Salmonella enterica bacteria have become increasingly
resistant to antimicrobial agents, partly as a result of genes
carried on integrons. Clonal expansion and horizontal gene
transfer may contribute to the spread of antimicrobial drug–
resistance integrons in these organisms. We investigated
this resistance and integron carriage among 90 isolates with
the ACSSuT phenotype (resistance to ampicillin, chloram-
phenicol, streptomycin, sulfamethoxazole, and tetracycline)
in a global collection of S. enterica isolates. Four integrons,
dfrA12/orfF/aadA2, dfrA1/aadA1, dfrA7, and arr2/blaOXA30/
cmlA5/aadA2, were found in genetically unrelated isolates
from 8 countries on 4 continents, which supports a role for
horizontal gene transfer in the global dissemination of S.
enterica multidrug resistance. Serovar Typhimurium iso-
lates containing identical integrons with the gene cassettes
blaPSE1 and aadA2 were found in 4 countries on 3 con-
tinents, which supports the role of clonal expansion. This
study demonstrates that clonal expansion and horizontal
gene transfer contribute to the global dissemination of anti-
microbial drug resistance in S. enterica.
many as 1.4 million cases of S. enterica–associated disease
occur annually (3,4). While usually self-limiting, salmonel-
losis may require antimicrobial drug treatment in infants,
the elderly, or immunocompromised persons. However,
almonella enterica bacteria are a leading cause of food-
borne disease worldwide (1,2). In the United States, as
antimicrobial drug resistance has become increasingly
common in S. enterica, which can complicate therapy. The
National Antimicrobial Resistance Monitoring System re-
ported that in 2004, 15.0% of non-Typhi isolates were re-
sistant to >2 classes of antimicrobial drugs, and 8.1% were
resistant to >5 classes. The most common S. enterica multi-
drug-resistance pattern in 2004 was ACSSuT (resistance to
ampicillin, chloramphenicol, streptomycin, sulfamethox-
azole, and tetracycline) (5).
Antimicrobial drug resistance can occur by point
mutations in the bacterial genome or through horizontal
transfer of genetic elements carrying resistance genes.
Resistance may be disseminated through clonal expansion
of drug-resistant strains or through horizontal transfer of
genetic elements coding for resistance determinants. S.
enterica populations change through the introduction
of strains that expand and displace existing populations
(6,7). Such population dynamics enable antimicrobial
drug resistance in S. enterica to spread as a result of clon-
al expansion. The global dissemination of the multidrug-
resistant (MDR) S. enterica serovar Typhimurim phage
type DT104 clone is an example of the role of clonal
expansion in the spread of antimicrobial drug resistance
determinants across multiple countries and continents (8).
Clonal expansion is also probably responsible for the dis-
semination of nalidixic acid resistance in S. enterica sero-
var Typhimurium isolates obtained in southern Asia and
Horizontal transfer of genetic material among S. enter-
ica or from other bacterial species also plays an important
role in the dissemination of drug resistance in this pathogen
(10). Evidence indicates that horizontal gene transfer plays
a major role in the dissemination of antimicrobial drug re-
Resistanc e in a Global Collec tion
of Nontyphoidal S almonella
enteric a Isolates
Mary G. Krauland, Jane W. Marsh, David L. Paterson, and Lee H. Harrison
388 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 15, No. 3, March 2009
Author affi liations: University of Pittsburgh School of Medicine and
Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
(M.G. Krauland, J.W. March, D.L. Paterson, L.H. Harrison); and
University of Queensland, Royal Brisbane and Women’s Hospital,
Brisbane, Queensland, Australia (D.L. Paterson)
Integron-mediated Drug Resistance in S. enterica
sistance in other bacterial species, such as Escherichia coli
(11) and Stenotrophomonas maltophilia (12). The location
of antimicrobial drug–resistant genes on mobile genetic el-
ements, such as plasmids, transposons, and integrons, fa-
cilitates the mobilization of resistance from one organism
to another (13).
