57
Introduction
Human population is increasing to reach 8 billion by the end of second decade of 22nd century. This situation triggered an increase in global food consumption and demand for food. Food producers apply new technolo-gies to respond this demand with limited sources. The increase in production capacities leads industrialization of food production. This is known to have an effect on contamination of food with pathogens, if no counter mea-sures are taken. There has been a bias for application of combating these foodborne pathogens. In facilities, there have been applications of many approaches like Good Manufacturing Practices (GMP), Hazard Analysis Critical Control Points (HACCP) etc. Likewise, Good Agricultural Practices (GAP) and Good Production Practices (GPP) have been taking place in farms. A widespread approach, traceability of foods is applied in developed countries.
Additionally, the food quality awareness has been increasing among the consumers.
Traditional production schemes could not responded to the increasing food demand. Producers have been seeking alternative feed additives that can be applied as growth promoters to respond the demand and addi-tional value in animal health. There have been different approaches to increase the growth of animals one of which is application of antibiotics. Application of antibi-otics as feed additives has been more popular until the super bugs emerged. This situation has been leading ban of antibiotics in farm level.
Antibiotic-resistant strains of termotolerant Campylobacter spp., Salmonella, Verotoxigenic Escherichia coli (VTEC) are mainly concern in food microbiology. As the antibiotic resistance of these bugs increase, more strict measures have been taken.
RevIew ARtIcle
Antimicrobial resistance of emerging foodborne pathogens: Status quo and global trends
Ahmet Koluman1 and Abdullah Dikici2
1Department of Microbiology, National Food Reference Laboratory, Fatih Sultan Mehmet Bulv., Tarim Kampusu, Yenimahalle, Ankara, Turkey and 2Department of Food Engineering, Engineering Faculty, Tunceli University, Tunceli, Turkey
AbstractEmerging foodborne pathogens are challenging subjects of food microbiology with their antibiotic resistance and their impact on public health. Campylobacter jejuni, Salmonella spp. and Verotoxigenic Escherichia coli (VTEC) are significant emerging food pathogens, globally. The decrease in supply and increase in demand lead developed countries to produce animal products with a higher efficiency. The massive production has caused the increase of the significant foodborne diseases. The strict control of food starting from farm to fork has been held by different regulations. Official measures have been applied to combat these pathogens. In 2005 EU declared that, an EU-wide ban on the use of antibiotics as growth promoters in animal feed would be applied on 1 January 2006. The ban is the final step in the phasing out of antibiotics used for non-medical purposes. It is a part of the Commission’s strategy to tackle the emergence of bacteria and other microbes resistant to antibiotics, due to their overexploitation or misuse. As the awareness raises more countries banned application of antibiotics as growth promoter, but the resistance of the emerging foodborne pathogens do not represent decrease. Currently, the main concern of food safety is counter measures against resistant bugs.Keywords: Campylobacter, Salmonella spp., verotoxigenic Esherichia coli, antibiotics, legislation
Address for Correspondence: Ahmet Koluman, Department of Microbiology, National Food Reference Laboratory, Microbiology, Fatih Sultan Mehmet Bulv., Tarim Kampusu No. 70, 06170 Yenimahalle, Ankara 06170, Turkey. E-mail: [email protected]
(Received 16 February 2012; revised 22 April 2012; accepted 03 May 2012)
Critical Reviews in Microbiology, 2013; 39(1): 57–69© 2013 Informa Healthcare USA, Inc.ISSN 1040-841X print/ISSN 1549-7828 onlineDOI: 10.3109/1040841X.2012.691458
Critical Reviews in Microbiology
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1
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16February2012
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03May2012
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© 2013 Informa Healthcare USA, Inc.
10.3109/1040841X.2012.691458
2013
Antimicrobial resistance of emerging foodborne pathogens
A. Koluman and A. Dikici
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emerging foodborne pathogens
Emerging pathogens can be classified as infectious agents that have only recently appeared in a population, or that are well recognized but their incidence is rapidly increasing, or they have the probability of increasing in the future (Morse, 2004; Schlundt et al., 2004; Duffy et al., 2008). Emerging infectious diseases are a significant bur-den on global economies and public health. Emergence or re-emergence of an organism can generally be related to a combination of factors and changes that occur along the farm to fork chain as well the inherent adaptability and genetic flexibility of micro-organisms. Changes in agri-food chain, social changes, bacterial adaptation, detection, reporting and surveillance systems determine whether a pathogen emerges or not (Duffy et al., 2008). The changes in emerging status of traditional foodborne pathogens are shown in Table 1.
