 2018, approximately 75 percent of strains from Africa
remain MDR, without significant change over the past 15 years [11].
However, some locations have reported a decrease in the prevalence of MDR strains. As an
example, in a surveillance study from Kolkata, India conducted from 2009 to 2013, 18
percent of S. Typhi and no S. Paratyphi isolates were MDR [12].These patterns of resistance
are reflected in travelers returning to nonendemic regions. In an analysis of over 1000
isolates submitted to the United States Centers for Disease Control and Prevention (CDC)
between 2008 and 2012, most of which were from infections acquired in South Asia, 13
percent of S. Typhi and no S. Paratyphi isolates were MDR strains [13]. In a subsequent
Surveillance of Enteric Fever in Asia Project study, a minority of strains from India, Nepal, and
Bangladesh were MDR, while the majority of strains from Pakistan continued to show
multidrug resistance [14].
Fluoroquinolone nonsusceptibility — Historically, resistance to the early generation

quinolone nalidixic acid served as an important marker for decreased susceptibility to
fluoroquinolones. However, because of the emergence of newer mechanisms of
fluoroquinolone resistance, some isolates may appear to be sensitive to nalidixic acid but
still have decreased sensitivity to clinically important fluoroquinolones, calling into question
the reliability of using nalidixic acid resistance as a marker of fluoroquinolone resistance. As
a result, both the Clinical and Laboratory Standards Institute (CLSI) in the United States and
European Committee on Antimicrobial Susceptibility Testing (EUCAST) have specific
fluoroquinolone breakpoints for Salmonella isolates [15-17].
In many parts of South Asia, over 80 percent of S. Typhi isolated among clinical cases are
nonsusceptible to fluoroquinolones [14]. A randomized trial in Nepal comparing ceftriaxone
with gatifloxacin, a fluoroquinolone that had proven highly successful in the country just
several years prior, had to be terminated early due to high rates of treatment failure in the
gatifloxacin arm, which was associated with fluoroquinolone nonsusceptibility. In contrast,
fluoroquinolone-nonsusceptibility appears less common in other parts of the world. In one
multi-country study in Africa, fluoroquinolone nonsusceptibility was only documented in one

(Kenya) [18] of six countries performing surveillance. More recently, fluoroquinolone
resistant isolates have been reported in Nigeria [19]. Throughout Africa, rates of
fluoroquinolone nonsusceptibility in typhoidal Salmonella remain low but are rising [11].
Increasing rates of full resistance to fluoroquinolones have also been reported; in some
cases, these resistant isolates have been classified as a subclass of the MDR H58 typhoid
strain that had widely disseminated throughout Asia and some African countries [20]. A
compilation of studies showed rates of fully quinolone-resistant organisms ranged from 0 to
13 percent, with cases reported from India, Korea, and Nepal [21]. In a systematic review of
studies from Nepal, the pooled rates of ciprofloxacin resistance increased in both S. Typhi
and S. Paratyphi A, from 1.6 and 3.9 percent in 1998 to 2002 to 10.6 and 14.3 percent in 2008
to 2011 [22]. Cases of high-level resistance to ciprofloxacin, often conferred by strains
containing multiple mutations in the quinolone resistance-determining region (QRDR) have
also been reported throughout South Asia in both S. Paratyphi and S. Typhi (MICs of 8
mcg/mL to 16 mcg/mL) [23-25]. Given the rapid global spread of prior drug-resistant
Salmonella strains from South Asia, there is concern that these highly resistant strains will
soon appear in other parts of the world.
Resistance to other agents — Most S. Typhi and S. Paratyphi isolates remain susceptible to

azithromycin and ceftriaxone, although resistant isolates have been reported.
In particular, resistance to ceftriaxone is increasing, with reports of patients with extended-

spectrum beta-lactamase-producing S. Typhi and S. Paratyphi infections [26-28]. (See
'Extensively drug-resistant typhoid' below.)
Clearly defined MIC breakpoints for azithromycin susceptibility have not been established,
but data suggest that S. Typhi isolates with an MIC ≤16 mcg/mL generally respond well to
azithromycin (which is concentrated intracellularly at levels 50 to 100 times greater than
serum levels) and can be considered susceptible [29]. A 15 mcg disk susceptibility zone size
of ≥13 mm appears consistent with an azithromycin MIC ≤16 mcg/mL (99.7 percent
sensitive). The first report of azithromycin resistance (MIC by E-test 64 mcg/mL) in S.
Paratyphi A resulting in treatment failure was reported in a traveler returning from Pakistan
to Great Britain [30]. The patient was successfully treated with a two-week course of
intravenous ceftriaxone, 2 g daily. A growing number of azithromycin-resistant S. Typhi and
S. Paratyphi A isolates have also been reported from South Asia, although this phenotype
has not been seen in ceftriaxone-resistant organisms [31-33]. It appears to be mediated by
R717Q/L mutations in the acrB gene [34].
Extensively drug-resistant typhoid — A large outbreak of typhoid fever caused by a strain

resistant to chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole, fluoroquinolones,
and third-generation cephalosporins started in Pakistan in 2016 [35,36]. By the end of 2018,
over 5000 cases of this extensively drug-resistant (XDR) S. Typhi strain were reported, with
imported cases in the United Kingdom and the United States [37-39]. An unrelated cluster of
ceftriaxone-resistant S. Typhi infections has also been linked to travel to Iraq [40]. In 2020,
several XDR typhoid cases in individuals without international travel were reported in the
United States, suggesting local transmission [41]. The strain remains susceptible to
azithromycin and carbapenems, which are the main treatment options for this strain. (See
'Empiric therapy' below.)
ANTIMICROBIAL THERAPY
Enteric fever is usually treated with a single antibacterial drug. Antibiotic selection depends
upon the severity of illness, local resistance patterns, whether oral medications are feasible,
the clinical setting, and available resources. The optimal choice of drug and duration of
therapy are uncertain [42-44]. The main options are fluoroquinolones, third-generation
cephalosporins, and azithromycin. Carbapenems are reserved for suspected infection with
extensively drug-resistant (XDR) strains. In some circumstances, older agents such as
chloramphenicol, ampicillin, or trimethoprim-sulfamethoxazole may be appropriate, but
these drugs are generally not used widely because of the prevalence of resistance. Oral
chloramphenicol is no longer available in the United States but is still used in other parts of
the world.
Empiric therapy — When treating presumptively for enteric fever or before results of

susceptibility testing are available, appropriate options for empiric therapy depend, in part,
on the severity of disease and the risk of infection with an antibiotic-resistant isolate.
Severe or complicated disease — For patients who have severe disease (eg, systemic
toxicity, depressed consciousness, prolonged fever, organ system dysfunction, or other
feature that prompts hospitalization), initial therapy with a parenteral agent is appropriate.
The geographic region where infection was likely acquired helps inform the choice of
parenteral agent because of the risk of resistance in certain locations:
● Infection acquired outside Pakistan or Iraq – For most patients with severe or
complicated enteric fever without recent travel to Pakistan or Iraq, we suggest empiric
therapy with ceftriaxone. If ceftriaxone is not available, cefotaxime is a reasonable
alternative. Although some studies have demonstrated slower time to defervescence
with cephalosporins (compared with fluoroquinolones), resistance to the third-
generation cephalosporins is uncommon in most locations, and so ceftriaxone is likely
to be an effective empiric agent in individuals without a history of travel to Pakistan or
Iraq [3]. However, if there is suspicion for ceftriaxone resistance, a carbapenem can be
used while awaiting susceptibility testing [41] (see 'Extensively drug-resistant typhoid'
above). Aztreonam has been effective in small trials and can be used for individuals
who cannot take cephalosporins because of allergy [45,46]. In situations where the risk
of decreased susceptibility to fluoroquinolones is low (eg, disease not acquired from
South Asia or Iraq), a parenteral fluoroquinolone is also an appropriate alternative.
● Infection acquired in Pakistan or Iraq – For patients with severe or complicated

enteric fever acquired in Pakistan or Iraq (eg, following recent travel to those
countries), we suggest empiric therapy with a carbapenem (eg, meropenem). This is
because of the presence of XDR S. Typhi in these regions. (See 'Extensively drug-
resistant typhoid' above.)
Antibiotic doses and durations are listed in the table ( table 1). Once symptoms improve,
the patient can be transitioned to an oral agent, selected based on results of susceptibility
testing, if available. Oral options and data evaluating the efficacy of antibiotic options for
enteric fever are discussed elsewhere. (See 'Directed therapy' below.)
Adjunctive corticosteroid is an additional consideration for patients with severe enteric fever.
(See 'Adjunctive corticosteroids for severe infection' below.)
Uncomplicated disease — Patients with uncomplicated disease have no evidence of