Integrons are genetic structures capable of capturing
and excising gene cassettes, which usually encode antimi-
crobial drug resistance determinants. Although integrons
are not self-mobilizable, they are usually found in associa-
tion with transposons and are often located on plasmids,
facilitating their mobility (13). Integrons are thus ideally
suited for the dissemination and recombination of antimi-
crobial drug–resistance genes. Integrons are common in S.
enterica and make an important contribution to the extent
of antimicrobial resistance in this species (10,13,14). Be-
cause of their plasmid and transposon association, inte-
grons are assumed to be mobilized predominantly through
horizontal gene transfer (10). However, the clonal nature
of S. enterica suggests that clonal expansion may also play
a role in dissemination of drug resistance. An example of
clonal expansion of integron bearing S. enterica is the glob-
al distribution of the serovar Typhimurium DT104 clone,
which harbors a genetic resistance island known as the Sal-
monella genomic island 1 (SGI1). This region contains a
number of drug resistance elements including 2 integrons
with the gene cassettes blaPSE1 and aadA2 and genes for
tetracycline and chloramphenicol resistance, which are not
integron associated (15).
Clonal expansion of integron-bearing S. enterica
would account for the occurrence of a particular genetic
lineage with a specifi c integron in a variety of regions.
Horizontal gene transfer would account for the existence
of identical integrons in isolates of different genetic
lineages. To explore the roles of clonal expansion and
horizontal gene transfer in the dissemination of antimi-
crobial drug resistance caused by class 1 integrons, we
investigated the integron structure and genetic lineage of
90 MDR nontyphoidal S. enterica isolates from a global
collection comprising >1,900 isolates from 13 countries
and 6 continents. A goal of this study was to improve
our understanding of the contributions of clonal expan-
sion and horizontal gene transfer to the dissemination of
integrons carrying antimicrobial drug–resistance genes in
S. enterica to enable the development of improved strate-
gies for the control of antimicrobial drug resistance in this
organism as well as other emerging pathogens of public
Materials and Methods
A total of 1,920 S. enterica isolates were investigated;
1,743 isolates were collected by laboratories in Argentina,
Australia, Belgium, Canada, Denmark, Germany, Italy,
the Philippines, South Africa, Spain, Taiwan, Uganda and
the United States during September 2001–August 2002
(Table 1). These isolates were collected as part of a separate
study that attempted to identify a genetically and geograph-
ically diverse group of S. enterica isolates with reduced
susceptibilities to fl uoroquinolones. The isolates were not
selected but rather were collected consecutively, without
regard to their antimicrobial drug susceptibility. In addi-
tion, 179 isolates were collected by the Allegheny County
Department of Health in Pennsylvania during 2002–2003
as part of routine surveillance. Serotyping was performed
by the collecting laboratories, except for isolates from Tai-
wan, which were serotyped by the Pennsylvania Depart-
ment of Health.
The ACSSuT resistance phenotype has become in-
creasingly prevalent in S. enterica, and that phenotype has
been commonly associated with class 1 integron carriage in
this species. For these reasons, we selected a subset of iso-
lates from the collection that exhibited the ACSSuT resis-
tance phenotype for further investigation. Isolates selected
for integron investigation were confi rmed to be S. enterica
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 15, No. 3, March 2009 389
Table 1. Laboratories that provided Salmonella enterica isolates for this study
United States Centers for Disease Control and Prevention, Foodborne and Diarrheal Diseases
Laboratory Section, Atlanta
CanadaOntario Public Health Laboratory, Toronto
CanadaLaboratory for Foodborne Zoonoses, Population and Public Health Branch, Guelph
ArgentinaCentro de Estudios en Antimicrobianos, Buenos Aires
Australia Queensland Health Scientific Services, Archerfield
BelgiumAntwerp University Hospital, Antwerp
Germany Bundesgesundheitsministerium für gesundheitlichen Verbraucherschutz und
South Africa South African Institute for Medical Research, Johannesburg
SpainInstitute of Health Carlos III, Enteric Bacteria Laboratory, Madrid
Italy Istituto Superiore di Sanita, Rome
Denmark Hvidovre Hospital, Copenhagen
Taiwan National Cheng Kung University, Tainan City
Institution Contact person
Timothy J. Barrett
Jose Maria Casellas
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Address for correspondence: Lee H. Harrison, University of Pittsburgh
Graduate School of Public Health, 521 Parran Hall, 130 Desoto St,
Pittsburgh, PA 15261, USA; email: firstname.lastname@example.org
396 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 15, No. 3, March 2009