An importantly data-indicating trend in foodborne infectious intestinal disease is limited to a few industrial-ized countries, and even fewer pathogens. It has been pre-dicted that the importance of diarrheal disease, mainly due to contaminated food and water, as a cause of death will decline worldwide. Evidence for such a downward trend is limited. This prediction presumes that improve-ments in the production and retail of microbiologically safe food will be sustained in the developed world and will be rolled out to those countries of the developing world increasingly producing food for a global market (Newell et al., 2010).
Developed countries have used for a long time systems of surveillance of food safety problems. Basic Surveillance Network (BSN), Unexplained Death and Critical Illnesses Project (UNEX), World Health Organization (WHO) Global Salm-Surv (GSS), CDC’s Emerging Infections Program, Foodborne Diseases Active Surveillance Network (FoodNet) are respected examples for surveil-lance of foodborne pathogens. However, many outbreaks of food poisoning are never recognized because known
pathogens are not accurately diagnosed or reported, and other causative foodborne agents are unknown and therefore unreported. This causes underestimation of foodborne disease incidences. Furthermore, industries check their products but usually do not report positive findings (Mor-Mur and Yuste, 2010).
termotolerant Campylobacter spp.
Campylobacter spp. is currently considered the leading cause of sporadic bacterial gastroenteritis, with C. jejuni being the most frequently implicated in clinical diagnosis. In Canada and the UK, among many other countries, the number of reported cases of campylobacteriosis exceeds the combined number of salmonellosis and shigellosis cases. Raw and undercooked poultry are the primary sources of campylobacteriosis. A considerable portion of broilers (88%) and poultry at retail (98%) has been found contaminated with the pathogen. Epidemiologic studies show that ca. 50% of sporadic cases of campylobacterio-sis are associated with handling or eating poultry. Meat products can also contribute to illness (Meng and Doyle, 1998; Chan et al., 2001; Inglis et al., 2004; Bostan et al., 2009; Koluman, 2010; Mor-Mur and Yuste, 2010).
Salmonella
Salmonella is an enteric pathogen associated with animal and slaughter hygiene. In the EU, eggs and egg products are the most frequently implicated sources of human sal-monellosis. Meat is also an important source, with poultry and pork implicated more often than beef and lamb (EFSA, 2008). The two most common Salmonella serotypes are Typhimurium and Enteritidis. In human salmonellosis, S. Typhimurium is the most frequent serotype. Salmonella Enteritidis is associated primarily with poultry and eggs. It has been observed that Salmonella spp. usually persist during chilling. Human salmonellosis infections can lead to uncomplicated enterocolitis and enteric (typhoid) fever, the latter being a serious disease that may involve diarrhea, fever, abdominal pain, and headache. Salmonella can also cause systemic infections, resulting in chronic reac-tive arthritis (Meng and Doyle, 1998; Echeita et al., 1999; D’Aoust and Maurer, 2007; Mor-Mur and Yuste, 2010).
verotoxigenic Escherichia coli
Enterohemorrhagic E. coli (EHEC), i.e. E. coli O157:H7 and other serotypes of Shiga toxin-producing E. coli, are foodborne pathogens of primary concern. They are etiological agents of hemorrhagic colitis. In some cases, complications may occur, e.g. hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. EHEC other than E. coli O157:H7 have been increasingly associated with such complications. The severity of the illness and the low infective dose (<100 organisms) make E. coli O157:H7 among the most serious foodborne pathogens (Meng and Doyle, 1998; Acheson, 2003; Meng
Table 1. Traditional food pathogens vs emerging foodborne pathogens (Mor-Mur and Yuste, 2010).“Traditional” pathogens Emerging pathogensCampylobacter spp. Campylobacter jejuni (O:19, O:4,
O:1), Campylobacter lanienaeSalmonella spp. Salmonella Typhimurium
(DT104, DTU302), S. Enteritidis (PT4, PT8, PT13, PT14b)
Escherichia coli Enterohemorrhagic Escherichia coli (EHEC)
Yersinia enterocolitica Listeria monocytogenesStaphylococcus aureus Arcobacter butzleriClostridium perfringens Mycobacterium avium subsp.
paratuberculosisClostridium botulinum Aeromonas hydrophilaBacillus cereus Enterobacter sakazakii
Helicobacter pyloriHelicobacter pullorum
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et al., 2007). The organism is not a rare contaminant in meats. Many outbreaks of EHEC have been associated with consumption of undercooked contaminated ground beef (Mor-Mur and Yuste, 2010).
