emergence of antibiotic resistance in listeria

Emergence of Antibiotic Resistance in Listeriamonocytogenes Isolated from Food Products: AComprehensive ReviewAmin 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. monocytogenesstrains isolated from food products. The present review summarizes the available evidence on the emergence of antibioticresistance 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 humanlisteriosis such as penicillin, ampicillin, tetracycline, and gentamicin, has been documented. Acquisition of movablegenetic elements is considered the major mechanism of antibiotic resistance development in L. monocytogenes. Effluxpumps 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 foodprocessing chains and environments (from farm to table) including extensive or sub-inhibitory antibiotics use, horizontalgene transfer, exposure to environmental stresses, biofilm formation, and presence of persister cells play crucial roles inthe 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

IntroductionListeria monocytogenes is an important, ubiquitous, foodborne

microbe that can contaminate food products during or afterprocessing. L. monocytogenes poses a significant risk to the foodindustry, particularly producers of ready-to-eat (RTE) foodsdue to its ability to proliferate over a vast range of adverseenvironmental conditions encompassing low temperature, lowpH, and high salt. L. monocytogenes represents a major public healthconcern because it may cause severe human illness with seriousconsequences. 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, Facultyof 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-Nabulsiand Osaili are with Dept. of Nutrition and Food Technology, Jordan Univ. of Scienceand Technology, P.O. Box 3030, Irbid, Jordan. Author Osaili is with Dept. of ClinicalNutrition and Dietetics, College of Health Sciences, Univ. of Sharjah, Sharjah, UnitedArab Emirates. Author Ayyash is with Dept. of Food Science, United Arab EmiratesUniv., Al Ain, United Arab Emirates. Author Holley is with Dept. of Food andHuman Nutritional Sciences, Faculty of Agricultural and Food Sciences, Univ. ofManitoba, Winnipeg, Manitoba, R3T 2N2, Canada. Direct inquiries to authorOlaimat (E-mail: [email protected]).

immuno-compromised individuals, invasive infections in thenewborn and elderly, and serious complications during pregnancy(abortion and stillbirth), with a fatality rate that can reach up to20% to 30% (Scallan et al., 2011; Swaminathan & Gerner-Smidt,2007). Therefore, treatment with antibiotics is usually needed forthe control of the infection caused by this bacterium. L. mono-cytogenes, in general, is considered vulnerable to a wide range ofantibiotics, which have bactericidal effects against Gram-positivebacteria, 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 strainsis needed. The aim of this study was to integrate the broadlyscattered information on the antibiotic resistance among L. mono-cytogenes isolated from food products and to define the possiblemechanisms involved in its development in these isolates. Inaddition, some suggestions for monitoring antibiotic resistance arediscussed.

C© 2018 Institute of Food Technologists®

doi: 10.1111/1541-4337.12387 Vol. 0, 2018 � Comprehensive Reviews in Food Science and Food Safety 1

http://orcid.org/0000-0001-7202-5440

http://orcid.org/0000-0002-9592-055X

http://orcid.org/0000-0001-6166-1388

http://orcid.org/0000-0002-9312-500X

Antibiotic resistance of L. monocytogenes . . .

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2 Comprehensive Reviews in Food Science and Food Safety � Vol. 0, 2018 C© 2018 Institute of Food Technologists®


General Features of the Genus ListeriaBased on the recently updated classification, the genus Listeria is

composed of 18 known species, and is organized into two groupsbased on their relationship to L. monocytogenes. Among the speciesof interest, L. monocytogenes is of particular importance in terms ofits implications on human health and the economy since it mayinflict serious diseases in both humans and animals. The first groupis the “Listeria sensu stricto” clade which consists of six speciesincluding: L. monocytogenes, L. innocua, L. welshimeri, L. ivanovii,L. seeligeri, and L. marthii. These species are commonly isolatedfrom intestinal tract of symptom-free animals and animal-originfood 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 environmentor food matrices, but they are unable to colonize mammalianhosts (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; Nunez-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 catalasetest (except L. costaricensis) and for the production of acid fromN-acetylglucosamine, arbutin, salicin, D-fructose, amygdalin,aesculin-ferric citrate, cellobiose, and D-mannose. However,all species fail to reduce nitrite, and cannot produce acid fromraffinose, glycogen, methyl β-d-xylopyranoside, d-arabinose,d-adonitol, and potassium 2-ketogluconate (Nunez-Monteroet al., 2018; Orsi & Wiedmann, 2016; Weller et al., 2015). Otherdifferences in biochemical reactions between L. monocytogenesand other members of Listeria are illustrated in Table 1. Weexpect that this classification will be updated in the future andnew species may be included in the “Listeria sensu lato” groupor in a new group. Changes in the taxonomy of Listeria spp.could have a significant effect on the food industry should a newpathogenic species emerge. Presently, the only known Listeriaspp. to cause disease to humans and animals are L. monocytogenesand L. ivanovii, although the latter has seldom been implicated inhuman listeriosis (Dussurget, 2008; Orsi & Wiedmann, 2016).

