antibiotics

Review
Salmonellosis: An Overview of Epidemiology, Pathogenesis,
and Innovative Approaches to Mitigate the Antimicrobial
Resistant Infections
Bibek Lamichhane 1 , Asmaa M. M. Mawad 2 , Mohamed Saleh 1 , William G. Kelley 1 , Patrick J. Harrington II 1 ,
Cayenne W. Lovestad 1 , Jessica Amezcua 1 , Mohamed M. Sarhan 3 , Mohamed E. El Zowalaty 4 ,
Hazem Ramadan 5 , Melissa Morgan 6 and Yosra A. Helmy 1, *

1 Department of Veterinary Science, Martin-Gatton College of Agriculture, Food and Environment,

University of Kentucky, Lexington, KY 40546, USA
2 Botany and Microbiology Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
3 Faculty of Pharmacy, King Salman International University (KSIU), Ras Sudr 8744304, Egypt
4 Veterinary Medicine and Food Security Research Group, Medical Laboratory Sciences Program,
Faculty of Health Sciences, Abu Dhabi Women’s Campus, Higher Colleges of Technology,
Abu Dhabi 41012, United Arab Emirates
5 Hygiene and Zoonoses Department, Faculty of Veterinary Medicine, Mansoura University,
Mansoura 35516, Egypt
6 Department of Animal and Food Sciences, Martin-Gatton College of Agriculture, Food and Environment,
University of Kentucky, Lexington, KY 40546, USA
* Correspondence: [email protected]

Abstract: Salmonella is a major foodborne pathogen and a leading cause of gastroenteritis in humans
and animals. Salmonella is highly pathogenic and encompasses more than 2600 characterized serovars.
The transmission of Salmonella to humans occurs through the farm-to-fork continuum and is com-
Citation: Lamichhane, B.; Mawad, monly linked to the consumption of animal-derived food products. Among these sources, poultry and
A.M.M.; Saleh, M.; Kelley, W.G.; poultry products are primary contributors, followed by beef, pork, fish, and non-animal-derived food
Harrington, P.J., II; Lovestad, C.W.; such as fruits and vegetables. While antibiotics constitute the primary treatment for salmonellosis,
Amezcua, J.; Sarhan, M.M.; El the emergence of antibiotic resistance and the rise of multidrug-resistant (MDR) Salmonella strains
Zowalaty, M.E.; Ramadan, H.; et al. have highlighted the urgency of developing antibiotic alternatives. Effective infection management
Salmonellosis: An Overview of necessitates a comprehensive understanding of the pathogen’s epidemiology and transmission dy-
Epidemiology, Pathogenesis, and namics. Therefore, this comprehensive review focuses on the epidemiology, sources of infection,
Innovative Approaches to Mitigate
risk factors, transmission dynamics, and the host range of Salmonella serotypes. This review also
the Antimicrobial Resistant Infections.
investigates the disease characteristics observed in both humans and animals, antibiotic resistance,
Antibiotics 2024, 13, 76. https://
pathogenesis, and potential strategies for treatment and control of salmonellosis, emphasizing the
doi.org/10.3390/antibiotics13010076
most recent antibiotic-alternative approaches for infection control.
Academic Editors: Carlos M. Franco
and Nicholas Dixon Keywords: Salmonella; Foodborne pathogens; antibiotics; antibiotic resistance; antibiotic-alternatives
Received: 21 November 2023
Revised: 24 December 2023
Accepted: 10 January 2024
Published: 13 January 2024 1. Introduction
Salmonella is a foodborne pathogen that belongs to the family Enterobacteriaceae. It
causes human gastroenteritis and can inhabit animals, amphibians, and reptiles [1,2]. The
transmission of Salmonella to a healthy host occurs through the consumption of contami-
Copyright: © 2024 by the authors.
nated food and water [3,4]. Salmonella has been causing a significant impact on health and
Licensee MDPI, Basel, Switzerland.
economics worldwide [5]. The World Health Organization (WHO) describes Salmonella as
This article is an open access article
one of the four most important causes of diarrhea worldwide [6]. The Centers for Disease
distributed under the terms and
Control and Prevention (CDC) estimates that approximately 1.35 million people are infected
conditions of the Creative Commons
with Salmonella, with about 420 deaths annually. The economic burden caused by Salmonella
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
comes at the third position among a list of the annual cost of illness caused by 14 foodborne
4.0/).
pathogens, with an annual cost of about $3.3 billion [7]. Annually, around 200 million

Antibiotics 2024, 13, 76. https://doi.org/10.3390/antibiotics13010076 https://www.mdpi.com/journal/antibiotics

Antibiotics 2024, 13, 76 2 of 51

to 1 billion cases of Salmonella infections are recorded worldwide, with 93 million cases
of gastroenteritis and 155,000 deaths; among them, approximately 85% of the cases are
associated with the consumption of contaminated food [8]. Salmonella outbreaks in 2022
alone in the US caused about 884 cases across 48 states between February and July, which
were mainly attributed to poultry and poultry products [9,10]. Salmonella is classified as
one of the category B pathogens with moderate morbidity and low death rates [11]. The
severity of the infection in humans varies depending on the serotype of the bacteria and the
immune status of the host, with the infection classified into typhoidal and non-typhoidal
types [12]. Non-typhoidal Salmonella infections are often associated with acute onset of
diarrhea, abdominal cramps, and fever [13]. It is usually self-limiting, resolving between
1 and 7 days without treatment, depending on the host status [14]. However, about 5% of
people, including immune-compromised patients, infants, and older adults, may develop
bacteremia or invasive infections such as meningitis, osteomyelitis, endovascular infections,
and septic arthritis [10,15]. The typhoidal Salmonella serovars are responsible for non-specific
disseminated infections, with symptoms including sustained fever (39–40 ◦ C), headache,
diarrhea or constipation, loss of appetite, and relative bradycardia [6,16–20].
Salmonella infects birds of all age groups. However, young chickens and turkeys
are highly susceptible within the first two weeks of age. The disease is characterized
by poor body condition, such as ruffled feathers, weakness, and anorexia. Additionally,
infected birds tend to huddle together, exhibit diarrhea and a pasty vent, with decreased
egg production, and post-mortem examination shows signs of a swollen liver and spleen
with hemorrhages [21–23]. Studies have suggested that over 52% of Salmonella infections
in poultry are caused by S. Enteritidis, making it one of the most prevalent serotypes of
Salmonella in the US [24], whereas, according to the National Veterinary Services Laboratory,
the most common serotype in livestock, especially cattle, was found to be S. Dublin (18%),
followed by S. Cerro (16%) and S. Typhimurium (13%) [25].
Treating salmonellosis in humans and animals typically relies on antibiotics [26].
Broad-spectrum antibiotics are normally used to treat highly susceptible individuals with
clinical complications [27]. Chloramphenicol and trimethoprim/sulfamethoxazole antibi-
otics were first used for the treatment of salmonellosis [28]. Currently, third-generation
quinolones such as fluoroquinolones, including ciprofloxacin and ofloxacin, are the drug of
choice for treating Salmonella infection in immunocompromised patients [29]. Due to the
increasing bacterial resistance against fluoroquinolones, cephalosporins like ceftriaxone and
macrolides like azithromycin are being used as empiric treatment to control Salmonella in-
fections [15,30,31]. Like antibiotics, vaccines are also used to prevent and control Salmonella
infections in humans and animals [32]. There are two vaccines for Salmonella approved
by the Food and Drug Administration (FDA): the live attenuated Ty21a oral vaccine and
intra-muscular Vi polysaccharide capsular vaccine, whereas several other vaccines such
as the GMMA-based vaccine, glycoconjugate vaccine, O-antigen glycoconjugate vaccines,
and new attenuated vaccines are still in development [33,34]. The effectiveness of vaccines
against Salmonella is constrained by various factors such as the presence of asymptomatic
carriers, which makes it difficult to design vaccines, complex immune evasion mecha-
nisms, and the presence of diverse serotypes [35]. Currently, available typhoid vaccines
provide only moderate and short-term protection in humans [36]. Additionally, Salmonella
serotypes are highly variable, with significant genetic diversity within and between hosts,
complicating the efforts to control the pathogen [37–40].
Therefore, there is a critical need for developing novel antibiotic alternative approaches
to control Salmonella infections in animals and humans, including probiotics, prebiotics
and bacteriophage, antimicrobial peptides, essential oils, and vaccines [40,41]. In this
review, we discuss the epidemiology of salmonellosis with emphasis on transmission
dynamics, host spectrum, clinical signs, the most recent outbreaks, and pathogenesis.
We also provide insights on the current antibiotic treatment and emphasize the novel
antibiotic alternatives developed/under development to control AMR-Salmonella infections
in animals and humans.
Antibiotics 2024, 13, 76 3 of 51

2. Epidemiology of Salmonellosis
2.1. Salmonella Serotypes and Host Spectrum
Approximately 2659 Salmonella serovars were identified according to the White–
Kauffmann–Le Minor scheme in the published supplement (no. 48–2014) [42]. Salmonella
serovars are classified into typhoidal and nontyphoidal (NTS) according to their ability
to develop specific pathogenicity in humans and animals [43]. Typhoidal serovars that
cause typhoid and paratyphoid fever in humans include S. Typhi, S. Paratyphi A, B, C, and
S. Sendai [44]. These serovars are highly host-specific and are only transmitted from in-
fected hosts or carriers through contaminated food and water [45]. Typhoidal salmonellosis
is characterized by high mortality and low morbidity [46]. However, NTS includes more
than 2000 serotypes, which predominantly include S. Enteritidis, S. Typhimurium, S. New-
port, and S. Heidelberg, and can infect both humans and animals [47]. Some NTS serovars
like S. Typhimurium phage type DT2, S. Abortusovis, S. Typhisuis, S. Gallinarum, and
S. Pullorum primarily infect pigeons, sheep, swine, aquatic birds, and poultry, respectively,
whereas S. Dublin and S. Choleraesuis primarily infect cattle and pigs [48–50]. Moreover,
NTS can easily adapt to a wide range of hosts and can quickly spread from infected hosts
by consuming contaminated food and water [51]. The invasive nontyphoidal Salmonella
[iNTS] are more virulent than other non-iNTS types; however, most of the iNTS serovars are
similar to non-iNTS in terms of the type of illness, susceptibility to the high-risk group, and
other characteristics such as the development of multidrug resistance [46]. The ability of
Salmonella to adapt to the host’s environment and trigger clinical symptoms in that specific
host is influenced by factors such as the dosage of the infecting bacteria, the host species
involved, the age of the host, and its immune status [52]. For example, S. Choleraesuis
serovar is a pig-adapted serovar, and it produces the most severe sickness in pigs compared
to humans [53]. Some serotypes like S. enterica serovar Typhimurium have been listed as
the prototypical broad host range serotype that can infect humans, livestock, domestic
fowl, horses, swine, pigeons, rodents, and birds [51]. Other serovars such as S. enterica
subspecies can be classified as host-generalist, host-adapted, or host-restricted [54]. They
have developed mechanisms for surviving within the host while avoiding immune re-
sponses via colonizing the non-phagocytic cells [55]. For example, S. Typhi spreads from
the gastrointestinal tract to the reticuloendothelial system. Moreover, it normally colonizes
the surface of gallstones upon dissemination [56]. Approximately 1–6% of people infected
with Salmonella Typhi do not display clinical symptoms after primary infections but be-
come asymptomatic and chronic bacterial carriers [57,58]. Conversely, the pathogenesis
of host-generalist serovars frequently results in gastroenteritis, and Salmonella shedding
occurs for a very short time [59]. Because of their limited long-term shedding capability,
the lifetime of host-generalist NTS is more dependent on their ability to survive in the
environment [60].

2.2. Source of Infection and Mode of Infection Transmission in Humans and Animals
Because Salmonella species are thought to be part of the normal microbiota of an
animal’s gut or gallbladder, these animals may also play a role in the pathogen’s indirect or
direct transmission to humans [61]. The sources of Salmonella infection include (1) Poultry
and poultry products, which are considered the primary source of Salmonella infection in
humans [62]. Meat contamination occurs generally as a result of improper handling of
the infected organs, such as the gut and liver, during carcass processing [63]. Salmonella
infection in 44 broiler and 51 layer farms was investigated, where Salmonella was found
in 41.3% of the broiler houses, and nearly 50% of the strains identified were capable of
producing biofilm [64]. In the US, a previous report demonstrated that the prevalence
of S. Enteritidis serovar in chicken products has grown from 0.45% to 1.5% within a
period of 10 years (2002–2012), implying that poultry meat is one of the substantial risk
factors for human infection [45]. Frozen raw breaded chicken products (FRBCP) have
also been recognized as a Salmonella risk factor in Canada and the US [65]. From a list of
18 food sources, eggs and egg products were the most frequent sources of salmonellosis
Antibiotics 2024, 13, 76 4 of 51