systemic toxicity and can tolerate oral therapy. Appropriate options for empiric therapy in
such patients depend on the risk of infection with an antibiotic-resistant isolate, which
differs based on the geographical area where infection was acquired. (See 'Fluoroquinolone
nonsusceptibility' above.)
● Fluoroquinolones (ciprofloxacin or ofloxacin) are the drugs of choice for empiric

therapy when infection is expected to be fluoroquinolone susceptible. This includes
infection acquired in most areas of sub-Saharan Africa (except for Kenya and Nigeria).
However, since fluoroquinolone resistance has emerged quickly in some areas,
susceptibility testing and continued surveillance of local resistance rates is
recommended to guide empiric treatment. Although fluoroquinolones are not
recommended for routine use in children in the United States because of arthropathy
and cartilage toxicity in exposed immature animals [47,48], clinical studies have not
demonstrated sustained injury to developing bones or joints in children treated with
available fluoroquinolones [49,50]. Thus, fluoroquinolone use in children is acceptable
for severe infection, such as enteric fever, when alternatives are not available or
appropriate.
● In contrast, for empiric oral therapy of patients with infections acquired in South Asia
or other areas with a high risk of reduced susceptibility to fluoroquinolones (eg,
nalidixic acid resistance), we suggest azithromycin, which achieves excellent
intracellular concentrations and has established efficacy. Azithromycin is also expected
to have activity against XDR isolates acquired in Pakistan. Increasing numbers of

azithromycin-resistant S. Typhi have been reported from South Asia, particularly

Bangladesh, so susceptibility testing should be performed. (See 'Fluoroquinolone
nonsusceptibility' above and 'Extensively drug-resistant typhoid' above.)
Infection with an isolate with reduced susceptibility to fluoroquinolones is associated with

longer time to defervescence and higher rates of treatment failure with ciprofloxacin,
ofloxacin, and gatifloxacin [42,51-54]. Over a period of 10 years, fluoroquinolone
effectiveness markedly declined in this setting as resistance emerged; at the same time,
azithromycin remained effective and minimum inhibitory concentrations (MICs) were low
and declining [55]. Resistance to azithromycin remains rare.
However, azithromycin may be costly or unavailable in certain parts of the world, and
parenteral therapy may not be necessary for many uncomplicated infections. In such cases,
cefixime is another alternative, but it has some drawbacks (see 'Fluoroquinolone-
nonsusceptible infection' below). If multidrug resistance is not prevalent, trimethoprim-
sulfamethoxazole, amoxicillin, and chloramphenicol (if available) are potential options (see
'Multidrug resistance' above). In resource-limited settings, options may be further
constrained by cost and availability.
Antibiotic doses and durations are listed in the table ( table 1). If susceptibility testing
demonstrates that an empirically chosen agent is active and the patient has improved, that
agent can be continued as directed therapy. Data evaluating the efficacy of antibiotic options
for enteric fever are discussed elsewhere. (See 'Directed therapy' below.)
Directed therapy — Ideally, definitive antimicrobial therapy for enteric fever should be

based on results of susceptibility testing. S. Typhi and S. Paratyphi isolates should be directly
tested for ciprofloxacin or ofloxacin sensitivity utilizing the breakpoints as described above
[15,56,57]. However, such testing may be technically challenging, especially in resource-
limited settings. Moreover, the diagnosis of enteric fever is often presumptive, without
isolation of an organism. In cases in which susceptibility testing cannot be performed,
options depend on the likelihood of antimicrobial resistance (see 'Empiric therapy' above).
Infectious disease consultation is warranted for such cases if clinicians are not familiar with
enteric fever and its treatment.
There are no trials demonstrating that combination antimicrobial therapy is superior to

monotherapy for enteric fever. In a study of 37 individuals with nalidixic acid-resistant S.
Paratyphi A bacteremia who were identified as part of an outbreak among Israeli travelers
returning from Nepal, all patients improved without complications, but time to
defervescence was shorter among those who were treated with ceftriaxone and
azithromycin compared with ceftriaxone alone [58]. Given the small size and observational
nature of the study and the finding that all patients were infected by a single strain,
additional study is needed to determine if there is any benefit of using two drugs over one.
Fluoroquinolone-susceptible infection — Fluoroquinolones are considered by many

experts to be the drug of choice for susceptible isolates. Of the fluoroquinolones,
ciprofloxacin and ofloxacin are widely available and effective. Norfloxacin is very poorly
absorbed and should not be used. If a fluoroquinolone cannot be used, alternatives include
azithromycin and third-generation cephalosporins. (See 'Fluoroquinolone-nonsusceptible
infection' below.)
Fluoroquinolones are bactericidal, are concentrated intracellularly and in the bile, and result
in rapid elimination of intracellular bacteria. They are more effective than beta-lactams
against susceptible organisms. As an example, in an open-label randomized trial among
patients older than 15 years, ofloxacin (200 mg orally twice daily for five days) resulted in
higher cure rates compared with ceftriaxone (3 g intravenously once daily for three days)
[59]. In a separate open-label randomized trial of 82 children, resolution of fever occurred
more rapidly (4.4 versus 8.5 days) with ofloxacin (10 mg/kg per day divided twice daily for
five days) compared with cefixime (20 mg/kg per day divided twice daily for seven days) [60].
There was one treatment failure in the ofloxacin group compared with 10 treatment failures
and one relapse in the cefixime group.
Although fluoroquinolones are not recommended for routine use in children in the United
States because of arthropathy and cartilage toxicity in exposed immature animals [47,48],
clinical studies have not demonstrated sustained injury to developing bones or joints in
children treated with available fluoroquinolones [49,50]. Thus, fluoroquinolone use in
children is acceptable for a severe infection, such as enteric fever, when alternatives are not
available or appropriate.
Fluoroquinolone-nonsusceptible infection — Fluoroquinolone nonsusceptible infections

include those with reduced susceptibility to the fluoroquinolones (ie, nalidixic acid-resistant)
and those with frank resistance. In infections with reduced fluoroquinolone susceptibility,
treatment with ciprofloxacin or ofloxacin is associated with longer time to defervescence and
higher rates of clinical treatment failure [42,61], and so should be avoided.
When fluoroquinolones cannot be used, we typically use azithromycin. If azithromycin

cannot be used because of cost, availability, or other reasons, other options include third-
generation cephalosporins and, if susceptibility is demonstrated, trimethoprim-
sulfamethoxazole, amoxicillin, or chloramphenicol.
● Azithromycin – Azithromycin has good efficacy for enteric fever. In a systematic review
that included seven randomized trials of adults and children with enteric fever,
azithromycin was at least as effective as comparators (fluoroquinolones,
chloramphenicol, ceftriaxone) with regards to clinical failure, time to defervescence,
and relapse [62]. For fluoroquinolone-nonsusceptible infection, azithromycin appears
superior to ofloxacin. As an example, in an open-label, randomized study among
Vietnamese adults and children with uncomplicated typhoid fever due to nalidixic acid-
resistant or multidrug-resistant isolates, azithromycin (1 g daily for five days) resulted
in a trend towards greater clinical cure rates (82 versus 64 percent), faster time to
defervescence (mean 5.8 versus 8.2 days) and lower rates of post-treatment fecal
carriage (1.6 versus 19 percent) [63]. Early convalescent fecal shedding may spread the
organism in a community even if few of these individuals become chronic carriers.
● Cephalosporins – Third-generation cephalosporins also have demonstrated efficacy

but require a longer duration of therapy. Although the optimal duration has not been
established, at least 10 to 14 days are warranted because of the risk of relapse with
shorter durations [45,64-66]. In two randomized trials, seven days of ceftriaxone (50 to
75 mg/kg per day) resulted in relapse within four weeks in 14 percent of children
[64,65]. In one of these studies, children were assigned to seven days of therapy with
either azithromycin (10 mg/kg per day; maximum 500 mg) or ceftriaxone (75 mg/kg per
day; maximum 2.5 g per day) [64]. There were four relapses with ceftriaxone compared
with none with azithromycin (14 versus 0 percent).
Among the third-generation cephalosporins, ceftriaxone may be superior to cefotaxime

