ORIGINAL CONTRIBUTION
Typhoid Fever in the United States,
1999-2006
Michael F. Lynch, MD, MPH
Elizabeth M. Blanton, MPH
Sandra Bulens, MPH
Christina Polyak, MD, MPH
Jazmin Vojdani, MPH
Jennifer Stevenson, MPH, PhD
Felicia Medalla, MD
Ezra Barzilay, MD
Kevin Joyce, BS
Timothy Barrett, PhD
Eric Daniel Mintz, MD, MPH
I
NFECTIONWITH SALMONELLASER TYPHI
causes an estimated 20 million cases
of typhoid fever and 200 000 deaths
annually worldwide.1 In the United
States, typhoid fever is now a rare disease,
with approximately 300 clinical cases re-
ported per year.2 Dramatic declines in in-
cidence of and mortality due to typhoid
fever were observed in the United States
after widespread implementation of mu-
nicipal water and sewage treatment sys-
tems in the first half of the 20th century.3
In recent years, the majority of cases in
the United States have been associated
with foreign travel.4-7
Although the risk of typhoid fever may
be reduced with attention to water qual-
ity, food hygiene, and vaccination, effec-
tive treatment of S Typhi infection is
needed when these measures fail. Over
the last 20 years, emergence of S Typhi
strains resistant to antimicrobial agents
has complicated treatment of infected
patients.8 Resistance to antimicrobial
agents has been documented from many
high-incidence areas and among iso-
See also p 898 and Patient Page.
©2009 American Medical Association. All rights reserved.
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Context Typhoid fever in the United States has increasingly been due to infection
with antimicrobial-resistant Salmonella ser Typhi. National surveillance for typhoid fe-
ver can inform prevention and treatment recommendations.
Objective To assess trends in infections with antimicrobial-resistant S Typhi.
Design Cross-sectional, laboratory-based surveillance study.
Setting and Participants We reviewed data from 1999-2006 for 1902 persons
with typhoid fever who had epidemiologic information submitted to the Centers for
Disease Control and Prevention (CDC) and 2016 S Typhi isolates sent by participating
public health laboratories to the National Antimicrobial Resistance Monitoring System
Laboratory at the CDC for antimicrobial susceptibility testing.
Main Outcome Measures Proportion of S Typhi isolates demonstrating resistance
to 14 antimicrobial agents and patient risk factors for antimicrobial-resistant infections.
Results Patient median age was 22 years (range, ⬍1-90 years); 1295 (73%) were
hospitalized and 3 (0.2%) died. Foreign travel within 30 days of illness was reported
by 1439 (79%). Only 58 travelers (5%) had received typhoid vaccine. Two hundred
seventy-two (13%) of 2016 isolates tested were resistant to ampicillin, chlorampheni-
col, and trimethoprim-sulfamethoxazole (multidrug-resistant S Typhi [MDRST]); 758
(38%) were resistant to nalidixic acid (nalidixic acid–resistant S Typhi [NARST]) and
734 NARST isolates (97%) had decreased susceptibility to ciprofloxacin. The propor-
tion of NARST increased from 19% in 1999 to 54% in 2006. Five ciprofloxacin-
resistant isolates were identified. Patients with resistant infections were more likely to
report travel to the Indian subcontinent: 85% of patients infected with MDRST and
94% with NARST traveled to the Indian subcontinent, while 44% of those with sus-
ceptible infections did (MDRST odds ratio, 7.5; 95% confidence interval, 4.1-13.8;
NARST odds ratio, 20.4; 95% confidence interval, 12.4-33.9).
Conclusion Infection with antimicrobial-resistant S Typhi strains among US pa-
tients with typhoid fever is associated with travel to the Indian subcontinent, and an
increasing proportion of these infections are due to S Typhi strains with decreased sus-
ceptibility to fluoroquinolones.
JAMA. 2009;302(8):859-865 www.jama.com
lates from patients diagnosed and treated 1997.6 In addition, identification of nali-
in the United States. Multidrug- dixic acid–resistant S Typhi (NARST)
resistant strains of S Typhi [MDRST] that and reports of infection with S Typhi
exhibit resistance to the commonly used
Author Affiliations: Enteric Diseases Epidemiology
first-line antimicrobial agents ampicil- Branch (Drs Lynch, Polyak, Stevenson, Medalla, Bar-
lin, chloramphenicol, and trimethoprim- zilay, and Mintz and Mss Blanton, Bulens, and Voj-
sulfamethoxazole emerged during the dani), Enteric Diseases Laboratory Branch (Mr Joyce
and Dr Barrett), Division of Foodborne, Bacterial and
1980s, predominantly from South Asia Mycotic Diseases, and Office of the Chief Science Offi-
and travelers returning from that cer (Dr Barrett), National Center for Zoonotic Vector-
borne and Enteric Diseases, Centers for Disease Con-
region.9,10 Recent estimates of the pro- trol and Prevention, Atlanta, Georgia.
portion of multidrug-resistant infec- Corresponding Author: Michael F. Lynch, MD, MPH,
Centers for Disease Control and Prevention, 4770 Bu-
tions among US patients range from 12% ford Hwy, MS F-22, Atlanta, GA 30341 (mlynch1
during 1985-19945 to 17% during 1996- @cdc.gov).