outbreaks [66]. (2) Ground meat: The CDC conducted a population survey which found
that 82.2% of Americans consume beef weekly, with 67% explicitly preferring ground
beef [10]. It was determined that chicken, pig, and beef were responsible for 34, 25, and 16%
of Salmonella outbreaks, respectively [27,67], and 10% of human salmonellosis is attributed
to beef consumption in the US [10]. A recent outbreak of salmonellosis has resulted in
over 400 reported infections, with more than 100 individuals requiring hospitalization. The
outbreak was attributed to antibiotic-resistant (AMR) S. Newport, which was traced back
to the consumption of ground beef in 30 different states [68]. (3) Pets may contaminate
the environment and transmit infection to other food-producing animals by sporadically
shedding bacteria in their feces [69]. Pets like dogs fed on raw food diets are more likely
to harbor Salmonella serovars such as S. Typhimurium, S. Heidelberg, and S. Kentucky.
Moreover, the probability of Salmonella shedding was around 23 times higher in dogs on
raw food diets than in dogs on commercial diets [70,71]. Furthermore, a case–control study
on salmonellosis in children in Michigan revealed that exposure to cats is one of the major
risk factors for Salmonella infection [72]. (4) Wild animals, including wild boar and feral pigs,
play a crucial role in transmitting Salmonella to both domesticated animals and humans
globally [73]. Salmonella is frequently detected in various wild mammals, such as opossums,
raccoons, foxes, mink, tigers, cougars, seals, white-tailed deer, and whales, as well as wild
birds [73]. Domesticated animals become infected through contact with the contaminated
feces of wild animals and birds [74]. In humans, transmission commonly takes place either
through direct contact with the contaminated feces from infected animals or from the
consumption of contaminated meat from wild birds and other wild animals such as deer
or wild boars [75]. Several studies have been conducted to determine the prevalence of
Salmonella in wild animals. For example, Cummings et al., found that out of 442 fecal
samples obtained from feral pigs across 50 counties in Texas, USA, 43% tested positive for
Salmonella. Among these samples, the most prevalent serovars were S. Montevideo (10%),
S. Newport (9.1%), and S. Give (8.2%) [76]. Likewise, Molino et al. demonstrated that upon
analyzing tissue samples from 1041 wild boars from central–western Spain, 7.7% were
positive for Salmonella and S. Newport was the most prevalent serovar [75]. Similarly, out
of 225 fecal samples collected from captive wildlife and exotic animals including giraffes,
cranes, and raccoons from Ohio, USA, 24.9% (n = 56) were positive for Salmonella and
the most common serovars included S. Typhimurium (64.3%), S. Newport (32.1%), and
S. Heidelberg (5.3%) [77]. (5) Insects are also one of the vectors for transmitting Salmonella in
the farm setting. Research has demonstrated that houseflies and dump flies, namely Musca
domestica and Hydrotaea aenescens, can carry S. Enteritidis, S. Heidelberg, and S. Infantis
serotypes [78]. Similarly, larvae and adult lesser mealworms (Alphitobius diaperinus) have
also been found to harbor AMR S. Enteritidis and transmit infections in farm settings [79].
Furthermore, 15 different serotypes, including S. Anatum, S. Choleraesuis var. kunzendorf,
and S. Derby, were found in common house flies (Musca domestica) on a swine farm [80].
Moreover, 13 of these serotypes were found in swine fecal samples, with S. Anatum and
S. Derby being the predominant ones [81]. (6) Rodents such as house mice are one of
the significant sources of infection on farms. It was reported that the house mouse (Mus
musculus) plays a crucial role in transmitting Salmonella Enteritidis infection among farm
animals [82]. Additionally, species such as the roof rat (Rattus rattus) are also known sources
of S. Enteritidis infections [83,84]. Various studies have reported that R. rattus, R. norvegicus,
and M. musculus domesticus are all implicated as sources of several Salmonella serotypes
in poultry and pig farms [83,85–87]. Similarly, the CDC defines other host species, such
as reptiles and amphibians, as hosts that can harbor Salmonella and transmit the infection
to humans and farm animals [9]. Additionally, the ability of Salmonella to form biofilms,
enabling it to attach to and endure various environmental surfaces, vegetables, fruits, and
chicken egg shells, as well as surfaces in proximity to animal living areas, like vacuum
cleaner bags, sink drains, and doorknobs in households, helps in the further transmission of
the bacteria to the mammalian hosts [46,88,89]. Other sources such as water, contaminated
 fines other host species, such as reptiles and amphibians, as hosts that can harbor Salmo-
nella and transmit the infection to humans and farm animals [88]. Additionally, the ability
of Salmonella to form biofilms, enabling it to attach to and endure various environmental
surfaces, vegetables, fruits, and chicken egg shells, as well as surfaces in proximity to an-
Antibiotics 2024, 13, 76 imal living areas, like vacuum cleaner bags, sink drains, and doorknobs in households, 5 of 51
helps in the further transmission of the bacteria to the mammalian hosts [46,89,90]. Other
sources such as water, contaminated floors, carts, using contaminated water for crop irri-
floors,
gation,carts, usingcontact
or direct contaminated
with feces water
from foranimals
crop irrigation,
carryingor direct contact
Salmonella withtransmit
can also feces fromthe
animals
infectioncarrying
to humans Salmonella
[91,92].can also transmit the infection to humans [90,91].
The
The transmission
transmission of ofSalmonella
Salmonella serotypes
serotypesoften oftenvaries
variessignificantly
significantlybetween
between human
human
and
andanimal
animalpopulations
populationsin inthe
thesame
samegeographical
geographicalregion region[92]. Various Salmonella
[93]. Various Salmonellaserotypes
serotypes
exhibit
exhibitdiffering
differingpotentials
potentialsfor forcausing
causinghumanhumandisease
disease[14].
[14].However,
However,the thetransmission
transmissionof of
Salmonella
Salmonella infections can occur through direct or indirect contact at home, hospital,or
infections can occur through direct or indirect contact at home, hospital, orfarm
farm
settings;
settings; however, most most of ofthe Salmonella-relatedillnesses
theSalmonella-related illnessesthat
that occur
occur globally
globally each
each year
year are
are foodborne
foodborne [94].[93].
TheThe transmission
transmission of Salmonella
of Salmonella may may occuroccur by direct
by direct contact
contact throughthrough
direct
direct consumption
consumption of fecal-contaminated
of fecal-contaminated food or food or water
water [94]. Vertical
[95]. Vertical transmission
transmission occursoccurs
typi-
typically in birds and reptiles where the bacteria from the female
cally in birds and reptiles where the bacteria from the female reproductive tract obtainreproductive tract obtain
access
access toto the
theeggs
eggs[95].
[96]. The
The introduction
introduction of of the
the pathogen
pathogen relies
relies upon
upon the
the thickness
thickness and
and
permeability of an eggshell, where the reptiles’ eggshell is more thinner
permeability of an eggshell, where the reptiles’ eggshell is more thinner and permeable and permeable than
avians [96], whereas
than avians indirectindirect
[97], whereas transmission occurs when
transmission occursthe bacteria
when are transmitted
the bacteria through
are transmitted
intermediate objects such
through intermediate as contaminated
objects utensils and
such as contaminated live orand
utensils inanimate vectors [46].
live or inanimate The
vectors
transmission cycle of Salmonella is shown in Figure
[46]. The transmission cycle of Salmonella is shown in Figure 1. 1.

Figure1.1.Transmission
Figure Transmissioncycle
cycleof
ofSalmonella
Salmonellabetween
betweenanimals
animalsand
andhumans.
humans.

2.3. Risk
2.3. Risk Factors
Factorsand
andHigh-Risk
High-RiskGroups
Groups
Risk factors
Risk factors for
for aaparticular
particularpathogen
pathogenvaryvary depending
depending onon the
theenvironmental
environmental stress
stress
thehost
the hostand
andthe
thepathogen
pathogenendure
endure[97].
[98].According
Accordingto tothe
theCDC,
CDC,infections
infectionswith
withSalmonella
Salmonella
are more
are more prevalent
prevalent during
during the
the summer
summer (June,
(June, July,
July, and
and August)
August) than
than in
in the
the winter
winter [98].
[99].
Moreover,poorly
Moreover, poorlybreastfed
breastfedinfants,
infants,young
youngchildren
childrennormally
normally under
under the
the age
age of
of five
five years,
years,
elderly, and immunocompromised individuals are the most vulnerable to severe Salmonella
infections [99,100]. Certain drugs, such as stomach antacids and antibiotics, can create
gut dysbiosis, thus increasing the risk of Salmonella infections [101]. The development
of clinical symptoms between animals can vary depending on various factors, including
animal species, age groups, and geographical area. The risk factors for animal infections
include stress, co-infection with another pathogen, and contaminated food [14]. The size of
animal herds increases the risk of salmonellosis in farm animals, and bacterial shedding
appears to be impacted by different factors such as production methods, housing types,
general cleanliness standards, management practices, and the age of the animals [102–105].
Moreover, environmental factors such as dust, dirty surfaces, and chicken excrement are
Antibiotics 2024, 13, 76 6 of 51

the known risk factors for acquiring the infections [106]. In humans, nail-biting, contact
with animal excreta, sucking the thumb in children, and eating without properly sanitizing
hands after farm work are considered potential risk factors for animal-acquired Salmonella
infections [14,107]. Consuming contaminated food is one of the most significant risk factors
in humans [108,109].

2.4. Clinical Signs in Humans and Animals

2.4.1. In Humans
Typhoidal Salmonella serovars, such as S. Typhi or S. Paratyphi, are the causative
agents of enteric fever, also known as typhoid or paratyphoid, respectively [110]. Globally,
there are 11–21 million instances of typhoid fever and 5 million cases of paratyphoid fever
each year, resulting in approximately 135,000–230,000 deaths annually. In the US, around
400 confirmed cases of typhoid fever and 5–100 cases of paratyphoid fever tested positive
in cultures between 2016 and 2018. Notably, more than 85% of these cases occurred in
individuals who had traveled internationally [94]. The incubation period of enteric fever
is marked by a duration of one week or longer, during which individuals experience
several symptoms, such as high fever, diarrhea, vomiting, and headache [92]. Throughout
enteric fever, a notable fever pattern emerges. It begins with a low-grade fever (>37.5 ◦ C
to 38.2 ◦ C) and gradually progresses to a high-grade fever (>38.2 ◦ C to 41.5 ◦ C) in the
second week [111]. The fever can persist without appropriate treatment for a month or
even longer [112]. In addition to fever, infected individuals may experience myalgia,
bradycardia, hepatomegaly (enlarged liver), splenomegaly (enlarged spleen), and rose
blotches on their chest and abdomen [113]. Approximately 15% of infected individuals
in endemic areas experience gastrointestinal problems such as pancreatitis, hepatitis, and
cholecystitis [114]. Hemorrhage is one of the most serious gastrointestinal complications
caused by the perforation of Peyer’s patches, the lymphatic nodules found in the terminal
ileum causing bloody diarrhea [115]. Furthermore, typhoidal Salmonella’s nature to live and
remain in the reticuloendothelial system results in recurrence in around 10% of infected
individuals [116].
Non-typhoidal Salmonella affects approximately 93.8 million people and causes
160,000 fatalities globally each year [6,117]. According to the current surveillance report
in the US on NTS infections in humans, most of the isolated serovars are S. Enteritidis,
S. Typhimurium, and S. Newport [118], while S. enteritidis are the most common serotype
recovered from clinical samples in Asia, Europe, and Latin America [119]. The infection
is typically self-limiting and the symptoms normally last for about a week [120]. The
incubation period ranges from 6 h to 6 days after initial inoculation and the infection
normally lasts for 4 to 7 days. Shedding of the bacteria via feces may last for a month or
longer [121]. The most common human symptoms include gastroenteritis, accompanied by
clinical signs including nausea, vomiting, headache, abdominal pain, non-bloody diarrhea,
and muscle pain [122]. The severity of the infections increases in susceptible individuals
such as babies and children under the age of five years, immunocompromised patients,
and immunocompromised elderly people [123]. Conditions like cholecystitis, pancreatitis,
and appendicitis may manifest and can escalate to severe levels, leading to life-threatening
conditions like meningitis and sepsis [124]. Inadequate fluid balance due to prolonged
loss of bodily fluids can lead to dehydration, which may be fatal in newborns and older
adults [125]. Reactive arthritis, a persistent autoimmune joint inflammation, may supervene
even after weeks or months of urogenital or digestive tract infections and occurs in around
20% of clinical cases reported in Europe and the US following Salmonella infections [126].
Furthermore, Salmonella infections are implicated in the development of colonic cancer in
patients suffering from chronic inflammatory bowel disease (IBD) [127], the risk factor for
colorectal and gallbladder cancer [128].
Antibiotics 2024, 13, 76 7 of 51

2.4.2. In Animals
Salmonella infections are prevalent among various animals, encompassing both do-
mesticated and wild species [129]. This bacterium typically affects the host gastrointestinal
tracts, often without readily apparent symptoms of illness [130]. Salmonella can present
itself at both clinical (symptomatic) and sub-clinical (asymptomatic) levels [131]. Poultry
can serve as healthy carriers and the clinical signs in poultry depend on the bacteria’s
serotype [132]. For instance, S. enterica serovar Pullorum causes anorexia, diarrhea, dehy-
dration, and death in young poults, and adult birds demonstrate diarrhea, decreased egg
production, poor hatchability, and increased mortality [133], whereas fowl typhoid can
be characterized by acute diarrhea, dehydration, weakness, septicemia, and death [129].
Nevertheless, regardless of the bacterial serotype, all Salmonella infections in poultry are
commonly characterized by pronounced symptoms, including extensive diarrhea, fever,
weight loss, dehydration, and death [130]. Similarly, Salmonella infections in animals vary
based on the age group and specific bacteria serotype, particularly in large and small
ruminant animals [134]. Ruminants and pigs commonly exhibit acute enteric infections,
characterized by clinical indications such as fever, reduced appetite, lethargy, and diarrhea.
Conversely, systemic infections tend to be more prevalent among younger animals [135].
Notably, abortion has been extensively recorded in cattle specifically attributed to NTS
serotypes S. Typhimurium and S. Dublin [136]. The infection in dogs and cats can be mani-
fested by anorexia, fever, nausea, vomiting, acute gastroenteritis anorexia, abdominal pain,
and diarrhea [137]. Similarly, horses are also considered a risk group for Salmonella infec-
tions, with atypical symptoms such as voluminous gastric reflux, diarrhea, and fever [138].
They can also serve as asymptomatic carriers of the bacteria, thereby shedding them into
the environment and disseminating the infection throughout the farm or facility [139,140].

2.5. Prevalence of Salmonellosis and the Most Recent Salmonella Outbreaks

Currently, the advancement of science and technology and globalization have made
international trade and travel easily accessible to the general population [43]. However, it
has increased the risk of the rapid spread of infectious diseases throughout the world [119].
Controlling an outbreak of foodborne pathogens such as Salmonella can be challenging due
to several factors, such as environmental factors and the high risk of indirect transmission
through the consumption of Salmonella-contaminated food and water, which may originate
from any source [130]. Salmonella infection presents significant public health concerns due
to its propensity for endemicity, high rates of morbidity and mortality, and the challenge of
implementing effective and timely control measures [119]. Salmonella causes approximately
1.35 million illnesses, with 26,500 annual hospitalizations and 420 fatalities in the US each
year, as tracked by the Foodborne Diseases Active Surveillance Network (FoodNet) [140].
It was suggested that there is a substantial relationship between Salmonella serovar and the
type and origin of the food commodity [141]. For example, outbreaks linked to poultry
are generally associated with S. Enteritidis, S. Heidelberg, and S. Hadar, while outbreaks
of S. Uganda have been associated with the consumption of contaminated pork and beef
meat [141]. Outbreaks associated with farm products such as fruits and vegetables have
also been documented [125]. Several reports suggest that improper handling of infected
chicks is also responsible for a considerable number of human outbreaks of salmonellosis,
mainly involving serovars such as S. Typhimurium, S. Johannesburg, S. Braenderup,
S. Thompson, and S. Montevideo [43]. The serovars S. Typhimurium and S. Enteritidis are
also linked with the zoonotic transmission of salmonellosis from companion animals such
as kittens, guinea pigs, hedgehogs, and turtles [98].
Salmonella is a highly virulent pathogen and the presence of as low as 10 CFU/mL
of bacteria typically represents a high potential for pathogenicity [142]. In 2018, about
92,000 confirmed human salmonellosis cases were documented in the US alone [143]. NTS
causes over 100,000 gastroenteritis illnesses in Canada annually [144]. S. Enteritidis stands
out as the predominant serovar, accounting for around 45% of human salmonellosis cases
in Canada, followed by S. Typhimurium and S. Heidelberg, constituting 8% and 6% of such
Antibiotics 2024, 13, 76 8 of 51

cases, respectively [145]. Similarly, S. Typhimurium is the most common serovar in humans
in North America and Oceania, regardless of the source, followed by S. Enteritidis [146].
In contrast, S. Enteritidis ranked as the most common serovar in the European Union,
followed by S. Typhimurium. However, S. Enteritidis was reported in pork only in Africa
and Asia [147,148]. In Europe, a total of 1508 Salmonella outbreaks were included in the
European Food Safety Authority (EFSA) analysis. Of these, 1040 were caused by foods,
including salads, steak, and ham, whereas 468 outbreaks were caused by unknown food
sources including complex foods like bakery products containing eggs, dairy products,
and grains [148]. Approximately 939 outbreaks were recorded to be caused by S. Enteri-
tidis, 130 by S. Typhimurium and its monophasic variant, 107 by other known serotypes,
and 332 by unknown types in the European Union [66]. In May 2022, 324 cases were
reported in 12 EU/EEA countries and the UK, including two distinct strains of monophasic
S. Typhimurium. Most cases were in children below ten years of age, and 41% of all
cases were hospitalized. Chocolate products in Belgium were reported to be a source
of infection [149]. The most recent Salmonella outbreaks in the US, their source, and the
identified serotype are shown in Table 1. Between 2012 and 2023, there were approximately
86 outbreaks, and 18,031 illnesses occurred in the US alone.

