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Antimicrobial Resistance in Nontyphoidal Salmonella
Isolates from Human and Swine Sources in Brazil:
A Systematic Review of the Past Three Decades
Grazielle Lima Rodrigues,
1,2
Pedro Panzenhagen,
1,2
Rafaela Gomes Ferrari,
1,2
Vania Margaret Flosi Paschoalin,
1
and Carlos Adam Conte-Junior
1–4
Salmonella are the leading cause of foodborne illnesses worldwide. The widespread use of antimicrobials as
prophylactic, therapeutic, and growth promoters in both livestock and human medicine has resulted in selective
pressure regarding antimicrobial-resistant (AMR) bacteria. This systematic review summarizes phenotypic antimi-
crobial resistance profiles in Salmonella isolates from human and swine sources between 1990 and 2018 in Brazil.
The 20 studies that matched the eligibility criteria—isolates from pigs and humans from Brazil, between 1990 and
2016, containing information on the number of Salmonella isolates, and applying the disk diffusion susceptibility
method—were included. During the assessed period, Salmonella strains isolated from swine sources displayed the
highest resistance rates for tetracycline (20.3%) and sulfonamides (17.4%). In contrast, human isolates displayed the
highest resistance rates against ampicillin (19.8%) and tetracycline (17%). Salmonella Typhimurium was the most
frequent AMR isolate from both swine and human sources, corresponding to 67% of all isolates. From 2001 to 2005,
tetracycline and ampicillin were the top antimicrobial resistance compounds, and the most frequently detected in
swine and human sources, respectively. A total of 63 and 58 multiple drug resistance profiles were identified in swine
and human isolates, respectively. Antimicrobial resistance has decreased throughout the 1990–2016 period, except
for gentamicin and nalidixic acid in swine and human isolates, respectively. The results indicate that Salmonella
isolated from human and swine display resistance against clinically important antimicrobials, indicating that swine
are possibly one of the main vectors for spreading human salmonellosis in Brazil.
Keywords: Salmonella serovars, multiple drug resistance, antimicrobial-resistant bacteria, food supply, control
Introduction
Salmonella is a member of the Enterobacteriaceae
family, a part of the intestine microbiome of healthy
humans and animals.
1
A variety of food matrices can serve
as vehicles for the transmission of these microorganisms
to humans, through fecal contamination.
2
Salmonella can
cause salmonellosis, a foodborne infection in the intestinal
tract, with symptoms such as fever, diarrhea, and abdominal
cramps. In the United States, health authorities estimate that
around 1.2 million individuals suffer from salmonellosis
every year, resulting in 23,000 hospitalizations and 450
deaths.
3
Approximately 94 million cases of salmonellosis a
year result in 155,000 deaths worldwide, and more than half
of these are caused by contaminated food.
4
About 2,659 Salmonella serovars, classified as typhoid or
nontyphoid, can cause salmonellosis.
5
Although their genomes
are very similar, about 90% of them can cause distinct diseases
and immune responses in humans.
6
Geographic and economic
aspects of different countries determine serovar frequency and
clinical symptoms. For example, nontyphoid Salmonella pre-
dominantly causes self-limiting diarrhea in healthy individuals
in developed countries,
7
whereas nontyphoid Salmonella is
frequently involved in systemic diseases with higher death ra-
tios in developing countries.
8
Therefore, antimicrobial treat-
ment should be prescribed for immune-compromised patients,
the elderly or children, as well as in cases of severe systemic
infections.
9
Since the discovery of penicillin, leading to a significant
breakthrough in modern medicine, antimicrobials have been
an effective method to control bacterial infections.
10
How-
ever, the misuse and overuse of these substances in livestock
has led to selective antimicrobial-resistant (AMR) bacteria
advantages. Bacteria develop resistance by various
1
Institute of Chemistry, Federal University of Rio de Janeiro, Cidade Universita
´ria, Rio de Janeiro, Brazil.
2
Center for Food Analysis, Technological Development Support Laboratory (LADETEC), Cidade Universita
´ria, Rio de Janeiro, Brazil.
3
Faculty of Veterinary Medicine, Analytical and Molecular Laboratory Center, Fluminense Federal University, Nitero
´i, Brazil.
4
National Institute of Health Quality Control, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
MICROBIAL DRUG RESISTANCE
Volume 00, Number 00, 2020
ªMary Ann Liebert, Inc.
DOI: 10.1089/mdr.2019.0475
1
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mechanisms, both intrinsic or acquired through mutations and
horizontal gene transfer, for example, transposons, plasmids,
and integrons.