[67]. Oral cefixime has not been extensively compared directly with ceftriaxone, but
appears to be of generally comparable efficacy [45,66]. Cefixime for 14 days was
comparable to azithromycin given for 7 days (93 versus 87 percent cure) in a study of
children with uncomplicated enteric fever in Bangladesh [68]. However, other studies
have reported a slower time to defervescence and a relatively high rate of on-treatment
failure with cefixime compared with other agents [60,69].
Although gatifloxacin had previously been proposed as an option for isolates with reduced
susceptibility to fluoroquinolones (ie, nalidixic acid-resistant isolates) because it appeared to
retain relatively good activity against them [70-72], the emergence of frankly
fluoroquinolone-resistant isolates has limited its utility. Moreover, it is not widely available,
having been withdrawn from most countries because of associated dysglycemia.
The rise and fall of gatifloxacin as an effective therapy for typhoid has been demonstrated in
several trials from Nepal. In an analysis of four trials conducted between 2005 and 2014,
gatifloxacin had equivalent or better fever clearance times in the first three trials when
compared with cefixime, chloramphenicol, and ofloxacin [55]. However, during the course of
the trials, MICs to fluoroquinolones steadily rose, and these higher MICs were associated
with slower time to defervescence with gatifloxacin. In the fourth randomized trial, which
was conducted from 2011 to 2014 and included children and adults with documented or
suspected enteric fever, treatment failure was similar with gatifloxacin versus ceftriaxone,
each given for seven days (15 and 16 percent, respectively) [54]. However, among those with
culture-confirmed S. Typhi infection, 25 percent had fluoroquinolone-resistant isolates, and

failure was greater with gatifloxacin (26 versus 7 percent). The trial was stopped early
because of the high rates of fluoroquinolone resistance identified. Fluoroquinolones are
therefore no longer considered appropriate empiric therapy for enteric fever in this region.
OTHER TREATMENT CONSIDERATIONS
Adjunctive corticosteroids for severe infection — For patients with suspected or known

enteric fever and severe systemic illness (delirium, obtundation, stupor, coma, or shock), we
suggest adjunctive dexamethasone (3 mg/kg followed by 1 mg/kg every 6 hours for a total
of 48 hours).
In a randomized, prospective, double-blind study performed in Indonesia in the early 1980s

among 38 adults and children with severe enteric fever (shock or obtundation), the addition
of high-dose dexamethasone to chloramphenicol treatment reduced mortality compared
with chloramphenicol alone (10 versus 55 percent) [73]. Adjunctive corticosteroids did not
increase the rate of other complications, carriage, or relapse. Subsequent observational
studies have also supported the benefit [74,75], but whether the adjunctive dexamethasone
is beneficial with other antibiotics or in different clinical settings remains uncertain.
Ileal perforation — For patients with ileal perforation, prompt surgical intervention is

usually indicated, as is broader antimicrobial coverage to cover peritonitis and potential
secondary bacteremia with enteric organisms (see "Antimicrobial approach to intra-
abdominal infections in adults"). The extent of surgical intervention remains controversial;
the best surgical procedure appears to be segmental resection of the involved intestine,
when possible [76,77].
In a retrospective review from West Africa including 112 patients undergoing laparotomy for
typhoid perforation, most of the perforations were single (77 percent) and in the terminal
ileum [78]. Primary repair was successful in 84 percent of cases, although reoperative
management was required in some patients who did not respond immediately. Even with
surgery, mortality rates of 14, 16, and 34 percent have been reported in series from Nigeria,
Togo, and the Ivory Coast, respectively [78-80].
FOLLOW-UP
Successful treatment in uncomplicated cases usually results in clinical improvement within

three to five days. In most clinical trials, the mean time to defervescence is four to six days,
so persistent fevers of this duration following treatment initiation does not imply therapeutic
failure. Patients should be subsequently monitored for or instructed to report recurrent
symptoms, which could reflect relapse.

Relapse — Relapse of enteric fever after clinical cure can occur in immunocompetent

individuals; in such cases, it typically occurs two to three weeks after resolution of fever. The
risk of relapse depends on the antibiotic used to treat the initial infection. Relapse rates with
chloramphenicol, a bacteriostatic agent, were 10 to 25 percent, but subsequent studies that
have included multidrug-resistant S. Typhi infections and newer antibiotics have noted lower
relapse rates of 1 to 6 percent [45,60,71].
Relapsed infection should be treated with an additional course of antibiotics, guided by

susceptibility testing. Usually, the isolate has the same susceptibility pattern as the initial
infection. A longer treatment course with a third-generation cephalosporin is also
reasonable.
Chronic carriage — Chronic carriage of Salmonellae is defined as excretion of the organism

in stool for more than 12 months after the acute infection. Post-illness screening for S. Typhi
carriage is not routinely performed. Chronic carriage is typically identified through public
health mandated screening of food handlers or health care personnel following enteric fever
or during an investigation of an outbreak or case in nonendemic areas.
Chronic carriage rates after S. Typhi infection range from 1 to 6 percent [81]; rates are higher
in patients with cholelithiasis or other biliary tract abnormalities [82]. Chronic Salmonella
carriage occurs much more frequently with typhoidal strains than nontyphoidal strains. (See
"Nontyphoidal Salmonella: Gastrointestinal infection and carriage".)
Although chronic carriers are asymptomatic, they represent an infectious risk to others,
particularly if involved in food preparation. For this reason, eradication of carriage is usually
attempted once such individuals are identified. Chronic carriage may also be an independent
risk factor for carcinoma of the gallbladder as well as other cancers [83], but the effect of
eradication on this association is unknown.
The optimal approach to eradication is uncertain. Fluoroquinolone therapy (eg, ciprofloxacin

500 to 750 mg orally twice daily or ofloxacin 400 mg orally twice daily) for four weeks is a
reasonable approach. If eradication is not achieved but thought necessary from a public
health perspective, an additional prolonged antibiotic course and cholecystectomy may be
warranted.
The fluoroquinolones are relatively effective for eradication of chronic carriage. In one study
of 23 carriers, the cure rate with norfloxacin (400 mg orally twice daily for 28 days) was 86
percent in those with normal gallbladders and 75 percent in those with gallstones [84].
Several smaller studies, evaluating 10 to 12 patients each, have found that ciprofloxacin (500
or 750 mg orally twice daily) for 14 to 28 days eliminated carriage in 90 to 93 percent of
cases [85].
https://www.uptodate.com/contents/treatment-and-prevention-of-enteric-typhoid-and-paratyphoid-fever/print?search=fiebre tifoidea&source=se… 10/27

The optimal approach to eradication of fluoroquinolone-nonsusceptible typhoidal Salmonella

is not known. There has been some experience with high-dose amoxicillin (eg, 75 to 100
mg/kg per day for four to six weeks) and trimethoprim-sulfamethoxazole with or without
rifampin, but the evidence base for these regimens is limited [86-90].
PROGNOSIS
Effective antibiotic therapy has dramatically impacted the outcomes of enteric fever. In the
pre-antibiotic era, mortality rates were 15 percent or greater [91,92] and survivors
experienced a prolonged illness lasting weeks, with months of subsequent debilitation.
Approximately 10 percent of untreated patients relapsed and up to 4 percent become
chronic carriers of the organism.
Among those receiving medical care in the post-antibiotic era, the average mortality rate
from enteric fever is estimated to be less than 1 percent [1]. Although a 2018 systematic
review reported a higher case-fatality rate, it was likely an overestimate of contemporary
mortality rates, as high rates were seen primarily in older or smaller studies [93]. Mortality
rates from more recent studies are low. As an example, in a study of nearly 3000 individuals
receiving care for culture-confirmed enteric fever in Pakistan from 2012 to 2014, there were
no deaths reported [94]. In the United States, a Centers for Disease Control and Prevention
(CDC) compilation of 10 hospital-based typhoid fever series reported a mean case-fatality
rate of 2 percent (range 0 to 14.8 percent), but noted that these series capture only the most
severe and hospitalized cases in those with access to care [95].
PREVENTION
Food and water safety — Enteric fever results from the ingestion of contaminated food or
water. The inoculum in food is likely higher than that in contaminated water. Access to fresh
water, prioritization of sanitation and hygiene, and education about food and water safety
are essential preventive strategies.
For travelers, the main mechanism of transmission is ingestion of the local cuisine or water
in areas where sanitation and personal hygiene may be poor. Travelers should be advised on
behavioral precautions. (See "Travel advice", section on 'Food and water'.)
Vaccination
In endemic areas — The World Health Organization (WHO) recommends implementation