Table 1. Salmonella outbreaks in the US through the last 10 years and their source according to CDC.

Number of Number of
Year Identified Serotypes Source
Outbreaks Illnesses
Bredeney, Braenderup, Typhimurium, Peanut butter, mangoes, cantaloupe, ground
2012 9 1217 Newport, Enteritidis, Bareilly, Nchanga, beef, raw scraped ground tuna product,
Hadar, Infantis, Newport, Lille hedgehogs, live poultry
Sandiego, Pomona, Poona, Heidelberg,
Small turtles, foster farms brand chicken,
Montevideo, Mbandaka, Saintpaul,
2013 9 2278 tahini sesame paste, cucumber, ground beef,
Typhimurium, Infantis, Lille,
live poultry
and Newport
Cotham, Heidelberg, Stanley, Bearded dragons, chicken, organic sprouted
2014 8 429 Typhimurium, Newport, Hartford, chia powder, nut butter, raw cashew cheese,
Oranienburg, and Braenderup frozen rodent feed, cucumbers
Bean sprouts, raw sprouted nut butter
Enteritidis, Paratyphi B variant L (+)
spreads, cucumbers, raw, frozen, stuffed
2015 8 1512 tartrate (+), Weltevreden, Sandiego,
chicken entrees, frozen raw tuna, live
Poona, Hadar, Indiana, and Muenchen.
poultry, and small turtles
Oranienburg, Reading, Abony, Shell eggs, alfalfa sprouts, pistachios,
2016 5 114 Montevideo, Senftenberg, Muenchen, organic shake and meal products, dairy
Kentucky, Virchow, and Heidelberg. calves, and live poultry
Pet turtles, live poultry,
2017 5 2171 Agbeni, and Typhimurium
laboratory exposure.
Cut fruit, ground beef, papayas, kawaran
Javiana, Dublin, Uganda, Concord,
brand tahini, pre-cut melon, butterball,
2019 9 1632 Carrau, Schwarzengrund,
brand ground turkey, pet turtles, backyard
Oranienburg, Typhimurium
poultry, and hedgehogs
Wood ear mushrooms, peaches, onions, pet
Stanley, Enteritidis, Newport, Muenster,
2020 8 3107 bearded dragons, pet hedgehogs, backyard
Typhimurium, Hadar
poultry, and small pet turtles
Seafood, pet turtles, Italian-style meats,
onions, prepackaged salads, frozen cooked
Thompson, Oranienburg, Typhimurium,
2021 10 2575 shrimp, raw frozen breaded stuffed chicken
Weltevreden, Infantis, Enteritidis, Hadar
products, cashew brie, ground turkey,
backyard poultry, wild songbirds
Antibiotics 2024, 13, 76 9 of 51

Table 1. Cont.

Number of Number of
Year Identified Serotypes Source
Outbreaks Illnesses
Typhimurium, Litchfield, Senftenberg, Alfalfa sprouts, fish, peanut butter, pet
2022 7 1469
Stanley, and Uganda bearded dragons, small turtles, poultry
Raw cookie dough, flour, ground beef, fresh
Enteritidis, Thompson, Saint Paul,
2023 8 1527 diced onion, cantaloupes, small turtles, dry
and Infantis
dog food, and poultry

3. Pathogenesis and Virulence Factors

The pathogenesis of Salmonella serotypes starts with the adherence of the bacteria to
the host cell surface [150]. After adhesion, bacteria’s internalization occurs either through
the uptake of bacteria via phagocytosis or by active invasion of both phagocytic and
non-phagocytic cells [27,151]. The phagocytosis process involves intricate mechanisms
that rely on the engagement of multiple receptors, such as Pattern Recognition Recep-
tors (PRRs) [152]. The PRRs include toll-like receptors (TLRs) and cytosolic nucleotide-
binding receptors, which recognize pathogen-associated molecular patterns (PAMPs) like
lipopolysaccharides (LPS) and flagellin located on either the cell surface or within phago-
somes [27]. This recognition influences the maturation of phagosomes, triggers signaling
pathways, and modulates gene expression [152–154]. Studies suggest that the interaction
between the TLR and LPS in NTS species plays a vital role in developing septic shock [155].
However, the typhoidal serovars, including S. Typhi, evade recognition by TLR4, thus pre-
venting the recruitment of neutrophils and the expression of pro-inflammatory molecules
such as TNF-α and Interleukin 1β (IL-1β) and preventing a typical antimicrobial response
in the host [154,156]. The level of production of the cytokines in human monocytes is,
however, similar to those elicited in the NTS infections [157,158]. This is an essential stage
in the invasion of Salmonella and occurs by infiltrating both phagocytic and non-phagocytic
cells [159]. Invasion and colonization of Salmonella in the host cells rely on several virulence
factors, including:

3.1. Virulence Plasmid

Virulence plasmids play a crucial role in bacteria by harboring genes related to an-
tibiotic resistance and virulence factors such as spvB (ADP-ribosylating toxin) and spvC
(inhibits pyroptosis and inflammation) [160,161]. Virulence plasmids are required to de-
velop the systemic disease in the host and can spread through horizontal gene transfer by
transformation and conjugation [162]. They are large and present in low copy numbers to
minimize the strain on the host’s cell metabolism, preventing them from being retained
during cell division [163]. In response, virulence plasmids have evolved to guarantee
distribution, preserving their presence [163].

3.2. Type III Secretion Systems

Type III secretion systems (T3SSs) are responsible for translocating effector proteins
from prokaryotic cytoplasm to the eukaryotic cytosol [164]. In Salmonella, the T3SS is en-
coded by two distinct pathogenicity islands, namely SPI1 and SPI2 [165]. SPI-1 encodes the
T3SS1 and plays a crucial role in invading non-phagocytic epithelia [166]. SPI-2 encodes the
T3SS2 effector proteins that function by regulating the dynamics of Salmonella-containing
vacuole (SCV) membranes, placing SCVs in specific positions within host cells, influencing
immune responses, modifying the cytoskeleton, and impacting the movement of infected
cells [167,168]. These effector proteins combine to undermine the cytoskeleton, signal
transduction pathways, and pro-inflammatory responses of the host [169].
Antibiotics 2024, 13, 76 10 of 51

3.3. Type 1 Secretion System (T1SS)

The Type 1 secretion system is responsible for delivering a wide range of molecules
like lipases, surface proteins, toxins, and adenylate cyclase into the extracellular space of
Salmonella [170]. It is also responsible for mediating adhesion and invasion into the host
immune cells and biofilm formation [171]. Two distinct surface-associated proteins, BapA,
responsible for adhering to host cells and forming biofilms, and SiiE, responsible for the
initial attachment to host cells followed by invasion, are transported through a specialized
Type 1 secretion system (T1SS) [172].

3.4. Superoxide Dismutase

Superoxide dismutase (SOD) is a group of enzymes that catalyze the conversion of
superoxide radicals (O2 − ) into molecular oxygen (O2 ) and hydrogen peroxide (H2 O2 ) [173].
Numerous host cells generate reactive oxygen species, primarily via the functioning of the
phagosome NADPH oxidase, which is essential for eliminating intracellular pathogens [174].
To counterbalance this effect, Salmonella uses superoxide dismutases and SodCI and SodCII
enzymes, which help the bacteria in cellular defense against reactive oxygen species [175].
Both of the enzymes are produced during the infections; however, SodCI relative to SodCII
is tethered within the periplasm and is resistant to proteases [176]. This allows the enzyme
to maintain functionality and help the bacteria survive in the phagosome’s challenging
environmental conditions [177].

3.5. Fimbriae
Adherence to the host cells plays a pivotal role in the progression of Salmonella infec-
tion [178]. Salmonella possesses fimbrial gene clusters (FGCs) within its genome, which
encodes extracellular fimbriae [178]. Among the extracellular fimbriae, one of the most
prevalent adhesive structures is known as type 1 fimbriae (T1F) [179]. T1F is primarily
composed of fimA protein and an adhesive protein fimH, which is critical in binding to
specific receptors, preferably glycoproteins that carry terminal mannose residues [180]. The
adhesive protein fimH is a pathogen-associated molecular pattern recognized by host TLRs
and significantly influences the expression of pro-inflammatory cytokines [181].

3.6. Flagella
The motility of Salmonella is driven by the activity of flagella [182]. Flagella participates
in adhesion, invasion, protein export, and biofilm formation [183]. Biofilm formation is
regulated through the transcription factor CsgD [184]. Salmonella has two genes for flagellin,
fljB and fliC [185]. Out of the two flagellin genes, the expression of fliC is more crucial in
identifying specific sites on host cells than fljB [186]. In bacteria with impaired flagellar
motility, there is an observable diminished adhesion and smaller colony formation in
biofilms [176].

3.7. Vi Antigen
The Salmonella enterica serovar Typhi differs from NTS due to the production of the
‘Vi antigen’, a polysaccharide capsule located on the cell surface [187]. The Vi antigen
inhibits phagocytosis and helps develop resistance against the host immune system [188]. It
is also responsible for the translocation of S. Typhi to the gallbladder as it helps the bacteria
to surpass the phagocyte-mediated barrier [189]. Ultimately, it prevents the binding of
IgM, which gives the pathogen the ability to hinder neutrophil chemotaxis, neutrophil
phagocytosis, and the neutrophil respiratory burst [190].

3.8. Toxins
One of the most significant features of S. Typhi is its ability to produce toxins resulting
in typhoid fever [187]. This typhoid toxin belongs to the group of AB toxins, which include
an enzymatic subunit (A) and a receptor subunit (B) [190]. Salmonella-containing vacuole
Antibiotics 2024, 13, 76 11 of 51

exports toxin from infected cells into the external environment, allowing it to affect other
target cells [190].

3.9. Lipopolysaccharides (LPS)

Lipopolysaccharides are a major component of the outer membrane of any Gram-
negative bacteria responsible for eliciting innate immune response in the host [191]. It
provides cell stability and acts as a permeability barrier [192]. LPS is made up of lipid A, core
oligosaccharide (C-OS), and O-antigen polysaccharide (O-PS) [193]. LPS is also responsible
for adherence or invasion of the host epithelial [192]. The proper distribution of O-antigen is
required to express virulence in S. Typhimurium [194]. It is also responsible for determining
antigenic specificity between and within the bacterial species [192].

3.10. Biofilms
Formation or the ability to develop biofilms is one of the major determinants of
virulence in Salmonella inside the host [195]. Biofilms are the adaptive response that
could alter the gene expression of the bacteria to promote resistance to both environmental
stressors and antibiotics [195]. A Salmonella biofilm is formed by the secretion of a polymeric
matrix characterized by the expression of different factors such as curli fimbriae and
cellulose, which are the two predominant components [196]. Biofilm formation in Salmonella
is regulated by csgD, a curli subunit gene belonging to the LuxR group [197]. The expression
of csgD is regulated by various environmental signals and transcription factors such as
c-di-GMP and sRNAs on a post-transcriptional level [198].

4. Control Strategies for Salmonella Infections

Various control strategies are employed to manage and prevent salmonellosis in hu-
mans. These measures encompass practices related to cleanliness and sanitation, consistent
screening and diagnosis of individuals responsible for food handling, regular surveillance
of potential carrier animals, and treating both carriers and those showing symptoms [20].
In animals, all stages of the production system should be regularly screened for Salmonella
infection, including breeding facilities, vehicles, slaughterhouses, and storage facilities [199].
Several strategies can be used to prevent or control Salmonella infections in humans and
animals, including:

4.1. Management and Biosecurity Measures

Control of salmonellosis in farm settings depends on good management and biosecu-
rity practices [200]. To apply successful biosecurity programs and to control the spread of
infection, the primary source of infection and the methods of transmission within the farm
must be well identified [201]. Any successful biosecurity program must include isolation
of sick animals, traffic limitation, disinfection, and sanitation of the farm [202]. Two types
of biosecurity measures can be conducted to prevent or reduce the risk of infection flowing
in and out of the farm, including external and internal biosecurity practices [203]. External
biosecurity measures are pivotal in minimizing the influx of infections originating outside
the farm premises. These strategies encompass the installation of perimeter fences, reg-
ulating the movement of vehicles to and from the farm and imposing restrictions on the
introduction of animals from external sources [204], whereas internal biosecurity measures
are designed to manage Salmonella transmission within the farm environment effectively.
These tactics include changing footwear and clothing when transitioning from outside to
inside the farm, isolating animals exhibiting symptoms from healthy ones, and routinely
decontaminating the bedding material and transporting vehicles including dead animal
transporters [205,206].
Farm visitors such as veterinarians, stakeholders, salespeople, and technicians are
among the highest-risk visitors as a source of infection [207,208]. Furthermore, the need
for more awareness among certain farmers regarding necessary safety precautions while
moving in and out of the farm can potentially introduce Salmonella infection from neighbor-
Antibiotics 2024, 13, 76 12 of 51

ing farms and the environment. Failure to adequately clean or dispose of their clothing,
boots, and tools can also result in contamination [208]. Several farm safety guidelines can
be implemented to decrease the risk of infection disseminating from personnel, which
includes (1) the movement of the visitors should be strictly restricted [209]; (2) visitors and
workers must be supplied with clean outer clothes and boots [210]; (3) regular organic
matter removal and provide footbaths with disinfectants, especially during working inside
the farm [211]; (4) caring of the animals should always start with the healthy and the
young stock and move to the sick and adult stocks [212]; (5) workers must not use the
same tools for handling both food and manures or at least must be disinfected between
use; (6) tools must not be borrowed from neighboring farms; (7) access to vehicles must
be limited, especially in the farm premise, and vehicles must be cleaned and disinfected
before entering the farm [208,213,214].