Listeria monocytogenes: A Foodborne PathogenL. monocytogenes constitutes a major burden for the food indus-

try and health agencies worldwide due to its ability to withstanda vast range of harsh environmental challenges. The organism isconsidered 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 capableof surviving for long periods in frozen food products (Ramaswamyet 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 (Dortetet al., 2009; Lado & Yousef, 2007). Moreover, L. monocytogenespossess 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 variousfood 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 safetyagencies around the globe to set criteria to reduce the presence ofL. monocytogenes in the food chain. For example, the United StatesDept. of Agriculture (USDA) has adopted a zero-tolerance policy(absence of the organism in 25 g food sample) for L. monocytogenesin RTE foods (Orsi et al., 2010). Because of its ubiquitous nature,L. monocytogenes has been isolated from a variety of environmentalsources 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 avariety of food products such as meat, chicken, smoked fish, un-pasteurized dairy products, and vegetables (Table 2).

Human ListeriosisL. monocytogenes causes a rare but serious life-threatening, inva-

sive disease called listeriosis, which has become a major foodborneillness in the last two decades. The occurrence of listeriosis variesbetween countries and usually occurs at a rate of between 0.1and 11.3 cases per million persons (FAO/WHO, 2004). Clinicalprogression 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 notablyhigher than illnesses caused by other foodborne pathogens (Scallanet al., 2011).

Usually, pregnant women, the newborn, elderly people, andimmunocompromised individuals are more susceptible to liste-riosis, but it may occasionally occur in healthy individuals. Theprevalence of listeriosis among pregnant women, neonates, andthe elderly is 12, 3.4, and 10 per 100,000, respectively, comparedwith 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% to30% even with the application of antibiotic therapy (Swaminathan& Gerner-Smidt, 2007). Invasive human listeriosis can present asa serious maternal fetal infection or neonatal listeriosis and bloodstream infection (bacteremia; Drevets & Bronze, 2008).

Symptoms of pregnant women with invasive listeriosis in-clude chills, fever, headache, and leukocytosis as early as 1 weekbefore illness diagnosis (McLauchlin, 1990; Mylonakis, Paliou,Hohmann, Calderwood, & Wing, 2002). The organism can beisolated 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 throughthe birth canal or through the transmission of the infection acrossthe placenta. Early-onset neonatal listeriosis can be observed asbacteremia, meningitis and pneumonia, but late-onset is usuallyassociated with meningitis (Jackson, Iwamoto, & Swerdlow, 2010).

Febrile gastroenteritis is a noninvasive disease that mainly affectshealthy individuals 9 to 32 hr after ingestion of food contaminatedwith 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, andmyalgias. The infection is a self-limiting disease that lasts for lessthan 48 hr and most healthy people recover without any medicalintervention (Dalton et al., 1997).

The third clinical manifestation of invasive human listerio-sis is bacteremia, which could be accompanied by cerebral

C© 2018 Institute of Food Technologists® Vol. 0, 2018 � Comprehensive Reviews in Food Science and Food Safety 3


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), 2013Estonia 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., 2017USA 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 themost frequent bacterial causes of meningitis (Wenger, Hightower,Facklam, Gaventa, & Broome, 1990). The majority of thecases presenting as meningitis or menigoencephalitis are usuallyobserved in patients aged more than 50 yr and symptomsinclude fever, neck stiffness, headache, and altered mentalstatus (Brouwer, van de Beek, Heckenberg, Spanjaard, & deGans, 2006). L. monocytogenes is distinguished among neu-roinvasive bacteria that can attack the central nervous systembased on the cellular route used, and whether the organismcrosses specialized epithelial cells of the blood–choroid plexusbarriers or endothelial cells of the blood–brain barrier. Thesemainly include: (1) passage across blood–choroid plexus barrierswithin parasitized leukocytes or the blood–brain barrier (2).Direct invasion of the extracellular blood–borne organism intothe endothelial cells, or (3) centripetal movement into thebrain within the axons of cranial nerves (Drevets, Leenen, &Greenfield, 2004).

Antibiotic Treatment of ListeriosisAntibiotics are natural, synthetic, or semisynthetic substances

that are often used to treat or sometimes prevent infections inhumans and animals (O’Neill, 2015; WHO, 2015). Antibioticscan have a bacteriostatic effect where they inhibit the growthof microorganisms temporarily or be bactericidal where they killbacterial 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 groupsaccording to their chemical structure (Table 3) or their mechanismof action (Table 4).

At present there is no vaccine available commercially to preventlisteriosis, thus early diagnosis is critical for the success of antibiotictreatment, especially for high-risk patients (Calderon-Gonzalezet al., 2014). An issue complicating investigations of large listeriosisoutbreaks is that the incubation time for L. monocytogenes is longand may reach up to 70 days after consumption of contaminatedfood. This long time makes it difficult to track the pathogen backto its origin because patients have difficulty remembering whatthey ate after lengthy periods (Dortet et al., 2009; Rhoades, Duffy,& Koutsoumanis, 2009).