There have been detailed studies for reporting food-borne pathogens and different surveillance systems have been built. Reports indicate a significant increase in Termotolerant Campylobacter spp., Salmonella and VTEC (indicated as Shiga Toxin Producing Escherichia coli-STEC in the report) infections. In a report about sur-veillance of foodborne illnesses in US it is reported that in 2007, FoodNet sites identified 18,039 laboratory-con-firmed infections caused by the pathogens under surveil-lance. Of 16,801 bacterial infections, most were caused by Salmonella (41%), followed by Campylobacter (35%), Shigella (17%), VTEC O157 (3%), VTEC non-O157 (2%), Yersinia (0.98%), Listeria (0.73%), Vibrio (0.65%), VTEC O Antigen Undetermined (0.07%), VTEC O Antigen rough (0.04%), and VTEC O Antigen not tested (0.01%). Of the 922 cases of parasitic infections, 99% were caused by Cryptosporidium and 1% by Cyclospora (CDC, 2009). The graphic summarizing the distribution of foodborne dis-eases in US is shown in Figure 1.
In European Union seasonal distribution of Campylobacter spp. has been reported with assem-bling individual country reports designed in Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, and UK. Likewise, Salmonella spp. distribution was reported with assembling country reports of Austria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Luxembourg, Malta, Netherlands, Portugal, Slovakia, Spain, Sweden, UK, Iceland and Norway. Lastly, VTEC seasonal distribution in EU was determined with assembling the country reports of Austria, Belgium, Bulgaria, Cyprus, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Malta, Netherlands, Poland, Romania, Slovakia, Slovenia, Spain, Sweden, UK, Iceland and Norway (ECDC, 2010).
EU Campylobacter spp. report indicated that in 2008, 193,814 cases (193,554 confirmed) were reported by 25 EU and EEA/EFTA countries. Compared with 2007 (203,736 cases), the number of confirmed cases in 2008 decreased slightly by 5%, but still exceeded the number of confirmed cases in 2006 (178,933 cases). Data on the importation status of reported cases (n = 132,677) were available from 21 EU Member States, Iceland and Norway. As in the pre-vious years, the infection is mainly domestically acquired (92% of all cases with information on importation status). Seven countries provided complete data (zero unknown) for importation status. Among these countries the pro-portion of domestic cases varied from 86% in Estonia to 100% in Malta and Spain. Three Scandinavian countries (Finland, Sweden, and Norway) reported high propor-tions of imported cases (77%, 71%, and 58%, respectively). The report indicates that there is an obvious increase in campylobacteriosis (ECDC, 2010). Seasonal distribution of campylobacteriosis in EU and EEA/EFTA countries from 2006 to 2008 is shown in Figure 2.
Figure 1. Relative rates of laboratory-confirmed infections with Campylobacter, STEC O157, Listeria monocytogenes, Salmonella, and Vibrio spp. compared with 1996–1998 rates, by year. Foodborne Diseases Active Surveillance Network (FoodNet), US, 1996–2009 (CDC, 2009).
Figure 2. Seasonal distribution of campylobacteriosis in EU and EEA/EFTA countries between 2006 and 2008.
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Salmonellosis cases (nontyphoidal) were a total of 138,469 in 2008, of which 136,681 were confirmed, by all EU and EEA/EFTA countries. The overall notifica-tion rate was 29.75 per 100,000 population, which is a significant decrease over the last three years. Slovakia, Czech Republic and Lithuania reported the highest notification rates (127, 103, and 98 cases per 100,000, respectively). Four countries reported fewer than 10 cases per 100,000 population, namely Greece, Portugal, Romania and Liechtenstein. Over the 3-year period, the largest decreases in notification rates were observed in Czech Republic, Austria, and Luxembourg, while the highest increases were observed in Malta and Denmark. The large decrease in Luxembourg and large increase in Denmark could be explained by the extensive salmonel-losis outbreaks occurring in these countries in 2006 in Luxembourg and in 2008 in Denmark (ECDC, 2010).
In 2008, the proportion of cases in the EU that were imported was 15% of all confirmed cases with known importation status (n = 90,982). The proportion of imported cases was highest in the Nordic countries of Finland, Sweden, Iceland and Norway (over 80%), fol-lowed by Ireland and the UK (over 50%) (ECDC, 2010). Seasonal distribution of salmonellosis in EU and EEA/
EFTA countries between 2006 and 2008 is shown in Figure 3.