(Reprinted) JAMA, August 26, 2009—Vol 302, No. 8 859
 TYPHOID FEVER IN THE UNITED STATES
Table 1. Number of Typhoid Fever Surveillance Reports, Number of Salmonella ser Typhi NARMS Isolates, and Matched Report-Isolate Pairs
by NARMS Participating States, United States, 1999-2006
NARMS Participating States
No. of Surveillance No. of NARMS
Year Reports Isolates
1999 153 167
2000 212 177
2001 189 197
2002 179 195
2003 279 334
2004 239 304
2005 203 318
2006 314 324
Total 1768 2016
Abbreviation: NARMS, National Antimicrobial Resistance Monitoring System for Enteric Bacteria.
strains resistant to ciprofloxacin from
typhoid-endemic areas have generated
concern that strains resistant to fluoro-
quinolones may become more preva-
lent.11 Rates of nalidixic acid resistance
are of particular concern. Although this
older antibacterial is rarely used for treat-
ment, resistance to nalidixic acid can be
a marker for decreased susceptibility to
fluoroquinolones.
Surveillance for typhoid fever cases
and resistance among S Typhi strains
isolated from patients diagnosed and
treated in the United States can be used
to inform treatment recommenda-
tions and provide guidance for US trav-
elers to typhoid-endemic countries.
Since most US patients acquire their in-
fections abroad, these cases also pro-
vide insight into global patterns of S
Typhi antimicrobial susceptibility.
Detailed epidemiologic information on
laboratory-confirmed cases of typhoid fe-
ver in the United States is collected from
state and local health departments
through the National Typhoid Fever Sur-
veillance System at the Centers for Dis-
ease Control and Prevention (CDC). Be-
fore 1999, information in typhoid fever
surveillance reports regarding antimi-
crobial susceptibility of S Typhi isolates
was limited by incomplete reporting and
nonuniform testing methods among
multiple reporting laboratories. In 1999,
national laboratory-based surveillance for
antimicrobial resistance of S Typhi iso-
lates was initiated through the National
Antimicrobial Resistance Monitoring
860 JAMA, August 26, 2009—Vol 302, No. 8 (Reprinted)
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No. of Surveillance
No. of Matched Pairs Reports in
(% of Reports) Non-NARMS States
63 (41) 32
125 (59) 45
127 (67) 36
98 (55) 21
200 (72)
164 (69)
132 (65)
222 (71)
1131 (64) 134
System for Enteric Bacteria (NARMS).
We linked ongoing national typhoid fe-
ver case surveillance and systematic labo-
ratory surveillance for antimicrobial re-
sistance of S Typhi isolates to assess
trends in risk factors and resistance pat-
terns among US typhoid fever cases from
1999 through 2006.
METHODS
Since 1975, the CDC has received sur-
veillance case reports from state and lo-
cal health officials on bacteriologically
confirmed cases of typhoid fever. A case
of typhoid fever is defined as an acute ill-
ness compatible with typhoid fever and
S Typhi isolated from a sterile site, stool
specimen, or urine culture. Patient demo-
graphic and clinical information, ty-
phoid vaccination, and travel history are
collected by state and local health de-
partment officials using a standard form
(CDC form 52.5). Travel-associated ty-
phoid fever is defined as a case of ty-
phoid fever meeting the national sur-
veillance case definition in a person who
traveled outside of the United States in
the 30 days before illness. Countries vis-
ited by travelers were categorized by con-
tinental and subcontinental regions ac-
cording to United Nations criteria.
Domestically acquired typhoid fever was
defined as typhoid fever meeting the na-
tional surveillance case definition in per-
sons who had not traveled outside the
United States in the 30 days before on-
set of symptoms. We reviewed reports
of outbreaks of typhoid fever from the
©2009 American Medical Association. All rights reserved.
Total, United States
No. of Surveillance % of Matched
Reports Pairs/Reports
185 34
257 49
225 56
200 49
279 72
239 69
203 65
314 71
1902 59
CDC Foodborne Outbreak Reporting
System for 1999-2006.