11
Because of this, it is important to monitor the
presence of resistant strains in livestock and control the ex-
cessive use of antimicrobials and the use of prohibited drugs.
12
In addition, recent studies based on whole genome sequencing
have evidenced pathogenic bacteria movements, especially
Salmonella, from livestock to humans,
13
resulting in AMR
infections that are more difficult to treat. This is a significant
current concern, as the transfer of AMRs to humans via animal-
based foods results in infections that are, increasingly, be-
coming more frequent, severe, and difficult to treat. AMR is,
thus, defined as a global public health concern.
11
Brazil ranks fourth worldwide in swine production and
exports, exporting around 264,532 tons, mainly to European
Union member countries, in 2017.
14
Brazil’s per capita
swine consumption has also increased since 2007, amount-
ing to 14.7 kg in 2017.
14
Swine are an important Salmonella
reservoir, since these animals can carry high microbial loads
in their tonsils, gut, and mesenteric lymph nodes. During
slaughter, poor hygiene during evisceration can disseminate
Salmonella, contaminating carcasses.
15–19
Therefore, Sal-
monella harboring antimicrobial resistance genes in their
genome can be spread by swine consumption, transmitting
resistant strains to consumers. The need for controlled an-
timicrobial use is a priority, to avoid increased bacterial
resistance and reach Brazilian international trade quality
standards for swine and derivatives.
The epidemiological surveillance of antimicrobial resis-
tance through systematic literature reviews can be applied as
a support tool for health authorities and epidemiologists in
bacteria AMR vigilance actions worldwide, as they may
complement information on bacteria reservoirs, identify an-
timicrobial resistance and geographical trends over time, as
well as generate hypotheses regarding resistant foodborne
pathogen sources and reservoirs and guide evidence-based
policies to control antimicrobial use in hospitals, communi-
ties, agriculture, aquaculture, and veterinary medicine.
20
An
efficient strategy to assess public health risk regarding AMRs
bacteria in the gut core microbiota of the farm animals
comprises determining the drug resistance profile of en-
terobacteria, especially pathogenic and resistant Salmonella
isolates. This strategy is possibly the best therapeutic ap-
proach to consider for the treatment of severe salmonellosis.
Several studies have been carried out in Brazil regarding
Salmonella resistance to antimicrobials, displaying regional
differences over time.
21–23
The metadata obtained from these
studies is variable, making it a challenge to comprehensively
interpret. Due to the lack of broad research comprising AMR
rates in Salmonella from farmed swine and humans in Brazil,
this study aims at carrying out a systematic literature review
by evaluating and comparing phenotypic Salmonella anti-
microbial resistance profiles isolated from humans and swine
during the past three decades in Brazil.
Methodology
A systematic review was performed to collect data on
antimicrobial resistance in Salmonella isolated from humans
and swine in Brazil. The study was performed in four stages:
identification, screening, eligibility, and inclusion, as re-
commended by the preferred reporting items for systematic
reviews and meta-analysis—PRISMA.
24
Data screening was
performed from July to August 2019, and no language re-
strictions were implemented. Editorials, letters, monographs,
Master’s dissertations, and PhD theses were excluded.
Focus questions
The following questions were formulated according to
the population, intervention, comparison, and outcome
parameters: (1) What is the current situation of Salmonella
antimicrobial resistance in Brazil? (2) How has the Sal-
monella antimicrobial resistance scenario changed in the
past three decades? (3) Which Salmonella serovar is
prevalent in humans and/or in swine reservoirs? (4) Which
Salmonella isolates from humans and/or swine display the
highest prevalence of antimicrobial resistance? (5) Does a
correlation between Salmonella serovar and antimicrobial
resistance exist?
Information sources
A literature search was performed by using Medical
Subject Headings (MeSH) terms at the Web of Science,
PubMed, SciELO, Science Direct, and Google Scholar
databases.
Search Component 1 (SC1)—Intervention: Brasil OR
Brazil. Search Component 2 (SC2)—Health problem:
(SC2a) ‘‘Salmonella’’; (SC2b). ‘‘antimicrobial resistance’’
OR ‘‘microbial resistance’’ OR ‘‘bacterial resistance’’ OR
‘‘resistance pattern’’ OR ‘‘resistance’’ OR ‘‘susceptibility.’’
Search Component 3 (SC3)—Population studied: (SC3a)
swine OR pigs OR porcine; (SC3b) human OR humans.
After retrieving the Search Component results, the
Boolean operator ‘‘AND’’ was used to combine SC1, SC2a,
SC2b, SC3a, and SC3b, respectively.