Verotoxigenic E.coli has been a sophisticated and complicated subject for medical doctors and food hygienists due complication in confirmation of pathogens listed in this class. In 2008, the overall notification rate in Europe was 0.66 cases per 100,000 population, relatively unchanged over the last few years. Children under five years old had the highest notification rate: 4.72 cases per 100,000 population. The number of reported cases with hemolytic uremic syndrome increased by 42% in 2008 compared with 2007. In 2008, 3210 confirmed cases of VTEC infection were reported by 27 EU and EEA/EFTA countries. The overall notification rate in 2008 was 0.66 cases per 100,000 population, more or less unchanged over the last few years. Notification rates increased in 14 Member States, with Ireland reporting the highest increase from 2.7 cases per 100,000 in 2007 to 4.8 cases per 100,000 in 2008. The largest decrease in notification rate was in Iceland from 4.2 cases per 100,000 in 2007 to 1.3 cases per 100,000. Notification rates in Bulgaria, Estonia, Latvia, Lithuania and Poland remained the same as in 2007 (ECDC, 2010). Seasonal distribution of VTEC in EU and EEA/EFTA countries from 2007 to 2008 is shown in Figure 4.
Figure 3. Seasonal distribution of salmonellosis in EU and EEA/EFTA countries between 2006 and 2008.
Figure 4. Seasonal distribution of VTEC in EU and EEA/EFTA countries between 2007 and 2008.
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Antibiotic application in farms as growth promoters
History of antibiotic growth promoter applicationThe growth-promoting properties of antimicrobials for farm animals were discovered in the late 1940s. The growth promoter effect of antibiotics was discovered in the 1940s, with observing that animals feed dried mycelia of Streptomyces aureofaciens containing chlor-tetracycline residues showing an improvement in their growth. In 1950, Stockestad, in the US, confirmed that the growth of animals, such as piglets and chicks, was promoted when a small amount of an antibiotic was supplemented in the feed. At this time, the mechanism of growth promotion was not clearly understood. The United States Food and Drug Administration approved the use of antibiotics as animal additives without vet-erinary prescription in 1951 (Jones and Ricke, 2003).However, taking into account that the antibiotics have to be taken orally to be effective, and that the growth-promoting antibiotics do not exert a favorable influence in the germ-free animals, it would be assumed that the antibiotics would change the balance of the intestinal flora in a way that promote the animal growth. The use of antibiotics in feeding stuffs was increased in line with the development of the intensive animal produc-tion. The practice of feeding subtherapeutic doses of antibiotics was readily adopted and antibacterial feed additives soon became an integrated part of the systems developed in the animal industry. Also in the 1950s and 1960s, each European state approved its own national regulations about the use of antibiotics in animal feeds (Castanon, 2007).
Antibiotics permitted in the European feeds were listed in the Annexes to Directive 70/524: Annex I listed antibiotics without marketing restrictions in all the European Community, and Annex II listed antibiotic that could be allowed by a state within its territory. When the use of certain additives authorized at national level had been widely tested, and the studies carried out and the experience gained indicated that these additives might be authorized throughout the community for the uses specified, those additives were included in Annex I. Annex II constituted therefore an intermediate stage in determining the inclusion of additives in the list of those permitted in the Community listed in the Annex I. Annexes to Directive 70/524 were regularly amended in the light of scientific and technical knowledge. Annex II to Directive 70/524 listed the following antibiotics: baci-tracin manganese, neomycin, framicetin, hygromycin-B, tylosin, and erythromycin. These antibiotics could be permitted at national scale with the conditions stated by each state. However, Directive 76/296 withdrew approval for these products after 30 June 1976 (31 December 1976 for hygromycin-B), except the use of erythromycin in feeds for fattening chicks, which was extended until the end of 1978 by Directive 78/58. Other antibiotics, which were later added to Annex II to be used in feeds for
poultry (excluding ducks, geese, and laying hens) up to 10 week old, were lincomycin (Directive 74/180, autho-rized until 30 June 1981) and bacitracin-methylene-disalicylate (Directive 75/267, until 31 December 1977). Also the following antibiotics were included in Annex II to be used only in feeds for chickens for fattening: mocimycin (Directive 78/743, until 30 November 1983), nosiheptide (Directive 79/1011, until 3 December 1986) and ardacin (Directive 94/77, until 30 November 1997) (Castanon, 2007).