The treatment of human listeriosis with antibiotics involves useof a β-lactam (penicillin and ampicillin) alone or combined with anaminoglycoside (gentamicin) as the treatment of choice (Alonso-Hernando, Prieto, Garcıa-Fernandez, Alonso-Calleja, & Capita,2012; Dortet et al., 2009; Ramaswamy et al., 2007). However, pa-tients who exhibit an allergic reaction to penicillin, a second choicetherapy is usually used that involves a combination of trimethoprimwith a sulfonamide, such as sulfamethoxazole in co-trimoxazole(Alonso-Hernando et al., 2012; Charpentier & Courvalin, 1999).Vancomycin is used to treat bacteremia, although erythromycin isused 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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In general, the majority of Listeria spp. isolated from food, clin-ical and environmental samples are sensitive to ordinarily usedantibiotic 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 strainsof L. monocytogenes show inherent resistance to cefotaxime, ce-fepime, fosfomycin, oxacillin, and lincosamides (CA-SFM, 2010;Lecuit & Leclercq, 2009).

Antibiotic ResistanceAntibiotic resistance can be defined as the ability of a microor-

ganism to resist (survive or grow) an antibiotic concentration thatis used in clinical practice where the organism changed its responseto the antibiotic (WHO, 2018). Antibiotic resistance is consideredone of the major threats to global public health, food security,and food development because it makes disease harder to treat asantibiotics 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, eitherdue to intrinsic differences or to the development of resistance byadaptation or genetic exchange (Calderon, & Sabundayo, 2007).

Factors Influencing the Antibiotic Resistance ofL. monocytogenes

In the last few decades, the extensive use of antibiotics hassometimes involved misuse of these drugs in humans and animals,and thus greatly contributed to the progression and spread ofantibiotic resistance among foodborne pathogens including L.monocytogenes (Wilson, Gray, Chandry, & Fox, 2018). Antibioticresistance is believed to develop in bacteria in a number ofdifferent ways. Some foodborne pathogens are intrinsicallyresistant to certain antibiotics and this is related to their generalphysiology, whereas other pathogens develop antibiotic resistanceby mutation or other types of genetic alteration. In addition,during their adaptation to environmental stresses, pathogens canbecome more resistant to antibiotics (Munita & Arias, 2016).Therefore, it is important to understand how specific preservationfactors as well as other environmental stress factors affect thesensitivity 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 manycountries (Economou & Gousia, 2015; Lungu et al., 2011; Wilsonet al., 2018). In 2015, approximately 15.6 million kg of antibioticsidentical to those for human use were sold in the United Statesfor use in food-producing animals. Tetracyclines accounted for44% and ionophores for 30% of these antibiotics (FDA, 2016a).In Europe, antibiotics were used as animal feed additive since thefifties of the previous century; however, their use as feed additiveshas been banned by the European Union since January 2006(Castanon, 2007). Although there are several possible waysantibiotic resistant strains can be transferred between animalsand humans, the most probable way is transmission through thefood chain. L. monocytogenes commonly encounters low levels ofantibiotics and other antimicrobials in the food production chain.This may serve as preexposure adaptation, which subsequentlyallows L. monocytogenes to resist higher levels of antibiotics orantimicrobial drugs.

There is a mounting evidence that the stressful environmentalconditions foodborne pathogens encounter in the food processingenvironment contribute to antibiotic resistance (Lungu et al.,

2011). L. monocytogenes may face a broad spectrum of sublethalenvironmental 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, whichinduces the bacterial cross-protection response that generates cellswith increased resistance to the same or other types of stresses(Wesche, Gurtler, Marks, & Ryser, 2009). The bacterial responseto stress includes changes in cell composition and physiologicalstate, which enable foodborne pathogens to maintain their normalfunctions and survive in foods during processing. Al-Nabulsiet al. (2015) indicated that exposure of L. monocytogenes foodisolates to pH, cold and salt stresses, increased their resistance todifferent antibiotics. The antibiotic resistance of L. monocytogeneswas enhanced as the salt concentration increased to 6% or 12%, asthe pH was reduced to pH 5 or as temperature was decreased to10 °C. Another study reported that exposure of exponential phaseL. monocytogenes cells to a concentration of 600 ppm hydrogenperoxide 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 wasreported 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 pathogenicand nonpathogenic bacteria (Beuls, Modrie, Deserranno,& Mahillon, 2012). Starvation stress may allow L. monocyto-genes cells to become more resistant to commonly used foodpreservation techniques such as heat and irradiation (Mendonca,Romero, Lihono, Nannapaneni, & Johnson, 2004); therefore,the lack of nutrients in areas of processing plants may result incross-protection against antibiotics as well. Yet, there is no enoughevidence available to confirm horizontal antimicrobial resistancegene transfer resulting from food chain stresses (Allen et al., 2016).