The primary article selection was based on the title and
abstract of the selected studies only. During a second
screening, all selected articles were thoroughly read and
those matching the following selection criteria were chosen:
1. Salmonella strains isolated in Brazil.
2. Salmonella strains isolated from pigs and/or humans.
3. Salmonella strain isolation conducted from January
1990 to December 2016.
4. Information of the number of Salmonella isolates and
the year they were isolated.
5. Use of the disk diffusion susceptibility method for
screening phenotypical Salmonella resistance.
All references cited in the selected articles were investi-
gated, to identify additional eligible studies, but none mat-
ched the eligible criteria. The time interval median was used
to represent the time isolation in studies in which the exact
year of strain isolation was not informed.
Finally, three criteria were used to qualify the studies to
be included in the final quantitative analysis:
1. Studies informing the criteria applied for interpreting
inhibition zones.
2. Studies used a standard strain as a control to qualify
inhibition tests.
3. Studies where tests were performed following Clinical
and Laboratory Standards Institute (CLSI) guidelines.
25
2 RODRIGUES ET AL.
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Statistical analyses
Prevalence was calculated by determining the ratio between
the number of antimicrobial Salmonella resistance by the total
number of AMR Salmonella strains isolated from each source.
Occurrence was calculated to analyze the temporal distribu-
tion of antimicrobial resistance throughout the three assessed
decades. The R software to cluster and construct prevalence
heat maps through the heatmap base function was used, and
the RColorBrewer package was used for graph preparation.
Risk of bias assessment
Possible bias sources include study inclusion/exclusion
criteria, the chosen database, date, and type of article se-
lected for the study. Another important bias assessment
concerns the analytical methodologies used by the different
researchers in Salmonella enterica antibiograms, that is,
disk diffusion brands, the choice of antimicrobials, non-
standardization of the number of isolates in geographical
regions over the years, specification of a time interval and
not specific year regarding isolates procurement, differences
in the number of isolates between studies, fieldwork, and
database articles. Isolates identified as monophasic variants
of Salmonella Typhimurium (S. 1,4,[5],12:i:-) were con-
sidered as a special Typhimurium serovar group.
Results
Systematic review characteristics
A summary of the criteria applied in systematic review
process is displayed in Fig. 1. Initially, 540 articles were
selected by the elected keywords, and 433 were excluded
due to duplicates. The remaining 107 records were consid-
ered for further screening. Eighty-nine full studies of the
107 records were selected for the eligibility step after the
exclusion of 18 unrelated articles. A further 69 articles were
excluded during the final quantitative eligibility analysis.
A total of 20 studies were included in the final quantita-
tive analyses. Out of these, nine articles reported AMR in
Salmonella strains isolated from humans, six from swine
sources, and five from humans and swine, concomitantly.
Qualitative evaluation
Antimicrobial tests were performed as recommended by
CLSI guidelines in the 20 included articles.
25
Eighteen ar-
ticles (90%) matched at least two of the three criteria es-
tablished for quality evaluation, whereas 14 informed the
criteria used for interpreting the inhibition zones and the use
of a standard strain for the quality control test.
Overall frequency of AMR Salmonella serovars
isolated from swine and human sources
The metadata from the 20 included articles indicated 779
nontyphoid AMR Salmonella isolates (Table 1). A total of
259 were isolated from swine (feces, carcass swabs, lymph
nodes, and urine) and 520 from human fluids and excreta
(blood, feces, urine, and brain abscess).
The most prevalent AMR Salmonella serovars isolated from
swine were Salmonella Typhimurium (158/259) (61.0%),
Salmonella Derby (25/259) (9.7%), Salmonella Branden-
burg (21/259) (8.1%), and Salmonella Panama (21/259)
(8.1%). In humans, there were Salmonella Typhimurium
(364/520) (70.0%), Salmonella Enteritidis (100/520)
(19.2%), and Salmonella Infantis (36/520) (6.9%). Regard-
ing geographic region (Table 1), Southeastern Brazil harbors
the most resistant isolates (n=345), whereas the Salmonella
resistant isolates from humans are found mainly in South-
eastern and Southern Brazil. In addition, Southern Brazil
presented the highest number of swine resistant strains, as
well as the highest serovar diversity. Overall, Salmonella
FIG. 1. Flowchart describ-
ing the eligible criteria used
in the systematic review
process.
ANTIMICROBIAL RESISTANCE IN SALMONELLA FROM BRAZIL 3
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Table 1. Total Number of Salmonella Isolates with Antimicrobial Resistance Extracted from Eligible Records and Included
in the Final Quantitative Synthesis of the Systematic Review
Brazilian geographic
region Period
Origin
of isolates Typhimurium Enteritidis Infantis Derby Brandenburg Panama Others
a
Total Refs.