Information on the number of US
residents traveling abroad and nonresi-
dent foreign visitors traveling to the
United States for 1999-2006 was ob-
tained from Tourism Industries, Inter-
national Trade Administration, US De-
partment of Commerce (http://tinet.ita
.doc.gov/about/index.html) and used to
estimate rates of typhoid fever among
travelers to specific regions and coun-
tries. The rate of travel-associated ty-
phoid fever was calculated using the
number of nonimmigrant travel-
associated cases each year divided by
the total number of US resident trav-
elers and foreign visitors.
The NARMS laboratory at the CDC
receives isolates from state and local pub-
lic health laboratories for antimicrobial
susceptibility testing. NARMS had 17
participating laboratories in states and
localities comprising 40% of the US
population during 1999-2001, 28 labo-
ratories in 2002, and beginning in 2003,
NARMS was nationwide in 54 labora-
tories. Since 1999, NARMS has re-
ceived all S Typhi isolates from partici-
pating laboratories for antimicrobial
susceptibility testing. During 1999-
2006, S Typhi isolates were tested in
the NARMS laboratory by broth micro-
dilution for susceptibility to at least 14
antimicrobial agents: amikacin, ampi-
cillin, amoxicillin–clavulanic acid, ceft-
iofur, ceftriaxone, chloramphenicol,
ciprofloxacin, gentamicin, kanamycin,

nalidixic acid, streptomycin, sulfa-
methoxazole/sulfisoxazole, tetracy-
cline, and trimethoprim-sulfamethoxa-
zole. (Additionally, isolates were tested
to cephalothin during 1999-2003 and to
cefoxitin during 2000-2006.) Clinical
and Laboratory Standards Institute mini-
mum inhibitory concentration (MIC) in-
terpretive standards for Enterobacteria-
ceae were used for resistance thresholds
for susceptibility testing.12 Multidrug-
resistant S Typhi isolates were defined
as those resistant to ampicillin, chlor-
amphenicol, and trimethoprim-
sulfamethoxazole. Nalidixic acid resis-
tance was defined as an MIC of 32 µg/mL
or more and resistance to ciprofloxacin
was defined as 4 µg/mL or more. De-
creased susceptibility to ciprofloxacin
was defined as an MIC of 0.125 µg/mL
or more. Susceptible strains were sen-
sitive to ampicillin, chloramphenicol, tri-
methoprim-sulfamethoxazole, and na-
lidixic acid.
Data from surveillance case reports
on US typhoid cases and laboratory data
from NARMS were linked by compar-
ing available identifying information:
state public health laboratory identifi-
cation number (when available) or state,
year of diagnosis, first 3 letters of sur-
name, date of birth, age, and sex. We
reviewed the combined data to assess
risk factors for S Typhi infection and
antimicrobial resistance of S Typhi iso-
lates. Statistical analyses were con-
ducted using SAS software, version 9
(SAS Institute Inc, Cary, North Caro-
lina). We calculated odds ratios and
95% confidence intervals (CIs) for cat-
egorical variables and compared differ-
ences in medians using the Wilcoxon
2-sample test. Trends were assessed
using the Cochran-Armitage trend test.
P values were 2-tailed and considered
significant at P⬍.05.
RESULTS
For the years 1999-2006, 1902 surveil-
lance case reports were received at the
CDC and 2016 isolates were received
and tested by the NARMS laboratory
(TABLE 1). We identified 1131 cases
with epidemiologic information from
case reports and antimicrobial testing
©2009 American Medical Association. All rights reserved.
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TYPHOID FEVER IN THE UNITED STATES
information from the NARMS labora-
Table 2. Typhoid Fever Surveillance Case
tory. The proportion of typhoid fever Reports by State, United States, 1999-2006
surveillance reports received from (n = 1900)
NARMS participating states for which State No. of Cases (%)
an isolate was identified in the NARMS California 550 (29)
laboratory increased from 41% (95% CI, New York 279 (15)
New Jersey 133 (7)
34%-48%) in 1999 to 71% (95% CI, Texas 96 (5)
67%-75%) in 2005. Since 2003, when Virginia 78 (4)
Florida 73 (4)
NARMS received isolates from all 50 Massachusetts 71 (4)
states, more than 65% of surveillance Michigan 59 (3)
Connecticut 56 (3)
reports could be matched to a NARMS Georgia 55 (3)
isolate each year. Other states (n = 36) 450 (24)
National Typhoid Fever
Surveillance Table 3. Countries Visited by Typhoid Fever
Patients in the 30 Days Before Illness Onset,
During 1999-2006, surveillance re- 1999-2006 (n = 1277) a
ports were received from 46 states on Countries b No. of Travelers (%)
1902 typhoid fever cases. More than half India 606 (47)
of the cases were reported from Califor- Pakistan 126 (10)
Bangladesh 124 (10)
nia, New York, and New Jersey Mexico 90 (7)
(TABLE 2). The median age of typhoid Philippines 57 (4)
Guatemala 30 (2)
patients was 22 years, with a range of El Salvador 29 (2)
younger than 1 year to 90 years. Of 1685 Indonesia 28 (2)
Haiti 25 (2)
patients whose age was known, 64 (4%; Cambodia 18 (1)
95% CI, 3%-5%) were younger than 2 Nigeria 17 (1)
years, 205 (12%; 95% CI, 11%-14%) Other countries (n = 41) 127 (10)
a Among patients who visited a single country.
were 2 to 5 years old, and 423 (25%; 95% b Listed countries were reported by 13 or more patients.