of national typhoid vaccination programs as part of broader control efforts in settings where
typhoid is endemic. Of available vaccines, it prefers typhoid conjugate vaccines for their
efficacy and established safety in infants and young children, as well as their greater and
more durable immunogenicity compared with other vaccines [96]. It recommends

administration of typhoid conjugate vaccine for infants and children six months of age or
older, with catch-up vaccination campaigns, if possible, for children up to 15 years old. (See
'Licensed vaccines' below.)
In nonendemic areas — Typhoid vaccination is indicated in travelers to endemic areas and

other individuals with risk for exposure, but available vaccines are not entirely protective.
Specific indications and vaccine options vary by country.
In the United States, typhoid vaccination is recommended for travelers (even short-term
travelers) to areas where there is risk of exposure to S. Typhi, for individuals with intimate
exposure to a documented S. Typhi chronic carrier (eg, household contacts), and for
individuals whose work exposes them to cultures or specimens containing S. Typhi (eg,
laboratory workers) [97]. Typhoid conjugate vaccine is not yet available in the United States.
Either the polysaccharide or oral vaccine formulation is appropriate, although the oral
vaccine should be avoided in immunocompromised and pregnant individuals since it is a live
vaccine. If repeated exposure to S. Typhi is expected, repeat typhoid vaccination is advised to
maintain immunity. (See "Immunizations for travel", section on 'Typhoid vaccine'.)
Vaccination is appropriate even in those who have a history of enteric fever, particularly in
those not living in endemic areas, if re-exposure is expected. Natural infection does not
provide complete protection against recurrent illness (which is not the same as relapsed
infection). One study suggests early treatment of natural infection may blunt humoral
responses to capsular antigens [98]. The optimal timing for vaccination following clinical
illness is not known.
Licensed vaccines — Several typhoid vaccines have been licensed, although they are not
all universally available. None are completely effective against S. Typhi and none have been
demonstrated to provide protection against paratyphoid fever caused by S. Paratyphi A.
● Vi-TT typhoid conjugate vaccine (TCV) – These vaccines consist of the Vi

polysaccharide antigen linked to tetanus toxoid protein. Typbar-TCV is the
representative vaccine of this type; it is administered as a single intramuscular dose.
The need for revaccination for continued protection is uncertain. It is licensed in India,
Nepal, and several other countries, but it is not yet available in Europe or the United
States. A second typhoid conjugate vaccine (Typhibev), containing Vi conjugated to
CRM197, was prequalified in December 2020. Two other Vi-TT conjugate typhoid
vaccines (PedaTyph and ZyVac-TCV) are available in India [99]. Other conjugate vaccines
are under investigation.
Emerging evidence suggests good efficacy of TCV. In several randomized trials from
Nepal, Bangladesh, and Malawi, which together included over 100,000 children, vaccine

efficacy of Typbar-TCV against culture-confirmed typhoid fever ranged from 81 to 85

percent compared with control vaccines [100-102]. As an example, in the trial from
Nepal, among over 20,000 children aged 9 months to 16 years, the incidence of typhoid
fever over the year following Typbar-TCV vaccination was 79 cases compared with 428
cases per 100,000 person-years after meningococcal conjugate vaccination (vaccine
efficacy 82 percent, 95% CI 59-92) [100]. Typbar-TCV was 97 percent (95% CI 95-98)
effective against extensively drug-resistant (XDR) S. Typhi [103]. No major vaccine-
associated adverse events were identified in any of the trials.
Conjugate vaccines appear to be more immunogenic and better at inducing long-term

memory responses compared with other typhoid vaccines [104-106]. In a randomized
trial of individuals aged 2 to 45 years in India, the conjugate vaccine (Typbar-TCV)
resulted in higher seroconversion rates and higher antibody titers after three to five
years than the polysaccharide vaccine, especially in young children [105]. It was also
safe and immunogenic in a parallel open-label trial of children aged 6 to 23 months,
with anti-Vi IgG antibodies persisting up to five years in approximately 85 percent.
● Vi polysaccharide vaccine – This consists of the Vi polysaccharide antigen. It is

administered as a single intramuscular dose. It can also be given subcutaneously. If
continued protection is needed, revaccination is recommended every two to three
years.
In a systematic review and meta-analysis of randomized controlled trials, efficacy at

one, two, and three years was 69, 59, and 55 percent [107].
● Ty21a vaccine – This is a live oral vaccine that consists of an attenuated S. Typhi strain
Ty21a. It is administered in three to four doses taken on alternate days. If continued
protection is needed, revaccination is recommended every three to five years.
In a systematic review and meta-analysis of randomized controlled trials, efficacy at

one, two, and three years was 45, 59, and 56 percent [107]. There is some evidence that
the Ty21a vaccine may confer partial protection against S. Paratyphi B [108].
Adverse effects associated with these vaccines are generally mild (eg, fever or injection
site pain or swelling) [100,105,108].
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Acute diarrhea in
adults" and "Society guideline links: Acute diarrhea in children" and "Society guideline links:
Travel medicine".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Enteric (typhoid and paratyphoid) fever (The
Basics)")
SUMMARY AND RECOMMENDATIONS
● Treatment of enteric fever has been complicated by the development of antimicrobial

resistance. In particular, resistance to clinically important fluoroquinolones has become
a major problem worldwide, particularly in Asia. Most Salmonella Typhi and Salmonella
Paratyphi isolates remain susceptible to azithromycin and third-generation
cephalosporins. However, an extensively drug-resistant (XDR) isolate has emerged in
Pakistan that is resistant to many agents, including third-generation cephalosporins
and fluoroquinolones. (See 'Antimicrobial resistance' above.)
● Antibiotic selection depends upon the severity of illness, local resistance patterns,
whether oral medications are feasible, the clinical setting, and available resources (
table 1). (See 'Antimicrobial therapy' above.)
• Patients with severe disease (systemic toxicity, depressed consciousness, prolonged

fever, organ system dysfunction, or other feature that prompts hospitalization)
should be treated initially with a parenteral antibiotic. For such patients, who have
acquired infection outside of Pakistan or Iraq, we suggest ceftriaxone (Grade 2B).
Cefotaxime or, if the risk of decreased susceptibility to fluoroquinolones is low (eg,
disease not acquired from South Asia or Iraq), a parenteral fluoroquinolone is an
alternative. If there is suspicion for ceftriaxone resistance, a carbapenem can be
used while awaiting susceptibility testing. For patients with severe typhoid fever

acquired in Pakistan or Iraq, we suggest empiric therapy with a carbapenem (eg,

meropenem) because of the risk of ceftriaxone-resistant and XDR typhoid (Grade
2C).
• For patients with uncomplicated enteric fever, antibiotic selection depends on the
likelihood of reduced susceptibility to fluoroquinolones, which is highest in
infections acquired in South Asia. In the absence of known or suspected reduced
fluoroquinolone susceptibility, we suggest antibiotic therapy with ciprofloxacin
(Grade 2B). For patients with uncomplicated enteric fever due to an isolate known
or suspected to have reduced fluoroquinolone susceptibility (including patients with
infection acquired in Pakistan), we suggest azithromycin (Grade 2B). Ceftriaxone is
an alternative (except for patients with infection acquired in Pakistan or Iraq). With
increasing reports of azithromycin-resistant S. Typhi from South Asia, susceptibility
testing should be performed.
• Empiric antibiotic regimens can be adjusted if and when formal sensitivities are
available.
● For patients with suspected or known enteric fever and severe systemic illness
(delirium, obtundation, stupor, coma, or shock), we suggest adjunctive dexamethasone
(3 mg/kg followed by 1 mg/kg every 6 hours for a total of 48 hours) (Grade 2B). (See
'Adjunctive corticosteroids for severe infection' above.)
● Treatment of ileal perforation warrants surgical therapy in addition to antibiotic therapy

to cover both enteric fever and enteric organisms. (See 'Ileal perforation' above.)
● Successful treatment in uncomplicated cases usually results in clinical improvement

