Emergence of Antibiotic Resistance in Listeria monocytogenes Isolated from Food Products: A Comprehensive Review

Abstract

Listeria monocytogenes is an opportunistic pathogen that has been involved in several deadly illness outbreaks. Future outbreaks may be more difficult to manage because of the emergence of antibiotic resistance among L. monocytogenes strains isolated from food products. This review summarizes the available evidence on the emergence of antibiotic resistance among L. monocytogenes strains isolated from food products and the possible ways this resistance has developed. Furthermore, the resistance of food L. monocytogenes isolates to antibiotics that are currently used in the treatment of human listeriosis such as penicillin, ampicillin, tetracycline and gentamicin, has been documented. Acquisition of movable genetic elements is considered the major mechanism of antibiotic resistance development in L. monocytogenes. Efflux pumps have also been linked with resistance of L. monocytogenes to some antibiotics including fluoroquinolones. It seems that some L. monocytogenes strains isolated from food products are intrinsically resistant to several antibiotics. However, factors in food processing chains and environments (from farm to table) including extensive or sub-inhibitory antibiotics use, horizontal gene transfer, exposure to environmental stress and biofilm formation play crucial roles in the development of antibiotic resistance by L. monocytogenes.

Full text

Emergence of Antibiotic Resistance in Listeria
monocytogenes Isolated from Food Products: A
Comprehensive Review
Amin N. Olaimat , Murad A. Al-Holy, Hafiz M. Shahbaz, Anas A. Al-Nabulsi , Mahmoud H. Abu Ghoush, Tareq M. Osaili ,
Mutamed M. Ayyash , and Richard A. Holley
Abstract: Listeria monocytogenes is an opportunistic pathogen that has been involved in several deadly illness outbreaks.
Future outbreaks may be more difficult to manage because of the emergence of antibiotic resistance among L. monocytogenes
strains isolated from food products. The present review summarizes the available evidence on the emergence of antibiotic
resistance among L. monocytogenes strains isolated from food products and the possible ways this resistance has developed.
Furthermore, the resistance of food L. monocytogenes isolates to antibiotics currently used in the treatment of human
listeriosis such as penicillin, ampicillin, tetracycline, and gentamicin, has been documented. Acquisition of movable
genetic elements is considered the major mechanism of antibiotic resistance development in L. monocytogenes. Efflux
pumps have also been linked with resistance of L. monocytogenes to some antibiotics including fluoroquinolones. Some L.
monocytogenes strains isolated from food products are intrinsically resistant to several antibiotics. However, factors in food
processing chains and environments (from farm to table) including extensive or sub-inhibitory antibiotics use, horizontal
gene transfer, exposure to environmental stresses, biofilm formation, and presence of persister cells play crucial roles in
the development of antibiotic resistance by L. monocytogenes.
Keywords: antibiotic resistance, biofilm formation, environmental stresses, food, horizontal gene transfer, Listeria monocy-
togenes, listeriosis, multidrug resistant bacteria
Introduction
Listeria monocytogenes is an important, ubiquitous, foodborne
microbe that can contaminate food products during or after
processing. L. monocytogenes poses a significant risk to the food
industry, particularly producers of ready-to-eat (RTE) foods
due to its ability to proliferate over a vast range of adverse
environmental conditions encompassing low temperature, low
pH, and high salt. L. monocytogenes represents a major public health
concern because it may cause severe human illness with serious
consequences. Septicemia,meningitis, meningoencephalitis in
CRF3-2018-0066 Submitted 3/29/2018, Accepted 6/7/2018. Authors Olaimat,
Al-Holy, and Abu Ghoush are with Dept. of Clinical Nutrition and Dietetics, Faculty
of Allied Health Sciences, Hashemite Univ., P.O. Box 150459, Zarqa, 13115,
Jordan. Author Shahbaz is with Dept. of Food Science and Human Nutrition, Univ.
of Veterinary and Animal Sciences, Lahore, 54000, Pakistan. Authors Al-Nabulsi
and Osaili are with Dept. of Nutrition and Food Technology, Jordan Univ. of Science
and Technology, P.O. Box 3030, Irbid, Jordan. Author Osaili is with Dept. of Clinical
Nutrition and Dietetics, College of Health Sciences, Univ. of Sharjah, Sharjah, United
Arab Emirates. Author Ayyash is with Dept. of Food Science, United Arab Emirates
Univ., Al Ain, United Arab Emirates. Author Holley is with Dept. of Food and
Human Nutritional Sciences, Faculty of Agricultural and Food Sciences, Univ. of
Manitoba, Winnipeg, Manitoba, R3T 2N2, Canada. Direct inquiries to author
Olaimat (E-mail: aminolaimat@hu.edu.jo).
immuno-compromised individuals, invasive infections in the
newborn and elderly, and serious complications during pregnancy
(abortion and stillbirth), with a fatality rate that can reach up to
20% to 30% (Scallan et al., 2011; Swaminathan & Gerner-Smidt,
2007). Therefore, treatment with antibiotics is usually needed for
the control of the infection caused by this bacterium. L. mono-
cytogenes, in general, is considered vulnerable to a wide range of
antibiotics, which have bactericidal effects against Gram-positive
bacteria, including, tetracyclines, erythromycin, ampicillin,
and gentamicin (Teuber, 1999). However, most strains of L.
monocytogenes exhibit native resistance to cefotaxime, cefepime,
fosfomycin, oxacillin, and licosamides (CA-SFM, 2010; Lecuit &
Leclercq, 2009). Recently, antibiotic resistance among L. mono-
cytogenes isolated from foods and the environment has increased,
particularly for those antibiotics commonly used to treat listeriosis.
Therefore, monitoring changes in the antibiotic resistance of L.
monocytogenes due to the continuing emergence of resistant strains
is needed. The aim of this study was to integrate the broadly
scattered information on the antibiotic resistance among L. mono-
cytogenes isolated from food products and to define the possible
mechanisms involved in its development in these isolates. In
addition, some suggestions for monitoring antibiotic resistance are
discussed.
C2018 Institute of Food Technologists®
doi: 10.1111/1541-4337.12387 Vol. 0, 2018 rComprehensive Reviews in Food Science and Food Safety 1

Antibiotic resistance of L. monocytogenes ...
Table 1–The differentiation of biochemical reactions among Listeria species.a
Speciesb
Characteristic
L.
monocy-
togenes
L.
innocua
L. seel-
igeri
L. ivan-
ovii
L. welsh-
imeri
L.
marthii L. grayi
L.
rocou-
rtiae
L. weihenst-
ephanensis
L.
cornell-
ensis
L.
riparia
L.
grande-
nsis
L.
fleischm-
annii
L.
aquatic
L. florid-
ensis
L.
newyork-
ensis
L.
booriae
L.
costari-
censis
Growth at 4 °C+ +++++++ + +++ –––++–
Voges–Proskauer + ++++++− − ––– – V–––+
Nitrate reduction − −−−−− V+++++++–+++
Motility + ++++++− − ––– – –– – –+
Methyl red + ++++++ VVV+V++++++
Catalase + +++++++ + +++ + ++ + +–
Hemolysis +–++−−−− − ––– – –– – ––
Arylamidase −++VV−+− − ––– – –– – ––
α-Mannosidase + +−−++ V+− –+––+––+–
phosphoinositide
phospholipase C
+ −−+−−−− − ––– – –– – ––
Acidification of:
D-Arabitol + ++++++− + ––V+–– – ++
D-Xylose − −+++−−+ + +++ + ++ + ++
L-Rhamnose +V−− V−−+ + –+–+++ V++
α-Methyl D-glucoside + +++++++ + +++ + –++++
D-Ribose − −−+−−++ − + V+++–+V+
Glucose 1-phosphate −−−V−−−− − ––– – –– – ––
D-Tagatose − −−−+−−− − ––– –+––––
D-Mannitol − −−−−−++ + –V–V––++–
Sucrose + ++++−−− − ––– V–– – –+
Turanose −V−−−+−− − ––– V–– – ––
Glycerol V++++− V++ VV–+V–+++
D-Galactose V−− V−−++ − –+–––++++
L-Arabinose − −−−−−−− − V+––++ + + –
L-Sorbose V!V!−V!−V!V!−− ––– V–– – ––
Inositol − −−−−−−− − –V–VV––––
Methyl α-D-mannose −−ND −ND −+− − ––– V–– – –+
Maltose + +++++++ + +++ + –++++
Lactose + +++++++ V!(+)+–+–++++
Melibiose V!V−−− V−+ − –V–V–– –+–
Inulin V!V!−−−−−− − ––– – –– – ––
D-Melezitose V VVVV−−− − ––– V–– – ––
D-Lyxose VV−− V−V−− ––– – V+–––
D-glucose V!V!+V!+V!++ + +++++++++
L-Fucose − −−−−−−− − ––– – –– – –+
Potassium 5-ketogluconate − −−−−−−− − ––– – –– – –+
aAdoptedfromN
´
u˜
nez-Montero et al. (2018), Orsi & Wiedmann (2016), Weller et al. (2015).