4.2. Vector Control and Eradication

According to the World Organization for Animal Health (WOAH), vectors are living
organisms that are not only capable of transmitting a pathogen but also help disseminate the
associated diseases in the population [215]. Some insects, rodents, and wild birds have been
reported as sources of infection incidence, transmission, spread, and maintenance [216].
Rodents and wild birds can harbor the infections from different sources and transmit the
infections to other farm animals through their feces on any part of the farm, including food
and water; therefore, repeated disinfection is required with rodent control [217]. A high
degree of sanitation must be applied, including litter and garbage disposal and proper
filling up of any holes or openings to prevent access for mice. Moreover, supplies must be
stored well in a clean area apart from the main building to avoid rodent access [218]. For the
control of the carrier insects, a high level of sanitation must be maintained in animal farms
and holdings, including regular and fast litter and waste removal, keeping the place well-
ventilated and dry without any stagnant water [218,219]. Synthetic chemical insecticides
and organophosphates can also be used regularly. These include permethrin, fenvalerate,
tetrachlorvinphos (TCVP), dichlorvos organophosphate (DDVP), methomyl, benomyl,
cyromazine, and dimethoate, but most of them have serious toxic effects on humans
and animals, so specific instructions must be followed during their application [220].
Natural extracts such as essential oils with insecticidal or insect repellent activities and
bioinsecticides formed of natural constituents can be used as a healthier and more eco-
friendly, economical, and effective alternative [221]. Pyrethrin, a natural extract from
chrysanthemum flowers, can be used with a lower level of toxicity [222]. Some essential
oils like thyme, cinnamon, rosemary, clove, mint, orange, eucalyptus, and tea tree are
considered to have established insecticide activity with lower toxicity and are registered to
be among the commercially available constitutes of natural pesticides [218,219,223].

4.3. Isolation and Quarantine

The principle of quarantine mainly focuses on two primary goals: prevention of
infection transmission to healthy animals and prevention of transmission in the hospital
setting to vulnerable individuals such as immune-compromised patients, children, and the
elderly [224]. Isolation of a sick person or animal and limiting contact with such individuals
will significantly reduce the risk of contamination and the spread of the disease between
humans and animals. The isolation units should be away from the healthy sheds and should
have a proper manure disposal facility [225]. Regularly cleaning the farm equipment,
utensils, feeders, and drinkers and relevant safe transportation and disposal procedures for
contaminated carcasses are urgently required [226]. The duration of the quarantine period
varies according to the type of pathogen and the status of exposure to the pathogen [112].
For individuals who are healthy and have been exposed, the quarantine period should align
with the pathogen’s incubation period. Conversely, for infected animals, the quarantine
duration should be determined by the time it takes for symptoms to manifest, along with
confirmation through laboratory diagnosis [227]. Together, applying these control measures
Antibiotics 2024, 13, 76 13 of 51

as “biosecurity and hygienic management” can positively impact food safety, and animal,
and human health.

4.4. Antibiotics Used for Salmonella Treatment and Antimicrobial Resistance

The treatment of Salmonella infections typically relies on supportive therapy [228].
The infection is normally self-limiting, and the individuals do not require therapeutic
treatment. However, individuals with weakened immune systems, underlying health
conditions, or severe infection might require antibiotics [229]. In the past, chloramphenicol
was utilized for treating Salmonella infections. The preferred antibiotic choices include
ampicillin, third-generation quinolones such as ciprofloxacin and levofloxacin, third gen-
eration cephalosporins like ceftriaxone, and macrolides [230]. Unfortunately, bacterial
resistance to these important antibiotics has been growing, posing a challenge to effective
treatment [231]. Antibiotic resistance has become a global concern in both non-Typhoidal
and Typhoidal Salmonella strains [232]. The emergence of antibiotic resistance has exhib-
ited an escalating trend of 20–30% per decade [233]. The extent of resistance, however,
varies across different antibiotics and serotypes of the bacteria, highlighting the delicate
interplay between microbial genetic factors, environmental conditions, and the selective
pressures that contribute to the diverse spectrum of AMR strains observed within bacterial
populations [234]. It is noteworthy that serotypes with higher prevalence tend to develop
resistance against commonly prescribed antibiotics more frequently [232]. It was reported
that 30.9% of isolated Salmonella strains from broiler farms exhibited resistance to strepto-
mycin, with 13.9% resistant to tetracycline, 12.6% resistant to gentamycin, and 8.6% resistant
to sulfamethoxazole-trimethoprim [26]. Similarly, a substantial level of resistance was noted
towards ceftriaxone (75%) and ceftiofur (44%) [235]. Multidrug-resistant Salmonella was
also identified in several studies before. For instance, MDR was detected in 17% of broiler
chickens in Egypt, with the highest resistance against neomycin (100%), nalidixic acid and
cefoxitin (95%), norfloxacin (86.3%), cefotaxime (77.2%), amikacin (72.7%), erythromycin
(68.1%), and chloramphenicol (40.9%) [236]. Similarly, 19.6% of S. Infantis isolates from
animals in the US possessed MDR, with the highest resistance observed against aminogly-
cosides, chloramphinecol, beta-lactams, and tetracyclines [237]. Furthermore, in Salmonella
isolated from equines between 2007 and 2015, 10.2% of the samples were MDR strains, with
the highest resistance against aminoglycosides (gentamycin and streptomycin), followed
by beta lactam inhibitors including penicillin (amoxicillin-clavulanic acid and ampicillin),
cephems (cefoxitin, ceftiofur, and ceftriaxone), and folate pathway inhibitors (sulfisoxazole
and trimethoprim), respectively [238]. Furthermore, MDR has also been demonstrated in
wild animals and birds. For example, Cilia et al. found that AMR strain prevalence in
European wild boar hunted in Central Italy possessed 55.6% resistance to streptomycin,
11.1% to cephalothin, and 5.6% to imipenem. Notably, a single isolate (S. Infantis) displayed
multidrug resistance (MDR) to tetracycline, enrofloxacin, nitrofurantoin, nalidixic acid, and
streptomycin [73].
Additionally, another investigation established a significant link between the isolation
of ceftiofur-resistant S. Heidelberg from chickens and subsequent clinical infections in
humans caused by the same bacterial strain [239]. Likewise, another study underscored the
elevated prevalence of AMR strains, including S. Bredeney, S. Kentucky, and S. Enteritidis,
as prominent AMR variants identified in chicken meat. These strains displayed resistance
against rifampicin, tetracycline, and oxyclozanide [240].

4.5. Novel Antibiotic Alternatives

4.5.1. Probiotics
Probiotics are a group of non-pathogenic microorganisms that can confer health
benefits to the host when administered sufficiently [241,242]. According to FAO/WHO
regulations, for probiotics to be used as therapeutic or prophylactic agents, they are required
to fulfill specific criteria such as safety margin, efficacy, immunomodulatory capabilities,
ability to effectively colonize the intestinal epithelium, resistance to bile salts and low pH
 4.5. Novel Antibiotic Alternatives
4.5.1. Probiotics
Probiotics are a group of non-pathogenic microorganisms that can confer health ben-
efits to the host when administered sufficiently [243,244]. According to FAO/WHO regu-
Antibiotics 2024, 13, 76 14 of 51
lations, for probiotics to be used as therapeutic or prophylactic agents, they are required
to fulfill specific criteria such as safety margin, efficacy, immunomodulatory capabilities,
ability to effectively colonize the intestinal epithelium, resistance to bile salts and low pH
conditions,
conditions, as as well
well asas maintaining
maintaining phenotypic
phenotypic and and genetic
genetic stability
stability[245,246].
[243,244].Probiotics
Probiotics
have different mechanisms of action (Figure 2) that include (i)
have different mechanisms of action (Figure 2) that include (i) improving the intestinal improving the intestinal
barrier and gut mucosal integrity, (ii) enhancing intestinal immunity,
barrier and gut mucosal integrity, (ii) enhancing intestinal immunity, (iii) reducing the (iii) reducing the
colonization of intestinal pathogens, (iv) maintaining the balance
colonization of intestinal pathogens, (iv) maintaining the balance between pathogenic and between pathogenic and
beneficial
beneficialmicrobes
microbesininthe thegastrointestinal
gastrointestinaltract,
tract,andand(v)(v)competitive
competitiveexclusion
exclusion and
and secretion
secre-
of antibacterial substances or metabolites such as bacteriocins
tion of antibacterial substances or metabolites such as bacteriocins that suppress that suppress the growth
the
of pathogenic
growth microorganisms,
of pathogenic stimulating
microorganisms, mucous
stimulating secretion
mucous by intestinal
secretion goblet
by intestinal cells
goblet
to limit
cells to epithelial invasion
limit epithelial by pathogens
invasion by pathogensand and
the production
the production of minerals,
of minerals,enzymes,
enzymes, and
trace elements [194,245–249]. Each probiotic strain has different
and trace elements [196,247–251]. Each probiotic strain has different properties and clini- properties and clinical
effects
cal effectson the
on host [250].
the host Probiotics
[252]. are are
Probiotics classified as mono-strain
classified as mono-strain or single-strain
or single-strain probiotics
probi-
(SSP), multi-strain probiotics (MSP), and multi-species probiotics
otics (SSP), multi-strain probiotics (MSP), and multi-species probiotics [253,254]. Single-[251,252]. Single-strain
probiotics (SSP) can
strain probiotics provide
(SSP) limitedlimited
can provide healthhealth
benefits to the to
benefits host
the[253]. Probiotics
host [255]. containing
Probiotics con-
multiple groups of bacteria with different mechanisms of action
taining multiple groups of bacteria with different mechanisms of action tend to have syn- tend to have synergistic
effects
ergisticon each on
effects other
eachand have
other a broad
and have aspectrum of activity
broad spectrum [252,254].
of activity For insistence,
[254,256]. For insist- the
MSP
ence,ofthe Bacillus
MSP of amyloliquefacrem, Enterococcus
Bacillus amyloliquefacrem, hirae, and Lysinibacillus
Enterococcus fusiformis was
hirae, and Lysinibacillus able to
fusiformis
significantly inhibit the growth
was able to significantly inhibitand biofilm and
the growth formation Aeromonasofhydrophila
biofilmofformation Aeromonascompared
hydrophilato
the individual probiotics [255]. Multi-species probiotics (L. reuteri,
compared to the individual probiotics [257]. Multi-species probiotics (L. reuteri, E. E. faecium, B. faecium,
animalis,
P.B.acidilactici, and L. salivarius) greatly reduce S. Enteritidis infections (up to 2.7
animalis, P. acidilactici, and L. salivarius) greatly reduce S. Enteritidis infections (up to 2.7 log reduction)
in
log poultry [256].in poultry [258].
reduction)

Figure2.
Figure 2. Mechanism
Mechanism of
of action
action of
of probiotics.
probiotics.

Several studies
Several studies have
haveshown
shownthat probiotics
that probioticscancan
profoundly affect
profoundly the growth
affect and vir-
the growth and
ulence of Salmonella
virulence in humans
of Salmonella and and
in humans animals [259].[257].
animals TheseThese
effectseffects
includeinclude
preventing adhe-
preventing
sion and and
adhesion invasion of the
invasion of bacteria into into
the bacteria the intestinal epithelial
the intestinal cells, cells,
epithelial alteration in thein
alteration
the expression of virulence genes, modulation of the host immune system through en-
hancing the cytokines’ expression, intestinal permeability, and increasing intestinal villi
height [258,259]. It was reported that Lactobacillus and Bifidobacteria are the most com-
mon probiotics used against Salmonella and are present as normal gut microflora in the
host [260,261]. Many studies have demonstrated that using single strains of probiotics indi-
vidually and in combination can show high efficacy in Salmonella-infected hosts (Table 2).
For example, L. salivarius CTC2197 alone completely inhibited S. Enteritidis C-114 from
the gut of a leghorn chicken 21 days post-infection [262]. Similarly, L. reuteri R-17485 alone
demonstrated more than 1 log reduction, whereas L. johnsonii R-17504 demonstrated a
2 log reduction in cecal Salmonella count in Lohmann White laying hens [263,264]. Another
study demonstrated that probiotic L. plantarum caused a 2.1 log reduction in cecal S. Hei-
delberg in broiler chicken 168 h post-infection [265]. In addition to this, other probiotics
Antibiotics 2024, 13, 76 15 of 51

such as E. faecium NCIMB 11181 demonstrated a reduction in colonization and transloca-

tion of Salmonella in liver tissue by 2.2 log and cecal content by 4.2 log in infected birds
pretreated with E. faecium [266]. Similarly, S. boulardii demonstrated enhanced survival
of the probiotic-treated mice (70%) compared to 40% in untreated ones, with reduced
translocation of Salmonella to the liver [267].
On the other hand, the combination of different Lactobacillus strains, including
L. murinus, L. salivarius, L. pentosus, and P. pentosaceous, demonstrated up to 99% inhi-
bition in Salmonella colonization in pigs, whereas the combination of other strains, such
as L. reuteri R-17485, L. johnsonii R-17504, and L. vaginalis R-17362, demonstrated up to
two-fold reduction in Salmonella cecal counts in chickens. Furthermore, the combination of
the probiotic Lactobacillus with other species such as Enterococcus faecium, Bacillus subtilis,
Bifidobacterium animalis, Clostridium butyricum, or Saccharomyces cervisae has a synergistic
action with a significant inhibition (up to 95%) of Salmonella colonization in poultry and
mice [256,268,269]. Several different experiments demonstrate that the combination of
either two or more probiotics for treating Salmonella can have synergistic effects and may
become more effective in inhibiting growth and colonization in the host (Table 2) [270].
However, the use of probiotics for the treatment of infectious diseases, including
Salmonella, presents itself as a multifaceted approach, and further studies need to be
conducted to determine whether their efficacy is contingent upon strain-specific factors of
the pathogen or influenced by variables such as probiotic dosage, administration method,
treatment duration, host characteristics (including age), and other management-related
factors [258]. Moreover, there is a pressing concern regarding the clinical applications
of probiotics, which includes issues such as the shelf life that may impact the viability
of probiotic strains, their ability to withstand the conditions of the gastrointestinal tract,
the potential for acquiring virulence or resistance genes from pathogenic or opportunistic
organisms, the capacity of specific probiotic strains to transfer antibacterial resistance genes
within the gastrointestinal tract, and the possibility of some probiotic strains like B. subtilis
secreting toxic substances which can potentially induce food poisoning [271].

Table 2. Probiotics and their therapeutic uses against Salmonella serotypes in different hosts.

Animal Salmonella
Probiotics Dose Dose Results References
Host Serotype
L. alvi An810,
Chicken
L. ingluviei An777, 107 No protective effect against
(male ISA S. Enteritidis 105 cfu/mL [272]
L. reuteri An769, and cfu/mL S. Enteritidis in the host.
Brown)
L. salivarius An63
Modulation of intestinal
L. acidophilus LAP5, microbiota, increases
L. fermentum P2, intestinal villi height and
107 Broiler S. enterica subsp.
Pediococcus 108 Cfu/mL short-chain fatty acids, [258]
CFU/mL chicken Enterica ST19
acidilactici LS, and restoring intestinal
L. casei L21 permeability by preventing
tight junction damage.
The growth and proliferation
of S. Enteritidis decreased to
L. reuteri, E. faecium, 87.4–99.5% in vitro, and
0.5 g/kg Cobb broiler
B. animalis, and S. Enteritidis 109 Cfu/mL Salmonella load decreased by [268]
feed chickens
P. acidilactici 0.85 and 1.5 log units/mL
for cecal and carcass
contents, respectively.
B. subtilis, A significant decrease
1.5
B. licheniformis and Hy-line 3 × 106 (1.94 log reduction) in
lbs/ton of S. Enteritidis [269]
Mannan layer hens cfu/bird Salmonella colonization in
feed
oligosaccharide the ceca.
Antibiotics 2024, 13, 76 16 of 51

Table 2. Cont.