within three to five days, with fever clearance at four to six days. Relapse of enteric
fever after clinical cure can occur two to three weeks after resolution of illness and
should be treated with an additional course of antibiotics, guided by susceptibility
testing. (See 'Relapse' above.)
● Chronic Salmonella carriage is defined as excretion of the organism in stool >12 months
after acute infection. Chronic carriers represent an infectious risk to others, particularly
in the setting of food preparation. We suggest treatment of chronic carriers with four
weeks of fluoroquinolone therapy for eradication of carriage if isolates are
fluoroquinolone susceptible (Grade 2C). (See 'Chronic carriage' above.)
● Enteric fever results from the ingestion of contaminated food or water; attention to
food safety is important for travelers to regions where sanitation and personal hygiene
may be poor. Three vaccines are available globally for protection against S. Typhi:
parenteral Vi polysaccharide vaccine, live oral S. Typhi vaccine strain Ty21a, and

parenteral Vi conjugate vaccine. None of these vaccines offer complete protection, and
periodic revaccination is needed if exposure risk continues.
In endemic areas, the World Health Organization (WHO) recommends implementation

of national typhoid vaccination programs, preferably with a conjugate typhoid vaccine,
as part of broader control efforts. The conjugate vaccine is not available in the United
States or Europe. (See 'Prevention' above and "Immunizations for travel", section on
'Typhoid vaccine'.)
ACKNOWLEDGMENT
The UpToDate editorial staff acknowledges Elizabeth L. Hohmann, MD, who contributed to
an earlier version of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Parry CM, Hien TT, Dougan G, et al. Typhoid fever. N Engl J Med 2002; 347:1770.
2. Vollaard AM, Ali S, Widjaja S, et al. Identification of typhoid fever and paratyphoid fever
cases at presentation in outpatient clinics in Jakarta, Indonesia. Trans R Soc Trop Med
Hyg 2005; 99:440.
3. Kariuki S, Gordon MA, Feasey N, Parry CM. Antimicrobial resistance and management of
invasive Salmonella disease. Vaccine 2015; 33 Suppl 3:C21.
4. Yan M, Li X, Liao Q, et al. The emergence and outbreak of multidrug-resistant typhoid
fever in China. Emerg Microbes Infect 2016; 5:e62.
5. Hendriksen RS, Leekitcharoenphon P, Lukjancenko O, et al. Genomic signature of

multidrug-resistant Salmonella enterica serovar typhi isolates related to a massive
outbreak in Zambia between 2010 and 2012. J Clin Microbiol 2015; 53:262.
6. Wain J, Hendriksen RS, Mikoleit ML, et al. Typhoid fever. Lancet 2015; 385:1136.
7. 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 2014; 2:88.
8. Marks F, von Kalckreuth V, Aaby P, et al. Incidence of invasive salmonella disease in sub-
Saharan Africa: a multicentre population-based surveillance study. Lancet Glob Health
2017; 5:e310.
9. Qamar FN, Yousafzai MT, Dehraj IF, et al. Antimicrobial Resistance in Typhoidal
Salmonella: Surveillance for Enteric Fever in Asia Project, 2016-2019. Clin Infect Dis 2020;

71:S276.
10. 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 2015; 47:632.
11. Britto CD, Wong VK, Dougan G, Pollard AJ. A systematic review of antimicrobial
resistance in Salmonella enterica serovar Typhi, the etiological agent of typhoid. PLoS
Negl Trop Dis 2018; 12:e0006779.
12. 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 2014; 9:e101347.
13. Date KA, Newton AE, Medalla F, et al. Changing Patterns in Enteric Fever Incidence and
Increasing Antibiotic Resistance of Enteric Fever Isolates in the United States, 2008-
2012. Clin Infect Dis 2016; 63:322.
14. Barkume C, Date K, Saha SK, et al. Phase I of the Surveillance for Enteric Fever in Asia
Project (SEAP): An Overview and Lessons Learned. J Infect Dis 2018; 218:S188.
15. Humphries RM, Fang FC, Aarestrup FM, Hindler JA. In vitro susceptibility testing of
fluoroquinolone activity against Salmonella: recent changes to CLSI standards. Clin
Infect Dis 2012; 55:1107.
16. EUCAST. Clinical breakpoints - breakpoints and guidance. https://www.eucast.org/clinica

l_breakpoints/ (Accessed on November 02, 2020).
17. CLSI. M100 online. http://em100.edaptivedocs.net/dashboard.aspx (Accessed on Novem

ber 02, 2020).
18. Al-Emran HM, Eibach D, Krumkamp R, et al. A Multicountry Molecular Analysis of

Salmonella enterica Serovar Typhi With Reduced Susceptibility to Ciprofloxacin in Sub-
Saharan Africa. Clin Infect Dis 2016; 62 Suppl 1:S42.
19. International Typhoid Consortium, Wong VK, Holt KE, et al. Molecular Surveillance
Identifies Multiple Transmissions of Typhoid in West Africa. PLoS Negl Trop Dis 2016;
10:e0004781.
20. Pham Thanh D, Karkey A, Dongol S, et al. A novel ciprofloxacin-resistant subclade of H58
Salmonella Typhi is associated with fluoroquinolone treatment failure. Elife 2016;
5:e14003.
21. Parry CM, Threlfall EJ. Antimicrobial resistance in typhoidal and nontyphoidal
salmonellae. Curr Opin Infect Dis 2008; 21:531.
22. Karki S, Shakya P, Cheng AC, et al. Trends of etiology and drug resistance in enteric fever
in the last two decades in Nepal: a systematic review and meta-analysis. Clin Infect Dis
2013; 57:e167.

23. Harish BN, Madhulika U, Parija SC. Isolated high-level ciprofloxacin resistance in
Salmonella enterica subsp. enterica serotype Paratyphi A. J Med Microbiol 2004; 53:819.
24. Renuka K, Sood S, Das BK, Kapil A. High-level ciprofloxacin resistance in Salmonella
enterica serotype Typhi in India. J Med Microbiol 2005; 54:999.
25. Mohanty S, Gaind R, Paglietti B, et al. Bacteraemia with pleural effusions complicating
typhoid fever caused by high-level ciprofloxacin-resistant Salmonella enterica serotype
Typhi. Ann Trop Paediatr 2010; 30:233.
26. Bayramoglu G, Ozgumus OB, Kolayli F, et al. [Molecular epidemiology, antimicrobial

resistance and characterization of extended-spectrum beta-lactamases of Salmonella
enterica serotype Paratyphi B clinical isolates]. Mikrobiyol Bul 2014; 48:191.
27. González-López JJ, Piedra-Carrasco N, Salvador F, et al. ESBL-producing Salmonella
enterica serovar Typhi in traveler returning from Guatemala to Spain. Emerg Infect Dis
2014; 20:1918.
28. Pokharel BM, Koirala J, Dahal RK, et al. Multidrug-resistant and extended-spectrum beta-
lactamase (ESBL)-producing Salmonella enterica (serotypes Typhi and Paratyphi A) from
blood isolates in Nepal: surveillance of resistance and a search for newer alternatives.
Int J Infect Dis 2006; 10:434.
29. 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 2015; 59:2756.
30. Molloy A, Nair S, Cooke FJ, et al. First report of Salmonella enterica serotype paratyphi A
azithromycin resistance leading to treatment failure. J Clin Microbiol 2010; 48:4655.
31. Iqbal J, Dehraj IF, Carey ME, et al. A Race against Time: Reduced Azithromycin
Susceptibility in Salmonella enterica Serovar Typhi in Pakistan. mSphere 2020; 5.
32. Carey ME, Jain R, Yousuf M, et al. Spontaneous Emergence of Azithromycin Resistance in
Independent Lineages of Salmonella Typhi in Northern India. Clin Infect Dis 2021;
72:e120.
33. Sajib MSI, Tanmoy AM, Hooda Y, et al. Tracking the Emergence of Azithromycin
Resistance in Multiple Genotypes of Typhoidal Salmonella. mBio 2021; 12.
34. Hooda Y, Sajib MSI, Rahman H, et al. Molecular mechanism of azithromycin resistance
among typhoidal Salmonella strains in Bangladesh identified through passive pediatric
surveillance. PLoS Negl Trop Dis 2019; 13:e0007868.
35. 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 2018; 9.
36. Qamar FN, Yousafzai MT, Khalid M, et al. Outbreak investigation of ceftriaxone-resistant
Salmonella enterica serotype Typhi and its risk factors among the general population in
Hyderabad, Pakistan: a matched case-control study. Lancet Infect Dis 2018; 18:1368.
37. Extensively Drug-Resistant Typhoid Fever in Pakistan https://wwwnc.cdc.gov/travel/notic