Some antimicrobials used in food preservation and safety mayhave an influence on antimicrobial resistance. Sodium diacetate,potassium lactate, and nisin are examples of generally recognizedas safe antimicrobials that are commonly approved for use in meatand cheese products. Treatment of L. monocytogenes inoculated ina model broth system with diacetate, lactate, or nisn was shown tomodify the expression of genes involved in regulating membranepermeability and other transport systems. Consequently, it washypothesized that these compounds could trigger certain effluxpumps to expel certain drugs and toxic substances out of the cellor limit entry into the cell (Stasiewicz, Wiedmann, & Bergholz,2011). In addition, there is a plenty of research addressing thegrowing demand for using natural and plant derived antimicro-bials as food preservatives. Clove oil, cinnamaldehyde, and vanillinwere used to inhibit the growth of L. monocytogenes in chicken,meat, and other food products. However, little research addressedpossible cross-protective effect of these substances to L. monocyto-genes against clinical antibiotics. In a study, it was reported that theessential oils (citral and carvacrol) substantiated the antimicrobialeffect 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 additionalworks are needed to reveal the relationship between commonlyused food preservatives and plant-derived antimicrobials from onehand and the evolution of resistance to commonly used antibioticsfrom the other hand.

Because of its ubiquitous nature, the presence of L. monocy-togenes in the food processing environment is ineluctable. Thus,



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 PenicillinsCephalosporinsVancomycinCarbapenemsAztreonamPolymyxinBacitracinMonobactamsCycloserine

Protein synthesis inhibitors Inhibit 30s SubunitAminoglycosides (gentamicin)TetracyclinesSpectinomycinStreptomycinKanamycinAmikacinNitrofuransInhibit 50s SubunitMacrolidesChloramphenicolClindamycinLinezolidStreptograminsLincomycin

DNA synthesis inhibitors FluoroquinolonesMetronidazole

RNA synthesis inhibitors RifamycinsStreptovaricins

Mycolic acid synthesis inhibitors IsoniazidFolic acid synthesis inhibitors Sulfonamides

TrimethoprimaAdopted 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 recommendedby the manufacturers, sanitizers may facilitate the developmentof antimicrobial resistance. Triggering hyperactivity of multidrugresistance 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 triclosanin vitro was concomitant with increased resistance to gentamicinand other aminoglycosides, with the minimum inhibitory con-centrations of these antimicrobials increasing by 16-fold (Nielsenet al., 2013). The intensive use of disinfectants such as triclosanand quaternary ammonium in the food processing environmentmay provide natural selection of more resistant strains that possessenhanced activity of multidrug resistance efflux pumps. This couldpotentially expel antimicrobial substances out of the cytosolic en-vironment and thus reduce cellular exposure, leading to reducedsusceptibility to a range of antimicrobial agents (Courvalin, 2005).Alonso-Hernando, Capita, Prieto, and Alonso-Calleja (2009) alsoindicated that L. monocytogenes exposed in a model broth systemto acidified sodium chlorite was more resistant to some antibi-otics. Nonetheless, more research is also needed to elucidate therelationship between frequent preexposure to disinfectants and thedevelopment of antibiotic resistance.

Many L. monocytogenes strains possess a strong biofilm form-ing capability. Biofilm forming bacteria pose a great challengeto the food industry because of its inherent resistance to the ac-tion of disinfectants (Jahid & Ha, 2012). Biofilm may provide aninexpugnable 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 environmentmay lead to the development of persister cells with improved effluxpump activity that may render increased expression of resistanceto 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 andextrinsic hurdles in the food processing environment (Buchanan,



Gorris, Hayman, Jackson, & Whiting, 2017). Persister cells aredormant, non-dividing state with enhanced capability to surviveenvironmental 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 fromunrelated bacterial species suggests that both Gram-negative andGram-positive bacteria may have a significant role in resistancegene acquisition by L. monocytogenes (Walsh et al., 2001; Wilsonet 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 acquisitionof antibiotic resistance in L. monocytogenes (Allen et al., 2016). Ex-change of genetic information through plasmid transfer within thespecies of L. monocytogenes is possible after the exposure to differentstresses in the food processing environment or after contaminationof RTE foods (Ferreira, Wiedmann, Teixeira, & Stasiewicz, 2014).It was postulated that certain niches and harboring sites within thefood processing environment would provide favorable conditionsfor persistent strains of L. monocytogenes and other species of Lis-teria to prevail. These niches could elicit appropriate conditionsfor 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 couldlead to the evolution of resistance to some types of antimicrobialagents (Allen et al., 2016; Fox, Solomon, Moore, Wall, & Fanning,2014). Also, it was shown that genetic material for antimicrobialresistance were readily transferable from lactic acid bacteria to L.monocytogenes either under laboratory conditions or in fermentedwhole milk (Toomey, Monaghan, Fanning, & Bolton, 2009). Amore recent study showed that it is possible to make a conjugativetransfer of transposon Tn6198 encoding trimethoprim resistancebetween Enterococcus faecalis and L. monocytogenes inoculated ontothe surface of smoked salmon and fermented cheese (Bertsch et al.,2013b). Also, acquisition of antimicrobials resistance genes may bethrough interaction of L. monocytogenes ingested in the contami-nated food with natural microflora present in the gut. A previousexposure of the food producing animals to therapeutic or prophy-lactic doses of antimicrobial treatments would probably increasethe 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 processingenvironment is the presence of Sigma factor B (σB). This factor is aprotein needed for initiation of transcription through enabling spe-cific binding of RNA polymerase to gene promoters involved inadapting and expressing increased tolerance to antimicrobial treat-ments of different Gram-positive bacteria (Palmer, Wiedmann, &Boor, 2009). It was reported that σB seems to be involved in acti-vating 18 genes responsible for maintaining cell wall integrity andresistance to vancomycin in L. monocytogenses (Shin et al., 2010).L. monocytogenes also possesses two-component signal transductionsystems (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 kinasesensor, which detects environmental stress, and a transcriptionalregulator responsible for mediation of the stress response, termedthe response regulator (Mascher, 2006). The 2CTTS contributesthe innate resistance of L. monocytogenes to β-lactaams includingdifferent 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 ofsalt (6% NaCl) and cold (4 °C) stresses resulted increased toleranceof 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 FoodIsolates of L. monocytogenes