CI, 23%-27%) were 6 to 17 years old.
Eight hundred seventy-four patients
(46%; 95% CI, 44%-48%) were female. cine within 5 years of their trip. Of the
Among 1765 patients with clinical in- 25 travelers who reported the type of vac-
formation, 1295 (73%; 95% CI, 71%- cine received, 5 had received the old par-
75%) were hospitalized for a median du- enteral typhoid vaccine (Wyeth-Ayerst,
ration of 6 days (range, 1-25 days). Three Collegeville, Pennsylvania), 13 had re-
patients died (case-fatality rate, 0.2%; ceived Typhim Vi (Sanofi Pasteur, Lyon,
95% CI, 0%-0.5%) Two of these pa- France),and7hadreceivedVivotif(Berna
tients were travelers who had arrived Biotech, Bern, Switzerland) oral typhoid
from India; 1 had immigrated from vaccines.
Mexico. Among 1277 travelers with typhoid fe-
Of 1830 typhoid cases with travel ver who reported visiting a single coun-
information, 1439 (79%; 95% CI, 77%- try, 78% (95% CI, 76%-80%) had trav-
81%) were travel-associated. The propor- eled to a country in Asia, while 17% (95%
tion of travel-associated cases increased CI, 15%-19%) had traveled to Mexico,
from 64% (95% CI, 62%-66%) in 1999 Central America, South America, or the
to85%(95%CI,83%-87%)in2006.Most Caribbean and 4% (95% CI, 3%-5%) had
travelers, 952 (66%; 95% CI, 64%-68%) traveled to Africa. Three countries on the
of 1439, reported that their reason for Indian subcontinent, India, Pakistan, and
travelwasvisitingfriendsandfamily;10% Bangladesh, were visited by 67% (95%
(95% CI, 8%-12%) were immigrants; 9% CI, 64%-70%) of patients with travel-
(95%CI,8%-11%)weretourists;3%(95% associated typhoid cases (TABLE 3).
CI, 2%-4%) traveled for business; and 6% The overall rate of travel-associated
(95% CI, 5%-7%) reported other reasons typhoid fever during 1999-2006 was 1.6
for travel. Only 58 (5%; 95% CI, 4%-7%) per 1 million travelers arriving in the
of 1094 travelers who reported vaccina- United States. The typhoid fever rate for
tion status had received any typhoid vac- travelers arriving from countries other
(Reprinted) JAMA, August 26, 2009—Vol 302, No. 8 861
 TYPHOID FEVER IN THE UNITED STATES
Figure 1. Proportion of Multidrug-Resistant
Salmonella ser Typhi (MDRST) and Nalidixic
Acid–Resistant S Typhi (NARST) Among
S Typhi Isolates Submitted to the National
Antimicrobial Resistance Monitoring System
(NARMS), by Year—1999-2006 (n=2016)
Salmonella ser Typhi Isolates, %
100
80
60
40
20
0
1999 2000 2001 2002 2003 2004 2005 2006
Isolates tested,
No. 167 177
Laboratories in NARMS,
No. 17 17 17
Figure 2. Proportion of Nalidixic
Acid–Resistant Salmonella ser Typhi (NARST)
Among S Typhi Isolates Submitted to the
National Antimicrobial Resistance Monitoring
System (NARMS), by NARMS Reporting
Cohort and Year—United States, 1999-2006
(n=2016)
100
80
NARST, %
60
40
20
0 5%) from other sterile sites.
1999 2000 2001 2002 2003 2004 2005 2006
Isolates tested, No.
1999 167 177
2002
2003
than Canada (from which no typhoid
patients had traveled) was 2.2 per 1 mil-
lion travelers. For travelers arriving
from Mexico, Central America, South
America, or the Caribbean, the ty-
phoid fever rate was 1.3 per 1 million;
for travelers arriving from Africa, the
rate was 7.6 per 1 million; and from
Asia, the rate was 10.5 per 1 million.
Among countries for which travel data
were available for the entire study pe-
riod, India had the highest rate, with
89 typhoid cases per 1 million travel-
ers. The rate for travel to India varied
from 55 per 1 million travelers in 1999
to 122 per 1 million in 2003.