es/alert/xdr-typhoid-fever-pakistan (Accessed on July 16, 2018).
38. Chatham-Stephens K, Medalla F, Hughes M, et al. Emergence of Extensively Drug-
Resistant Salmonella Typhi Infections Among Travelers to or from Pakistan - United
States, 2016-2018. MMWR Morb Mortal Wkly Rep 2019; 68:11.
39. World Health Organization, Regional Office for Eastern Mediterranean, Cairo, Egypt. We
ekly Epidemiological Monitor, December 2018. http://applications.emro.who.int/docs/ep
i/2018/Epi_Monitor_2018_11_52.pdf?ua=1 (Accessed on January 10, 2019).
40. François Watkins LK, Winstead A, Appiah GD, et al. Update on Extensively Drug-Resistant
Salmonella Serotype Typhi Infections Among Travelers to or from Pakistan and Report
of Ceftriaxone-Resistant Salmonella Serotype Typhi Infections Among Travelers to Iraq -
United States, 2018-2019. MMWR Morb Mortal Wkly Rep 2020; 69:618.
41. Centers for Disease Control and Prevention. Health Alert Network: Extensively Drug-Resi
stant Salmonella Typhi Infections Among U.S. Residents Without International Travel. ht
tps://emergency.cdc.gov/han/2021/han00439.asp (Accessed on February 23, 2021).
42. Wain J, Hoa NT, Chinh NT, et al. Quinolone-resistant Salmonella typhi in Viet Nam:
molecular basis of resistance and clinical response to treatment. Clin Infect Dis 1997;
25:1404.
43. Limson BM. Short course quinolone therapy of typhoid fever in developing countries.
Drugs 1995; 49 Suppl 2:136.
44. Thaver D, Zaidi AK, Critchley J, et al. Fluoroquinolones for treating typhoid and
paratyphoid fever (enteric fever). Cochrane Database Syst Rev 2005; :CD004530.
45. Girgis NI, Sultan Y, Hammad O, Farid Z. Comparison of the efficacy, safety and cost of
cefixime, ceftriaxone and aztreonam in the treatment of multidrug-resistant Salmonella
typhi septicemia in children. Pediatr Infect Dis J 1995; 14:603.
46. Gotuzzo E, Echevarría J, Carrillo C, et al. Randomized comparison of aztreonam and
chloramphenicol in treatment of typhoid fever. Antimicrob Agents Chemother 1994;
38:558.
47. Burkhardt JE, Walterspiel JN, Schaad UB. Quinolone arthropathy in animals versus
children. Clin Infect Dis 1997; 25:1196.
48. Schaad U. Toxicity of quinolones in paediatric patients. Adv Antimicrob Antineoplast

Chemother 1992; 11:259.
49. Jackson MA, Schutze GE, COMMITTEE ON INFECTIOUS DISEASES. The Use of Systemic
and Topical Fluoroquinolones. Pediatrics 2016; 138.

50. American Academy of Pediatrics. Antimicrobial agents and related therapy. In: Red Boo
k: 2018-2021 Report of the Committee on Infectious Diseases, 31st ed, Kimberlin DW, Br
ady MT, Jackson MA, Long SS (Eds), American Academy of Pediatrics, Itasca, IL 2018. p.9
03.
51. Asna SM, Haq JA, Rahman MM. Nalidixic acid-resistant Salmonella enterica serovar Typhi
with decreased susceptibility to ciprofloxacin caused treatment failure: a report from
Bangladesh. Jpn J Infect Dis 2003; 56:32.
52. Slinger R, Desjardins M, McCarthy AE, et al. Suboptimal clinical response to ciprofloxacin
in patients with enteric fever due to Salmonella spp. with reduced fluoroquinolone
susceptibility: a case series. BMC Infect Dis 2004; 4:36.
53. Kadhiravan T, Wig N, Kapil A, et al. Clinical outcomes in typhoid fever: adverse impact of
infection with nalidixic acid-resistant Salmonella typhi. BMC Infect Dis 2005; 5:37.
54. 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 2016; 16:535.
55. Thompsom 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 2,092
participants enrolled into four randomised controlled trials in Nepal. Clin Infect Dis
2017.
56. Crump JA, Mintz ED. Global trends in typhoid and paratyphoid Fever. Clin Infect Dis
2010; 50:241.
57. Parry CM, Thuy CT, Dongol S, et al. Suitable disk antimicrobial susceptibility breakpoints
defining Salmonella enterica serovar Typhi isolates with reduced susceptibility to
fluoroquinolones. Antimicrob Agents Chemother 2010; 54:5201.
58. Meltzer E, Stienlauf S, Leshem E, et al. A large outbreak of Salmonella Paratyphi A

infection among israeli travelers to Nepal. Clin Infect Dis 2014; 58:359.
59. Smith MD, Duong NM, Hoa NT, et al. Comparison of ofloxacin and ceftriaxone for short-
course treatment of enteric fever. Antimicrob Agents Chemother 1994; 38:1716.
60. 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 1999; 18:245.
61. Parry CM. The treatment of multidrug-resistant and nalidixic acid-resistant typhoid fever
in Viet Nam. Trans R Soc Trop Med Hyg 2004; 98:413.
62. Effa EE, Bukirwa H. Azithromycin for treating uncomplicated typhoid and paratyphoid
fever (enteric fever). Cochrane Database Syst Rev 2008; :CD006083.
63. Parry CM, Ho VA, Phuong le T, 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 2007;
51:819.
64. Frenck RW Jr, Nakhla I, Sultan Y, et al. Azithromycin versus ceftriaxone for the treatment
of uncomplicated typhoid fever in children. Clin Infect Dis 2000; 31:1134.
65. Bhutta ZA, Khan IA, Shadmani M. Failure of short-course ceftriaxone chemotherapy for
multidrug-resistant typhoid fever in children: a randomized controlled trial in Pakistan.
Antimicrob Agents Chemother 2000; 44:450.
66. Bhutta ZA, Khan IA, Molla AM. Therapy of multidrug-resistant typhoid fever with oral
cefixime vs. intravenous ceftriaxone. Pediatr Infect Dis J 1994; 13:990.
67. Bhutta ZA. Therapeutic aspects of typhoidal salmonellosis in childhood: the Karachi
experience. Ann Trop Paediatr 1996; 16:299.
68. Begum B, Haque MA, Ahmed MS, et al. Comparison between azithromycin and cefixime
in the treatment of typhoid fever in children. Mymensingh Med J 2014; 23:441.
69. 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 2007; 2:e542.
70. Arjyal A, Basnyat B, Koirala S, et al. Gatifloxacin versus chloramphenicol for
uncomplicated enteric fever: an open-label, randomised, controlled trial. Lancet Infect
Dis 2011; 11:445.
71. Dolecek C, Tran TP, 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 2008; 3:e2188.
72. 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 2013; 7:e2523.
73. Hoffman SL, Punjabi NH, Kumala S, et al. Reduction of mortality in chloramphenicol-
treated severe typhoid fever by high-dose dexamethasone. N Engl J Med 1984; 310:82.
74. Chisti MJ, Bardhan PK, Huq S, et al. High-dose intravenous dexamethasone in the
management of diarrheal patients with enteric fever and encephalopathy. Southeast
Asian J Trop Med Public Health 2009; 40:1065.
75. Punjabi NH, Hoffman SL, Edman DC, et al. Treatment of severe typhoid fever in children
with high dose dexamethasone. Pediatr Infect Dis J 1988; 7:598.
76. Ameh EA, Dogo PM, Attah MM, Nmadu PT. Comparison of three operations for typhoid
perforation. Br J Surg 1997; 84:558.
77. Nasir AA, Abdur-Rahman LO, Adeniran JO. Predictor of mortality in children with typhoid
intestinal perforation in a Tertiary Hospital in Nigeria. Pediatr Surg Int 2011; 27:1317.