+, Positive; (+), weakly positive; ̶, negative; V, variable (between replicates and/or between strains); V!, variable between studies; ND, not determined.
bAll species are positive for aesculin and acid production from N-acetylglucosamine, amygdalin, arbutin, cellobiose, D-fructose, D-mannose, and salicin. All species/strains are negative for nitrite reduction and acid production from D-adonitol, D-arabinose, glycogen, methyl
b-D-xylopyranoside, potassium 2-ketogluconate and raffinose.
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Antibiotic resistance of L. monocytogenes ...
General Features of the Genus Listeria
Based on the recently updated classification, the genus Listeria is
composed of 18 known species, and is organized into two groups
based on their relationship to L. monocytogenes. Among the species
of interest, L. monocytogenes is of particular importance in terms of
its implications on human health and the economy since it may
inflict serious diseases in both humans and animals. The first group
is the “Listeria sensu stricto” clade which consists of six species
including: L. monocytogenes,L. innocua,L. welshimeri,L. ivanovii,
L. seeligeri,andL. marthii. These species are commonly isolated
from intestinal tract of symptom-free animals and animal-origin
food products (Chiara et al., 2015; Orsi & Wiedmann, 2016;
Schardt et al., 2017). The second group is the “Listeria sensu lato”
clade and consists of 12 species including: L. weihenstephanensis,
L. fleischmannii, L. rocourtiae,L. booriae, L. riparia, L. grayi,L.
floridensis,L. aquatica,L. newyorkensis,L. cornellensis,L. grandensis,
and L. costaricensis, which have been isolated from the environment
or food matrices, but they are unable to colonize mammalian
hosts (Bertsch et al., 2013a; Chiara et al., 2015; den Bakker et al.,
2014; Graves et al., 2010; Lang Halter, Neuhaus, & Scherer,
2013; Leclercq et al., 2009; N´
u˜
nez-Montero et al., 2018; Orsi
& Wiedmann, 2016; Orsi, den Bakker, & Wiedmann, 2010;
Schardt et al., 2017; Weller, Andrus, Wiedmann, & den Bakker,
2015). Metabolically, all Listeria spp. are positive for the catalase
test (except L. costaricensis) and for the production of acid from
N-acetylglucosamine, arbutin, salicin, D-fructose, amygdalin,
aesculin-ferric citrate, cellobiose, and D-mannose. However,
all species fail to reduce nitrite, and cannot produce acid from
raffinose, glycogen, methyl β-d-xylopyranoside, d-arabinose,
d-adonitol, and potassium 2-ketogluconate (N´
u˜
nez-Montero
et al., 2018; Orsi & Wiedmann, 2016; Weller et al., 2015). Other
differences in biochemical reactions between L. monocytogenes
and other members of Listeria are illustrated in Table 1. We
expect that this classification will be updated in the future and
new species may be included in the “Listeria sensu lato” group
or in a new group. Changes in the taxonomy of Listeria spp.
could have a significant effect on the food industry should a new
pathogenic species emerge. Presently, the only known Listeria
spp. to cause disease to humans and animals are L. monocytogenes
and L. ivanovii, although the latter has seldom been implicated in
human listeriosis (Dussurget, 2008; Orsi & Wiedmann, 2016).
Listeria monocytogenes: A Foodborne Pathogen
L. monocytogenes constitutes a major burden for the food indus-
try and health agencies worldwide due to its ability to withstand
a vast range of harsh environmental challenges. The organism is
considered a psychrotroph, and it can grow at 0.5 to 45 °C, al-
though the optimum temperature range is 30 to 37 °C(Dortet,
Veiga-Chacon, & Cossart, 2009; Farber, 2000; Lado & Yousef,
2007; Low & Donachie, 1997). Further, the organism is capable
of surviving for long periods in frozen food products (Ramaswamy
et al., 2007; Yan et al., 2010). L. monocytogenes is capable of grow-
ing at pH 4.3 to 9.6 with optimal growth at neutral pH (Dortet
et al., 2009; Lado & Yousef, 2007). Moreover, L. monocytogenes
possess an extraordinary ability to survive in 20% (w/v) NaCl
(Gandhi & Chikindas, 2007; Lado & Yousef, 2007; Warriner &
Namvar, 2009; Zunabovic, Domig, & Kneifel, 2011). In addi-
tion, L. monocytogenes is capable of biofilm formation on various
food contact surfaces including stainless steel and plastic (Bremer,
Monk, & Osborne, 2001; Gandhi & Chikindas, 2007; Oliveira,
Brugnera, Alves, & Piccoli, 2010), which may protect the or-
ganism from environmental stresses and increases its resistance to
cleaners and sanitizers used in the food industry. All these char-
acteristics of L. monocytogenes forced governments and food safety
agencies around the globe to set criteria to reduce the presence of
L. monocytogenes in the food chain. For example, the United States
Dept. of Agriculture (USDA) has adopted a zero-tolerance policy
(absence of the organism in 25 g food sample) for L. monocytogenes
in RTE foods (Orsi et al., 2010). Because of its ubiquitous nature,
L. monocytogenes has been isolated from a variety of environmental
sources including soil, sewage, silage, water, waste effluent, and fe-
ces of humans and animals (Buchrieser, Rusniok, Kunst, Cossart,
& Glaser, 2003; Jeyaletchumi et al., 2010); animals such as cattle,
goats, sheep, and poultry (Farber & Peterkin, 1991); food (dairy)
processing plants (Fox, Hunt, O’Brien, & Jordan, 2010); and a
variety of food products such as meat, chicken, smoked fish, un-
pasteurized dairy products, and vegetables (Table 2).
Human Listeriosis
L. monocytogenes causes a rare but serious life-threatening, inva-
sive disease called listeriosis, which has become a major foodborne
illness in the last two decades. The occurrence of listeriosis varies
between countries and usually occurs at a rate of between 0.1
and 11.3 cases per million persons (FAO/WHO, 2004). Clinical
progression of listeriosis is affected by the physiological, patho-
logical, and immunological (T-cell immunity) status of the host.
Foodborne listeriosis has a fatality rate of ࣘ30%, which is notably
higher than illnesses caused by other foodborne pathogens (Scallan
et al., 2011).
Usually, pregnant women, the newborn, elderly people, and
immunocompromised individuals are more susceptible to liste-
riosis, but it may occasionally occur in healthy individuals. The
prevalence of listeriosis among pregnant women, neonates, and
the elderly is 12, 3.4, and 10 per 100,000, respectively, compared
with 0.7 per 100,000 in the general population (Goulet, Hedberg,
Le Monnier, & De Valk, 2008; Sapuan et al., 2017; Southwick
& Purich, 1996). Listeriosis has an average fatality rate of 20% to
30% even with the application of antibiotic therapy (Swaminathan
& Gerner-Smidt, 2007). Invasive human listeriosis can present as
a serious maternal fetal infection or neonatal listeriosis and blood
stream infection (bacteremia; Drevets & Bronze, 2008).
Symptoms of pregnant women with invasive listeriosis in-
clude chills, fever, headache, and leukocytosis as early as 1 week
before illness diagnosis (McLauchlin, 1990; Mylonakis, Paliou,
Hohmann, Calderwood, & Wing, 2002). The organism can be
isolated from amniotic fluid, the cervix, and placenta. Compli-
cations of the disease may include spontaneous abortion or still-
birth, pre-term delivery, or neonatal infection (Mylonakis et al.,
2002). Neonates born to mothers that have been previously di-
agnosed with listeriosis may develop neonatal infection through
the birth canal or through the transmission of the infection across
the placenta. Early-onset neonatal listeriosis can be observed as
bacteremia, meningitis and pneumonia, but late-onset is usually
associated with meningitis (Jackson, Iwamoto, & Swerdlow, 2010).
Febrile gastroenteritis is a noninvasive disease that mainly affects
healthy individuals 9 to 32 hr after ingestion of food contaminated
with high numbers of L. monocytogenes, and has a median incu-
bation period of 20 hr. The manifested symptoms include fever,
diarrhea, abdominal pain, headache, chills, nausea, fatigue, and
myalgias. The infection is a self-limiting disease that lasts for less
than 48 hr and most healthy people recover without any medical
intervention (Dalton et al., 1997).
The third clinical manifestation of invasive human listerio-
sis is bacteremia, which could be accompanied by cerebral
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Antibiotic resistance of L. monocytogenes ...
Table 2–Selected studies on the prevalence of L. monocytogenes in food products in different countries from 2005 to 2018.