Antibiotic resistance, particularly multidrug resistance, amongfoodborne bacteria including L. monocytogenes has emerged andevolved 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 unsuccessfultreatment resulting in increased costs/mortality associated withfoodborne 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 andincreased mortality rate (WHO, 2014). It is anticipated that globaldeaths from infection caused by antibiotic resistant pathogens willincrease 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 meningoencephalitisin 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 isolatedfrom different sources including food, environmental, and humanclinical samples.

The antibiotic resistance of 21 of L. monocytogenes isolates fromwater, 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 atleast two or more commonly used antibiotics. Among the 20multidrug-resistant isolates, 17 were resistant to penicillin and oneisolate 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 allL. monocytogenes isolates from raw or cooked meat product sam-ples in Turkey were resistant to cephalothin and nalidixic acidand 66% of isolates were resistant to sulfamethoxazole, ampicillin,and trimethoprim. In China, 73% of 167 L. monocytogenes isolatedfrom retail food products were resistant to sulfonamide, 8.4% wereresistant to tetracycline and 1.8% were resistant to ciprofloxacin(Zhang et al., 2007). The antibiotic susceptibility of 13 strainsof L. monocytogenes isolated from homemade white cheeses wasexamined (Arslan & Ozdemir, 2008), and three were resistant toclarithromycin 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 inIran to 10 antibiotics and found that all isolates were resistant to atleast 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 handlingand processing environments to 19 antibiotics. Fourteen strains(11.7%) exhibited resistance to at least one antibiotic. Theisolates displayed maximum resistance to clindamycin, followed bylinezolid, ciprofloxacin, ampicillin, and rifampicin, trimethoprim-sulphamethoxazole and they were least resistant to vancomycinand tetracycline. Rahimi, Ameri, and Momtaz (2010) reported



that 74.3% of L. monocytogenes isolates from dairy products wereresistant to at least one antibiotic, however, multidrug resistancewas found only in two isolates. The percentage of resistance forampicillin and penicillin among isolates were 26.3% and 31.6%, re-spectively. Yan et al. (2010) observed that 36.7% of L. monocytogenesisolates 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. monocytogenesisolates showed multidrug resistance. However, the percentageof 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 toclindamycin, 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) studiedthe antibiotic resistance of L. monocytogenes in chicken slaughter-houses and found that all 55 L. monocytogenes isolates displayedresistance to nalidixic acid and oxolinic acid whereas 83.6%were resistant to clindamycin. Notwithstanding, all the isolateswere 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 theantibiotic resistance of 17 L. monocytogenes isolates from raw orRTE chicken. Most of the isolates were sensitive to antibiotics,however, three isolates (17.6%) were resistant to tilmicosin andtwo isolates were resistant to tetracycline. Only one isolatewas 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 strainsisolated from different types of cheeses, all 39 were resistant tofosfomycin, 92.3% (36/39) were resistant to oxacillin, and 56.4%(22/39) were resistant to clindamycin. However, the isolatesshowed sensitivity or intermediate susceptibility to gentamicin,imipenem, teicoplanin, rifampicin, linezolid, ciprofloxacin,fusidic acid, vancomycin, trimethoprim-sulfamethoxazole, ben-zylpenicillin, erythromycin, and tetracycline. Five isolates wereresistant to three or more antimicrobials. Also, it was reportedthat all 60 L. monocytogenes strains isolated from meat products inJordan were sensitive to ampicillin, gentamicin, and vancomycinwhereas 56.6%, 10.0%, 6.7%, 5.0%, and 3.3% of isolates wereresistant to neomycin, tetracycline, kanamycin, erythromycin,and streptomycin, respectively (Al-Nabulsi et al., 2014).

Terzi, Gucukoglu, Cadirci, Uyanik, and Alisarli (2015) observedthat one-fourth L. monocytogenes isolates from RTE products wasresistant to oxytetracycline and one isolate was resistant to van-comycin. Jamali et al. (2015) observed that the resistance amongL. 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 resistanceof 248 L. monocytogenes isolates from raw retail foods and foundthat 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% (sevenisolates) to chloramphenicol, and 2.4% (6 isolates) to cephalothin.Moreover, seven L. monocytogenes isolates were resistant to morethan 10 antibiotics. Garedew et al. (2015) found that 16 (66.7%),12 (50%), 9 (37.5%), and 4 (16.6%) isolates of 24 L. monocytogenesisolates from RTE foods of animal origin exhibited resistancefor penicillin, nalidixic acid, tetracycline, and chloramphenicol,respectively. Further, four (16.7%) were multidrug-resistant iso-lates. Nonetheless, all 24 L. monocytogenes isolates were sensitive toamoxicillin, sulfamethoxazole-trimethoprime, cephalothin, van-comycin, gentamicin, and cloxacillin.