Animal Salmonella
Probiotics Dose Dose Results References
Host Serotype
Significant reduction in
colonization and
4 × 108 Broiler translocation of Salmonella in
E. faecium NCIMB S. Typhimurium
cfu/kg of chickens 109 cfu/mL liver tissue (2.172 logs) and [266]
11181 CVCC 2232
diet (Arbor cecal content (4.2 logs) of
infected birds pretreated
with E. faecium.
Complete clearance of
L. salivarius 105 Leghorn S. Enteritidis
108 cfu/mL Salmonella in chicken’s gut [262]
CTC2197 cfu/mL chickens C-114
21 days post-infection.
L. fermentum IKP 23, Intestinal villus height was
L. fermentum IKP 111 107 Broiler improved. Significantly high
S. Enteritidis 106 cfu/mL [273]
and L. salivarius cfu/mL chickens concentration of D-xylose in
IKP 333) the plasma of broilers.
S. Heidelberg count was
1.8 × 108 Cobb 2.5 × 108
L. plantarum S. Heidelberg decreased in the caeca (2.1 [265]
cfu/mL broilers cfu/mL
log reduction).
No indication of protection
L. salivarius L38 and 109 Swiss NIH against Salmonella isolates
S. Typhimurium 107 cfu/mL [274]
L. acidophilus L36 cfu/mL mice after pre-treatment with L36
or L38 probiotic strains.
One-fold reduction in the
L. reuteri R-17485,
Lohmann cecal Salmonella count by
L. johnsonii R-17504 2 × 108
White S. Enteritidis 104 cfu/mL L. reuteri R-17485, whereas [263,264]
and L. vaginalis cfu/mL
laying hens significant (2-log) reduction
R-17362
by L. johnsonii R-17504.
L. reuteri, E. faecium, Administration of probiotics
2 × 109
B. animalis, Cobb 6 × 105 to birds resulted in 2.7 log
cfu/kg S. Enteritidis [256]
P. acidilactici and broilers cfu/mL reduction in Salmonella in
diet
L. salivarius the cecum.
Low- and high-dose
treatment with probiotics
resulted in 1.2 and 3 log
reductions in
L. acidophilus, 1 × 105 to Female
S. Typhimurium load in
B. bifidum, and 1 × 106 crossbred S. Typhimurium 104 cfu/mL [275]
chickens’ cecum,
Streptococcus faecalis cfu/mL broiler
respectively, and decreased
IFN-γ gene expression in the
cecal tonsils of the
treated chickens.
L. murinus,
2.4 log reduction (from 3.68
L. salivarius, 4 × 109
Pigs S. Typhimurium 108 cfu/mL to 1.4 log CFU) in the fecal [276]
L. pentosus, and cfu/mL
count of Salmonella.
P. pentosaceous
No significant difference
L. fermentum and 108
Mice S. Typhimurium 105 cfu/mL between treated and [277]
L. acidophilus cfu/mL
nontreated mice.
Significant reduction in
108 Broiler 108 cfu/ Salmonella from the cecal
L. plantarum Z01 S. Typhimurium [278]
cfu/mL chicken 0.2 mL content of treated chicken
(5.24 out of 252 cfu × 105 /g).
Antibiotics 2024, 13, 76 17 of 51

Table 2. Cont.

Animal Salmonella
Probiotics Dose Dose Results References
Host Serotype
High inhibition of
S. Enteritidis (11–12 mm)
108 Intestinal S. Enteritidis,
B. subtilis 108 cfu/mL and S. Typhimurium [257]
cfu/mL epithelium S. Typhimurium
(11–15 mm zone
of inhibition).
Significant reduction
(p < 0.0001) in diarrheal
3.48 × 108 , symptoms and severity of
E. faecalis, Hospitalized
2.0 × 107 , diarrhea significantly
C. butyricum, and infants and Salmonella spp. - [279]
1.1 × 107 improved (p < 0.01) 3 days
B. mesentericus children
cfu/mL and no diarrhea was
observed 5–7 days
post-treatment.
Salmonella counts in piglets
after B. subtilis and
B. subtilis RX7 and B. methylotrophicus treatment
Weaned 1011
B. methylotrophicus 109 cfu/g S. Typhimurium have been reduced to [280]
pigs cfu/mL
C14 3.57–3.69 log cfu/g
compared to the
control group.
L. plantarum, L. casei,
Up to 65% reduction in fecal
L. acidophilus, and 107 cfu/g Horses S. Typhimurium - [281]
Salmonella shedding.
E. faecium
Enhanced survival up to 70%
in treated mice as compared
to 40% in untreated ones.
109
S. boulardii Mice S. Typhimurium 105 cfu/mL Decreased Salmonella [267]
cfu/mL
translocation, reduced liver
damage, and decreased
inflammatory cytokines
Reduction of 2 log in the
invasion of Salmonella in
Day-old chicken fibroblast cells and
E. coli Nissle 109
laying S. pullorum 107 cfu/mL 60% survival rate in [282]
1917 (EcN) cfu/mL
chicken EcN-treated group
compared to 40% in the
untreated ones.
L. lactis IBB 500, Reduction of 2-fold in cecal
L. casei ŁOCK 0915, Ross-308 Salmonella 14 days
109
L. plantarum ŁOCK broiler S. Enteritidis 105 cfu/mL post-infection followed by [283,284]
cfu/mL
0862 and chickens 0.5-fold reduction (p < 0.05)
S. cerevisiae at 42 days post-infection.

4.5.2. Prebiotics
Prebiotics are defined as the non-digestible components that undergo selective fer-
mentation, resulting in targeted modifications to the composition and behavior of the gas-
trointestinal microbiota. When the microbiota utilizes these components, they contribute to
beneficial effects on the health of the host [285]. Prebiotics are usually combined with pro-
biotics in commercial products and are known as: “Synbiotics, beneficial microorganisms
with selective substrates”. This combination has great therapeutic efficacy against various
animal and human diseases [286–288]. Several prebiotic compounds are available, includ-
ing fructooligosaccharides (FOS), galactooligosaccharides (GOS), mannan-oligosaccharides
(MOS), xylooligosaccharides (XOS), transgalactic-oligosaccharides (TGOS), arabinoxylo-
Antibiotics 2024, 13, 76 18 of 51

oligosaccharides, lactulose, and inulin [289,290]. The human digestive enzymes do not
normally digest these compounds but they could be introduced into the diet in certain quan-
tities to stimulate the gut microbiota, which, in turn, can provide the host with the essential
nutrients and energy [291]. The mechanism of action of prebiotics can be summarized
into direct and indirect pathways [292–296]. The indirect pathway is through nourishing
beneficial gut flora and maintaining gut health, thereby conferring health benefits to the
host, whereas the direct pathway acts through the inhibition of pathogenic microorganisms
and reduces the risk of infection with infectious pathogens [297]. Several studies have been
conducted to determine the protective effects of probiotics and prebiotics in experimental
animals, including poultry infected with Salmonella [298]. For example, it was reported that
the administration of B. subtilis, Bacillus licheniformis, and mannan-oligosaccharide revealed
a significant (up to 2 logs) reduction in S. Enteritidis colonization in layers of ovaries and
the intestine [269]. Similarly, chickens administered with inulin and oligofructose had up
to a four-log reduction in cecal Salmonella counts possibly due to the effect of administered
prebiotics on the pH and the level of produced volatile fatty acids [299]. Similar results
were reported on the supplementation of broiler chickens with 0.75% oligofructose, where
a four-fold reduction in cecal Salmonella counts was demonstrated [300]. Furthermore, the
dietary supplementation of broiler chickens with fructooligosaccharides demonstrated
a log reduction in intestinal colonization and count of S. Typhimurium [301]. Similarly,
feeding broiler chickens with a combination of prebiotics (fructooligosaccharides) and
probiotics (B. animalis, L. reuteri, P. acidilactici, and E. faecium), as well as prebiotics with
antibiotics, resulted in decreased S. Enteritidis load by 1.4 and 1.5 log units/mL of carcass
rinse and 0.90 and 0.85 log units/g of cecal contents, respectively [268]. In another study,
the treatment of S. Enteritidis challenged turkey poults with Lactobacillus spp. And dietary
lactose (0.1%) revealed significant improvement in body weight and feed conversion ratio
with a 2 log reduction in cecal S. Enteritidis count [302]. Furthermore, a study for the evalu-
ation of the effectiveness of synbiotics alone or in combination with organic acids on carcass
and cecal Salmonella load in challenged one-day-old broiler chicks revealed a 0.34 to 0.58 log
reduction in the Salmonella cecal contents compared to the controls, whereas no difference
was observed between the dietary treatments [303]. Similarly, the treatment combination of
synbiotics with organic acids revealed a 1.7 log reduction in carcass bacterial count, whereas
a 1.3 and 0.53 log reduction was observed in Salmonella loaded with synbiotics alone and
synbiotics combined with organic acids, respectively [303]. Nevertheless, some studies
have demonstrated no effect of prebiotics in protective efficacy against and susceptibility to
pathogenic infections. For example, S. Typhimurium translocation in the liver, mesenteric
lymph nodes, spleen, and intestine have been increased, with an approximate 1.6–1.8 mean
CFU in mice fed on a diet containing 10% of fructooligosaccharide, xylooligosaccharides,
or apple pectin [304]. Similarly, no effect was observed in the production of anti-Salmonella
antibodies in birds challenged with S. Enteritidis or broiler chickens fed with a combi-
nation of probiotics (Lac XCL 5x™) and prebiotics (MOS) [305]. Furthermore, another
study demonstrated that no anti-Salmonella effect was seen in birds tested for the symbi-
otic effect of B. longum, and L. rhamnosus combined with oligofructose-enriched inulin on
S. Typhimurium-challenged pigs [306]. In addition to this, evaluation of the efficacy of
probiotics alone (L. acidophilus, B. subtilis, L. casei, B. longum, and E. faecium), prebiotics
alone (fructooligosaccharide, inulin, oligosaccharide, and mannanoligosaccharide), and
synbiotics (combined pro- and prebiotics) on S. Enteritidis challenged one-day-old layer
and broiler chicks and concluded that the group of chicks supplemented with prebiotics
only demonstrated a higher reduction in SE colonization (3 log reduction) when compared
to groups supplemented with probiotics alone or synbiotics alone [307]. Hence, prebiotics
play a vital role in maintaining gut health, linked to a range of health advantages like better
digestion, synergistic actions along with the gut microbiota and supplemented probiotics,
exclusion of pathogens, and improved growth performance [303].
Antibiotics 2024, 13, 76 19 of 51

4.5.3. Antimicrobial Peptides

Antimicrobial peptides (AMPs) are a diverse group of small peptides that are an
essential part of the innate immune system of different organisms [308]. The updated
AMPs database reports more than 3569 AMPs identified, most of which originated from
bacteria, followed by animals, plants, fungi, protists, and archaea [292]. There are sev-
eral types of AMPs with various numbers of amino acid residues ranging from 10 to
60 amino acids, most of which are cationic, and some are non-cationic AMPs [309,310].
AMPs have two mechanisms of action: membrane-targeting and non-membrane-targeting
mechanisms [309]. The membrane-targeting mechanism can be classified into three models:
(1) carpet-like model in which AMPs are arranged parallel to the cell membrane like a
carpet and destroy the pathogen’s membrane [311], (2) the barrel-stave model in which
AMPs aggregate with each other and penetrate the membrane bilayer, forming channels
that cause cytoplasmic leakage, thus resulting in cell death [312] and, (3) the toroidal pore
model through which AMPs are vertically embedded in the cell membrane and bend to
form a ring hole [310].
The non-membrane-targeting mechanism can be classified according to the targets
by which AMPs act after entering the cytoplasm, which includes (i) protein biosynthe-
sis inhibition [313,314], (ii) nucleic acid biosynthesis inhibition [315], (iii) inhibition of
metabolic activities [316], and (iv) inhibition of DNA replication and cell division [317].
In addition to the broad-spectrum antimicrobial properties of AMPs, they are potential
antibiotic substitutes with a low probability of developing AMR strains [318].
Several studies have evaluated the antimicrobial efficacy of AMPs against foodborne
pathogens including Salmonella [318]. These studies evaluate their efficacy on immune
regulation, growth performance, and intestinal microbiota in different animal species.
For example, Festa et al. demonstrated the in vitro effect of peptide 1018-K6 against
S. enterica (1 × 103 cfu/mL) with a Minimum inhibitory Concentration (MIC) and Minimum
Bactericidal Concentration (MBC) of 8–64 µg/mL and 16–128 µg/mL, respectively, and
the sub inhibitory dose significantly reduced the biofilm formation of S. Enteritidis [319].
In vitro, evaluation of the effect of novel AMP “A11” modified from acidocin J1132β against
S. Typhimurium demonstrated a complete inhibitory effect of A11 against S. Typhimurium,
with an MIC ranging from 15.6 to 125 µg/mL [320]. Similarly, the screening of six differ-
ent AMPs (KLK and KLK1) derived from flesh fly larva, BmKn-2, and BmKn-22 derived
from scorpion venom, and Pug-1 and Pug-4 derived from pomegranate fruit), against
eight multidrug-resistant Salmonella isolates showed that BmKn-2 derived from scorpion
venom has the highest and most potent antibacterial activity against all isolates and the
highest inhibition of Salmonella biofilm formation compared with other peptides [321].
Another in vitro study determining the antimicrobial activity of the modified thermostable
cathelicidin-derived peptide, P7, against drug-resistant S. Typhimurium showed that
P7 decreased the S. Typhimurium viable cells to more than 103 and 104 cfu/mL within
2 to 4 h, respectively, and also demonstrated complete clearance of Salmonella 24 h post
incubation [322]. Furthermore, it was reported that AMP (Microcin J25) could significantly
reduce the infection rate of Salmonella CVCC519 by approximately 30% in challenged Arbor
Acres male broiler chickens at day 42 compared to non-treated birds [183]. Moreover, the
AMP (Microcin J25) secreted by ECN has been recorded to lower the in vitro growth of
S. Enteritidis on agar plates and also resulted in a 25× reduction in S. Enteritidis count
and colonization in turkey cecum [323]. Similarly, an investigation determining the effi-
cacy of AMP (HJH-3) in challenged chickens with S. Pullorum demonstrated a more than
48-fold reduction in total bacteria in the spleen of the HJH-3 group compared to the non-
treated group [324]. Yeom et al. also reported that AMP (C-terminally hexahistidine-tagged
A3-APO) loaded onto gold nanoparticle DNA conjugate completely inhibited and elim-
inated intracellular S. Typhimurium in challenged mice, resulting in 100% survival of
infected mice [325]. Two AMPs (IK12 and TS10) were compared for their efficacy against
S. enterica in fish, and the results demonstrated that AMP (IK12) exhibited a significant in-
hibition zone (20 ± 1 mm) against S. enterica at a concentration of 625 µg/mL, while
Antibiotics 2024, 13, 76 20 of 51

concentrations of 1000 µg/mL and 2500 µg/mL decreased the Salmonella load up to
6 log [326]. In addition to this, the treatment of S. Typhimurium-challenged mice with AMP
(Css54) demonstrated that Css54 can inhibit S. Typhimurium growth at a concentration
of 6.25 µg/mL, while complete bactericidal activity can be obtained at a concentration of
25 µg/mL [327]. Similarly, supplementing S. Enteritidis-challenged female laying chicks
with two different doses of AMP (Ctx(Ile21 )-Ha) at the rate of 20–40 mg/kg feed for
28 days revealed a reduced mortality rate in young chickens by 69%; however, no difference
in the mortality rate was observed even after increasing the Ctx(Ile21 )-Ha dose concentra-
tion [328]. Maiti et al. demonstrated that avian defensin 7 (AvBD7) significantly reduced
S. Typhimurium load in the liver (80% reduction) of treated mice 24 h post-infection in
intraperitoneally challenged mice [329]. In addition to this, evaluating the efficacy of
two human β-defensins (hBD-1 and hBD-2) in mice challenged intraperitoneally with
S. Typhi demonstrated the 50% lethal doses of hBD-1 and hBD-2 to be 0.36 and 0.38 µg/µL
respectively, with a significant reduction in Salmonella load in the peritoneal fluid, spleen,
and liver of treated mice whether hBD-1 and hBD-2 is delivered individually or in combi-
nation [330]. A study to evaluate the antimicrobial activity of three gallinacin AMPs (GALL
4, 7, 9) against S. enteritidis revealed that the antimicrobial potency was in the following
peptide order (Gall 9 > 4 > 7), with a synergistic action observed between Gall 7 and 9,
whereas an in vivo study in non-domesticated fowl demonstrated no significant effect in
the expression of gal4 or gall9 [331].
The capacity of AMPs to effectively target a wide range of bacterial pathogens, in-
cluding Salmonella, holds significant promise in addressing the persistent problem of AMR
strains. Nonetheless, despite their immense potential, several obstacles, such as the bacte-
ria’s ability to develop resistance to these compounds and potential toxicity to host cells,
pose significant challenges in developing them as alternatives to antibiotics. Thus, it be-
comes imperative to embark on further research to gain a more profound understanding
of the precise mechanisms by which AMPs operate, improving their bioavailability and
allowing us to devise cost-effective methods for their production. This holistic approach is
essential to harnessing the full potential of AMPs as alternatives to traditional antibiotics
and addressing the pressing global concerns surrounding AMR strains.