Location Prevalence (%) Food items References
Turkey 9/146 (6.16%) Raw and cooked meats Yucel et al. (2005)
USA 91/3063 (3.0%) RTE products Shen et al. (2006)
Canada 124/800 (15.5%) Raw and RTE meat and poultry products Bohaychuck et al. (2006)
Italy 121/5788 (2.1%) Plant and animal origin foods Latorre et al. (2007)
Lebanon 30/160 (18.8%) Dairy products Harakeh et al. (2009)
Iran 5/290 (1.7%) Traditional Iranian dairy products Rahimi et al. (2010)
China 90/2177 (4.1%) Different food products Yan et al. (2010)
Ethiopia 21/391(5.4%) Animal origin foods Gebretsadik, Kassa, Alemayehu, Huruy, and Kebede (2011)
Jordan 51/280 (18.2%) Raw chicken and RTE chicken products Osaili et al. (2011)
Greece 38/100 (38%) Chicken carcasses Sakaridis et al. (2011)
Jordan 39/350 (11.1%) Brined white cheese Osaili et al. (2012)
India 25/650 (3.8%) Raw meats and dairy products Khan, Rathore, Khan, and Ahmad (2013)
Sudan 34/250 (13.6%) RTE chicken Products Alsheikh, Mohammed, and Abdalla (2013)
EU 310/2994 (10.4%) Smoked and graved fish European Food Safety Authority (EFSA), 2013
Estonia 554/21574 (2.6%) Different food products Kramarenko et al. (2013)
Iran 21/182 (11.5%) Dairy and meat products Hosseini, Sharifan, and Tabatabaee (2014)
Jordan 59/270 (21.9%) Raw and processed meats Al-Nabulsi et al. (2014)
Turkey 4/100 (4.0%) RTE products Terzi et al. (2015)
Malaysia 45/396 (11.4%) RTE products Jamali, Chai, and Thong (2013)
India 3/200 (1.5%) Animal origin foods Nayak, Savalia, Kalyani, Kumar, and Kshirsagar (2015)
China 207/1036 (20.0%) Retail raw foods Wu et al. (2015)
Ethiopia 24/384 (6.3%) RTE foods of animal origin Garedew et al. (2015)
Nigeria 16/205 (7.8%) Raw meats Peter et al. (2016)
Nigeria 36/550 (6.5%) Milk products Usman, Kwaga, Kabir, and Olonitola (2016)
Brazil 4/132 (3%) Raw and RTE vegetables de Vasconcelos Byrne, Hofer, Vallim, and de Castro Almeida
(2016)
Japan 52/2980(1.7%) RTE foods Shimojima et al. (2016)
USA 10/1606 (0.6%) Raw milk cheese FDA (2016b)
Turkey 52/210 (24.8%) Raw milk and dairy products Kevenk and Gulel (2016)
India 37/113 (32.7%) Seafood products Jeyasanta and Patterson (2016)
Iran 36/200 (18.0%) chicken carcasses Zeinali et al. (2017)
Iran 8/267 (3.0%) Different food products Lotfollahi et al. (2017)
China 21/900 (2.3%) Chinese foods Du et al. (2017)
Uruguay 71/635 (11.2%) Frozen and RTE foods Braga et al., 2017
USA 102/27389 (0.4%) RTE foods Luchansky et al. (2017)
Egypt 47/331 (14.2%) Frozen vegetables Mohamed et al. (2018)
Morocco 16/1096 (1.5%) Different food products Amajoud et al. (2018)
Brazil 35/195 (17.9%) chicken carcasses and cuts Oliveira et al. (2018)
infections including rhombencephalitis, meningitis, brain abscess,
or meningoencephalitis. L. monocytogenes is ranked fifth among the
most frequent bacterial causes of meningitis (Wenger, Hightower,
Facklam, Gaventa, & Broome, 1990). The majority of the
cases presenting as meningitis or menigoencephalitis are usually
observed in patients aged more than 50 yr and symptoms
include fever, neck stiffness, headache, and altered mental
status (Brouwer, van de Beek, Heckenberg, Spanjaard, & de
Gans, 2006). L. monocytogenes is distinguished among neu-
roinvasive bacteria that can attack the central nervous system
based on the cellular route used, and whether the organism
crosses specialized epithelial cells of the blood–choroid plexus
barriers or endothelial cells of the blood–brain barrier. These
mainly include: (1) passage across blood–choroid plexus barriers
within parasitized leukocytes or the blood–brain barrier (2).
Direct invasion of the extracellular blood–borne organism into
the endothelial cells, or (3) centripetal movement into the
brain within the axons of cranial nerves (Drevets, Leenen, &
Greenfield, 2004).
Antibiotic Treatment of Listeriosis
Antibiotics are natural, synthetic, or semisynthetic substances
that are often used to treat or sometimes prevent infections in
humans and animals (O’Neill, 2015; WHO, 2015). Antibiotics
can have a bacteriostatic effect where they inhibit the growth
of microorganisms temporarily or be bactericidal where they kill
bacterial cells. Antibiotics may reduce growth or viability of bac-
teria by inhibiting cell wall, protein, or DNA synthesis (Perichon
& Courvalin, 2009). Antibiotics are classified in different groups
according to their chemical structure (Table 3) or their mechanism
of action (Table 4).
At present there is no vaccine available commercially to prevent
listeriosis, thus early diagnosis is critical for the success of antibiotic
treatment, especially for high-risk patients (Calder ´
on-Gonz´
alez
et al., 2014). An issue complicating investigations of large listeriosis
outbreaks is that the incubation time for L. monocytogenes is long
and may reach up to 70 days after consumption of contaminated
food. This long time makes it difficult to track the pathogen back
to its origin because patients have difficulty remembering what
they ate after lengthy periods (Dortet et al., 2009; Rhoades, Duffy,
& Koutsoumanis, 2009).
The treatment of human listeriosis with antibiotics involves use
of a β-lactam (penicillin and ampicillin) alone or combined with an
aminoglycoside (gentamicin) as the treatment of choice (Alonso-
Hernando, Prieto, Garc´
ıa-Fern´
andez, Alonso-Calleja, & Capita,
2012; Dortet et al., 2009; Ramaswamy et al., 2007). However, pa-
tients who exhibit an allergic reaction to penicillin, a second choice
therapy is usually used that involves a combination of trimethoprim
with a sulfonamide, such as sulfamethoxazole in co-trimoxazole
(Alonso-Hernando et al., 2012; Charpentier & Courvalin, 1999).
Vancomycin is used to treat bacteremia, although erythromycin is
used to treat infected pregnant women (Alonso-Hernando et al.,
2012). Rifampicin, tetracycline, chloramphenicol, and fluoro-
quinolones are also used to treat listeriosis (Allerberger & Wag-
ner, 2010; Conter et al., 2009; Walsh, Duffy, Sheridan, Blair, &
McDowell, 2001).
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Antibiotic resistance of L. monocytogenes ...
Table 3–Classification of antibiotics based on chemical structure.a
Penicillins Cephalosporins Fluoroquinolones Tetracyclines Aminoglycosides Monobactams Carbapenems Macrolides Others
Natural
penicillin:
Penicillin G
Penicillin V
Penicillin VK
Procaine penicillin
First Generation
Cephalothin
Cefazolin
Cephapirin
Cephalexin
Cephradine
Cefadroxil
First Generation
Nalidixic acid
Cinoxacin
First Generation
Tetracycline
Chlortetracycline
Amikacin
Gentamicin
Kanamycin
Neomycin
Tobramycin
Aztreonam Ertapenem
Imipenem
Meropenem
Azithromycin
Clarithromycin
Dirithromycin
Erythromycin
Clindamycin
Vancomycin
Rifampin
Doxycycline
Linezolid
Trimethoprim-
sulfamethox-
azole
Semisynthetic
Penicillinase Resistant
antibiotics
Cloxacillin,
Dicloxacillin,
Methicillin, Nafcillin,
Oxacillin
Aminopenicillins
Ampicillin, amoxicillin
Antipseudomonal
penicillins
Carboxypenicillins
(Carbenicillin,
Ticarcillin)
Ureidopenicillins
(Piperacillin,
Azlocillin, and
Mezlocillin).
Second Generation
Cefamandole
Cefuroxime
Cefonicid
Ceforanid
Cefoxitin
Cefmetazole
Cefminox
Cefotetan
Second Generation
Ciprofloxacin
Norfloxacin
Lomefloxacin
Ofloxacin Levofloxacin
Second Generation
Doxycycline
Lymecycline
Meclocycline
Methacycline
Minocycline
Rolitetracycline
Third Generation
Cefotaxime
Ceftizoxime
Ceftriaxone
Ceftazidime
Cefoperazone
Cefixime
Ceftibuten
Cefdinir
Third Generation
Sparfloxacin
Gatifloxacin
Grepafloxacin
Third Generation
Tigecycline
Fourth Generation
Cefpirome
Cefepime
Fourth Generation
Moxifloxacin
Trovafloxacin
Gemifloxacin
Fifth Generation
Ceftobiprole
Ceftaroline
aAdopted from: Dumancas, Hikkaduwa Koralege, Mojica, Murdianti, & Pham (2014); Fernandes, Amador, & Prudˆ
encio (2013); Fuoco (2012); Moore (2014); Redgrave, Sutton, Webber, & Piddock (2014).
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Antibiotic resistance of L. monocytogenes ...