Southern 1995–1997 Human 17 17 Dias de Oliveira et al.
21
1995–2003 Human 3 3 Vaz et al.
56
1999–2000 Swine 65 65 Bessa et al.
57
1999–2001 Swine 4 4 Michael et al.
58
1999–2006 Human 77 77 de Oliveira et al.
59
2000–2012 Swine 17 21 Almeida et al.
60
Human 4
2005 Swine 8 11 14 12 45 Mu
¨rmann et al.
50
2005–2006 Swine 12 5 11 6 4 17 55 Spricigo et al.
61
2007–2011 Swine 39 39 Lopes et al.
62
Southeastern 1986–2010 Human 23 24 Campioni et al.
22
Swine 1
1990–2001 Human 35 35 Ghilardi et al.
63
1990–2008 Human 251 251 Eliane Moura Falavina
dos Reis et al.
64
1996–2001 Human 35 35 Fonseca et al.
65
Central West 2010–2011 Human 3 1 4 Corre
ˆaet al.
66
Multiple regions,
except North Brazil
1983–2013 Swine 4 6 Almeida et al.6
60
Human 2
1983–2013 Swine 12 24 Almeida et al.
67
Human 12
1983–2016 Human 16 16 Vilela et al.
23
Not specified 1995–1997 Swine 2 5 Nunes et al.
68
Human 3
2003–2004 Swine 3 1 5 6 15 Ribeiro et al.
69
2009–2013 Human 34 1 3 38 Pribul et al.
70
Total 522 102 41 25 21 21 47 779
a
Other serovars: Dublin, Agona, Schwarzengrund, Mbandaka, Heidelberg, Anatum, Muenchen, Rissen, Bredeney, monophasic 1,4,[5],12:i:-, Cerro and London.
4
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Typhimurium was the most frequently detected among
isolates from Southeastern, Southern, and Central-West
Brazil.
All Salmonella isolates displaying resistance to at least
one antimicrobial drug were listed and included herein
(Fig. 2A/B). A total of 2,571 antimicrobial drug resistance
combinations were detected among swine (920) and human
(1,651) isolates. Resistance against 19 and 28 distinct anti-
microbial drugs was observed among isolates from swine
and human sources, respectively.
AMR prevalence among Salmonella
serovars from swine origin
The highest AMR rates in swine isolates were against
tetracycline (187/920) (20%), followed by sulfonamides (160/
920) (17%), ampicillin (102/920) (11%), streptomycin (102/
920) (11%), and nalidixic acid (97/920) (10.5%) (Fig. 2A).
Regarding Salmonella serovars, AMR was detected mainly
for Salmonella Typhimurium (622/920) (68%), Salmonella
Panama (93/920) (10%), Salmonella Derby (71/920) (8%),
and Salmonella Brandenburg (57/920) (6%). Most Salmo-
nella Typhimurium strains were resistant to tetracycline (125/
920) (13.6%), followed by sulfonamide (102/920) (11%) and
ampicillin (76/920) (8%). Regarding Salmonella Panama, the
highest prevalences were observed against tetracycline (15/
920) (1.6%), ampicillin (15/920) (1.6%), streptomycin, and
chloramphenicol (14/920) (1.5%) and against tetracycline
(22/920) (2.4%), sulfonamide (19/920) (2.1%), and strepto-
mycin (11/920) (1.2%) for Salmonella Derby. Finally, in
Salmonella Brandenburg, AMR was observed against tetra-
cycline and sulfonamide (15/920) (1.6%) and trimethoprim-
sulfamethoxazole (14/920) (1.5%) (Fig. 2A).
Salmonella Anatum, Salmonella Enteritidis, Salmonella
Cerro, and Salmonella Heidelberg presented the lowest AMR
rates. Regarding Salmonella Anatum, the lowest resistances
were equally detected against streptomycin, sulfonamide, and
tetracycline (1/920) (0.1%). Salmonella Cerro and Salmonella
Heidelberg displayed discrete resistance to sulfonamide
(1/920) (0.1%), also observed for Salmonella Enteritidis,
although only against sulfonamide and tetracycline (1/920)
(0.1%) (Fig. 2A).