Growth promotersAntibiotics are used for three major purposes in domestic animals: (i) for therapy, to treat an identified illness; (ii) for prophylaxis, to prevent illness in advance; and (iii) for performance enhancement, to increase feed conversion, growth rate or yield. Of special interest is the usage of a convenient method for administering the pharmacologically active substance to large numbers of intensively raised animals to ensure that each animal receives an appropriate oral dose. Antibiotics are now commonly included in the feed of chickens, turkeys, pigs, cattle, and furbearing animals. For growth-promoting purposes, they are included in the feed at low levels where they also improve the rate of live weight gain and the efficiency of feed utilization. For therapeutic purposes, they are used in feed usually at higher levels fort their antibacterial, antifungal, anthelmintic, or antiprotozoal effects. The use of growth promoters in feeds for growth enhancement can give improvements in daily weight gain and feed conversion efficiency of the order of 34% in broilers, 4–5% in pigs and veal calves and as much as 10% in beef cattle. The main advantages to producers from regular use of the growth promoters may be: economic benefits, greater uniformity of growth, stabilization of gut flora, and maintenance of the animal health in the face of environmental stress (to this extent they are acting prophylactically, i.e. reduction in morbidity). The antibacterial growth promoter feed additives, which are approved in the EU according the EC Directives are the following: ardacin, avilamycin, bacitracin, flavophospholipol, monensin, salinomycin, spiramycin, tylosin, virginiamycin, carbadox, and olaquindox. The antibacterial growth promoters are belonging to several groups of antibiotics not being structurally related and exerting their antibacterial activity by different mechanisms either by disturbing the bacterial cation homeostasis or by inhibiting the formation of an intact bacterial wall or inhibiting the bacterial synthesis of proteins or DNA. Except the quinoxalines, these substances have a narrow antimicrobial spectrum restricted to Gram-positive bacteria. Furthermore, the ionophores possess an antiprotozoal effect leading to their additional use as coccidiostatic feed additives mainly in poultry. The growth-promoting effect of the antibiotics, and the synthetic products carbadox and
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olaquindox, is supposed to be primarily caused by a stabilization of the intestinal microflora improving the feed conversion and reducing the formation of toxins.
The combined potential of microbial activities to negatively impact intestinal functions clearly sup-ports the hypothesis that certain bacterial popula-tions commonly inhabiting the pig small intestine, though not necessarily pathogenic, cause a depres-sion in growth which is reversed when the respon-sible organism(s) are metabolically inhibited or eliminated by feed-grade antibiotics (Gaskins et al., 2002). The mechanism of growth promoters is shown in Figure 5 (Anderson et al., 1999).
Antibiotic resistance of emerging foodborne pathogens
Antibiotic resistance of Campylobacter spp.Thermotolerant Campylobacter spp. is subject to many foodborne illness and veterinary disease. Not only the infection caused but also the resistance of the patho-gen is questions of concern globally. Although cam-pylobacteriosis is not associated with high mortality rates and is generally self-limited, it has a significant impact on the economy and public health in industri-alized countries (Josefsen et al., 2004). Antimicrobial resistance has become a major public health concern in both developed and developing countries in recent years (Isenbarger et al., 2002; Nachamkin et al., 2002). Campylobacter with resistance to ciprofloxacin or other fluoroquinolones, macrolides and lincosamides, chlor-amphenicol, aminoglycosides, tetracycline, ampicillin and other β-lactams, cotrimoxazole, and tylosin have been reported (Padungton and Kaneene, 2003; Moore et al., 2006; Alfredson and Korolik, 2007). In the past decade, a rapidly increasing proportion of Campylobacter strains worldwide have developed resistance to the fluoro-quinolones. In 1995, the incidence of fluoroquinolone
resistance in Campylobacter isolates from Thailand was reported as 84% and, in 1997–1998, the incidence of fluoroquinolone resistance in Spain was reported as 72%. Incidence of resistance to the fluoroquinolones has also increased in the US, UK, and the Netherlands. In 1998–1999, the proportion of Campylobacter isolates resistant to fluoroquinolones was reported as 10%, 18%, and 29%, respectively (Allos, 2001).
Different resistances are recorded from different food types in different countries. Some of the selected publica-tions are given in Table 2. According to the table it is obvi-ous that resistances to some antibiotics are significant.