In general, the majority of Listeria spp. isolated from food, clin-
ical and environmental samples are sensitive to ordinarily used
antibiotic therapy that is usually applied against Gram-positive bac-
teria including tetracyclines, ampicillin, penicillin G, imipenem,
amoxicillin, sulfonamides, aminoglycosides, macrolides, chloram-
phenicol, and glycopeptides (Dortet et al., 2009). Yet, most strains
of L. monocytogenes show inherent resistance to cefotaxime, ce-
fepime, fosfomycin, oxacillin, and lincosamides (CA-SFM, 2010;
Lecuit & Leclercq, 2009).
Antibiotic Resistance
Antibiotic resistance can be defined as the ability of a microor-
ganism to resist (survive or grow) an antibiotic concentration that
is used in clinical practice where the organism changed its response
to the antibiotic (WHO, 2018). Antibiotic resistance is considered
one of the major threats to global public health, food security,
and food development because it makes disease harder to treat as
antibiotics become ineffective, which may increase the mortal-
ity rate, the recovery time in hospitals, as well as medical costs
(WHO, 2018). Microorganisms, particularly bacteria respond dif-
ferently to antibiotics and other antimicrobial compounds, either
due to intrinsic differences or to the development of resistance by
adaptation or genetic exchange (Calderon, & Sabundayo, 2007).
Factors Influencing the Antibiotic Resistance of
L. monocytogenes
In the last few decades, the extensive use of antibiotics has
sometimes involved misuse of these drugs in humans and animals,
and thus greatly contributed to the progression and spread of
antibiotic resistance among foodborne pathogens including L.
monocytogenes (Wilson, Gray, Chandry, & Fox, 2018). Antibiotic
resistance is believed to develop in bacteria in a number of
different ways. Some foodborne pathogens are intrinsically
resistant to certain antibiotics and this is related to their general
physiology, whereas other pathogens develop antibiotic resistance
by mutation or other types of genetic alteration. In addition,
during their adaptation to environmental stresses, pathogens can
become more resistant to antibiotics (Munita & Arias, 2016).
Therefore, it is important to understand how specific preservation
factors as well as other environmental stress factors affect the
sensitivity of L. monocytogenes to antibiotics (Figure 1).
Antibiotics are extensively used in animals to prevent, control,
and treat illnesses as well as enhance the growth of animals in many
countries (Economou & Gousia, 2015; Lungu et al., 2011; Wilson
et al., 2018). In 2015, approximately 15.6 million kg of antibiotics
identical to those for human use were sold in the United States
for use in food-producing animals. Tetracyclines accounted for
44% and ionophores for 30% of these antibiotics (FDA, 2016a).
In Europe, antibiotics were used as animal feed additive since the
fifties of the previous century; however, their use as feed additives
has been banned by the European Union since January 2006
(Castanon, 2007). Although there are several possible ways
antibiotic resistant strains can be transferred between animals
and humans, the most probable way is transmission through the
food chain. L. monocytogenes commonly encounters low levels of
antibiotics and other antimicrobials in the food production chain.
This may serve as preexposure adaptation, which subsequently
allows L. monocytogenes to resist higher levels of antibiotics or
antimicrobial drugs.
There is a mounting evidence that the stressful environmental
conditions foodborne pathogens encounter in the food processing
environment contribute to antibiotic resistance (Lungu et al.,
2011). L. monocytogenes may face a broad spectrum of sublethal
environmental stresses during food production and processing in-
cluding; physical stressors such as heat, high pressure, desiccation,
and irradiation; chemical stressors, such as acids, salts, and oxidants;
and biological stressors, such as microbial antagonism, which
induces the bacterial cross-protection response that generates cells
with increased resistance to the same or other types of stresses
(Wesche, Gurtler, Marks, & Ryser, 2009). The bacterial response
to stress includes changes in cell composition and physiological
state, which enable foodborne pathogens to maintain their normal
functions and survive in foods during processing. Al-Nabulsi
et al. (2015) indicated that exposure of L. monocytogenes food
isolates to pH, cold and salt stresses, increased their resistance to
different antibiotics. The antibiotic resistance of L. monocytogenes
was enhanced as the salt concentration increased to 6% or 12%, as
the pH was reduced to pH 5 or as temperature was decreased to
10 °C. Another study reported that exposure of exponential phase
L. monocytogenes cells to a concentration of 600 ppm hydrogen
peroxide and nonlethal heat (45 °C) significantly increased their re-
sistance to antibiotics including penicillin, ampicillin, tetracycline,
chloramphenicol, gentamycin, rifampicin, and trimethoprim-
sulfamethoxazole (Faezi-Ghasemi & Kazemi, 2015). Also, it was
reported that sublethal hurdles (low water activity, reduced pH, os-
motic pressure, and reduced temperature applied in food preserva-
tion may trigger conjugative plasmid transfer between pathogenic
and nonpathogenic bacteria (Beuls, Modrie, Deserranno,
& Mahillon, 2012). Starvation stress may allow L. monocyto-
genes cells to become more resistant to commonly used food
preservation techniques such as heat and irradiation (Mendonca,
Romero, Lihono, Nannapaneni, & Johnson, 2004); therefore,
the lack of nutrients in areas of processing plants may result in
cross-protection against antibiotics as well. Yet, there is no enough
evidence available to confirm horizontal antimicrobial resistance
gene transfer resulting from food chain stresses (Allen et al., 2016).
Some antimicrobials used in food preservation and safety may
have an influence on antimicrobial resistance. Sodium diacetate,
potassium lactate, and nisin are examples of generally recognized
as safe antimicrobials that are commonly approved for use in meat
and cheese products. Treatment of L. monocytogenes inoculated in
a model broth system with diacetate, lactate, or nisn was shown to
modify the expression of genes involved in regulating membrane
permeability and other transport systems. Consequently, it was
hypothesized that these compounds could trigger certain efflux
pumps to expel certain drugs and toxic substances out of the cell
or limit entry into the cell (Stasiewicz, Wiedmann, & Bergholz,
2011). In addition, there is a plenty of research addressing the
growing demand for using natural and plant derived antimicro-
bials as food preservatives. Clove oil, cinnamaldehyde, and vanillin
were used to inhibit the growth of L. monocytogenes in chicken,
meat, and other food products. However, little research addressed
possible cross-protective effect of these substances to L. monocyto-
genes against clinical antibiotics. In a study, it was reported that the
essential oils (citral and carvacrol) substantiated the antimicrobial
effect of bacitracin, colistin and erythromycin against L. monocyto-
genes and L. innocua (Zanini, Silva-Angulo, Rosenthal, Rodrigo,
& Martinez, 2014). Yet, limited research is available and additional
works are needed to reveal the relationship between commonly
used food preservatives and plant-derived antimicrobials from one
hand and the evolution of resistance to commonly used antibiotics
from the other hand.
Because of its ubiquitous nature, the presence of L. monocy-
togenes in the food processing environment is ineluctable. Thus,
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Antibiotic resistance of L. monocytogenes ...
Figure 1–Food chain and agricultural factors influencing the antibiotic resistance among L. monocytogenes food isolates.
Table 4–Classification of antibiotics based on mechanism of action.a
Mechanism of action Antibiotic
Cell wall synthesis inhibitors Penicillins
Cephalosporins
Vancomycin
Carbapenems
Aztreonam
Polymyxin
Bacitracin
Monobactams
Cycloserine
Protein synthesis inhibitors Inhibit 30s Subunit
Aminoglycosides (gentamicin)
Tetracyclines
Spectinomycin
Streptomycin
Kanamycin
Amikacin
Nitrofurans
Inhibit 50s Subunit
Macrolides
Chloramphenicol
Clindamycin
Linezolid
Streptogramins
Lincomycin
DNA synthesis inhibitors Fluoroquinolones
Metronidazole
RNA synthesis inhibitors Rifamycins
Streptovaricins
Mycolic acid synthesis inhibitors Isoniazid
Folic acid synthesis inhibitors Sulfonamides
Trimethoprim
aAdopted from: Etebu & Arikekpar (2016), Fernandes et al. (2013), Moore (2014).
frequent exposure of this foodborne pathogen to sanitizers is in-
evitable. When used at concentrations below those recommended
by the manufacturers, sanitizers may facilitate the development
of antimicrobial resistance. Triggering hyperactivity of multidrug
resistance efflux pumps are a primary means contributing to resis-
tance. The sublethal exposure to disinfectants may elicit indirect
resistance to antimicrobial treatments, a phenomenon called co-
selection (Kovacevic, Sagert, Wozniak, Gilmour, & Allen, 2013).
Repeated exposure of eight strains of L. monocytogenes to triclosan
in vitro was concomitant with increased resistance to gentamicin
and other aminoglycosides, with the minimum inhibitory con-
centrations of these antimicrobials increasing by 16-fold (Nielsen
et al., 2013). The intensive use of disinfectants such as triclosan
and quaternary ammonium in the food processing environment
may provide natural selection of more resistant strains that possess
enhanced activity of multidrug resistance efflux pumps. This could
potentially expel antimicrobial substances out of the cytosolic en-
vironment and thus reduce cellular exposure, leading to reduced
susceptibility to a range of antimicrobial agents (Courvalin, 2005).