AMR prevalence among Salmonella
serovars from human origin
The highest AMR rates among Salmonella serovars iso-
lated from human sources were against ampicillin (327/
1,651) (20%), followed by tetracycline (280/1,651) (17%),
chloramphenicol (195/1,651) (12%), and sulfonamide (144/
1,651) (9%) (Fig. 2B). Salmonella Typhimurium, Salmo-
nella Infantis, and Salmonella Enteritidis comprised 1,617
out of 1,651 AMR isolates (97.94%) from human sources.
Regarding Salmonella Typhimurium isolates, the highest
FIG. 2. Antimicrobial resistance prevalence in nontyphoid Salmonella isolates from swine (A) and humans (B) between
1990 and 2016. *STX: trimethoprim-sulfamethoxazole; Monophasic Salmonella Typhimurium 1,4,[5],12:i:-. Color images
are available online.
ANTIMICROBIAL RESISTANCE IN SALMONELLA FROM BRAZIL 5
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AMR prevalences were noted against tetracycline (221/
1,651) (13.4%), ampicillin (215/1,651) (13%), and chlor-
amphenicol (166/1,651) (10.1%); whereas the Salmonella
Infantis displayed antimicrobial resistance to ampicillin (34/
1,651) (2.1%), tetracycline (33/1,651) (2.0%), cefalotin, and
aztreonam (31/1,651) (1.9%). Regarding Salmonella En-
teritidis, the highest identified AMR rates were against
ampicillin (73/1,651) (4.4%), followed by nalidixic acid (28/
1,651) (1.7%) (Fig. 2B).
Salmonella Muenchen was susceptible to almost all tested
antimicrobials, presenting resistance only to nalidixic acid
and enrofloxacin (2/1,651) (0.1%) (Fig. 2B).
Occurrence of temporal AMR distribution among
Salmonella isolates from human and swine
Antimicrobial occurrence increased from 1995 to 2000,
except for gentamicin (Fig. 3A). Between 2001 and 2005,
Salmonella isolates displaying resistance to tetracycline,
trimethoprim-sulfamethoxazole, streptomycin, nalidixic acid,
chloramphenicol, and ampicillin increased significantly. On
the other hand, the overall resistance of isolates against the
majority of antimicrobials reduced after 2005. Resistance to
gentamicin remained very low, with small variations from
1995 to 2012 (Fig. 3A).
Isolates from human sources displayed an increase in an-
timicrobial resistance from 1990 to 2000 (Fig. 3B) and a
subsequent increase in resistance against ampicillin, tetracy-
cline, chloramphenicol, and nalidixic acid until 2005; whereas
sulfonamide, streptomycin, trimethoprim-sulfamethoxazole,
and gentamicin resistance decreased from 2001 to 2005. Na-
lidixic acid increased throughout almost the entire period and
reached first in occurrence by 2010. In general, the oc-
currence of human isolates with resistance decreased after
2005 (Fig. 3B).
Multiple drug resistance in Salmonella
isolated from swine and humans
A total of 213 out of 259 (82.2%) Salmonella isolates
from swine displayed resistance to multiple drugs (multiple
drug resistance [MDR] profile). Overall, 57 distinct MDR
profiles were detected (Supplementary Table S1), the most
frequent being the combination of ampicillin, chloram-
phenicol, nalidixic acid, streptomycin, trimethoprim-
sulfamethoxazole, and tetracycline (42/213) (19.72%),
followed by ampicillin, chloramphenicol, streptomycin,
trimethoprim-sulfamethoxazole, and tetracycline (12/213)
(5.63%); and ampicillin, nalidixic acid, streptomycin, sulfon-
amide, tetracycline, and trimethoprim (12/213) (5.63%).
Among these profiles, 37.09% (79/213) of the isolates dis-
played resistance against a combination of six antimicrobials,
28.17% (60/213), against five, and 21.6% (46/213), against
four antimicrobials (Supplementary Table S1). Regarding the
MDR profiles of isolates grouped by antimicrobial classes, 26
distinct combinations of classes were found. From this com-
bination, 42.3% (11/26) of the isolates presented resistance
against four classes. Combined resistance against aminogly-
cosides, sulfonamides, penicillin, phenicol, quinolones, and
tetracycline was the most common profile (55/213) (25.82%),
displaying resistance against five out of the seven screened
classes.
In humans, 217 out of 520 isolates (41.7%) presented MDR
profiles. Overall, 54 distinct MDR profiles were detected: 53.0%
(115/217) resistant against 3 antimicrobials, 22.6% (49/217)
against 5, and 6.5% (14/217) against 14 (Supplementary
Table S2). In addition, 3 MDR profiles presented the same
prevalence of 16.6% (36 out of 217) (Supplementary Table S2).