4.5.4. Bacteriophages
Bacteriophages, also known as phages, are viruses with the unique capability to infect
bacteria [332]. A bacteriophage consists of a protein capsid housing containing DNA or
RNA as its nucleic acid core [333]. They can undergo replication within the bacterial cell
through two distinct cycles: the lytic cycle and the lysogenic cycle [332]. (1) The lytic
cycle is when a bacteriophage takes control of a bacterial cell and replicates itself, causing
the lysis of the bacteria [334]. This process involves the bacteriophage reprogramming
the host cell, transforming it into a phage-replicating unit, leveraging its ribosomes and
ATP resources normally employed for the host’s benefit to its advantage [335]. Phage-
specified proteins that are translated after the host cell infection from phage mRNA can
reprogram these energetic pathways in the bacteria [335]. When the host cell is lysed, all of
the bacteriophages are released into the environment, allowing them to infect a new host
cell [333]. (2) A lysogenic cycle is very similar to the lytic, except that the phages replicate
and pass themselves onto the bacterial daughter cells without killing the bacteria [333].
Bacteriophages cannot infect and replicate within human or animal cells; instead, they
exclusively target bacterial cells [333].
The effectiveness of phages in the treatment of bacterial infections depends on factors
such as the phage’s form and type, the level of lytic activity, and the method and timing
of administration [336]. Different researchers have demonstrated that the use of phages
over a long period has been effective in reducing Salmonella in the digestive tract [337].
The mode of administration includes oral administration by mixing with water or feed,
spraying the surface of the eggs, or by the addition of bacteriophage suspension directly into
infected products [338]. Henriques et al. demonstrated that administrating phages through
Antibiotics 2024, 13, 76 21 of 51

aerosol spray during the transfer of eggs from incubators to hatchers can be a cost-effective
and efficient method to reduce the horizontal transmission of Salmonella in poultry [339].
Bacteriophage treatment is a novel strategy for providing prophylactic treatment against
poultry pathogens including Salmonella [340]. It can be used safely without altering the gut
microbiota [341]. Wattana et al. demonstrated that the novel Salmonella phages showed a
significantly high bacterial lysis effect (93.3%) on ciprofloxacin-resistant Salmonella strains
in broilers [342].
Furthermore, Spricigo et al. demonstrated that the use of three Salmonella-phage
cocktails (UAB_Phi 20, UAB_Phi78, and UAB_Phi87) showed two log reductions in pig
skin and lettuce and one log reduction in Salmonella count in chicken breast contaminated
with the bacteria [343]. In addition, the administration of five Salmonella-phase cocktails
demonstrated an up to 3.1 log-reduction reduction in Salmonella count in contaminated
raw chicken breast [344]. The complete list of bacteriophages used in treating Salmonella
infection is shown in Table 3.
While phage therapy holds promise in combatting MDR pathogens like Salmonella,
it does come with certain limitations [345]. These limitations include the phages’ narrow
host spectrum, which restricts their effectiveness to specific bacterial genera [346], the
potential development of bacterial resistance through CRISPR-Cas adaptive immunity
against commonly encountered bacteriophages [347], and the lack of comprehensive data
on the pharmacokinetic properties of these viruses [345]. Additionally, there are concerns
about the adverse effects of bacterial toxins released during the phage-mediated lysis
process [348]. These factors collectively challenge the widespread adoption and efficacy
of phage therapy in clinical settings [349]. Despite these disadvantages, ongoing research
and development are exploring ways to harness the potential of bacteriophages and use
them against bacterial pathogens like Salmonella for both prophylactic and therapeutic
purposes [350].

Table 3. Different studies for the evaluation of the efficacy of bacteriophages against Salmonella
serotypes.

Phages Target Serotypes PFU/mL Phase Application Results References

Single oral Decrease in the occurrence of
CNPSA1, CPNSA3, S. Enteritidis PT4
1011 application of S. Enteritidis strains by [337]
CNPSA4 P125589
phage cocktail 3.5 logs.
Around 58% and
Phage isolated and 76% reduction in the cecal and
applied by aerosol visceral Salmonella count,
F1055S, F12013S S. Enteriditis 2 × 102 [339]
spray on respectively, without any loss
fertile eggs in the body weight compared
to the control group.
Salmonella count reduced by
2.9 log10 CFU/mL within 6 h
S. Typhimurium Intraclocal
Φ st1 1012 of challenge. S. Typhimurium [351]
and S. Hadar inoculation
had no trace of detection
after 24 h.
S. Typhimurium count was
SPGH1, SPGH3 S. Typhimurium 8.3 log10 Spotted significantly reduced by [352]
4.2 log10.
Cecal Salmonella count
significantly decreased by
UAB_Phi20,
S. Enteriditis and 5.3 log upon administration of
UAB_Phi78, 1011 Oral [353]
S. Typhimurium three phage cocktails one day
UAB_Phi87
before or after
bacterial infection.
Antibiotics 2024, 13, 76 22 of 51

Table 3. Cont.

Phages Target Serotypes PFU/mL Phase Application Results References

Reduced cecal colonization by
S. Enteritidis
S. Enteritidis and
P125109,
φ10, φ25, φ151 109−11 Oral S. Typhimurium by ≥4.2 log10 [354]
Hadar 18, and
CFU and ≥2.9 log10 CFU,
Typhimurium 4/74
respectively.
No bacteria were detected in
Wide-Host-Range S. Enteritidis (SE), Sprayed with 5 mL
two trials and a greater than
bacteriophages S. Typhimurium 109 of WHR and rinsed [355]
70% reduction was seen in the
(WHR) (ST) with sterile water
other two trials.
Moderate decrease (1 log
reduction) in Salmonella loads
S. Enteritidis (SE),
Bacteriophages of 3 days post-infection (dpi),
and 1.18 × 1011 –
S. Typhimurium Oral with a greater reduction of [356]
S. Typhimurium 1.03 × 102
and S. enteritidis 2 log at 5 dpi and complete
(ST)
clearance of the bacteria
at 7 dpi.
After 3 weeks of treatment, no
intestinal Salmonella was
ΦCJ07 S. Enteritidis (SE) 105 , 107 109 Oral detected in 70% of hens [357]
treated with 109 PFU/g
of bacteriophage.
Three logs reduction in
Salmonella count was observed
PSE5 S. Enteritidis (SE) 4 × 107 Immersion after 30 min of phage [358]
treatment of the
contaminated eggs.
The phages demonstrated
1.06 and 1.12 log reduction in
Pu20 S. Pullorum 108 or 109 Direct inoculation [359]
S. Pullorum in eggs stored at
4 ◦ C and 25 ◦ C, respectively.
One log reduction in both
UAB_Phi 20, S. Enteritidis (SE), Soaking in
109 and S. Enteritidis and
UAB_Phi78, and S. Typhimurium suspension and [343]
1 × 1010 S. Typhimurium in
UAB_Phi87 (ST) spraying
chicken breast.
S. Enteritidis and
SEG5, SES8, STG2, S. Enteritidis, Suspension added S. Typhimurium reduced by
3× 108 [344]
STG5, and STS9 S. Typhimurium on the surface 3.06 and 2.21 log CFU/piece
of chicken breast, respectively,
Significant reduction in
Salmonella count (by 2.5 logs)
STGO-35-1 S. Enteritidis 4× 106 Direct addition [360]
in each piece of the
chicken meat.

4.5.5. Small Molecules and Quorum-Sensing Inhibitors

Small molecules (SMs) are low-molecular-weight compounds that can be directed to
specific cellular processes of bacterial physiology to perform a broad to narrow spectrum of
activity and can be used as growth inhibitors or virulence inhibitors [361]. These molecules
can be obtained from natural sources or be synthesized [362–364]. The natural compounds
may include phytochemicals, including fruit extracts (grape seed extract), plant extracts
(punicalagin), spice oils (thyme, basil, rosemary, ginger, garlic), and phenolic compounds
such as Gallo tannins, coumarins (furocoumarin), benzoates, and terpenes (monoterpenes,
diterpenes, and triterpenes) [365–367]. The synthetic compounds may include furanone,
chitosan, thiophene inhibitors, and limonene nanoemulsion [368,369]. Different studies
Antibiotics 2024, 13, 76 23 of 51

evaluating the effect of small molecules on the growth and virulence of Salmonella are
demonstrated in Table 4. For example, Li et al. demonstrated that using Quercitrin, a
flavonoid with antioxidant properties, significantly inhibited the adhesion, invasion, and
survival of Salmonella in HeLa cell lines by about 70% [370]. Similarly, Deblais et al. and
Rajashekara et al., in two different independent experiments, demonstrated that the com-
pounds imidazole and methoxybenzylamine were able to cause complete clearance of S.
Typhimurium in vitro in Caco-2 cells with minimal toxicity to chicken RBC [371]. Fur-
thermore, another study conducted by Jacob et al. demonstrated that compound 7955004
can cause 55% inhibition of preformed biofilms, with complete clearance of planktonic
S. Typhimurium in vitro [372]. Similarly, Nagy et al. demonstrated an up to 2 log reduc-
tion in the colonization of S. Typhimurium in the spleen and liver 48 h post-infection in
mice [373]. These compounds have demonstrated their effectiveness in disrupting crucial
bacterial processes, including metabolism, virulence factor inhibition, and infection preven-
tion, which positions them as a viable alternative to antibiotics for managing Salmonella
infections [374]. Consequently, they provide a versatile and precisely targeted strategy for
controlling this bacterium [375]. However, the intricate nature of Salmonella, its adaptability,
and its potential to develop resistance to these molecules emphasize the imperative need
for ongoing research and refinement of these compounds. In summary, small molecules
possess the ability to inhibit the growth and virulence of Salmonella without the inherent
risk of developing antibiotic resistance, thus positioning them as important candidates for
the development of antibiotic-alternative therapeutics.
Quorum sensing (QS) is a bacterial cell-to-cell communication process that is regulated
by the production, release, and uptake of particular signal molecules known as autoin-
ducers (AI) [376]. It is a complex inter/intra-species process that allows a bacterium to
carry out colony-wide functions such as biofilm formation, bioluminescence, sporulation,
conjugation, and expression of the virulence factors [377–379]. Gram-negative bacteria like
Salmonella produce autoinducers called autoinducer-2 (AI-2), a furanosyl borate diester that
is found in both Gram-negative and Gram-positive bacteria [380]. Unlike Gram-positive
bacteria, which use the LuxI gene that codes with the AHL molecule to activate the tran-
scription of the LuxICDBAE operon to produce bioluminescence, Salmonella lacks the LuxI
gene encoded in their genome [381]. Salmonella instead uses the LuxR homolog called SdiA
to produce AI-2 molecules and regulate the expression of virulence genes [382]. These
genes serve specific functions in facilitating host invasion and colonization, developing
antibiotic resistance, evading complement systems, expressing fimbriae, and producing
anti-phagocytic factors [383]. Therefore, the inhibition of LuxS and AI-2 activity can offer a
promising strategy to decrease the virulence of Salmonella [384]. Quorum-sensing inhibitors
(QSIs), which include small molecules, natural extracts, and oils, are increasingly being
considered as promising alternatives to antibiotics for salmonellosis [385]. By disrupting
quorum sensing, QSIs can effectively interfere with various colony-wide bacterial activ-
ities, including the formation of biofilms, the production of virulence factors, and the
development of antibiotic resistance [385]. Unlike antibiotics, the QSIs inhibit the micro-
bial quorum or prevent forming a quorum rather than exerting selection pressure and
interfering with the cellular and metabolic process, thus making the bacteria less likely
to develop resistance [386]. The QSIs were also reported to show high efficacy in vitro
when combined with small molecules’ growth inhibitors [387]. Several studies have been
conducted on compounds that can inhibit QS and AI-2 production by downregulating
QS-associated genes and inhibiting the virulence of Salmonella (Table 4). For example, the
use of punicalagin led to a reduction in motility and the downregulation of the QS-related
genes flhC, sdiA, and srgE in S. Typhimurium; carvacrol, thymol, and eugenol downreg-
ulated the genes associated with host colonization, such as flgG, fimD, sopB, and invH,
as well as genes related to macrophage survival like ssaV and pipB in S. Enteritidis; and
furanone caused significant downregulation of QS-associated genes like sdiA and srgE in
S. Typhimurium in vitro [388–391]. Similarly, dephostatin and homocysteine thiolactone
are capable of downregulating QS-regulated spiA genes responsible for the adhesion and
Antibiotics 2024, 13, 76 24 of 51

invasion of Salmonella to the host cells [390,392]. In addition, fluorothiazinon, fusaric acid,
and cytosporone B have been found to inhibit the QS-regulated Type-3 secretion system
apparatus, which is responsible for host cell adhesion and invasion [393–395]. In summary,
QSIs offer significant promise as alternative strategies for managing Salmonella infections
in humans and animals. Their capacity to interfere with bacterial communication, hinder
the establishment of infections, evade host immune responses, and cause disease without
impacting bacterial growth highlights their potential as valuable targets for developing
antibiotic-alternative therapeutics to combat MDR Salmonella infections in both human and
animal populations. However, it is essential to acknowledge the challenges associated with
QSIs. Achieving high specificity to target a single bacterial species without affecting the
normal microbiota can be challenging. Furthermore, our understanding of QS mechanisms
in various pathogenic bacteria still needs to be broadened [396]. Ensuring the bioavailabil-
ity and effective delivery of QSIs to complex environments like biofilms within the host
body presents a significant hurdle. Additionally, the high cost and time required for QSI
development pose practical challenges in their widespread use as therapeutic agents [397].