Alonso-Hernando, Capita, Prieto, and Alonso-Calleja (2009) also
indicated that L. monocytogenes exposed in a model broth system
to acidified sodium chlorite was more resistant to some antibi-
otics. Nonetheless, more research is also needed to elucidate the
relationship between frequent preexposure to disinfectants and the
development of antibiotic resistance.
Many L. monocytogenes strains possess a strong biofilm form-
ing capability. Biofilm for ming bacteria pose a great challenge
to the food industry because of its inherent resistance to the ac-
tion of disinfectants (Jahid & Ha, 2012). Biofilm may provide an
inexpugnable haven to bacteria through the production of ex-
opolysaccharides, the presence of persister cells, quorum sensing,
and efflux pumps (De La Fuente-Nunez, Freffuveille, Fernandez,
& Hancock, 2013; Soto, 2013). Frequent sublethal exposure of L.
monocytogenes to disinfectants in the food processing environment
may lead to the development of persister cells with improved efflux
pump activity that may render increased expression of resistance
to clinically used antimicrobials (Allen et al., 2016). In addition,
formation of persister cells by L. monocytogenes represents a remark-
able strategy through which this pathogen could resist intrinsic and
extrinsic hurdles in the food processing environment (Buchanan,
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Antibiotic resistance of L. monocytogenes ...
Gorris, Hayman, Jackson, & Whiting, 2017). Persister cells are
dormant, non-dividing state with enhanced capability to survive
environmental stresses (Buchanan et al., 2017; Knudsen, Holch, &
Gram, 2012). It could also contribute to L. monocytogenes protec-
tion against cleaning and sanitation in food processing environment
(Abee, Koomen, Metselaar, Zwietering, & den Besten, 2016).
The presence of the mobile genetic elements originating from
unrelated bacterial species suggests that both Gram-negative and
Gram-positive bacteria may have a significant role in resistance
gene acquisition by L. monocytogenes (Walsh et al., 2001; Wilson
et al., 2018). It is well established that genes encoding for an-
tibiotic resistance are carried on mobile genetic material. Thus,
factors that trigger gene transfer may contribute to the acquisition
of antibiotic resistance in L. monocytogenes (Allen et al., 2016). Ex-
change of genetic information through plasmid transfer within the
species of L. monocytogenes is possible after the exposure to different
stresses in the food processing environment or after contamination
of RTE foods (Ferreira, Wiedmann, Teixeira, & Stasiewicz, 2014).
It was postulated that certain niches and harboring sites within the
food processing environment would provide favorable conditions
for persistent strains of L. monocytogenes and other species of Lis-
teria to prevail. These niches could elicit appropriate conditions
for genetic material exchange between persistently established L.
monocytogenes strains or other Listeria spp. and other bacterial gen-
era in the food processing environment. Consequently, this could
lead to the evolution of resistance to some types of antimicrobial
agents (Allen et al., 2016; Fox, Solomon, Moore, Wall, & Fanning,
2014). Also, it was shown that genetic mater ial for antimicrobial
resistance were readily transferable from lactic acid bacteria to L.
monocytogenes either under laboratory conditions or in fermented
whole milk (Toomey, Monaghan, Fanning, & Bolton, 2009). A
more recent study showed that it is possible to make a conjugative
transfer of transposon Tn6198 encoding trimethoprim resistance
between Enterococcus faecalis and L. monocytogenes inoculated onto
the surface of smoked salmon and fermented cheese (Bertsch et al.,
2013b). Also, acquisition of antimicrobials resistance genes may be
through interaction of L. monocytogenes ingested in the contami-
nated food with natural microflora present in the gut. A previous
exposure of the food producing animals to therapeutic or prophy-
lactic doses of antimicrobial treatments would probably increase
the chance of disseminating genes conferring antimicrobials resis-
tance (Allen et al., 2016).
One of the plausible factors responsible for the survival of food-
borne bacteria under stressful conditions in the food processing
environment is the presence of Sigma factor B (σB).Thisfactorisa
protein needed for initiation of transcription through enabling spe-
cific binding of RNA polymerase to gene promoters involved in
adapting and expressing increased tolerance to antimicrobial treat-
ments of different Gram-positive bacteria (Palmer, Wiedmann, &
Boor, 2009). It was reported that σBseems to be involved in acti-
vating 18 genes responsible for maintaining cell wall integrity and
resistance to vancomycin in L. monocytogenses (Shin et al., 2010).
L. monocytogenes also possesses two-component signal transduction
systems (2CSTS), which play roles in response to various envi-
ronmental stresses including resistance to antimicrobial substances.
The 2CSTS are comprised of a membrane bound histidine kinase
sensor, which detects environmental stress, and a transcriptional
regulator responsible for mediation of the stress response, termed
the response regulator (Mascher, 2006). The 2CTTS contributes
the innate resistance of L. monocytogenes to β-lactaams including
different types of cephalosporins (Collins, Guinane, Cotter, Hill,
& Ross, 2012). Bergholz, Tang, Wiedmann, and Boor (2013) re-
ported that exposing L. monocytogenes to the combined effect of
salt (6% NaCl) and cold (4 °C) stresses resulted increased tolerance
of the organism to the antimicrobial effect of nisin and this was ex-
plained by activating the LiaSR system which is part of the 2CSTS.
Prevalence of Antibiotic Resistance Among Food
Isolates of L. monocytogenes
Antibiotic resistance, particularly multidrug resistance, among
foodborne bacteria including L. monocytogenes has emerged and
evolved during the past few decades (White, Zhao, Simjee,
Wagner, & McDermott, 2002; Zhang et al., 2007), and now repre-
sents a public health concern as it may contribute to unsuccessful
treatment resulting in increased costs/mortality associated with
foodborne disease (Pesavento, Ducci, Nieri, Comodo, & Lo Nos-
tro, 2010). Apparently, the effect of antibiotic resistance is more ob-
vious among vulnerable patients, resulting in prolonged illness and
increased mortality rate (WHO, 2014). It is anticipated that global
deaths from infection caused by antibiotic resistant pathogens will
increase from 700,000 to 10 million annually, and costs are pre-
dicted to reach US $100 trillion by 2050 (O’Neill, 2014).
The first multidrug (chloramphenicol, erythromycin, strep-
tomycin, and tetracycline) resistant strain of L. monocyto-
genes was isolated from a patient with meningoencephalitis
in France in 1988 (Poyart-Salmeron, Carlier, Trieu-Cuot,
Courtieu, & Courvalin, 1990). Subsequently, many L. monocyto-
genes strains resistant to at least one antibiotic have been isolated
from different sources including food, environmental, and human
clinical samples.
The antibiotic resistance of 21 of L. monocytogenes isolates from
water, cabbage, and different environmental samples in Texas,
USA, was investigated by Prazak, Murano, Mercado, and Acuff
(2002) who found that 20 isolates (95%) were resistant to at
least two or more commonly used antibiotics. Among the 20
multidrug-resistant isolates, 17 were resistant to penicillin and one
isolate was resistant to gentamycin. In Italy, Aureli et al. (2003) re-
ported that all of the 148 L. monocytogenes strains isolated from dif-
ferent food products were resistant to phosphomycin, lincomycin,
and flumequine. Yucel, Citak, and Onder (2005) indicated that all
L. monocytogenes isolates from raw or cooked meat product sam-
ples in Turkey were resistant to cephalothin and nalidixic acid
and 66% of isolates were resistant to sulfamethoxazole, ampicillin,
and trimethoprim. In China, 73% of 167 L. monocytogenes isolated
from retail food products were resistant to sulfonamide, 8.4% were
resistant to tetracycline and 1.8% were resistant to ciprofloxacin
(Zhang et al., 2007). The antibiotic susceptibility of 13 strains
of L. monocytogenes isolated from homemade white cheeses was
examined (Arslan & Ozdemir, 2008), and three were resistant to
clarithromycin while one isolate was resistant to each of ampicillin,
penicillin, and tetracycline. Harakeh et al. (2009) evaluated the an-
tibiotic resistance of 30 L. monocytogenes dairy product isolates in
Iran to 10 antibiotics and found that all isolates were resistant to at
least one antibiotic. The highest frequency of resistance was no-
ticed against oxacillin (approximately 93%) followed by penicillin
(90%) and ampicillin (60%).
Conter et al. (2009) evaluated the resistance of 120 L.
monocytogenes strains isolated from foods and food handling
and processing environments to 19 antibiotics. Fourteen strains
(11.7%) exhibited resistance to at least one antibiotic. The
isolates displayed maximum resistance to clindamycin, followed by
linezolid, ciprofloxacin, ampicillin, and rifampicin, trimethoprim-
sulphamethoxazole and they were least resistant to vancomycin
and tetracycline. Rahimi, Ameri, and Momtaz (2010) reported
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Antibiotic resistance of L. monocytogenes ...
that 74.3% of L. monocytogenes isolates from dairy products were
resistant to at least one antibiotic, however, multidrug resistance
was found only in two isolates. The percentage of resistance for
ampicillin and penicillin among isolates were 26.3% and 31.6%, re-
spectively. Yan et al. (2010) observed that 36.7% of L. monocytogenes
isolates from different foods displayed resistance to one or more an-
tibiotics and 18.9% of the isolates were multidrug resistant. Overall,
antibiotic resistance was noticed in 14 of the 18 tested antibiotics.