The MDR profiles considering antimicrobial compound classes
presented 35 different combinations, and 42.9% (15/35) of the
isolates displayed resistance against three classes. The MDR
profile aminoglycosides—sulfonamide, penicillin, phenicol,
and tetracycline—was the most frequent (43/217) (19.8%),
demonstrating resistance against 5 out of 12 screened com-
pound classes.
Discussion
In 1980, Brazilian swine producers followed the suc-
cessful example from other countries and implemented ge-
netic animal enhancement methods.
26
Subsequently, swine
weight gain until slaughter increased gradually, intensifying
in the 1990s, due to advances in industrial swine husbandry,
based on intensive and technically raised livestock.
26
These
changes in swine farming methods increased consumption,
FIG. 3. Occurrence of temporal distribution of antimicrobials resistance within Salmonella isolates from swine (A) and
humans (B) from 1990 to 2016. AMP, ampicillin; C, chloramphenicol; GEN, gentamicin; NAL, nalidixic acid; STR,
streptomycin; STX, trimethoprim-sulfamethoxazole; SUL, sulfonamides; TET, tetracycline. Color images are available
online.
6 RODRIGUES ET AL.
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guaranteeing greater reliability of Brazilian swine meat.
The emergence of several Salmonella serovars resistant to
multiple antimicrobials was observed in parallel to the
Brazilian meat production chain development, becoming a
serious concern, as these bacteria can cause severe invasive
infections in humans, which often require antimicrobial
treatment.
Epidemiological data collected in Brazil since the 1990s
provide useful information, aiding in the treatment of salmo-
nellosis and in tracing the relationships between pathogenic
strains from foods to humans, elucidating contamination routes
and improving monitoring and the implementation of control
programs. The extensive use of antimicrobials as growth pro-
moters, prophylaxis, and treatment in swine seems to be related
to the development of Salmonella resistance in humans in
Brazil from 1990 to 2016. To the best of our knowledge, this
review is the first to compile data from Salmonella strains
isolated from both swine and humans in Brazil.
In 2006, 63% of small swine establishments were located
in Northeastern and Northern Brazil, comprising 18% of the
swine herd in the country. However, only 2% of the
slaughterhouses in these regions are efficiently inspected by
Brazilian authorities,
27
resulting in a gap between inspection
and epidemiological survey data when compared with other
geographic regions presenting higher socioeconomic de-
velopment. Small establishments located in the South
(16.0%), Southeast (15.6%), and Midwest (5.2%) regions
were still the minority in 2006. However, the economic
development of these regions is higher, making them more
active pork production chain actors.
27
Currently, Southern
and Southeastern Brazilian harbor the majority (*85%) of
swine herds compared with the North, Central West, and
Northeastern regions.
14
This may explain why Southeastern
and Southern Brazil harbor most resistant isolates and the
highest diversity of serovars.
Salmonella Enteritidis and Salmonella Infantis were the
most prevalent among the Salmonella serovars found in
humans, although they are not significantly prevalent in
swine. Salmonella Enteritidis is traditionally associated with
the consumption of contaminated poultry meat, eggs, and
egg derivatives in outbreaks or isolated cases world-
wide.
28,29
The high prevalence of Salmonella Enteritidis
isolated from humans and poultry
9
corroborates the results
reported herein and highlights the hypothesis that poultry or
eggs are likely the main origins of Salmonella Enteritidis
foodborne transmission to humans.
Salmonella Infantis has been grouped within the 15 most
frequent serovars detected worldwide, including in Latin
America.
30
Moreover, Salmonella Infantis is reported as the
sixth most frequent serovar isolated from humans and swine in
Brazil from 1996 to 2003.
31
Although Salmonella Infantis
usually originates from the contamination of food sources,
32–34
it has been mostly detected in human clinical samples and
described in a single study. This sporadic high detection of
single serovar isolates is likely a consequence of a specific
outbreak. Careful monitoring of Salmonella Infantis is re-
commended, as other evidence has demonstrated its broad
distribution throughout other food matrices.
35
In this study, Salmonella Typhimurium is reported as the
most isolated in both humans and swine. This serovar is
known as a generalist and cosmopolitan
35
and has been as-
sociated mainly with swine meat and swine.
36–38
Experi-
mental studies demonstrated that swine can asymptomatically
transport Salmonella Typhimurium in tonsils, intestines, and
mesenteric lymph nodes; whereas Salmonella canalsobe
spread throughout the swine processing line during slaughter,
contaminating equipment, and carcasses.
15–17,19,39,40
This
contributes to the dissemination and prevalence of Salmonella
Typhimurium in swine and, consequently, transmission from
contaminated swine and swine products to humans.