862 JAMA, August 26, 2009—Vol 302, No. 8 (Reprinted)
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Among 391 domestically acquired
cases, 54 (17%; 95% CI, 14%-22%) of 313
cases for which information was reported
were traced to a typhoid carrier; 7 (13%;
95% CI, 4%-22%) of these carriers were
previously known to the reporting health
department. Seventy-five (22%; 95% CI,
NARST 18%-26%) of 346 domestically acquired
MDRST
cases for which information was reported
werepartoftyphoidoutbreaks.However,
only 3 outbreaks with a total of 13
laboratory-confirmedcaseswerereported
to the CDC Foodborne Outbreak Report-
ing System during this time: 1 outbreak
Year in Texas (6 confirmed cases) due to con-
197 195 334 304 318 324
taminated oysters harvested from the US
Gulf Coast13; 1 in Florida (3 cases) due
28 54 54 54 54 to beverages prepared from frozen im-
ported tropical fruit,14 and 1 in Maryland
(4 cases) associated with a restaurant.
NARMS Laboratory Testing
of S Typhi Isolates
During 1999-2006, the NARMS labo-
ratory received 2016 isolates for anti-
microbial susceptibility testing from 46
1999 Cohort (17 laboratories)
states. Specimen source was identified
2002 Cohort (28 laboratories) for 1985 isolates tested: 1413 (71%;
2003 Cohort (54 laboratories)
95% CI, 69%-73%) were from blood,
460 (23%; 95% CI, 21%-25%) were
from stool, 36 (2%; 95% CI, 1%-3%)
from urine, and 76 (4%; 95% CI, 3%-
Year Among 2016 isolates tested, 1155
isolates (57%; 95% CI, 55%-59%) were
197 167 229 218 194 211 susceptible to all 14 agents tested, while
28 35 35 51 42
70 51 73 71
861 (43%; 95% CI, 41%-45%) were re-
sistant to at least 1 antimicrobial agent.
Multidrug resistance was found in 272
isolates (13%; 95% CI, 12%-15%); na-
lidixic acid resistance was found in 758
isolates (38%; 95% CI, 35%-40%). Two
hundred eight isolates (10%; 95% CI,
9%-12%) were both MDRST and
NARST. Among NARST isolates, 734
tested throughout the study period had
decreased susceptibility to ciprofloxa-
cin (MIC ⬎0.12 µg/mL), representing
97% (95% CI, 96%-98%) of NARST and
36% (95% CI, 34%-38%) of all iso-
lates tested. Of 770 total isolates with
decreased susceptibility to ciprofloxa-
cin, 36 (5%; 95% CI, 3%-6%) were not
NARST. Five isolates (0.2%; 95% CI,
0.03%-0.5%) were resistant to cipro-
©2009 American Medical Association. All rights reserved.
floxacin (all MICs=4 µg/mL) and 2 iso-
lates were resistant to ceftriaxone (both
MICs=64 µg/mL).
The proportion of S Typhi isolates
with multidrug resistance and nalidixic
acid resistance varied by year (FIGURE 1).
The proportion of all isolates that were
MDRST ranged from a high of 19%
(95% CI, 15%-23%) in 2001 and 2006
to a low of 6% (95% CI, 3%-9%) in
2002. The proportion of isolates that
were NARST increased from 19% (95%
CI, 13%-25%) in 1999 to 54% (95% CI,
49%-59%) in 2006 (P =.001).
A similar trend for NARST was seen
for S Typhi isolates submitted by the
17 sites participating in NARMS
throughout 1999-2006 (FIGURE 2).
Cases From National Typhoid Fever
Surveillance With S Typhi Isolate
Testing by the NARMS Laboratory
We identified 1131 typhoid fever cases
from 39 states with both a surveil-
lance case report and associated anti-
microbial susceptibility testing infor-
mation on an S Typhi isolate from the
same patient. The descriptive epidemi-
ology and proportion of resistant iso-
lates associated with these 1131 cases
were similar to that of all typhoid cases.
Patient median age was 21 years (range,
⬍1-90 years) and 47% (95% CI, 44%-
50%) were female. Among 1070 pa-
tients with reported clinical out-
comes, 806 (75%; 95% CI, 73%-78%)
were hospitalized and 1 (0.1%; 95% CI,
0%-0.3%) died. Travel outside the
United States in the month before ill-
ness onset was reported by 869 (80%;
95% CI, 77%-82%) of 1088 patients. Of
1131 S Typhi isolates tested for these
cases, 482 (43%; 95% CI, 40%-46%)
were resistant to at least 1 antimicro-
bial agent; 142 (13%; 95% CI, 11%-
14%) were MDRST and 440 (39%; 95%
CI, 36%-42%) were NARST.