Two isolates were found resistant to more than five antibiotics.
Pesavento et al. (2010) reported that 20% of L. monocytogenes
isolates showed multidrug resistance. However, the percentage
of antibiotic resistance among isolates was 20% for ampi-
cillin, 22.5% for methicillin, 27.5% for clindamycin, and 75%
for oxacillin. Ruiz-Bolivar, Neuque-Rico, Poutou-Pinales,
Carrascal-Camacho, and Mattar (2011) reported that 64.8%
of L. monocytogenes food isolates (70/108) were resistant to
clindamycin, 40.7% (44/108) were resistant to rifampin, 1.9%
(2/108) were resistant to azithromycin, although 0.9% (1/108)
were resistant to erythromycin. Sakaridis et al. (2011) studied
the antibiotic resistance of L. monocytogenes in chicken slaughter-
houses and found that all 55 L. monocytogenes isolates displayed
resistance to nalidixic acid and oxolinic acid whereas 83.6%
were resistant to clindamycin. Notwithstanding, all the isolates
were found to be sensitive to ampicillin, cephalothin, amox-
icillin, ciprofloxacin, penicillin, cefotaxime, chloramphenicol,
gentamicin, enrofloxacin, erythromycin, kanamycin, neomycin,
vancomycin, streptomycin, and sulfamethoxazole-trimethoprim.
In Jordan, Osaili, Alaboudi, and Nesiar (2011) studied the
antibiotic resistance of 17 L. monocytogenes isolates from raw or
RTE chicken. Most of the isolates were sensitive to antibiotics,
however, three isolates (17.6%) were resistant to tilmicosin and
two isolates were resistant to tetracycline. Only one isolate
was resistant to both tilmicosin and tetracycline. However,
all of the isolates were sensitive to enrofloxacin, doxycycline,
chloramphenicol, amoxycillin, or trimethoprim, and 94.1%
were sensitive to erythromycin or gentamycin. In another study,
Osaili et al. (2012) indicated that of L. monocytogenes strains
isolated from different types of cheeses, all 39 were resistant to
fosfomycin, 92.3% (36/39) were resistant to oxacillin, and 56.4%
(22/39) were resistant to clindamycin. However, the isolates
showed sensitivity or intermediate susceptibility to gentamicin,
imipenem, teicoplanin, rifampicin, linezolid, ciprofloxacin,
fusidic acid, vancomycin, trimethoprim-sulfamethoxazole, ben-
zylpenicillin, erythromycin, and tetracycline. Five isolates were
resistant to three or more antimicrobials. Also, it was reported
that all 60 L. monocytogenes strains isolated from meat products in
Jordan were sensitive to ampicillin, gentamicin, and vancomycin
whereas 56.6%, 10.0%, 6.7%, 5.0%, and 3.3% of isolates were
resistant to neomycin, tetracycline, kanamycin, erythromycin,
and streptomycin, respectively (Al-Nabulsi et al., 2014).
Te r z i , G ¨
uc¨
uko˘
glu, C¸ adirci, Uyanik, and Alis¸arli (2015) observed
that one-fourth L. monocytogenes isolates from RTE products was
resistant to oxytetracycline and one isolate was resistant to van-
comycin. Jamali et al. (2015) observed that the resistance among
L. monocytogenes isolates from fish products was 20.9% to 27.9%
to tetracycline and ampicillin, 14.0% to 16.3% to cephalothin,
penicillin G, and streptomycin, and 2.3% to rifampicin and chlo-
ramphenicol. Wu et al. (2015) studied the antibiotic resistance
of 248 L. monocytogenes isolates from raw retail foods and found
that only 59 (23.8%) were susceptible to all 14 tested antibiotics,
whereas resistance was observed in 46.8% (116 isolates) to clin-
damycin, 10.1% (25 isolates) to tetracycline, 6.9% (17 isolates) to
ampicillin, 4.8% (12 isolates) to streptomycin, 4.0% (10 isolates)
to ciprofloxacin, 3.2% (eight isolates) to kanamycin, 2.8% (seven
isolates) to chloramphenicol, and 2.4% (6 isolates) to cephalothin.
Moreover, seven L. monocytogenes isolates were resistant to more
than 10 antibiotics. Garedew et al. (2015) found that 16 (66.7%),
12 (50%), 9 (37.5%), and 4 (16.6%) isolates of 24 L. monocytogenes
isolates from RTE foods of animal origin exhibited resistance
for penicillin, nalidixic acid, tetracycline, and chloramphenicol,
respectively. Further, four (16.7%) were multidrug-resistant iso-
lates. Nonetheless, all 24 L. monocytogenes isolates were sensitive to
amoxicillin, sulfamethoxazole-trimethoprime, cephalothin, van-
comycin, gentamicin, and cloxacillin.
Peter, Umeh, Azua, and Obande (2016) indicated that 16
isolates of L. monocytogenes from pork, beef, and chicken were
susceptible to gentamycin, cotrimoxazol, erythromycin, and
chloramphenicol, but were resistant to amoxicillin, augmentin,
cloxacillin, and tetracycline. Abdollahzadeh et al. (2016) found
that seven L. monocytogenes isolates from seafood were resistant
to ampicillin and cefotaxime whereas four isolates were resistant
penicillin. Also, they found that all the isolates were susceptible
to trimethoprim-sulfamethoxazole, chloramphenicol, and tetra-
cycline. In another study, Kevenk and Gulel (2016) found that
15.3% (8/52) of L. monocytogenes isolates from raw milk and dairy
products were resistant to at least one antibiotic and 36.5% (19/52)
were multidrug resistant. In contrast, 48.0% (25 isolates) did not
show any resistance to antibiotics. The most common antibiotic
resistance encountered was to tetracycline (34.6%), followed
by chloramphenicol (25%) and penicillin G (23%). In India,
Jeyasanta and Patterson (2016) reported that 100%, 78.4%, 75.7%,
and 73.0% of 37 L. monocytogenes isolates from seafood products
were resistant to nalidixic acid, streptomycin, gentamycin, and
kanamycin, respectively. All isolates were sensitive to amoxicillin.
Recently, Shar ma et al. (2017) reported that all five isolates of L.
monocytogenes from bovine raw milk were resistant to the majority
of antibiotics tested and were designated as multidrug resistant.
Lee, Ha, Lee, and Cho (2017) reported that all strains of L. monocy-
togenes which, were isolated from RTE seafood and food processing
environments were resistant to benzyl penicillin, clindamycin, and
oxacillin; 97% (32/33) of isolates were resistant to ampicillin, and
18% (6/33) were resistant to tetracycline. Further, 82% of isolates
(27/33) showed resistance to four antibiotics and 18% (6/33) were
resistant to five antibiotics. Noll, Kleta, and Al Dahouk (2017)
investigated the susceptibility of 259 L. monocytogenes strains,
which had been isolated over a period of 40 yr from food, food
processing environments, and patient samples in Germany, to 14
antibiotics widely used in veterinary and human medicine. They
indicated that 145 strains (56%) had multidrug resistance and they
were mainly resistant to daptomycin, tigecycline, tetracycline,
ciprofloxacin, ceftriaxone, trimethoprim-sulfamethoxazole, and
gentamicin. G´
omez et al. (2014) tested the antibiotic resistance
of L. monocytogenes isolates from RTE meat products and meat-
processing environments. Resistance to one or two antimicrobials
was observed in 71 (34.5%) of L. monocytogenes isolates, although
multidrug resistance was identified in 2.9% of the organisms.
All isolates showed resistance to oxacillin while only 0.5% were
resistant to tetracycline. Haubert, Mendonc, Lopes, de Itapema
Cardoso, & da Silva (2015) studied the antibiotic resistance
of 50 L. monocytogenes strains isolated from foods and food
environment in Brazil, between 2001 and 2010. They found that
all isolates were resistant to nalidixic acid and cefoxitin. Further,
high prevalence of resistance was observed to clindamycin (68%),
streptomycin (10%), meropenem (10%), rifampicin (10%), and
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Antibiotic resistance of L. monocytogenes ...
trimethoprim–sulfamethoxazole (10%). Although all isolates
examined were sensitive to ampicillin, gentamycin, penicillin G,
amikacin, chloramphenicol, vancomycin, and ciprofloxacin.