Peter, Umeh, Azua, and Obande (2016) indicated that 16isolates of L. monocytogenes from pork, beef, and chicken weresusceptible to gentamycin, cotrimoxazol, erythromycin, andchloramphenicol, but were resistant to amoxicillin, augmentin,cloxacillin, and tetracycline. Abdollahzadeh et al. (2016) foundthat seven L. monocytogenes isolates from seafood were resistantto ampicillin and cefotaxime whereas four isolates were resistantpenicillin. Also, they found that all the isolates were susceptibleto trimethoprim-sulfamethoxazole, chloramphenicol, and tetra-cycline. In another study, Kevenk and Gulel (2016) found that15.3% (8/52) of L. monocytogenes isolates from raw milk and dairyproducts were resistant to at least one antibiotic and 36.5% (19/52)were multidrug resistant. In contrast, 48.0% (25 isolates) did notshow any resistance to antibiotics. The most common antibioticresistance encountered was to tetracycline (34.6%), followedby 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 productswere resistant to nalidixic acid, streptomycin, gentamycin, andkanamycin, respectively. All isolates were sensitive to amoxicillin.

Recently, Sharma et al. (2017) reported that all five isolates of L.monocytogenes from bovine raw milk were resistant to the majorityof 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 processingenvironments were resistant to benzyl penicillin, clindamycin, andoxacillin; 97% (32/33) of isolates were resistant to ampicillin, and18% (6/33) were resistant to tetracycline. Further, 82% of isolates(27/33) showed resistance to four antibiotics and 18% (6/33) wereresistant 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, foodprocessing environments, and patient samples in Germany, to 14antibiotics widely used in veterinary and human medicine. Theyindicated that 145 strains (56%) had multidrug resistance and theywere mainly resistant to daptomycin, tigecycline, tetracycline,ciprofloxacin, ceftriaxone, trimethoprim-sulfamethoxazole, andgentamicin. Gomez et al. (2014) tested the antibiotic resistanceof L. monocytogenes isolates from RTE meat products and meat-processing environments. Resistance to one or two antimicrobialswas observed in 71 (34.5%) of L. monocytogenes isolates, althoughmultidrug resistance was identified in 2.9% of the organisms.All isolates showed resistance to oxacillin while only 0.5% wereresistant to tetracycline. Haubert, Mendonc, Lopes, de ItapemaCardoso, & da Silva (2015) studied the antibiotic resistanceof 50 L. monocytogenes strains isolated from foods and foodenvironment in Brazil, between 2001 and 2010. They found thatall 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



trimethoprim–sulfamethoxazole (10%). Although all isolatesexamined 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 resistanceto oxacillin, 31.6% and 8.8% were resistant to ceftriaxone or clin-damycin, respectively, and only two isolates showed resistance tothe three antibiotics. Kuan et al. (2017) tested the antibiotic re-sistance of 58 L. monocytogenes isolates from vegetable farms andretail markets in Malaysia. They found that 100%, 70.7%, and41.4% of isolates exhibited resistance to penicillin G, meropenem,and rifampicin. Although 100%, 91.4%, and 84.5% of isolateswere susceptible to ampicillin, gentamicin, and trimethoprim-sulfamethoxazole, respectively. Zeinali, Jamshidi, Bassami, andRad (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, Gomez, Del Carmen Rota Garcıa,Conchello, and Herrera (2017) reported that 100% and 42.9% ofseven L. monocytogenes isolates from RTE meat and dairy prod-ucts were resistant to clindamycin and ciprofloxacin, respectively.In Egypt, Mohamed, Abdelmonem, and Amin (2018) reportedthat all 47 L. monocytogenes isolates from frozen vegetables wereresistant 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 trimethoprim-sulfamethoxazole.Akrami-Mohajeri et al. (2018) found that all 22 L. monocytogenesisolates from raw milk and traditional dairy products in Iran wereresistant to tetracycline, penicillin, chloramphenicol, and amoxi-cillin/clavulanic acid.