Antibiotic resistance of SalmonellaFoodborne diseases caused by nontyphoid Salmonella represent an important public health problem worldwide. Nearly 1.4 million cases of salmonellosis occur each year in the US. Most Salmonella infections in humans result from the ingestion of contaminated poultry, beef, pork, eggs, and milk. Intestinal salmonellosis typically resolves in five to seven days and does not require treatment with antibiotics. However, bacteremia occurs in 3–10% of reported, culture-confirmed cases and is particularly common among patients at the extremes of age and those who are immunocompromised. When infection spreads beyond the intestinal tract, appropriate antimicrobial therapy (e.g. ciprofloxacin in adults and ceftriaxone in children) can be lifesaving. The use of antimicrobial agents in any environment creates selection pressures that favor the survival of antibiotic-resistant pathogens. According to the infectious-disease report that was released by the World Health Organization in 2000, such organisms have become increasingly prevalent worldwide. The routine practice of giving antimicrobial agents to domestic livestock as a means of preventing and treating diseases, as well as promoting growth, is an important factor in the emergence of antibiotic-resistant bacteria that are subsequently transferred to humans through the food chain. Most infections with antimicrobial-resistant Salmonella are acquired by eating contaminated foods of animal origin (White et al., 2001).
The ease with which people can travel between distant countries and the exchange of food between countries by global trade has contributed significantly to the spread of foodborne diseases. Multidrug-resistant (MDR) Salmonella isolates are a direct threat to human health when this multidrug resistance interferes with treatment and an indirect threat when resistance can be transferred to other human pathogens. Therefore, antimicrobial susceptibility monitoring is important for the detection of resistant clinical isolates and for the surveillance of antimicrobial resistance (Vo et al., 2010).
Salmonella Typhimurium phage type (PT) or defini-tive type (DT) 104 is virulent both for humans and ani-mals, especially cattle. It has been isolated increasingly from humans and animals in the European countries and, more recently, in the US and Canada. Humans may acquire the infection from foods of animal origin
Figure 5. The mechanism of growth promoters.
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Tab
le 2
. So
me
sele
cted
pu
blic
atio
ns
abou
t th
e an
tib
ioti
c re
sist
ance
of C
amp
ylob
acte
r sp
p.
Cou
ntr
ySa
mp
le
typ
e
Nu
mb
er
of
sam
ple
Inci
den
ce o
f C
amp
ylob
acte
r (%
)
Nu
mb
er
of
stra
ins
An
tib
ioti
c re
sist
ance
of a
ll st
rain
s (%
)%
MR
AM
PC
TE
TC
NN
AD
CIP
EA
MC
KN
EN
RST
RST
XR
efer
ence
sC
zech
Ch
illed
p
oult
ry24
056
88N
A79
.10
NA
07.
7564
.80.
75N
AN
AN
AN
A4.
75N
AB
ard
on a
l., 2
011
Ch
ina
Bro
iler
ceca
l76
735
.926
1N
AN
A30
.710
027
.299
99.5
26.7
NA
NA
NA
98N
AN
AC
hen
et a
l., 2
010
Den
mar
kP
oult
ryN
AN
A76
720
.1N
A0.
37.
8N
AN
A4.
30.
5N
AN
AN
AN
A0.
9N
AA
nd
erse
n e
t al.,
20
06E
ston
iaP
oult
ry68
010
.29
70N
A34
NA
44N
A66
6614
NA
NA
NA
NA
NA
NA
Pra
akle
-Am
in e
t al.,
20
07Fi
nla
nd
Pou
ltry
305
10.5
32N
A3
NA
00
00
0N
AN
AN
AN
AN
AN
ALy
hs
et a
l., 2
010
Ger
man
yP
oult
ryN
AN
A43
0N
A12
.8N
A38
NA
NA
45.1
NA
NA
NA
NA
NA
NA
50A
tan
asso
va a
nd
R
ing,
199
9G
ren
ada
Bro
iler
ceca
l12
579
.264
15.6
9.4
050
0N
A12
.53.
1N
AN
AN
AN
AN
AN
AH
arih
aran
et a
l.,
2009
Iran
Pou
ltry
494
37.9
187
44.9
312.
171
054
49.7
1.1
NA
NA
NA
11.8
2.1
NA
Rah
imi a
nd
Am
eri,
2011
Ital
yM
eat
481
30.9
614
6N
AN
AN
A32
1.4
59.7
52.8
12.5
NA
NA
NA
52.8
5.6
93.1
Pez
zott
i et a
l., 2
003
Jap
anP
oult
ry11
86N
AN
A39
.91.
543
2.6
44.9
416
NA
38.5
NA
NA
8.2
100
On
o an
d
Yam
amot
o, 1
999
Kor
eaC
hic
ken
265
68.3
332
NA
43.1
2.6
996.