The median age of patients infected
with MDRST, NARST, or susceptible
strains was similar (TABLE 4). Patients
with MDRST and NARST were no more
likely to be hospitalized than patients
with susceptible infections, and the me-
dian number of days hospitalized was the
same. A higher proportion of MDRST pa-
 TYPHOID FEVER IN THE UNITED STATES

Table 4. Selected Exposures Among Patients With Typhoid Fever, by Antimicrobial Susceptibility Profile of Salmonella ser Typhi
Isolate—United States, 1999-2006 (n = 1131) a
Odds Ratio (95% Confidence Interval)
MDRST NARST Susceptible
Exposure (n = 142) (n = 440) (n = 646) MDRST vs Susceptible NARST vs Susceptible
Female, No. (%) 59/140 (42) 195/435 (45) 294/641 (46) 0.9 (0.6-1.3) 1.0 (0.8-1.2)
Age, median (range), y 18 (⬍1-68) 21 (⬍1-86) 22 (⬍1-90)
Traveled outside United States, No. (%) 134/140 (96) 407/427 (95) 422/617 (68) 10.3 (4.3-26.4) 9.4 (5.7-15.7)
Traveled to Indian subcontinent, No. (%) 94/110 (85) 352/374 (94) 166/378 (44) 7.5 (4.1-13.8) 20.4 (12.4-33.9)
Hospitalized, No. (%) 112/134 (84) 315/418 (75) 459/610 (75) 1.7 (1.0-2.8) 1.0 (0.8-1.4)
No. hospitalized, median (IQR) 6 (4-9) 6 (4-8) 6 (4-8)
Abbreviations: IQR, interquartile range; MDRST, multidrug-resistant Typhi; NARST, nalidixic acid–resistant S Typhi.
a Salmonella Typhi isolates from 97 patients were both MDRST and NARST.

tients (96%; 95% CI, 92%-99%) had trav-

eled outside of the United States com-
pared with patients who had susceptible
infections (68%; 95% CI, 65%-72%).
Among 110 patients with MDRST infec-
tions who reported travel to a single
country, India (n=37 [34%; 95% CI,
Figure 3. Proportion of Multidrug-Resistant Salmonella ser Typhi (MDRST) and Nalidixic
Acid–Resistant S Typhi (NARST) Isolates Among Typhoid Fever Cases Associated With Travel
to India, and Proportion of Typhoid Fever Cases Associated With Travel to India Among
Travel-Associated Cases Linked to National Antimicrobial Resistance Monitoring System
Isolate, by Year—United States, 1999-2006
Resistant isolates among typhoid Proportion of travel-associated typhoid
fever cases traveling to India (n = 367) fever cases who traveled to India (n = 802)

23%-42%]), Bangladesh (n=30 [26%;

Travel-Associated Cases, %
100 NARST 100
95% CI, 19%-36%]), Pakistan (n=27
Among India Travelers, %

MDRST

Travel to India Among

MRDST or NARST

[25%; 95% CI, 17%-33%]), and Cam- 80 80

bodia (n=8 [7%; 95% CI, 2%-12%]) were 60 60

most commonly named. Among 374 pa-
tients with NARST infections who re-
ported travel to a single country, 361
(97%; 95% CI, 95%-98%) had traveled
to these same 4 countries: 278 (74%; 95%
CI, 70%-79%) traveled to India, 41 (11%;
95% CI, 8%-14%) to Bangladesh, 33 (9%;
95% CI, 6%-12%) to Pakistan, and 9 (2%;
95% CI, 1%-4%) to Cambodia. Infec-
tion with resistant strains of S Typhi was
strongly associated with travel to 1 of 3
countries on the Indian subcontinent, In-
dia, Pakistan, or Bangladesh (MDRST
odds ratio, 7.5; 95% CI, 4.1-13.8; NARST
odds ratio, 20.4; 95% CI, 12.4-33.9).
The proportion of resistant infec-
tions among 864 travel-associated cases
varied by the region to which patients
had traveled. Among patients with ty-
phoid fever who had traveled to the In-
dian subcontinent, 17% (95% CI, 15%-
20%) were infected with MDRST and
65% (95% CI, 62%-68%) with NARST.
The corresponding proportion of
MDRST and NARST infections among
patients who had traveled to South-
east Asia was 14% (95% CI, 12%-
16%) and 20% (95% CI, 17%-23%); for
Central or South America was 1% (95%
CI, 0.3%-2%) and 3%(95% CI, 2%-
©2009 American Medical Association. All rights reserved.
40
20
0 0
1999 2000 2001 2002 2003 2004 2005 2006
Year
Isolates tested,
No. 9 39 44 21 65
4%); and for Africa was 24% (95% CI,
21%-27%) and zero. For individual
countries, typhoid patients who had
traveled to India had the highest rate
of drug-resistant infections. The pro-
portion of typhoid patients who had
traveled to India and were infected with
MDRST varied by year (FIGURE 3),
whereas the proportion of patients in-
fected with NARST after traveling to In-
dia increased steadily during this pe-
riod, from 44% (95% CI, 12%-76%) in
1999 to 88% (95% CI, 82%-94%) in
2006. Among cases linked to a NARMS
isolate, the proportion of travel-
related typhoid cases associated with
travel to India varied little during this
time.