It is worth noting that other studies have shown a low prevalenceof antibiotic resistance among L. monocytogenes strains isolatedfrom food sources. Walsh et al. (2001) found that only 2/351(0.6%) of L. monocytogenes food isolates were resistant to at leastone antibiotic. Mayrhofer, Paulsen, Smulders, and Hilbert (2004)investigated the vulnerability of L. monocytogenes isolates from304 meat samples to antibiotics and found no resistant isolates totetracycline, penicillin, gentamicin, vancomycin, co-trimoxazol,erythromycin, chloramphenicol, or streptomycin. Aarestrup,Knochel, and Hasman (2007) found that the 114 L. monocytogenesisolates they examined from food products were susceptible to all12 antibiotics used except ceftiofur. Vitas, Sanchez, Aguado, andGarcia-Jalon (2007) pointed out that 401 L. monocytogenes isolatesexamined were susceptible to the majority of the antimicrobialstested (penicillin G, ampicillin, cephalothin, gentamicin, chloram-phenicol, tetracycline, doxycycline, trimethoprim, erythromycin,and clindamycin), and only five isolates (1.2%) were resistantto tetracycline and doxycycline. Filiousis, Johansson, Frey, andPerreten (2009) studied the antibiotic resistance of 30 food isolatesof L. monocytogenes and observed that all, except for one withresistance to tetracycline, were susceptible to 16 antimicrobials.In Poland during 2004 to 2010, 471 L. monocytogenes culturesisolated from various types of foods were found sensitive togentamicin, 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 fromAustralian food production chains between 1988 and 2016. Theyfound that all isolates were sensitive to penicillin G and tetracy-cline. However, only two isolates were resistant to ciprofloxacinand an isolate was resistant to erythromycin. Further, Amajoudet al. (2018) reported that all 16 food L. monocytogenes isolateswere susceptible to penicillin G, chloramphenicol, rifampicin,streptomycin, vancomycin, fusidic acid, trimethoprim, lev-ofloxacin, moxifloxacin, ciprofloxacin, erythromycin, amikacin,kanamycin, amoxicillin, ampicillin, gentamicin, imipenem, andtobramycin. However, all isolates showed resistance to cefotaxime,sulfonamide, nalidixic acid, fosfomycine, and lincosamide. Inaddition, two isolates were resistant to tetracycline. Oliveira et al.(2018) also found that 100% of 35 L. monocytogenes isolates fromchicken 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 productsare susceptible to a wide range of antibiotics. However, the inci-dence of resistance to some antibiotics among the food isolates hasbeen increasing. Furthermore, it is also evident that L. monocyto-genes strains from food products exhibit resistance to several typesof 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 ofthe 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. monocytogenesisolates from poultry products in North-Western Spain, Alonso-Hernando et al. (2012) pointed out that, excluding nalidixic acidto which most isolates were inherently resistant, 37.2% and 96.0%of L. monocytogenes isolated in 1993 and 2006, respectively, showedresistance to at least one antibiotic. Multidrug resistance was alsomore 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) thanin 1993 (1.6). A remarkable increase in the number of resistantstrains 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 ofantibiotic resistance in L. monocytogenes (Charpentier & Cour-valin 1999). However, efflux pumps were also suggested to belinked with fluoroquinolone, macrolide, and cefotaxime resistancein L. monocytogenes (Godreuil, Galimand, Gerbaud, Jacquet, &Courvalin, 2003; Mata, Baquero, & Perez-Diaz, 2000).

Antibiotic resistance mediated by conjugationIt 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 mainreservoirs of resistance genes for L. monocytogenes. Conjugation is aprocess by which genetic materials transfer from a donor to a recip-ient cell. The genome of bacteria is composed of the chromosome



and accessory movable genetic elements such transposons and plas-mids (Perichon & Courvalin, 2009). Conjugation is divided intothree 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 geneticelements, transposons and plasmids, in enterococci and streptococciwere 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 toL. monocytogenes most likely takes place in the gastrointestinal tractof humans (Doucet-Populaire, Trieu-Cuot, Dosbaa, Andremont,& Courvalin, 1991). Furthermore, it has been found that L.monocytogenes isolates from food and food processing environmentsharbored the benzalkonium chloride resistance transposon Tn6188that encodes the tolerance to quaternary ammonium compoundsin Staphylococcus aureus and other Firmicutes (Muller et al., 2013;Ortiz, Lopez-Alonso, Rodrıguez, & Martınez-Suarez, 2016).

Tetracycline resistance is believed to be the most frequentresistance trait in L. monocytogenes isolated from human and foods(Charpentier & Courvalin 1999; Walsh et al., 2001). Six classes oftetracycline resistance genes have been described in Gram-positivebacteria (tetK, tetL, tetM, tetO, tetP, and tetS). However, onlytetS, tetM, and tetL have been identified in L. monocytogenes(Charpentier & Courvalin, 1999; Escolar et al., 2017; Granieret al., 2011). It has also been reported that 19 of 38 L. monocy-togenes isolates (50%) from dairy farms harbored more than oneantibiotic resistance gene sequence. A high incidence of floRgene was detected in 66% of L. monocytogenes strains followed bypenA (37%), strA (34%), tetA (32%), and sulI (16%). Nevertheless,other tetracycline resistance genes (tetE, tetC, tetB, tetD, and tetG)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 apork processing plant and its respective meat markets in Chinacarried the tetM gene. Similarly, the genes ermB, tetM, and dfrD,were detected in L. monocytogenes strains isolated from food andenvironmental samples in France during 1996 to 2006; but thetetS, tetK, and tetL genes were not detected (Granier et al., 2011).The antibiotic resistance genes tetM and ermB were also identifiedin L. monocytogenes isolated from fresh mixed sausage and chickenslaughterhouse, respectively (Haubert et al., 2015). Recently, Lim,Yap, and Thong (2016) found that two L. monocytogenes isolatesfrom fried fish and salad carried five genes including tetA, lmrB,mecC, msrA, and fosX 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. monocytogenesis 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 hasalso carried other antibiotic resistance to L. monocytogenes fromEnterococcus, Streptococcus, or other Listeria species (Charpentier &Courvalin 1999).