992
.292
.20
NA
NA
NA
NA
NA
NA
Han
et a
l., 2
007
Sou
th
Afr
ica
Pou
ltry
NA
NA
155
NA
43N
AN
AN
A64
NA
50N
AN
AN
AN
AN
AN
AB
este
r an
d E
ssac
k,
2008
Spai
nP
oult
ry10
154
.4N
AN
A40
2.4
654.
976
.974
.417
.1N
A19
.5N
AN
AN
AN
ASá
enz
et a
l., 2
000
Swit
zerl
and
Nec
k sk
in80
0N
A19
51
3.07
NA
0N
AN
A0.
5N
AN
AN
AN
AN
A17
.4N
AFr
edia
ni-
Wol
f an
d
Step
han
, 200
3
UK
Raw
red
m
eat
3959
7.2
211
85.8
583.
6343
0.28
16.9
13.7
11.1
NA
2.02
2.02
NA
NA
NA
Pid
doc
k et
al.,
200
8
Rep
ub
lic o
f Tu
rkiy
eB
roile
r ce
cal
240
52.5
126
NA
NA
NA
76N
A79
.474
.2N
AN
AN
AN
A15
.5N
AN
AY
ildir
im e
t al.,
200
5
AM
P, A
mp
icill
in; C
, Ch
lora
mp
hen
icol
; TE
T, T
etra
cycl
ine;
CN
, Cep
hal
oth
in; N
AD
, Nal
idix
ic A
cid
; CIP
, Cip
rofl
oxax
in; E
, Ery
thro
myc
in; A
MC
, Am
oxic
illin
Cla
vulo
nic
Aci
d; K
, Kan
amyc
in; N
, N
eom
ycin
; EN
R, E
nro
flox
acin
; ST
R, S
trep
tom
ycin
; ST
X, T
rim
eth
opri
m S
ulfa
xaxo
l; N
A, N
ot A
vaila
ble
.
Cri
tical
Rev
iew
s in
Mic
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64 A. Koluman and A. Dikici
Critical Reviews in Microbiology
contaminated with the infective organism. Farm families are particularly at risk of acquiring the infection by con-tact with infected animals or by drinking unpasteurized milk. Symptoms in humans are diarrhea, fever, headache, nausea, abdominal pain, vomiting, and, less frequently, blood in the stool. Salmonella Typhimurium DT104 strains are resistant to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline (ACSSuT) (Poppe et al., 1998; Cardoso et al., 2006).
For Salmonella, the resistance phenotypes develop primarily in response to selective pressures from anti-microbial use in food animals, such as fluoroquino-lones. Fluoroquinolones were subsequently banned from the use in poultry farms as of September 2005 and the effect of this ban on antimicrobial resistance in Salmonella remains to be determined (Lestari et al., 2009).
Selected studies in this subject are given in Table 3.
Antibiotic resistance of VTECThe use of antimicrobials in medicine (clinical and vet-erinary), coupled with their application in animal hus-bandry (often at a subtherapeutic levels), is regarded as a potential driving force for the selection of antimicrobial-resistant bacteria. The increased use of antimicrobial agents has resulted in phenotypic changes, often due to chromosomal mutation or the acquisition of extraneous DNA as part of mobile genetic element such as plasmids or other related structures (Fischbach and Walsh, 2009).
Although treatment of E. coli O157 infections with antibiotics is generally contra-indicated, numerous studies have been performed to evaluate antimicrobial resistance patterns (Karmali et al., 2010). Antimicrobial resistance is common in E. coli O157 and other VTEC serotypes, including multiple drug resistance to strepto-mycin, sulfisoxazole, and tetracycline (Kim et al., 1994; Mora et al., 2005), and there is some evidence that resis-tance may be increasing over time (Kim et al., 1994; White et al., 2002). Mora et al. (2005) have shown a higher rate of antimicrobial resistance in E. coli O157 bovine strains compared to human strains.
Selected studies from different countries show differ-ent distribution in resistance profiles of VTEC. The data are shown in Table 4.
Combating the resistance a global perspectiveThe emerging foodborne pathogens are main concern in public health. Global counter measures and studies guide countries and unions in enacting and designing new regulations. Antibiotics have been widely used in animal production for decades worldwide. These substances are added in low doses to feed of farm animals. They improve their growth performance. However, due to the emergence of microbes resistant to antibiotics which are used to treat human and animal infections. The Commission decided to phase out, and ultimately ban the marketing and use of antibiotics as growth promoters in feed. Antibiotics will now only Ta
ble
3.