Table 4. Quorum sensing and small molecule inhibitors of Salmonella serotypes.

Effect on Quorum Sensing

Small
Action Target Strains Concentration/Dose Regulatory Process/ References
Molecules
Growth Inhibition
Downregulation of motility (flhC) and
Punicalagin QSI S. Typhimurium 15.6 µg/mL [388]
QS-associated genes (sdiA and srgE)
Significant downregulation of genes
Carvacrol, related to host colonization (flgG,
0.5 mM, 0.5 mM,
Thymol, QSI S. Enteritidis fimD, sopB, invH, and TTSS genes) [389]
1.2 mM
Eugenol and macrophage survival
(ssaV and pipB)
Downregulation of quorum-sensing
regulatory genes targets srgE and lsrA
S. Typhimurium
Furanone QSI 500 uM of sdiA and AI-2 followed by [390]
14028
downregulation of genes related to
flagellar biosynthesis and biofilms
Downregulation of QS-associated
M-gallate QSI S. Typhimurium 128 µg/mL genes sdiA and srgE by 92.6 and [398]
77.7% respectively.
Reduction in AI-2 production by
73.5% compared to the control with
Berberine QSI S. Typhimurium 0.019 mg/mL [399]
exogenously supplied C4-HSL
reporter molecule
Drastically inhibited swarming
S. Typhi motility, a major phenotype of
Tannic acids QSI 400 µg/mL [400]
S. Paratyphi quorum sensing without any impact
on the growth of the bacteria
A 60–70% inhibition in Ai-2
S. Typhimurium
Xanthones QSI 100 µM production, effective efflux [401]
21 SL1344
pump inhibitors
N-(3-oxo
octanoyl) DL- SdiA gene downregulation and
QSI S. Typhimurium 10 nM [392]
homoserine inhibition of biofilm formation
lactone
Antibiotics 2024, 13, 76 25 of 51

Table 4. Cont.

Effect on Quorum Sensing

Small
Action Target Strains Concentration/Dose Regulatory Process/ References
Molecules
Growth Inhibition
Homocysteine Effect on SdiA gene expression with
QSI S. Typhimurium 10 µM [402]
thiolactone no effect on bacterial growth
SPI-2 virulence genes inhibitor and
Dephostatin QSI S. Typhimurium 100 µM [403]
restoring sensitivity to the colistin
Suppression of Type-3 secretion
Fluorothiazinon QSI S. Typhimurium 10 mg/kg [393]
system of Salmonella in vivo
Type-3 secretion system inhibitor
Fusaric acid QSI S. Typhimurium 100 µM [394]
with anti-invasion activity
INP0007 and Inhibition of Type-3 secretion system
QSI S. Typhimurium 100 µM [395]
INP0403 1-associated virulence and invasion.
Cytosporone B QSI S. Typhimurium 25 µM Type-3 secretion system inhibition [404]
Reduction in Salmonella adhesion,
invasion, and survival in the HeLa
Growth
Quercitrin S. Typhimurium 32 µg/mL cell lines by 70%. Blocks effector SipA [370]
inhibitors
translocation important for the
invasion of the host cells
Complete inhibition of growth and
intracellular clearance of Salmonella
Imidazole,
Growth from Caco-2, HD11, and THP-1
Methoxyben- S. Typhimurium 10 µM [371]
inhibitors cell lines.
zylamine
Clearance of biofilm-embedded
bacteria at 4 µM concentration
More than 55% inhibition of
Compound Growth S. Typhimurium preformed biofilms
5 µM [372]
7955004 inhibitors 14028 Complete clearance of the planktonic
bacteria
Bactericidal effect on WT
SM4
S. Typhimurium with minimal
(Imidazole
toxicity on eukaryotic cell models
class) Growth MIC: 10 µM
S. Typhimurium including Caco-2, HD11, chicken [371]
SM 5 (Methoxy- inhibitors and 25 µM
macrophage cell lines, sheep or
benzylamine
chicken RBCs, and complete
class)
clearance of internalized bacteria

4.5.6. Vaccines
Vaccines are preparations of antigens or a part of the pathogen which, when ad-
ministered to a host, can safely induce an immune response against infection by specific
pathogens upon future exposure, thereby preventing severe infections [405,406]. Vac-
cines mimic the natural infection without causing severe illness, enabling the body to
build immunity against diseases, helping prevent infection, reducing the severity of the
infection, and lowering the risk of complications and transmission to others [406]. Vac-
cines help reduce the incidence of infectious diseases worldwide including fowl (avian)
cholera, coronavirus, anthrax, polio, norovirus, Rift Valley fever, and rabies [407–411]. The
mode of action of vaccines depends on their formulations [412]. For example, (1) Live
attenuated vaccines contain a weakened, live version of the pathogen, capable of elicit-
ing an immune response without causing disease [413]. The purpose of attenuation is to
eliminate pathogen’s infectivity but preserve their immunogenicity [414]. These vaccines
can effectively stimulate humoral and secretory antibodies, as well as activate cytotoxic
T-cells [415]; (2) Killed-whole-cell vaccines are the vaccines in which the pathogens are
Antibiotics 2024, 13, 76 26 of 51

killed but maintain their epitope structures intact to preserve their immunogenicity, while
simultaneously eliminating their capacity to replicate or cause disease [416]; (3) Toxoid
vaccines are a type of vaccine in which a pathogen’s toxin is purified and subjected to
formalin treatment to deactivate its harmful effects but retains its immunogenicity against
the associated pathogen [417]; (4) Subunit vaccines are a class of vaccines which contain
fragments of the pathogen, such as polysaccharides, nucleic acids, or proteins like flagellin
or synthetic peptides [418]; (5) Outer membrane vesicle (OMV) vaccines are made up of
naturally discharged constituents of OMVs from the bacterial outer membrane, featuring
vital antigenic elements capable of eliciting an immune response without triggering any
illness [419]; (6) Protein-polysaccharide conjugate vaccines consist of bacterial polysaccha-
rides which are bound to proteins that enable a desired immune response [420]. These
vaccines induce polysaccharide-specific B-cell immunity, help prevent colonization, and
block person-person transmission, thus generating herd immunity [421]; (7) Recombinant
viral and bacterial vector vaccines employ non-pathogenic viruses or bacteria as vectors to
deliver genetic information encoding the antigens of the pathogen into the host cells, which
subsequently elicits the immune response [422]; (8) Nanovaccines are an innovative class
of vaccines that employ nanoparticles (NPs) as carriers or adjuvants. These nanoparticles
enable precise targeting of the specific site where the disease originated, distinguishing
them from vaccines that exert systemic effects [423].
Currently, two different forms of vaccines are widely available to control typhoid
and paratyphoid fever in humans [424]. These vaccines are available in the form of orally
administered live-attenuated Ty21a vaccine and injectable Vi capsular polysaccharide vac-
cine [425]. Ty21a vaccine has an efficacy of 51% in adults and children above 5 years
with high cross-protection against both S. Typhi and S. Paratyphi B [426]. The vaccine
has been reported to develop IgA antibody response and mediate CD4+ T-cell mediated
antibody-dependent cellular cytotoxicity against S. Typhi and S. Paratyphi [427]. Antibody-
dependent enhanced phagocytosis of S. Typhi has also been reported in orally administrated
Ty21a vaccines [428]. MacLennan et al. and Wahid et al. have separately reported robust
production of T-cell-mediated immune stimulation, with increased production of IgA an-
tibodies. They have also reported cross-reactive immunity against S. Typhi (56%) and
S. Paratyphi (38%) [424,429]. Different from Ty21a, the Vi capsular polysaccharide vaccine
acts through the activation of T-cell-independent IgG antibody production and has an
efficacy of 55%, with cumulative immunity up to 3 years through a single dose [430]. The
administration of a S. Typhi Vi polysaccharide with the tetanus toxoid conjugate vaccine
(Tybar) vaccine has shown to have an efficacy of up to 85% in children under the age of
2 years, with a high increase in T-cell-independent IgG production [431]. Similarly, another
Vi-polysaccharide based Vi Conjugate (Vi-CRM197 ) and Vi Conjugate (Vi-rEPA) vaccine
has demonstrated up to 90% efficacy in children and a similar increase in IgG production
lasting up to 4 years post-vaccination against S. Typhi [432,433]. In addition to this, other
forms of vaccines are also available or are currently in development (Table 5). For exam-
ple, Lyon et al. found that the administration of a single-dose independently attenuated
deletion S. Typhi (Ty2∆aroC∆ssaV) ZH9 vaccine produced complete fecal clearance of
S. Typhi 7 days post-infection, with rapid and high production of S. Typhi-specific IgG
and IgA production [434]. Similarly, a new formulation of vaccines, Generalized Modules
for Membrane Antigens (GMMA), containing bacterial surface immunogens such as LPS,
has shown increased production and stimulation of peripheral blood mononuclear cells
and elicit production of strong bacteriocidal anti-LPS O-antibody and IgG antibody with
complete clearance of S. Typhimurium, S. Typhi, and S. Paratyphi A [37,40]. Furthermore,
the modified live S. Dublin vaccine (EnterVene-d) has shown increased cell-mediated, hu-
moral, and mucosal immunity against S. Dublin in cattle with antibody titer, increased by
49% in vaccinated cows and by 88.56% in calves from the vaccinated cows, demonstrating
substantial horizontal transfer [435]. Several vaccines have been developed to prevent
Salmonella infections in poultry. Renu et al. have demonstrated that the oral administra-
tion of a chitosan-adjuvanted Salmonella subunit nanoparticle vaccine containing outer
Antibiotics 2024, 13, 76 27 of 51

membrane proteins (OMPs), and flagellins (F) coated with nanoparticles (NPs) can cause
significant stimulation of gut mucosal immunity upregulating TLRs, Th1, and Th2 cytokine
mRNA, with increased production of OMPs-specific IgY and IgA antibodies in saliva
and intestine [436]. Similarly, the commercially available modified-live S. Typhimurium
vaccine (Poulvac® ST; Zoetis Inc., Parsippany, NJ, USA), one of the most effective poultry
vaccines commercially available, has demonstrated an up to 50% reduction in S. Kentucky,
S. Enteritidis, S. Heidelberg, S. Typhimurium, and S. Hadar in the liver and spleen [437].
Another trivalent but inactivated Salmonella enterica vaccine (Nobilis® Salenvac T; Intervet
International B.V., Boxmeer, The Netherlands) has shown an up to 3.9 log increase in mean
antibody titer after the administration of the booster dose in chicken, along with a 2.6 log
reduction in cecal shedding of S. Typhimurium and S. Enteritidis, followed by a 1.3 log
reduction in S. Infantis [438]. Unfortunately, due to the presence of variations in the cellular
structures and antigens between the typhoidal and non-typhoidal Salmonella species, the
technology used in typhoid vaccine development has not benefited the development of a
vaccine against non-typhoidal Salmonella species [430].
While vaccines have played a pivotal role in mitigating the severity of infections,
progress in the development of vaccines against Salmonella has been limited. One of the
primary challenges is the extensive genetic variability among Salmonella serovars, each
possessing distinct surface antigens. This variability poses a significant obstacle to creating
effective Salmonella vaccines [439]. Additionally, various other factors contribute to the
difficulty faced in Salmonella vaccine development [413]. These include the risk of vaccine
failure due to improper handling, the potential for live-attenuated vaccines to regain
virulence after administration, the development of tolerance to toxoids when high doses
are used in toxoid vaccines, and the relatively low immunogenicity of outer membrane
vesicle vaccines [440]. These combined factors collectively have limited the progress in
the field of Salmonella vaccine development [441]. Considering these limitations, it is
crucial to emphasize the necessity of ongoing research in vaccine development. Vaccines
have undeniably established themselves as fundamental pillars of public health, offering
substantial advantages in preventing and mitigating infectious diseases. The efforts should
focus on creating more effective vaccines and addressing the complexities associated
with specific pathogens, variable immune responses, and the ever-evolving nature of
infectious diseases. In doing so, we can harness the full potential of vaccines as vital tools
in safeguarding public health, while simultaneously working to overcome their constraints.

Table 5. Commercially available vaccines against Salmonella in humans and animals.

Vaccines Target Pathogens Indications Notable Observations References

Up to 90% efficacy in children between
2 and 5 years old. Rapid production of
Vi Conjugate (Vi-rEPA) S. Typhi Human [432]
Vi-specific IgM and IgG with 2 logs
reduction in shedding of the bacteria.
Stimulated cell-mediated immunity with
antibody titer increased by 49% in
Modified live S. Dublin vaccinated cows.
S. Dublin Cattle [435]
vaccine (EnterVene-d) Antibody titer increased by 88.56% in
calves from the vaccinated cows,
demonstrating strong horizontal transfer.
Cross-reactive multifunctional T-cell
response with an increase in IgA
S. Typhi and
Ty21a Human production of 56% against S. Typhii and [424,429]
S. Paratyphi B
38% against S. Paratyphi B compared to
the control.
Antibiotics 2024, 13, 76 28 of 51

Table 5. Cont.

Vaccines Target Pathogens Indications Notable Observations References

M01ZH09, Single dose Rapid and high production of IgG and
independently attenuating IgA with the fecal clearance of the bacteria
S. Typhi Human [434]
deletion (S. Typhi within 7 days post-infection without any
(Ty2∆aroC∆ssaV) ZH9) severe symptoms.
Increased stimulation of peripheral blood
mononuclear cells with increased IL-6
GMMA, Generalized S. Typhimurium,
production. Elicit strong bacteriocidal
Modules for S. Typhi, Human [37,40]
anti-LPS O-antigen antibody and IgG
Membrane Antigens S. Paratyphi A
production and complete clearance
of the bacteria.
Demonstrated 89% protective efficacy
against typhoid fever and the protection
Vi Conjugate (Vi-CRM197 ) S. Typhi Human [433]
lasted at least 4 years, significantly
increased IgG antibody titer.
Robust anti-Vi IgG response in all age
S. Typhi Vi polysaccharide groups with significant protection across
tetanus toxoid conjugate S. Typhi Human all age groups, including infants (children [431]
vaccine (Tybar) under the age of 2 years), with an efficacy
of 85% without any side effects.
Complete clearance of S. Enteritidis by
S. Typhimurium, 10 days post-infection with positive cases
AviPro Megan
S. Enteritidis and Poultry reduced to 6% on secondary inoculation. [442]
Vac 1 + A12:E13
S. Heidelberg No vertical transfer of the
antibodies observed.
Upregulation of TLRs and Th1 and Th2
Chitosan-adjuvanted cytokine mRNA with increased
Salmonella subunit OMPs-specific IgY and IgA antibodies in
S. Enteritidis Poultry [436]
nanoparticle vaccine saliva and intestine on oral administration.
(OMPs-F-CS NPs) Salmonella shedding was reduced by
7 times compared to the mock challenge.
A 3.9 log increase in mean antibody titer
Inactivated trivalent
upon administration of the booster dose
Salmonella enterica vaccine S. Typhimurium,
in chicken with 2.6 log reduction in cecal
(Nobilis® Salenvac T; S. Enteritidis and Poultry [438]
shedding of S. Typhimurium and
Intervet International B.V., S. Infantis
S. Enteritidis, followed by 1.3 log
Boxmeer, The Netherlands)
reduction in S. Infantis
S. Typhimurium, A % reduction in S. Kentucky,
S. Kentucky, S. Enteritidis, S. Heidelberg,
Poulvac® ST (Zoetis Inc.
S. Enteritidis, Poultry S. Typhimurium, and S. Hadar in liver [437]
New Jersey, USA)
S. Heidelberg and and spleen, with cross-protection between
S. Hadar all 5 strains.
In total, 58% of the cloacal swabs from the
S. Typhimurium,
Autologous killed trivalent infected birds demonstrated complete
S. Enteritidis and Poultry [442]
vaccine (Tri-Vaccine) clearance of the bacteria 8 days
S. Heidelberg
post-infection.