Antibiotic resistance mediated by efflux pumpsL. 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 tofluoroquinolones (Guerin, Galimand, Tuambilangana, Courvalin,& Cattoir, 2014). Mata et al. (2000) reported that the sequenceof the MdrL (multidrug efflux transporter of Listeria) protein ishighly homologous to the sequence of protein YfmO, a putativechromosomal multidrug efflux transporter in Bacillus subtilis. Anallele-substituted mutant of this gene in L. monocytogenes failed topump out ethidium bromide and yielded increased susceptibilityto cefotaxime, heavy metals, and macrolides.

It has been reported that five families are included in drug effluxsystems: the major facilitator superfamily (MFS), the resistance-nodulation-cell division, the small multidrug resistance, as well asthe 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 associatedwith overexpression of MFS pumps, such as NorA in Staphy-lococcus aureus and PmrA (pneumoniae multidrug resistance) inStreptococcus pneumoniae, which specifically extrudes hydrophilicfluoroquinolones (Poole, 2007). Godreuil et al. (2003) reportedthat the Lde protein of L. monocytogenes showed 44% homologywith PmrA of S. pneumoniae, which belongs to the MFS family ofsecondary multidrug transporters. The insertional inactivation ofthe gene lde results in increased susceptibility of L. monocytogenes tofluoroquinolones. In another study, overexpression of the lde geneinduced by ciprofloxacin was detected in two resistant L. mono-cytogenes isolates from food in China. However, the researcherssuggested that overexpression of the lde gene was not the onlyreason for ciprofloxacin resistance (Jiang et al., 2012). Romanova,Wolffs, Brovko, and Griffiths (2006) reported that the efflux pumpMdrl in L. monocytogenes is partially accountable for the adaptationto antibiotic resistance. Recently, Guerin et al. (2014) character-ized the MATE efflux pump, which is linked to the resistance of L.monocytogenes to fluoroquinolones. The transcriptional regulationof the expression of a MATE family efflux pump-encoding geneoccurs through a TetR-like repressor. Lim et al. (2016) detectedtwo efflux pump-related genes, mdrL and lde, which confer resis-tance to macrolides and quinolone, respectively, in the genomes oftwo L. monocytogenes isolates from fried fish and salad. In anotherstudy, it was suggested that the mutation in the fluoroquinoloneefflux protein (fepA) regulator, fepR, is responsible in part for theresistance of L. monocytogenes to ciprofloxacin (Wilson et al., 2018).

Conclusions and Future ResearchL. monocytogenes poses a persistent threat to the food industry,

particularly operations preparing RTE foods. Antibiotic resistancein L. monocytogenes isolated from food products has been develop-ing over the past few decades, and represents a serious public healthrisk worldwide. In general, most Listeria spp. isolated from clinical,food, and environmental sources are susceptible to those antibioticsnormally effective against Gram-positive bacteria. Yet, there is analarming increase in the prevalence of multidrug-resistant strainsof L. monocytogenes from various sources, and therefore monitoringL. monocytogenes for changes in its antimicrobial resistance appearsprudent.

The antibiotic resistance profile of L. monocytogenes is partic-ularly important for people with immune-compromised systemswho are most susceptible to listeriosis. Acquisition of resistanceby L. monocytogenes to commonly prescribed antibiotics wouldpose a major therapeutic challenge in clinical settings. Based onclinical experience with virulent strains of Staphylococcus, Entero-coccus, and Pseudomonas, it is not hard to imagine that increases in



mortality rates and costs of patient care due to multidrug-resistantL. 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 reasonsthat are not clearly understood. Some plausible factors influencingthe emergence of antibiotic resistant strains may be the indiscrimi-nate use or overuse of antibiotics in treating human infections, thesomewhat arbitrary prophylactic use of antibiotics in animal breed-ing and their use as growth supplements in animal feed. Transferof antibiotic resistance genes from other bacteria is possibly themain reason for the increased antibiotic resistance of L. monocyto-genes. Many mechanisms have been suggested responsible for thedevelopment of antibiotic resistance by L. monocytogenes, but themost likely mechanism involves conjugative plasmids and trans-posons from other bacteria such as Enterococcus and Streptococcusspp. There is also evidence that other putative mechanisms involv-ing efflux pumps that secrete antibiotics and other antimicrobialagents outside the cell may be responsible.

Future studies need to investigate the influence of the pathogensource (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 andpesticides 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 infood production and preservation should be explored in terms oftheir effects on the emergence of antibiotic resistance among L.monocytogenes strains. In addition, other species of the genus Listeriamust be examined, as they may constitute reservoirs of antibioticresistance genes, which may be transferred to L. monocytogenes. Inaddition, the necessity of broad and continuous surveillance todetect any evolution in the susceptibility of L. monocytogenes toantibiotics should be emphasized in future research.

AcknowledgmentsThe authors acknowledge financial support from the Deanship

of Research at Hashemite Univ., Zarqa, Jordan.

Authors’ ContributionsConception 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 InterestThe authors declare that they have no conflicts of interest.

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https://doi.org/10.3390/genes9020080

https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance

emergence of antibiotic resistance in listeria

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