Wieczorek and Osek (2017) found that 57.9% of L. monocyto-
genes strains isolated from fresh and smoked fish showed resistance
to oxacillin, 31.6% and 8.8% were resistant to ceftriaxone or clin-
damycin, respectively, and only two isolates showed resistance to
the three antibiotics. Kuan et al. (2017) tested the antibiotic re-
sistance of 58 L. monocytogenes isolates from vegetable farms and
retail markets in Malaysia. They found that 100%, 70.7%, and
41.4% of isolates exhibited resistance to penicillin G, meropenem,
and rifampicin. Although 100%, 91.4%, and 84.5% of isolates
were susceptible to ampicillin, gentamicin, and trimethoprim-
sulfamethoxazole, respectively. Zeinali, Jamshidi, Bassami, and
Rad (2017) indicated that 52.8%, 44.5%, 41.0%, 25.0%, and 16.7%
of 36 L. monocytogenes isolates from fresh chicken carcasses were re-
sistant to erythromycin, tetracycline, clindamycin, trimethoprim,
and chloramphenicol. Escolar, G´
omez, Del Carmen Rota Garc´
ıa,
Conchello, and Herrera (2017) reported that 100% and 42.9% of
seven L. monocytogenes isolates from RTE meat and dairy prod-
ucts were resistant to clindamycin and ciprofloxacin, respectively.
In Egypt, Mohamed, Abdelmonem, and Amin (2018) reported
that all 47 L. monocytogenes isolates from frozen vegetables were
resistant to amoxicillin, gentamicin, and norfloxacin. In addition,
90%, 86%, and 84% of the isolates were resistant to ciprofloxacin,
ceftazidime/clavulanic acid, and amikacin, respectively. In con-
trast, all isolates were sensitive to tr imethoprim-sulfamethoxazole.
Akrami-Mohajeri et al. (2018) found that all 22 L. monocytogenes
isolates from raw milk and traditional dairy products in Iran were
resistant to tetracycline, penicillin, chloramphenicol, and amoxi-
cillin/clavulanic acid.
It is worth noting that other studies have shown a low prevalence
of antibiotic resistance among L. monocytogenes strains isolated
from food sources. Walsh et al. (2001) found that only 2/351
(0.6%) of L. monocytogenes food isolates were resistant to at least
one antibiotic. Mayrhofer, Paulsen, Smulders, and Hilbert (2004)
investigated the vulnerability of L. monocytogenes isolates from
304 meat samples to antibiotics and found no resistant isolates to
tetracycline, penicillin, gentamicin, vancomycin, co-trimoxazol,
erythromycin, chloramphenicol, or streptomycin. Aarestrup,
Kn¨
ochel, and Hasman (2007) found that the 114 L. monocytogenes
isolates they examined from food products were susceptible to all
12 antibiotics used except ceftiofur. Vitas, Sanchez, Aguado, and
Garcia-Jalon (2007) pointed out that 401 L. monocytogenes isolates
examined were susceptible to the majority of the antimicrobials
tested (penicillin G, ampicillin, cephalothin, gentamicin, chloram-
phenicol, tetracycline, doxycycline, trimethoprim, erythromycin,
and clindamycin), and only five isolates (1.2%) were resistant
to tetracycline and doxycycline. Filiousis, Johansson, Frey, and
Perreten (2009) studied the antibiotic resistance of 30 food isolates
of L. monocytogenes and observed that all, except for one with
resistance to tetracycline, were susceptible to 16 antimicrobials.
In Poland during 2004 to 2010, 471 L. monocytogenes cultures
isolated from various types of foods were found sensitive to
gentamicin, amoxicillin, rifampicin, ampicillin, sulfamethoxazole,
trimethoprim, erythromycin, vancomycin, and chloramphenicol.
Only two L. monocytogenes strains (0.42%) showed antibiotic resis-
tance and one strain was resistant to tetracycline and minocycline
(Korsak, Borek, Daniluk, Grabowska, & Pappelbaum, 2012).
Recently, Lotfollahi, Chaharbalesh, Rezaee, and Hasani (2017)
reported that all 22 L. monocytogenes isolates from clinical, food,
and livestock samples were vulnerable to kanamycin, gentamicin,
amoxicillin-clavulanic acid, chloramphenicol, linezolid, tetracy-
cline, trimethoprim-sulfamethoxazole, and ampicillin. However,
six isolates were resistant to penicillin G. Wilson et al. (2018)
tested the antibiotic resistance of 100 L. monocytogenes isolates from
Australian food production chains between 1988 and 2016. They
found that all isolates were sensitive to penicillin G and tetracy-
cline. However, only two isolates were resistant to ciprofloxacin
and an isolate was resistant to erythromycin. Further, Amajoud
et al. (2018) reported that all 16 food L. monocytogenes isolates
were susceptible to penicillin G, chloramphenicol, rifampicin,
streptomycin, vancomycin, fusidic acid, trimethoprim, lev-
ofloxacin, moxifloxacin, ciprofloxacin, erythromycin, amikacin,
kanamycin, amoxicillin, ampicillin, gentamicin, imipenem, and
tobramycin. However, all isolates showed resistance to cefotaxime,
sulfonamide, nalidixic acid, fosfomycine, and lincosamide. In
addition, two isolates were resistant to tetracycline. Oliveira et al.
(2018) also found that 100% of 35 L. monocytogenes isolates from
chicken carcasses and cuts were sensitive to tested antibiotics,
except for clindamycin, where 5% of the isolates were resistant.
It seems that the L. monocytogenes isolates from food products
are susceptible to a wide range of antibiotics. However, the inci-
dence of resistance to some antibiotics among the food isolates has
been increasing. Furthermore, it is also evident that L. monocyto-
genes strains from food products exhibit resistance to several types
of antibiotics including some of those that are frequently pre-
scribed to treat human listeriosis such as tetracycline, ampicillin,
penicillin, and gentamicin. Although the isolation of multidrug-
resistant strains of L. monocytogenes is not common, evidence of
the emergence of multidrug-resistant food isolates of L. mono-
cytogenes has been documented. In a study comparing the preva-
lence of antibiotic and multidrug resistance among L. monocytogenes
isolates from poultry products in North-Western Spain, Alonso-
Hernando et al. (2012) pointed out that, excluding nalidixic acid
to which most isolates were inherently resistant, 37.2% and 96.0%
of L. monocytogenes isolated in 1993 and 2006, respectively, showed
resistance to at least one antibiotic. Multidrug resistance was also
more common in 2006 (84.0%) as compared to 1993 (18.6%).
Furthermore, the average number of antibiotics to which the L.
monocytogenes strains were resistant was higher in 2006 (4.2) than
in 1993 (1.6). A remarkable increase in the number of resistant
strains isolated in 2006 was observed for neomycin, gentamicin,
enrofloxacin, streptomycin, furazolidone, and ciprofloxacin.
Mechanisms of Antibiotic Resistance in L.
monocytogenes
Acquisition of movable genetic elements including self-
transferable plasmids, mobilizable plasmids, and conjugative trans-
posons, is the major mechanism responsible for development of
antibiotic resistance in L. monocytogenes (Charpentier & Cour-
valin 1999). However, efflux pumps were also suggested to be
linked with fluoroquinolone, macrolide, and cefotaxime resistance
in L. monocytogenes (Godreuil, Galimand, Gerbaud, Jacquet, &
Courvalin, 2003; Mata, Baquero, & Perez-Diaz, 2000).
Antibiotic resistance mediated by conjugation
It has been reported that L. monocytogenes used the conjugation
as a main strategy to acquire resistance to antibiotic (Perichon &
Courvalin, 2009). Enterococci and Streptococci represent the main
reservoirs of resistance genes for L. monocytogenes. Conjugation is a
process by which genetic materials transfer from a donor to a recip-
ient cell. The genome of bacteria is composed of the chromosome
10 Comprehensive Reviews in Food Science and Food Safety rVol. 0, 2018 C2018 Institute of Food Technologists®

Antibiotic resistance of L. monocytogenes ...
and accessory movable genetic elements such transposons and plas-
mids (Perichon & Courvalin, 2009). Conjugation is divided into
three stages including: direct cell-to-cell contact, mating pair for-
mation, and transfer of plasmid DNA through a conjugative pilus.
Conjugation studies indicated that two types of movable genetic
elements, transposons and plasmids, in enterococci and streptococci
were responsible for the emergence of antibiotic resistance in L.
monocytogenes (Charpentier & Courvalin 1999; White et al., 2002).
Apparently, the acquisition of novel genetic material from the con-
jugative plasmids or transposons from Enterococcus or Streptococcus to
L. monocytogenes most likely takes place in the gastrointestinal tract
of humans (Doucet-Populaire, Tr ieu-Cuot, Dosbaa, Andremont,
& Courvalin, 1991). Furthermore, it has been found that L.
monocytogenes isolates from food and food processing environments
harbored the benzalkonium chloride resistance transposon Tn6188
that encodes the tolerance to quaternary ammonium compounds
in Staphylococcus aureus and other Firmicutes (M¨
uller et al., 2013;
Ortiz, L ´
opez-Alonso, Rodr´
ıguez, & Mart´
ınez-Su´
arez, 2016).