78. Saxe JM, Cropsey R. Is operative management effective in treatment of perforated

typhoid? Am J Surg 2005; 189:342.
79. Kouame J, Kouadio L, Turquin HT. Typhoid ileal perforation: surgical experience of 64
cases. Acta Chir Belg 2004; 104:445.
80. Ugwu BT, Yiltok SJ, Kidmas AT, Opaluwa AS. Typhoid intestinal perforation in north
central Nigeria. West Afr J Med 2005; 24:1.
81. Levine MM, Black RE, Lanata C. Precise estimation of the numbers of chronic carriers of
Salmonella typhi in Santiago, Chile, an endemic area. J Infect Dis 1982; 146:724.
82. Hofmann E, Chianale J, Rollán A, et al. Blood group antigen secretion and gallstone
disease in the Salmonella typhi chronic carrier state. J Infect Dis 1993; 167:993.
83. Nagaraja V, Eslick GD. Systematic review with meta-analysis: the relationship between
chronic Salmonella typhi carrier status and gall-bladder cancer. Aliment Pharmacol Ther
2014; 39:745.
84. Gotuzzo E, Guerra JG, Benavente L, et al. Use of norfloxacin to treat chronic typhoid
carriers. J Infect Dis 1988; 157:1221.
85. Zavala Trujillo I, Quiroz C, Gutierrez MA, et al. Fluoroquinolones in the treatment of
typhoid fever and the carrier state. Eur J Clin Microbiol Infect Dis 1991; 10:334.
86. Simon HJ, Miller RC. Ampicillin in the treatment of chronic typhoid carriers. Report on
fifteen treated cases and a review of the literature. N Engl J Med 1966; 274:807.
87. Farid Z, Bassily S, Mikhail IA, et al. Treatment of chronic enteric fever with amoxicillin. J
Infect Dis 1975; 132:698.
88. Nolan CM, White PC Jr. Treatment of typhoid carriers with amoxicillin. Correlates of
successful therapy. JAMA 1978; 239:2352.
89. Iwarson S. Long-term co- trimoxazole treatment of chronic Salmonella carriers. Scand J
Infect Dis 1977; 9:297.
90. Freerksen E, Rosenfeld M, Freerksen R, Krüger-Thiemer M. Treatment of chronic
salmonella carriers. Study with 40 cases of S. typhi, 19 cases of S. paratyphi b and 28
cases of S. enteritidis strains. Chemotherapy 1977; 23:192.
91. STUART BM, PULLEN RL. Typhoid; clinical analysis of 360 cases. Arch Intern Med (Chic)
1946; 78:629.
92. WOODWARD TE, SMADEL JE. Preliminary report on the beneficial effect of chloromycetin
in the treatment of typhoid fever. Ann Intern Med 1948; 29:131.
93. Pieters Z, Saad NJ, Antillón M, et al. Case Fatality Rate of Enteric Fever in Endemic
Countries: A Systematic Review and Meta-analysis. Clin Infect Dis 2018; 67:628.
94. Qamar FN, Yousafzai MT, Sultana S, et al. A Retrospective Study of Laboratory-Based
Enteric Fever Surveillance, Pakistan, 2012-2014. J Infect Dis 2018; 218:S201.
95. Crump JA, Ram PK, Gupta SK, et al. Part I. Analysis of data gaps pertaining to Salmonella
enterica serotype Typhi infections in low and medium human development index
countries, 1984-2005. Epidemiol Infect 2008; 136:436.
96. World Health Organization. Typhoid vaccines: WHO position paper. March 2018. http://a
pps.who.int/iris/bitstream/handle/10665/272272/WER9313.pdf (Accessed on April 04, 20
18).
97. Jackson BR, Iqbal S, Mahon B, Centers for Disease Control and Prevention (CDC).
Updated recommendations for the use of typhoid vaccine--Advisory Committee on
Immunization Practices, United States, 2015. MMWR Morb Mortal Wkly Rep 2015;
64:305.
98. House D, Ho VA, Diep TS, et al. Antibodies to the Vi capsule of Salmonella Typhi in the
serum of typhoid patients and healthy control subjects from a typhoid endemic region. J
Infect Dev Ctries 2008; 2:308.
99. Syed KA, Saluja T, Cho H, et al. Review on the Recent Advances on Typhoid Vaccine
Development and Challenges Ahead. Clin Infect Dis 2020; 71:S141.
100. Shakya M, Colin-Jones R, Theiss-Nyland K, et al. Phase 3 Efficacy Analysis of a Typhoid
Conjugate Vaccine Trial in Nepal. N Engl J Med 2019; 381:2209.
101. Patel PD, Patel P, Liang Y, et al. Safety and Efficacy of a Typhoid Conjugate Vaccine in
Malawian Children. N Engl J Med 2021; 385:1104.
102. Qadri F, Khanam F, Liu X, et al. Protection by vaccination of children against typhoid
fever with a Vi-tetanus toxoid conjugate vaccine in urban Bangladesh: a cluster-
randomised trial. Lancet 2021; 398:675.
103. Yousafzai MT, Karim S, Qureshi S, et al. Effectiveness of typhoid conjugate vaccine
against culture-confirmed Salmonella enterica serotype Typhi in an extensively drug-
resistant outbreak setting of Hyderabad, Pakistan: a cohort study. Lancet Glob Health
2021; 9:e1154.
104. Jin C, Gibani MM, Moore M, et al. Efficacy and immunogenicity of a Vi-tetanus toxoid
conjugate vaccine in the prevention of typhoid fever using a controlled human infection
model of Salmonella Typhi: a randomised controlled, phase 2b trial. Lancet 2017;
390:2472.
105. Mohan VK, Varanasi V, Singh A, et al. Safety and immunogenicity of a Vi polysaccharide-
tetanus toxoid conjugate vaccine (Typbar-TCV) in healthy infants, children, and adults in
typhoid endemic areas: a multicenter, 2-cohort, open-label, double-blind, randomized
controlled phase 3 study. Clin Infect Dis 2015; 61:393.
106. Voysey M, Pollard AJ. Seroefficacy of Vi Polysaccharide-Tetanus Toxoid Typhoid

Conjugate Vaccine (Typbar TCV). Clin Infect Dis 2018; 67:18.

107. Milligan R, Paul M, Richardson M, Neuberger A. Vaccines for preventing typhoid fever.
Cochrane Database Syst Rev 2018; 5:CD001261.
108. Levine MM, Ferreccio C, Black RE, et al. Ty21a live oral typhoid vaccine and prevention of
paratyphoid fever caused by Salmonella enterica Serovar Paratyphi B. Clin Infect Dis
2007; 45 Suppl 1:S24.
Topic 2712 Version 44.0

GRAPHICS
Antibiotic options and doses for treatment of typhoid fever
Adults Children Duration

Ciprofloxacin Oral: 500 mg twice Oral: 30 mg/kg per day 7 to 10 days
daily in two divided doses
(maximum 1000 mg
per day)*
IV: 400 mg twice daily IV: 20 mg/kg per day in

two divided doses
(maximum 800 mg per
day)*
Ofloxacin¶ 400 mg orally or IV 15 to 30 mg/kg per day 7 to 10 days

twice daily orally in two divided
doses (maximum 800
mg per day)*¶ based
upon limited
experience; optimal
pediatric dose is not
known
Ceftriaxone 2 g IV once or twice 50 to 100 mg/kg IV in 10 to 14 days

daily one or two divided
doses (maximum 4 g
per day)
Cefotaxime 1 to 2 g IV every six or 150 to 200 mg/kg IV 10 to 14 days

eight hours per day in three to four
divided doses
(maximum 8 g per day)
Cefixime 200 mg orally twice 20 mg/kg orally in two 10 to 14 days

daily divided doses
(maximum 400 mg per
day)
Azithromycin 1 g orally once then 10 to 20 mg/kg orally 5 to 7 days

500 mg orally daily OR once per day
1 g orally once daily (maximum 1000 mg
per day)
MeropenemΔ 1 to 2 g IV every eight 20 to 40 mg/kg every 10 to 14 days

hours eight hours (maximum
6000 mg per day)
Agents of limited usefulness due to the high prevalence of multidrug resistance
Chloramphenicol◊ Oral: 500 to 750 mg 50 to 100 mg/kg per 14 to 21 days

four times per day day orally or IV in four

IV: 50 to 100 mg/kg per divided doses

day in four divided (maximum 3 g per day)
doses (maximum 3 g
per day)
Amoxicillin 1 g orally three times 100 mg/kg per day 10 to 14 days

daily orally in three divided
doses (maximum 3 g
per day)
TMP-SMX 1 double-strength 8 mg/kg TMP and 40 10 to 14 days