Salmonella Derby carrying antimicrobial resistance was the
second most frequent serovar detected in swine sources in
Brazil. This serovar is one of the most often associated with
swine,
35,41
as well as the most abundant regarding this source
in Asia and Europe.
39,42,43
Ferrari et al. reported swine as the
main Salmonella Derby reservoir.
35
The mechanism beyond
the global prevalence emergence of Salmonella Derby re-
mains unclear. However, Salmonella Derby infection in hu-
mans may be less epidemiological important than the most
commonly associated Salmonella Typhimurium and Salmo-
nella Enteritidis. It has been demonstrated that Salmonella
Derby lacks a combination of important virulence genes (irsA
and msgA, among others), as well as the Salmonella Patho-
genicity Island—SPI-3 integrity and multiple prophages
lacking in several human associates isolates.
44
It may be
speculated that the lack of many important virulence genes
may make Salmonella Derby less virulent to humans.
Salmonella Typhimurium and Salmonella Enteritidis are
the main serovars found in different Salmonella surveys.
Our metadata reveal that these serovars isolated from human
sources display broad and high antimicrobial resistance.
Hendriksen et al., in 2011 and Quesada et al., in 2014,
reported similar behavior for these Salmonella serovars
isolated in Latin America.
30,31
Salmonella Enteritidis was
the most frequently isolated, followed by Salmonella Ty-
phimurium, in 1990 and 1995, among 191 World Health
Organization (WHO) member countries.
45
In agreement
with these data, these serovars presented the highest AMR
levels in this study. The high prevalence of Salmonella
Enteritidis and Salmonella Typhimurium serovars in dif-
ferent sources worldwide can increase the transfer of resis-
tance genes from animals to humans throughout the food
chain.
The WHO does not recommend the use of the same
classes of antimicrobials employed in human therapeutics or
known to cause cross-resistance as growth promoters in
animal husbandry.
46
However, some antimicrobials tradi-
tionally used in swine husbandry as growth promoters an-
d/or for the treatment of gastrointestinal infections
47
are also
used to control human infectious diseases in Brazil (e.g.,
quinolones, tetracyclines). Antimicrobial misuse in agri-
culture and clinical and veterinary medicine has resulted in
an increase in AMR bacteria, including Salmonella. Ques-
ada et al. demonstrated that Salmonella isolated from
animal-based food displays significant antimicrobial resis-
tance in Latin American countries, including Brazil.
31
The
prophylactic, metaphylactic, and therapeutic use of antimi-
crobial compounds in animal husbandry for extended peri-
ods is the probable cause for the widespread resistance
against antimicrobials observed in Brazil. In addition, clin-
ical and microbiological evidence indicate that resistant
bacterial are frequently transmitted from animals to humans,
resulting in AMR infections that are more difficult and ex-
pensive to treat.
46
ANTIMICROBIAL RESISTANCE IN SALMONELLA FROM BRAZIL 7
Downloaded by University Of Melbourne from www.liebertpub.com at 05/16/20. For personal use only.
Regarding isolates from humans, the highest Salmonella
resistance was found against ampicillin, tetracycline, chlor-
amphenicol, and sulfonamide. It is important to note that
tetracycline, sulfonamide, trimethoprim-sulfamethoxazole,
ampicillin, and nalidixic acid use has been reported in swine
husbandry as growth promoters.
48
It is also important to note
Salmonella strains isolated from both humans and swine in
Brazil displaying MDR combination (Fig. 3). Swine isolates
displayedhighresistancetotetracycline and sulfonamide, with
a considerable resistance decrease against these drugs after
2005. As discussed by Voss-Rech et al., the probable reason
for the noted decrease in antimicrobial resistance among these
isolates is restrictions on their use in animal husbandry for
clinical treatment, as set by Brazilian authorities in 1998.
9
Similarly, aminoglycosides have been widely applied in Bra-
zilian animal husbandry, and both human and swine isolates
display a high mutual frequency of streptomycin resistance. In
general, a notable decrease in antimicrobial resistance against
almost all antimicrobials observedinhumanandswineisolates
after 2001–2005 (Fig. 3) is observed. However, an increase in
nalidixic acid resistance in human isolates was also noted
throughout this period. This corroborates the results reported
by Gorman and Adley, who report that nalidixic acid resistance
has followed increased resistance to quinolones,
49
the main
antimicrobial class used to treat salmonellosis.