4.5.7. Organic Acids

Organic acids (OAs) are acidic organic compounds, primarily consisting of short-
chain fatty acids (SCFAs) and medium-chain fatty acids (MCFAs) [443]. Organic acids are
typically produced by the native gut microbiota residing in the intestines of animals, as
well as in crops and within the ceca of birds [444]. These compounds exert antimicrobial
activities, like restraining the growth and colonization of pathogenic bacteria in the gut, by
reducing the pH within microbial cytoplasm, disrupting energy production and regulation,
Antibiotics 2024, 13, 76 29 of 51

and causing the accumulation of dissociated acid ions to toxic levels inside microbial
cells [445,446]. This improves digestibility, gut health, and immunity [447]. They also hold
significant importance in the animal production industry [448]. Traditionally, they have
been employed as fungistats in the animal food industry and have demonstrated strong
antibacterial properties against foodborne pathogens such as Salmonella [449]. They are
primarily used in the form of salts, either monocarboxylic acids like acetic, butyric, formic,
and propionic acids, or based on the side chains available [450].
The short-chain fatty acids encompass organic acids like formic acid, acetic acid,
propionic acid, and butyric acid, along with acids containing additional hydroxyl (OH)
groups such as citric, lactic, malic, and tartaric acids [451], whereas, the medium-chain
fatty acids include organic acids like caproic acid, caprylic acid, capric acid, and lauric
acid [452,453]. Several studies have indicated that MCFAs can have more potent effects
compared to SCFAs, but it is important to distinguish between their bactericidal and
bacteriostatic activities [199]. For example, caprylic acids and capric acids, which are known
as MCFAs, exhibited bactericidal properties and completely cleared Salmonella Enteritidis
in vitro compared to other organic acids at the same concentration [454]. Similarly, MCFAs
C6 and C10 had bacteriostatic effects on S. Enteritidis at a concentration of 25 mM, whereas
the same strain showed complete resistance to 100 mM of SCFAs [455].
Organic acids can significantly impact the growth of and colonization by enteric
pathogens like Salmonella within the host and in the host’s feed products [456]. Koyuncu et al.
demonstrated a significant reduction (up to 2.5 log) in the numbers of S. Infantis, S. Put-
ten, S. Senftenberg, and S. Typhimurium in mash and rapeseed feed containing formic acid,
propionic acid, and sodium formate. Moreover, the combination of propionic acid and
sodium formate was more efficacious [457]. Similarly, dietary supplementation of a com-
bination of organic acid mixture of formic acids and sodium formate in broiler chicken
showed a significant (1.5 logs) reduction in the cecal colonization of S. Typhimurium [458].
Furthermore, Ruhnke et al. also demonstrated that the use of formic acids (1 kg/ton),
or propionic acid (5 kg/ton) as feed additives in broiler chicken can cause low cecal
retention (35%) of S. Typhimurium compared to the control group (60%) at 6 weeks
of age [459]. Moreover, a significant reduction (up to 90%) in fecal Salmonella shed-
ding in pigs was observed 7 days post-exposure after supplementation with sodium
butyrate, formic, and citric acid as acidifiers [460]. Additionally, the normal gut mi-
croflora and oral supplementation of probiotics and prebiotics was shown to stimulate
the production of short-chain fatty acids in poultry GIT, thus limiting Salmonella colo-
nization, causing complete clearance of the bacteria and modulation of gut immunity
in mice [461]. It was also demonstrated that lactic acid bacteria can work synergisti-
cally in lowering the gut pH and modulating the gut immunity in 160-day-old broiler
chicken [462].
While organic acids have shown promise in antimicrobial drug development and
pathogen inhibition, notable concerns and limitations exist associated with their utiliza-
tion [463]. The most significant limitation is the dissociation of the organic acids and their
ability to reach the lower portion of the gastrointestinal tract [464]. The organic acids
are digested and metabolized, and, as a result, the concentration is decreased, leading
to dissociation when reaching the lower GIT, which is the primary site for Salmonella
infection. Resistance is also possible as pathogenic species adapt to treatment [450].
Despite the limitations, it is worth noting that organic acids, indeed, are promising
tools for mitigating Salmonella contamination in food. Their application should be con-
sidered an integral component of a comprehensive food safety strategy aimed at con-
trolling and preventing foodborne infections, particularly those caused by antibiotic-
resistant Salmonella.

4.5.8. Essential Oils (EOs)

Essential oils (EOs), also referred to as volatile oils, are a mixture of aromatic com-
pounds with characteristic flavors and aromas [465]. They are derived from various
Antibiotics 2024, 13, 76 30 of 51

plant parts, including stems, flowers, fruits, buds, leaves, and even wood [466]. Essential
oils consist of a wide range of compounds such as alcohol, acetones, phenolic acids, ter-
penes, aldehydes, and esters, which can play a significant role as antimicrobial agents or
nutrient supplements [221]. For example, citrus based EOs comprises more than 2000 dif-
ferent types of organic compounds [466,467]. Essential oils exist in a highly bioactive
vapor phase and typically do not require physical contact with the pathogen to demon-
strate antimicrobial action [468]. In plants, they also play significant role in protecting
against bacterial, viral, or fungal infections and help attract insects that can directly help in
the pollination process [469,470]. Essential oils possess numerous therapeutic properties
for humans and animals, including antimicrobial, antioxidant, anticancer, antidiabetic,
spasmolytic, and insect repellent. Moreover, they have long been utilized in aromather-
apy to promote relaxation, stabilize moods, and provide physical and psychological re-
lief [471]. These compounds are regularly used in the food industry as preservatives
for preventing the growth of foodborne bacteria such as Salmonella, E. coli, Listeria, and
Campylobacter [472].
Essential oils have been used as antimicrobial compounds and food preservatives
to control Salmonella [473]. It has been reported that EOs like cinnamon oils result in
a 2.7 log reduction in S. Typhimurium and can have synergistic effects in vitro when
used with antibiotics such as cefotaxime [474]. Similarly, lemongrass, cinnamon, geraniol,
and palmarosa-based EOs against can cause complete clearance of S. Enteritidis in fruit
juices [475]. Furthermore, in vitro, assessment of the antimicrobial effect of C. zelanicum
and S. aromaticum against the Salmonella enterica serotypes Enteritidis and S. Typhimurium
from poultry demonstrated a high inhibitory effect, with MIC ranging from 1.26 mg/mL to
0.63 mg/mL for C. zelanicum and 2.637 mg/mL to 0.164 mg/mL for S. aromaticum and an
MIC of 1.289 mg/mL to 0.322 mg/mL for the mixture of both [476]. However, laurel leaves,
cardamom, ginger, and rosemary based EOs had moderate inhibitory activity against
different Salmonella serotypes isolated from humans [477]. Similarly, another in vitro study
showed that thyme oil had the highest inhibitory effect (22.5–38.5 mm zone of inhibition)
against S. Enteritidis, S. Montevideo, and S. Heidelberg, followed by clove oil and rosemary
oil, whereas orange oil had no significant inhibitory effect on S. Heidelberg [478]. Also,
oregano, thyme, clove, and arborvitae based EOs showed significant inhibitory effects
(p < 0.001), with complete clearance of S. Typhimurium at 0.125% with no genotoxic effect
on human embryo lung cells after 24 h of administration in vitro [479]. Different studies on
evaluating the effect of EOs on the growth of Salmonella are shown in Table 6.
While EOs have found diverse applications, ranging from feed additives and crop
protectants to food preservatives and treatments for human ailments, it is essential to
exercise caution when considering their extended utilization due to the potentially toxic
effects of these compounds [480]. The widespread use of essential oils has been hindered
by their adverse impact on organoleptic characteristics, limited stability under standard
environmental conditions, volatility, poor solubility in water, and possible toxicity [481].
Toxicological concerns related to essential oils have been documented, including findings by
Millet et al. who reported instances of neurotoxicity and tonic-clonic convulsions in humans
due to the use of commercially available extracts from sage, hyssop, thuja, and cedar [482].
Similarly, severe effects, including dermatitis, hospitalizations, and, in severe cases, fatalities
have also been reported following aromatherapy using lavender, peppermint, and ylang-
ylang [483]. Looking forward, the integration of EOs into a comprehensive food safety
strategy demands a holistic and multidisciplinary approach, and further research is essential
for their production to guarantee uniform quality, efficacy, and safety.
Antibiotics 2024, 13, 76 31 of 51

Table 6. Different organic acids used for the control of Salmonella infection in humans and animals.

Major Salmonella
Plant MIC Activity References
Components Serotype
Thymol (37.5%), The zone of inhibition in the
p-cymene (14.49%), agar-well diffusion assay was
γ-terpinene S. Typhimurium found to be 25.5 mm against
Thymus vulgaris 0.25% v/v [484]
(11.15%), linalool ATCC 14028 S. Typhimurium, with
(4.71%), and complete clearance of the
carvacrol (4.62%) bacteria at MIC 0.25% v/v
120 µg/mL Complete clearance of the
Thymol- and
S. enteritidis ATCC (carvacrol), bacteria at 120 µg/mL
Origanum vulgare carvacrol- [485]
13076 130 µg/mL (carvacrol) and 130 µg/mL
based EO
(Thymol) (Thymol) in vitro
Complete clearance of
Pistacia atlantica S. Typhimurium S. Typhimurium was found to
α-Pinene (10.8%) 0.26 mg/mL [486]
subsp. Kurdica ATCC 14028 be at 0.5 mL/mL with a zone
of inhibition of 22 mm
The zone of inhibition of all of
S. enteritidis,
Cinnamomum the strains was found to be
Not identified S. Typhimurium, >20 µL/mL [487]
verum higher than 20 mm on agar
S. Heidelberg
well diffusion assay.
The zone of inhibition was
found to be 20 mm and the
Citrus medica L. d-Limonene
S. Typhimurium 2.0 mg/mL inhibition of biofilm [58]
Var. Sarcodactylis terpinene
formation was found
to be 90%.
linalool,
Two log reduction in the
1,8-cineole,
number of Salmonella when
eugenol,
Ocimum basilicum S. Enteritidis 20 µg/mL used in food products, [488]
α-terpineol,
colonization resistance
ρ-cymene, and
was evident
germacrene D
Inhibition of biofilm
formation by 23%,
Allium sativum MIC/8
diallyl disulfide S. Typhimurium downregulation of virulence [489]
(Garlic) (1/512) µg/mL
genes including invA
and sdiA genes
Complete clearance of illeal
Commercially and cecal Salmonella in broiler
Thymol, carvacrol,
available S. Enteritidis 4.6 mg/mL chicken at 10 dpi, improved [33]
cinnamaldehyde
Essential oils. illeal integrity, gut
immunity modulation
In vitro: complete clearance of
the bacteria at 4 mg/mL and
8 mg/mL, respectively
S. Typhimurium 4 mg/mL
Aniba rosaeodora Linaloo In vivo: complete clearance [490]
S. Pullorum 8 mg/mL
and systemic protection in
chicks, modulate host
inflammatory process
Significant reduction in
Cymbopogon
Neral, Citral, bacterial population by 1 log
citrates S. Newport --- [491]
Geranyl acetate CFU/g when co-cultured
(Lemongrass)
with S. Newport
Antibiotics 2024, 13, 76 32 of 51

5. Conclusions
Foodborne pathogens such as Salmonella pose a formidable challenge to human and
animal health and significant economic loss in the healthcare and agricultural sectors
worldwide. The widespread use of antibiotics in food animals for growth promotion,
therapeutic applications, and preventative measures has played a significant role in the
swift rise and global dissemination of AMR Salmonella. Furthermore, the indiscriminate use
of antibiotics, particularly in sub-therapeutic doses, has significantly contributed to the rise
of MDR strains. The rapid emergence and spread of MDR Salmonella have necessitated the
development of alternative strategies for treating and controlling the infection. Addressing
the issue of AMR strains calls for a multifaceted strategy involving early detection of
infections and the implementation of necessary biosecurity measures to effectively contain
outbreaks within the infected individual or the animal farm. Early detection of the infection
allows for the timely initiation of appropriate targeted treatment and avoids the need for
broad-spectrum antibiotics, which lowers the selective pressure that drives the development
and spread of AMR strains in a bacterium. In addition to the early detection of the outbreak,
the use of antibiotic-alternative therapeutics holds a promising role in combating AMR
strains. Several research efforts have been made to limit the spread of AMR Salmonella
by exploring various alternative intervention strategies, including the use of probiotics
and prebiotics, antimicrobial peptides, phage therapy, small molecule growth inhibitors,
quorum sensing/virulence inhibitors, vaccines, organic acids, and essential oils. These
strategies can be used individually or in combination.
Nonetheless, each alternative approach carries its distinct advantages and limitations.
It is crucial to approach them carefully, and additional research is required to ascertain their
effectiveness, safety, and viability when implemented on a larger scale. As we transition
to a future where traditional treatments like antibiotics could progressively lose efficacy,
adopting a contemporary and enhanced strategy is crucial. These strategies involve syner-
gistic application of these antibiotic alternatives, complemented by enhanced biosecurity
protocols and judicious antibiotic use. Such a comprehensive approach will prove pivotal
in controlling the dissemination of AMR-Salmonella infection. Furthermore, applying a
One Health approach and continued collaboration between researchers, healthcare profes-
sionals, veterinarians, and policymakers in antibiotic stewardship is crucial in safeguard-
ing public health and food safety from the threat of prevalent foodborne pathogens like
MDR Salmonella.

Author Contributions: Conceptualization, supervision, and funding, Y.A.H.; data curation, B.L. and
Y.A.H.; original draft preparation, B.L., A.M.M.M., M.S., M.M.S., P.J.H.II, J.A., W.G.K., C.W.L. and
Y.A.H.; Review and editing, B.L., A.M.M.M., M.S., M.M.S., P.J.H.II, J.A., W.G.K., C.W.L., M.E.E.Z.,
H.R., M.M. and Y.A.H. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data are contained within the article.
Conflicts of Interest: The authors declare no conflicts of interest.

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