Tetracycline resistance is believed to be the most frequent
resistance trait in L. monocytogenes isolated from human and foods
(Charpentier & Courvalin 1999; Walsh et al., 2001). Six classes of
tetracycline resistance genes have been described in Gram-positive
bacteria (tetK,tetL,tetM,tetO,tetP,andtetS). However, only
tetS,tetM,andtetL have been identified in L. monocytogenes
(Charpentier & Courvalin, 1999; Escolar et al., 2017; Granier
et al., 2011). It has also been reported that 19 of 38 L. monocy-
togenes isolates (50%) from dairy farms harbored more than one
antibiotic resistance gene sequence. A high incidence of floR
gene was detected in 66% of L. monocytogenes strains followed by
penA (37%), strA (34%), tetA (32%), and sulI (16%). Nevertheless,
other tetracycline resistance genes (tetE, tetC,tetB,tetD,andtetG)
or other antibiotic resistance genes (vanA,vanB,aadA,cmlA,
ereB,ereA,strB,sulI,ampC, and ermB) were not detected in L.
monocytogenes strains (Srinivasan et al., 2005). Li et al. (2016)
reported that 12 of 78 L. monocytogenes isolates (15.4%) from a
pork processing plant and its respective meat markets in China
carried the tetM gene. Similarly, the genes ermB,tetM,anddfrD,
were detected in L. monocytogenes strains isolated from food and
environmental samples in France during 1996 to 2006; but the
tetS,tetK,andtetL genes were not detected (Granier et al., 2011).
The antibiotic resistance genes tetM and ermB were also identified
in L. monocytogenes isolated from fresh mixed sausage and chicken
slaughterhouse, respectively (Haubert et al., 2015). Recently, Lim,
Yap, and Thong (2016) found that two L. monocytogenes isolates
from fried fish and salad carried five genes including tetA,lmrB,
mecC,msrA,andfosX that confer resistance to tetracycline, lin-
comycin, beta-lactam, erythromycin, and fosfomycin, respectively.
Wilson et al. (2018) also detected the ermB gene in an food L.
monocytogenes isolate that showed high resistance to erythromycin.
The emergence of tetracycline resistance in L. monocytogenes
is mainly due to the conjugative plasmids and transposons orig-
inating from Enterococcus or Streptococcus (Poyart-Salmeron et al.,
1992). The conjugative transfer of plasmids and transposons has
also carried other antibiotic resistance to L. monocytogenes from
Enterococcus, Streptococcus,orotherListeria species (Charpentier &
Courvalin 1999).
Antibiotic resistance mediated by efflux pumps
L. monocytogenes has three efflux pumps; one operates to ex-
trude antibiotics, heavy metals, and ethidium bromide (Mata et al.,
2000), and the second pump is associated with resistance to flu-
oroquinolone and, partially, the resistance of L. monocytogenes to
acridine orange and ethidium bromide (Godreuil et al., 2003).
The third pump is involved in resistance of L. monocytogenes to
fluoroquinolones (Gu´
erin, Galimand, Tuambilangana, Courvalin,
& Cattoir, 2014). Mata et al. (2000) reported that the sequence
of the MdrL (multidrug efflux transporter of Listeria) protein is
highly homologous to the sequence of protein YfmO, a putative
chromosomal multidrug efflux transporter in Bacillus subtilis.An
allele-substituted mutant of this gene in L. monocytogenes failed to
pump out ethidium bromide and yielded increased susceptibility
to cefotaxime, heavy metals, and macrolides.
It has been reported that five families are included in drug efflux
systems: the major facilitator superfamily (MFS), the resistance-
nodulation-cell division, the small multidrug resistance, as well as
the multidrug and toxic compound extrusion (MATE) families,
plus the ATP-binding cassette family (Piddock, 2006). The ac-
tive efflux system in Gram-positive bacteria is mainly associated
with overexpression of MFS pumps, such as NorA in Staphy-
lococcus aureus and PmrA (pneumoniae multidrug resistance) in
Streptococcus pneumoniae, which specifically extrudes hydrophilic
fluoroquinolones (Poole, 2007). Godreuil et al. (2003) reported
that the Lde protein of L. monocytogenes showed 44% homology
with PmrA of S. pneumoniae, which belongs to the MFS family of
secondary multidrug transporters. The insertional inactivation of
the gene lde results in increased susceptibility of L. monocytogenes to
fluoroquinolones. In another study, overexpression of the lde gene
induced by ciprofloxacin was detected in two resistant L. mono-
cytogenes isolates from food in China. However, the researchers
suggested that overexpression of the lde gene was not the only
reason for ciprofloxacin resistance (Jiang et al., 2012). Romanova,
Wolffs, Brovko, and Griffiths (2006) reported that the efflux pump
Mdrl in L. monocytogenes is partially accountable for the adaptation
to antibiotic resistance. Recently, Gu´
erin et al. (2014) character-
ized the MATE efflux pump, which is linked to the resistance of L.
monocytogenes to fluoroquinolones. The transcriptional regulation
of the expression of a MATE family efflux pump-encoding gene
occurs through a TetR-like repressor. Lim et al. (2016) detected
two efflux pump-related genes, mdrL and lde, which confer resis-
tance to macrolides and quinolone, respectively, in the genomes of
two L. monocytogenes isolates from fried fish and salad. In another
study, it was suggested that the mutation in the fluoroquinolone
efflux protein (fepA) regulator, fepR, is responsible in part for the
resistance of L. monocytogenes to ciprofloxacin (Wilson et al., 2018).
Conclusions and Future Research
L. monocytogenes poses a persistent threat to the food industry,
particularly operations preparing RTE foods. Antibiotic resistance
in L. monocytogenes isolated from food products has been develop-
ing over the past few decades, and represents a serious public health
risk worldwide. In general, most Listeria spp. isolated from clinical,
food, and environmental sources are susceptible to those antibiotics
normally effective against Gram-positive bacteria. Yet, there is an
alarming increase in the prevalence of multidrug-resistant strains
of L. monocytogenes from various sources, and therefore monitoring
L. monocytogenes for changes in its antimicrobial resistance appears
prudent.
The antibiotic resistance profile of L. monocytogenes is partic-
ularly important for people with immune-compromised systems
who are most susceptible to listeriosis. Acquisition of resistance
by L. monocytogenes to commonly prescribed antibiotics would
pose a major therapeutic challenge in clinical settings. Based on
clinical experience with virulent strains of Staphylococcus,Entero-
coccus,andPseudomonas, it is not hard to imagine that increases in
C2018 Institute of Food Technologists®Vol. 0, 2018 rComprehensive Reviews in Food Science and Food Safety 11

Antibiotic resistance of L. monocytogenes ...
mortality rates and costs of patient care due to multidrug-resistant
L. monocytogenes strains is a likely outcome.
In this review, it has been demonstrated that isolates of L. mono-
cytogenes from different food sources show resistance to antibiotics,
and some of these antibiotics are commonly used for the treat-
ment of listeriosis. Although the rate of multidrug resistance of L.
monocytogenes is low, the rate is continuously increasing for reasons
that are not clearly understood. Some plausible factors influencing
the emergence of antibiotic resistant strains may be the indiscrimi-
nate use or overuse of antibiotics in treating human infections, the
somewhat arbitrary prophylactic use of antibiotics in animal breed-
ing and their use as growth supplements in animal feed. Transfer
of antibiotic resistance genes from other bacteria is possibly the
main reason for the increased antibiotic resistance of L. monocyto-
genes. Many mechanisms have been suggested responsible for the
development of antibiotic resistance by L. monocytogenes,butthe
most likely mechanism involves conjugative plasmids and trans-
posons from other bacteria such as Enterococcus and Streptococcus
spp. There is also evidence that other putative mechanisms involv-
ing efflux pumps that secrete antibiotics and other antimicrobial
agents outside the cell may be responsible.
Future studies need to investigate the influence of the pathogen
source (food, clinical, or environmental) on the antibiotic resis-
tance of L. monocytogenes. Also, the influence of agricultural prac-
tices such as the extent of use and the types of fertilizers and
pesticides used to cultivate crops should be studied. Furthermore,
the effect of food processing steps such as heating, chilling, salting,
preservatives, and the use of sanitizers and antimicrobial agents in
food production and preservation should be explored in terms of
their effects on the emergence of antibiotic resistance among L.
monocytogenes strains. In addition, other species of the genus Listeria
must be examined, as they may constitute reservoirs of antibiotic
resistance genes, which may be transferred to L. monocytogenes.In
addition, the necessity of broad and continuous surveillance to
detect any evolution in the susceptibility of L. monocytogenes to
antibiotics should be emphasized in future research.
Acknowledgments
The authors acknowledge financial support from the Deanship
of Research at Hashemite Univ., Zarqa, Jordan.
Authors’ Contributions
Conception of study: A.N. Olaimat; Planning: A.N. Olaimat,
M.A. Al-Holy, and M.H. Abu Ghoush; Drafting of study sections:
A.N. Olaimat, M.A. Al-Holy, M.H. Abu Ghoush, H. Shahbaz,
A.A. Al-Nabusli, T.M. Osaili, M.M. Ayyash and R.A. Holley;
Interpretation of data, writing, critical review of manuscript: A.N.
Olaimat, M.A. Al-Holy, M.H. Abu Ghoush, H. Shahbaz, A.A.
Al-Nabusli, T.M. Osaili, M.M. Ayyash, and R.A. Holley.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
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16 Comprehensive Reviews in Food Science and Food Safety rVol. 0, 2018 C2018 Institute of Food Technologists®