Limited epidemiologic information
was available for the 5 cases of cipro-
floxacin-resistant S Typhi infection. They
40
20
1999 2000 2001 2002 2003 2004 2005 2006
Year
Travel-related typhoid cases,
67 45 77 No. 27 84 96 61 143 131 94 166
were reported from 4 states, Arizona,
California (n=2), Massachusetts, and
Texas. One case occurred in 2003, 1 in
2005, and 3 in 2006. Patient ages ranged
from 1 to 26 years; 4 patients were
younger than 9 years. Four patients were
hospitalized; none died. None of these
patients were reported to be typhoid vac-
cine recipients, though 2 were younger
than 2 years old and therefore below the
recommended age for any available ty-
phoid fever vaccine. All 5 patients had
arrived from India; 4 reported visiting
family and 1 was immigrating to the
United States.
COMMENT
Although typhoid fever remains a rare
disease in the United States, it contin-
ues to cause substantial morbidity
among affected patients. Patients with
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 TYPHOID FEVER IN THE UNITED STATES
typhoid fever during the period of this
study were hospitalized in nearly three-
quarters of reported cases, half for more
than a week. The low case-fatality rate
among reported typhoid fever cases in
the United States (0.1%) compared with
published reports from other re-
gions15-17 may be due in part to greater
access to supportive care and appro-
priate antibiotic therapy. However,
proper treatment of infected patients
with effective antibiotic therapy is in-
creasingly complicated by strains re-
sistant to available antimicrobial agents.
During 1999-2006, resistance to anti-
microbial agents was common among
S Typhi isolates from patients with ty-
phoid fever in the United States. Strains
resistant to first-line agents have been
noted for some time and the propor-
tion of MDRST infections in this re-
port (13%) is comparable with other re-
cent estimates.5,6 This proportion of
MDRST infections among typhoid pa-
tients is, in turn, comparable with sus-
ceptibility testing reports from typhoid-
endemic areas.9,10 In a recent summary
of typhoid disease burden in 5 Asian
countries, the overall percentage of
MDRST was 23%.18
Notably, about one-third of all S Typhi
isolates in this study were resistant to the
quinolone nalidixic acid, and the pro-
portion of NARST strains among US pa-
tients steadily increased during the study
period. During 1996-1997, enhanced
surveillance revealed that 7% of S Typhi
strains tested were resistant to nalidixic
acid; by 2006, 54% of strains were
NARST. This increase appears to be re-
lated to an increase in the proportion of
NARST infections among patients with
typhoid fever who traveled to southern
Asia, rather than changes in reporting to
NARMS or an increase in travel to south-
ern Asia among all typhoid cases. Sur-
veillance for antimicrobial resistance
among S Typhi isolates conducted re-
cently in this region yielded similarly
high proportions of nalidixic acid resis-
tance: 57% of S Typhi isolates from In-
dia and 59% of isolates from Pakistan
were NARST.18
Although nalidixic acid is not com-
monly used for treatment of S Typhi in-
864 JAMA, August 26, 2009—Vol 302, No. 8 (Reprinted)
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fections, resistance to nalidixic acid is
a marker for decreased susceptibility to
fluoroquinolones. Nearly all NARST
isolates in this study had decreased sus-
ceptibility to ciprofloxacin, a com-
monly used oral agent for S Typhi in-
fection.8 In addition, a high proportion
of isolates with decreased susceptibil-
ity to ciprofloxacin were NARST. How-
ever, since NARST may not identify all
isolates with decreased susceptibility to
ciprofloxacin, the MIC for clinically
used fluoroquinolones should be mea-
sured when possible. Recent reports in-
dicate NARST infection has been asso-
ciated with poor clinical outcomes
among US patients, including pro-
longed fever and a higher rate of treat-
ment failure.19 Although decreased sus-
ceptibility to ciprofloxacin was common
among the S Typhi isolates tested, in-
fection with a ciprofloxacin-resistant S
Typhi strain has, so far, been rare. The
5 cases of infection with ciprofloxacin-
resistant strains are the first reported
among typhoid fever patients treated in
the United States and follow reports of
ciprofloxacin-resistant cases from other
countries.20
These data indicate that recommen-
dations for appropriate empirical therapy
for typhoid fever patients should be made
with caution. Resistance to ampicillin and
to trimethoprim-sulfamethoxazole re-
mains prevalent and precludes the use
of these agents as initial therapy. Al-
though nalidixic acid resistance and de-
creased susceptibility to ciprofloxacin is
of concern, a fluoroquinolone remains
an appropriate choice for empirical
therapy in adults. Among children, in
whom fluoroquinolones are limited to
off-label use, third-generation cephalo-
sporins are appropriate. Further therapy
should be guided by close monitoring of
patients’ clinical response and antimi-
crobial susceptibility testing of S Typhi
isolates at a clinical diagnostic labora-
tory.21 At the national level, resistance
among S Typhi isolates will be moni-
tored closely in NARMS for trends that
may influence therapeutic recommen-
dations.