50,51
In 1999, the Brazilian National Program to Control Re-
sidues and Contaminants in Animal-Based Food (PCRC)
was instituted by the Federal Inspection Service, belonging
to The Ministry of Agriculture, with the aim of controlling
veterinary drug residues, agrochemicals, and environmental
contaminants, and ensuring the safety of animal-based food
offered for consumption.
52
The observed decline in the oc-
currence of antimicrobial resistance in swine and human
isolates after 2001 may be a consequence of the controlled
use policy established by federal authorities, as the PCRC
supervises the safety limits of antimicrobials in food and
distributes penalties to producers who do not respect those
limits. Since the implementation of the control program in
2010, no nonconformities were found for the swine matrix
regarding permitted antimicrobial levels. However, before
the program implementation, antimicrobials belonging to
the tetracycline class were the most commonly detected at
nonconformity levels.
The World Organization for Animal Health (OIE) appoints
seven antimicrobial classes as veterinary critically important
antimicrobials.
53
The present assessment demonstrates that
Salmonella isolates from swine presented resistance to five of
eight classes of antimicrobials (aminoglycosides, amphenicols,
cephalosporins, macrolides, penicillin, quinolones, sulfon-
amides, and tetracycline), namely aminoglycosides (172/920)
(19%); sulfonamides (247/920) (27%); penicillin (102/920)
(11%); quinolones (103/920) (11%); and tetracycline (206/
920) (22%) (results not shown). On the other hand, the WHO
also appoints certain antimicrobial classes as critically impor-
tant (aminoglycosides, cephalosporins, macrolides, penicillins,
polymixins, quinolones, and others) for human treatment and
strongly advises for their moderate and conscious use,
54
and
antimicrobial resistance against at least four classes has been
reported in Salmonella isolated from humans, namely peni-
cillin (20%) (330/1,651), aminoglycosides (201/1,651) (12%),
quinolones (195/1,651) (12%), and cephalosporins (30/1,651)
(2%) (results not shown). The results reported herein revealed
serious public health issues and require attention and new
measures to minimize resistant bacterial infection risks.
Another important issue is that two of the most frequent
MDR profiles found in swine isolates presented resistance
against nalidixic acid, one of the main antimicrobials chosen
to treat salmonellosis in humans, as previously indicated. In
addition, the number of isolates from swine displaying an
MDR profile (213/259) (82.2%) is considered extremely
high and dangerous to public health. Further, 16.21% (42/
259) of the isolates displayed an MDR profile with resis-
tance against six of the seven detected antimicrobial classes.
These findings demonstrate the high risk regarding con-
sumption of swine contaminated by Salmonella strains that
are resistant to multiple antimicrobial compounds in Brazil.
On the other hand, of the 520 Salmonella isolated from
humans, 217 (41.73%) presented an MDR profile, most
frequent being a combination of ampicillin, chlorampheni-
col, streptomycin, sulfonamide, and tetracycline (ACSSuT)
resistance. This profile is commonly found in Salmonella
Typhimurium phage type DT 104, whose genes are chro-
mosomally encoded, involving integrons, and are horizon-
tally widely and quickly transferred to other bacteria.
55
Conclusions
This systematic review indicates that Salmonella serovars
detected in swine have developed resistance against clinically
relevant antimicrobials such as quinolones, tetracycline, and
penicillin. It seems that this resistance originates from the
extensive use of these antimicrobials for control contamina-
tion and support growth in animal husbandry. All major re-
sistance determinants, including those conferring resistance to
b-lactams, extended-spectrum b-lactams, fluoroquinolones,
aminoglycosides, tetracyclines, and chloramphenicol, have
been identified in various Salmonella serovars isolated from
the food supply, indicating that swine are possibly one of the
leading vectors in spreading human salmonellosis in Brazil.
The emergence of MDR in Salmonella isolated from swine
and human indicates risk for possible failures in invasive
salmonellosis treatments, requiring the control of AMR bac-
teria throughout the food chain. The results compiled herein
contribute toward the epidemiological surveillance of resistant
Salmonella and the control of widespread antimicrobial re-
sistance in Brazil.
Disclosure Statement
No competing financial interests exist.
Funding Information
This study was financed in part by the Coordenac¸a
˜ode
Aperfeic¸oamento de Pessoal de Nı
´vel Superior—Brasil
(CAPES)—Finance Code 001.
Supplementary Material
Supplementary Table S1
Supplementary Table S2
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Address correspondence to:
Pedro Panzenhagen, PhD
Institute of Chemistry
Federal University of Rio de Janeiro-UFRJ
Av. Athos da Silveira Ramos 149
Cidade Universita
´ria 21941-909
Rio de Janeiro
Brazil
E-mail: panzenhagen@ufrj.br
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