tablet (160/800 mg) mg/kg SMX orally in
orally twice daily two or four divided
doses (maximum 320
mg TMP/1600 mg SMX
per day)
Antibiotic selection depends upon the severity of illness, local resistance patterns, whether oral
medications are feasible, the clinical setting, and available resources. Refer to the topic on treatment
of typhoid fever for detailed discussion. The doses listed above are intended for patients with normal
renal function; the doses of some of these agents must be adjusted in patients with renal
insufficiency.
IV: intravenous; TMP-SMX: trimethoprim-sulfamethoxazole (co-trimoxazole).
* Although fluoroquinolones are not routinely used as first-line therapy for children <18 years old,
their use in children is justified in severe infections, such as typhoid fever, when alternatives are not
appropriate or available.
¶ IV ofloxacin formulation is not available in North America but may be available elsewhere.
Δ Carbapenems should be reserved for patients who have severe or complicated infection with a
suspected extensively drug-resistant strain. These include patients with infection acquired in Pakistan.
Imipenem and ertapenem are other carbapenems that can be used instead of meropenem. The
optimal doses of carbapenems for typhoid fever have not been established.
◊ Chloramphenicol use is restricted in many countries due to a low risk of fatal aplastic anemia. Oral
chloramphenicol formulation is not available in North America but may be available elsewhere.
References:
1. Bhutta ZA. Current concepts in the diagnosis and treatment of typhoid fever. BMJ 2006; 333:78.
2. Harris JB and Brooks WA. Typhoid and paratyphoid fever. In: Hunter's Tropical Medicine and Emerging Infectious
Disease, 9th edition, Magill AJ, Ryan ET, Hill DR, and Solomon T (Eds), Saunders Elsevier, 2013.
3. Levine M, Tapia MD, and Zaidi AKM. Typhoid and paratyphoid (enteric) fever. In: Tropical Infectious Diseases: Principles,
Pathogens and Practice, 3rd edition, Guerrant RL, Walker DH, and Weller PF (Eds), Saunders Elsevier, 2011.
4. World Health Organization Department of Vaccines and Biologicals. Background document: the diagnosis, prevention
and treatment of typhoid fever. Geneva, 2003; 1:19.
Graphic 109995 Version 4.0

Contributor Disclosures
Edward T Ryan, MD, DTMH Grant/Research/Clinical Trial Support: Sanofi [Yellow fever]. All of the
relevant financial relationships listed have been mitigated. Jason Andrews,
MD Grant/Research/Clinical Trial Support: NIH; Bill and Melinda Gates Foundation. All of the relevant
financial relationships listed have been mitigated. Jacob John, MD No relevant financial relationship(s)
with ineligible companies to disclose. Stephen B Calderwood, MD Consultant/Advisory Boards: Day
Zero Diagnostics [Whole genome sequencing for microbial identification and determination of
antimicrobial susceptibility]. All of the relevant financial relationships listed have been mitigated. Elinor
L Baron, MD, DTMH No relevant financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

Treatment and Prevention of Enteric (Typhoid and Paratyphoid) Fever - UpToDate

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Treatment and Prevention of Enteric (Typhoid and Paratyphoid) Fever - UpToDate

Uploaded by

Copyright:

Available Formats

2/12/21 11:35 Treatment and prevention of enteric (typhoid and paratyphoid) fever - UpToDate

Official reprint from UpToDate®

Treatment and prevention of enteric (typhoid and

Multidrug resistance — Multidrug-resistant (MDR) strains (ie, those resistant to ampicillin,

https://www.uptodate.com/contents/treatment-and-prevention-of-enteric-typhoid-and-paratyphoid-fever/print?search=fiebre tifoidea&source=sear… 1/27

Fluoroquinolone nonsusceptibility — Historically, resistance to the early generation

multi-country study in Africa, fluoroquinolone nonsusceptibility was only documented in one

Resistance to other agents — Most S. Typhi and S. Paratyphi isolates remain susceptible to

In particular, resistance to ceftriaxone is increasing, with reports of patients with extended-

Extensively drug-resistant typhoid — A large outbreak of typhoid fever caused by a strain

Empiric therapy — When treating presumptively for enteric fever or before results of

● Infection acquired in Pakistan or Iraq – For patients with severe or complicated

Uncomplicated disease — Patients with uncomplicated disease have no evidence of

● Fluoroquinolones (ciprofloxacin or ofloxacin) are the drugs of choice for empiric

https://www.uptodate.com/contents/treatment-and-prevention-of-enteric-typhoid-and-paratyphoid-fever/print?search=fiebre tifoidea&source=sear… 5/27

azithromycin-resistant S. Typhi have been reported from South Asia, particularly

Infection with an isolate with reduced susceptibility to fluoroquinolones is associated with

Directed therapy — Ideally, definitive antimicrobial therapy for enteric fever should be

There are no trials demonstrating that combination antimicrobial therapy is superior to

Fluoroquinolone-susceptible infection — Fluoroquinolones are considered by many

Fluoroquinolone-nonsusceptible infection — Fluoroquinolone nonsusceptible infections

When fluoroquinolones cannot be used, we typically use azithromycin. If azithromycin

● Cephalosporins – Third-generation cephalosporins also have demonstrated efficacy

Among the third-generation cephalosporins, ceftriaxone may be superior to cefotaxime

https://www.uptodate.com/contents/treatment-and-prevention-of-enteric-typhoid-and-paratyphoid-fever/print?search=fiebre tifoidea&source=sear… 8/27

OTHER TREATMENT CONSIDERATIONS

Adjunctive corticosteroids for severe infection — For patients with suspected or known

In a randomized, prospective, double-blind study performed in Indonesia in the early 1980s

Ileal perforation — For patients with ileal perforation, prompt surgical intervention is

Successful treatment in uncomplicated cases usually results in clinical improvement within

https://www.uptodate.com/contents/treatment-and-prevention-of-enteric-typhoid-and-paratyphoid-fever/print?search=fiebre tifoidea&source=sear… 9/27

Relapse — Relapse of enteric fever after clinical cure can occur in immunocompetent

Relapsed infection should be treated with an additional course of antibiotics, guided by

Chronic carriage — Chronic carriage of Salmonellae is defined as excretion of the organism

The optimal approach to eradication is uncertain. Fluoroquinolone therapy (eg, ciprofloxacin

https://www.uptodate.com/contents/treatment-and-prevention-of-enteric-typhoid-and-paratyphoid-fever/print?search=fiebre tifoidea&source=se… 10/27

The optimal approach to eradication of fluoroquinolone-nonsusceptible typhoidal Salmonella

In endemic areas — The World Health Organization (WHO) recommends implementation

more durable immunogenicity compared with other vaccines [96]. It recommends

In nonendemic areas — Typhoid vaccination is indicated in travelers to endemic areas and

● Vi-TT typhoid conjugate vaccine (TCV) – These vaccines consist of the Vi

https://www.uptodate.com/contents/treatment-and-prevention-of-enteric-typhoid-and-paratyphoid-fever/print?search=fiebre tifoidea&source=se… 12/27

efficacy of Typbar-TCV against culture-confirmed typhoid fever ranged from 81 to 85

Conjugate vaccines appear to be more immunogenic and better at inducing long-term

● Vi polysaccharide vaccine – This consists of the Vi polysaccharide antigen. It is

In a systematic review and meta-analysis of randomized controlled trials, efficacy at

In a systematic review and meta-analysis of randomized controlled trials, efficacy at

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

● Treatment of enteric fever has been complicated by the development of antimicrobial

• Patients with severe disease (systemic toxicity, depressed consciousness, prolonged

https://www.uptodate.com/contents/treatment-and-prevention-of-enteric-typhoid-and-paratyphoid-fever/print?search=fiebre tifoidea&source=se… 14/27

acquired in Pakistan or Iraq, we suggest empiric therapy with a carbapenem (eg,

● Treatment of ileal perforation warrants surgical therapy in addition to antibiotic therapy

● Successful treatment in uncomplicated cases usually results in clinical improvement

https://www.uptodate.com/contents/treatment-and-prevention-of-enteric-typhoid-and-paratyphoid-fever/print?search=fiebre tifoidea&source=se… 15/27

In endemic areas, the World Health Organization (WHO) recommends implementation

Use of UpToDate is subject to the Subscription and License Agreement.

5. Hendriksen RS, Leekitcharoenphon P, Lukjancenko O, et al. Genomic signature of

https://www.uptodate.com/contents/treatment-and-prevention-of-enteric-typhoid-and-paratyphoid-fever/print?search=fiebre tifoidea&source=se… 16/27

16. EUCAST. Clinical breakpoints - breakpoints and guidance. https://www.eucast.org/clinica

17. CLSI. M100 online. http://em100.edaptivedocs.net/dashboard.aspx (Accessed on Novem

18. Al-Emran HM, Eibach D, Krumkamp R, et al. A Multicountry Molecular Analysis of