Typhoid fever in the United States and
infection with resistant S Typhi strains
©2009 American Medical Association. All rights reserved.
continues to be associated with foreign
travel, specifically with travel to the In-
dian subcontinent. The proportion of US
typhoid cases associated with foreign
travel has increased steadily over the past
several decades. During 1975-1984, 62%
of typhoid fever cases were related to for-
eign travel4; during 1985-1994, 72% of
cases were travel-related5; 74% in 1995-
19997; and 79% in this study. In 2006,
foreign travel was reported by more than
85% of typhoid fever patients. An in-
crease in the proportion of typhoid fe-
ver patients reporting travel to south-
ern Asia and a concomitant decline in
the proportion of typhoid patients re-
porting travel to Mexico has been an on-
going trend since the 1980s.5 In this
study, we observed a higher rate of ty-
phoid fever among travelers returning
from Asia (10.5 per 1 million travelers)
or Africa (7.6 per 1 million) than among
those returning from Mexico, Central
America, South America, or the Carib-
bean (1.3 per 1 million). Improved sani-
tation in response to the cholera epi-
demic in South America during the
1990s may have played a role in lower
rates of endemic typhoid in this region
and, consequently, lower rates of ty-
phoid fever among travelers to that re-
gion.22
With the threat of increased antimicro-
bial resistance, prevention remains para-
mount.23 Travelers to the Indian sub-
continent and those visiting friends and
familyaresingularlyimportantgroupson
whichtofocusenhancedoutreachandty-
phoid fever prevention efforts.24 Travel-
ers to high-risk areas should ensure they
are vaccinated against typhoid fever and
take appropriate precautions regarding
food and beverages. More than 96% of
travel-related cases occurred in persons
who were older than 2 years, an age group
for which typhoid vaccine is available.
Currently licensed typhoid vaccines, Vi-
votif and Typhim Vi, are reportedly 70%
and 90% effective in preventing typhoid
infection among residents of typhoid-
endemicareas.8 Recentanalysesoftyphoid
fever among US travelers indicate that
typhoid vaccines are well-tolerated and
vaccination should be considered even
amongtravelersplanningtripsoflessthan

2 weeks’ duration to typhoid-endemic
areas.7 Because neither commercially
available vaccine is 100% effective, food
and water precautions remain important.
Further advice on food and water safety
while traveling can be found at http:
//www.cdc.gov/ncidod/dbmd/diseaseinfo
/typhoidfever_g.htm. Currently avail-
able vaccines are not licensed in the
United States for children younger than
2 years, so efforts aimed at reducing ex-
posure to contaminated water and food
are especially important for this age
group.
This report has several limitations. We
were able to link laboratory testing re-
sults to approximately 60% of typhoid
fever cases reported to national surveil-
lance during the study period. Linkage
was limited by missing information and
the small number of laboratories sub-
mitting isolates to NARMS early in the
study period. However, similar descrip-
tive epidemiology of typhoid cases linked
to NARMS and of all cases, as well as a
similar proportion of resistant isolates
among those linked to cases and among
all isolates tested, suggest that the linked
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Author Contributions: Dr Lynch had full access to all
of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data
analysis.
Study concept and design: Lynch, Blanton, Polyak,
Barrett, Mintz.
Acquisition of data: Lynch, Blanton, Bulens, Polyak,
Vojdani, Stevenson, Medalla, Barzilay, Joyce, Barrett,
Mintz.
Analysis and interpretation of data: Lynch, Blanton,
Polyak, Vojdani, Barzilay, Barrett, Mintz.
Drafting of the manuscript: Lynch, Polyak, Vojdani,
Joyce, Mintz.
Critical revision of the manuscript for important in-
tellectual content: Lynch, Blanton, Bulens, Polyak,
Stevenson, Medalla, Barzilay, Barrett, Mintz.
Statistical analysis: Lynch, Blanton, Polyak.
Administrative, technical, or material support: Blanton,
Bulens, Vojdani, Joyce.
Study supervision: Barrett, Mintz.
Financial Disclosures: None reported.
Additional Contributions: We thank the public health
officials in state and local health departments and pub-
lic health laboratories in all 50 states, the District of
Columbia, and the US territories for their assistance
in conducting typhoid fever surveillance.
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