Som
e se
lect
ed p
ub
licat
ion
s ab
out t
he
anti
bio
tic
resi
stan
ce o
f Sal
mon
ella
.
Cou
ntr
ySa
mp
le ty
pe
Nu
mb
er o
f sa
mp
le
Inci
den
ce o
f Sa
lmon
ella
(%
)
Nu
mb
er
of
stra
ins
Nu
mb
er o
f st
rain
s M
DR
An
tib
ioti
c re
sist
ance
of a
ll st
rain
s (%
)%
MR
AM
PC
TE
TC
NA
CA
NA
DC
IPE
AM
CK
CN
STX
STR
Ref
eren
ces
US
Gro
un
d m
eat
200
2045
2453
2716
804
160
0N
AN
A7
1618
73W
hit
e et
al.,
200
1C
hin
aM
eat,
seaf
ood
an
d
milk
pow
der
387
20.9
8124
29.6
1616
22.3
8.6
NA
39.5
11.1
NA
14N
A3.
749
.346
.9Ya
n e
t al.,
201
0
Iran
Fres
h c
hic
ken
an
d
bee
f mea
t37
933
124
8568
.54
1.6
690
NA
820
NA
3.2
NA
NA
6342
Dal
lal e
t al.,
201
0
Sou
th
Kor
eaC
hic
ken
farm
s13
1N
A91
1819
.78
16.5
5.5
28.6
4.4
NA
63.7
1.1
NA
18.7
NA
4.4
4.4
38.5
Ray
amaj
hi e
t al.,
20
10U
SC
hic
ken
car
cass
194
2212
6N
A52
.419
.83.
247
.66.
316
.70.
80
NA
NA
3.2
NA
2.4
51.6
Les
tari
et a
l., 2
009
Rep
ub
lic o
f Tu
rkiy
eC
hic
ken
car
cass
200
3468
6697
587
4610
NA
NA
NA
61N
AN
A36
NA
42Y
ildir
im e
t al.,
201
1
Uru
guay
NA
NA
NA
258
3814
.717
.80
725
.60
6.2
NA
12.8
0N
AN
A10
.913
.60
11.2
59.3
Mac
edo-
Viñ
as e
t al.,
20
09Se
neg
alM
eat
435
6327
511
NA
NA
0.8
0.4
00
0.4
0N
A0
NA
00
21.5
Stev
ens
et a
l., 2
006
Bra
zil
Bro
iler
carc
ass
NA
NA
80N
AN
AN
AN
A10
00
NA
NA
010
0N
A1.
25N
AN
AN
AC
ard
oso
et a
l., 2
006
AM
P, A
mp
icill
in; C
, Ch
lora
mp
hen
icol
; TE
T, T
etra
cycl
ine;
CN
, Cep
hal
oth
in; N
AD
, Nal
idix
ic A
cid
; CIP
, Cip
rofl
oxax
in; E
, Ery
thro
myc
in; A
MC
, Am
oxic
illin
Cla
vulo
nic
Aci
d; K
, Kan
amyc
in; N
, N
eom
ycin
; EN
R, E
nro
flox
acin
; ST
R, S
trep
tom
ycin
; ST
X, T
rim
eth
opri
m S
ulfa
xaxo
l; A
CA
, Am
pic
illin
Cla
vulo
nic
Aci
d; N
A, N
ot A
vaila
ble
.
Cri
tical
Rev
iew
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Mic
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Antimicrobial resistance of emerging foodborne pathogens 65
© 2013 Informa Healthcare USA, Inc.
Tab
le 4
. So
me
sele
cted
pu
blic
atio
ns
abou
t th
e an
tib
ioti
c re
sist
ance
of V
TE
C.
Cou
ntr
ySa
mp
le ty
pe
Nu
mb
er o
f sa
mp
le
Inci
den
ce
of V
TE
C
(%)
Nu
mb
er o
f st
rain
s
Nu
mb
er o
f st
rain
s M
DR
An
tib
ioti
c re
sist
ance
of a
ll st
rain
s (%
)%
MR
AM
PC
TE
TC
NN
AD
CIP
AM
XK
NC
NST
XSL
STR
Ref
eren
ces
Ger
man
y an
d
Bos
nia
Cat
tle
slau
ghte
r an
d b
eef
reta
il
NA
NA
29N
AN
A10
NA
NA
0N
AN
AN
AN
A3
03.
1010
0N
Avo
n M
üffl
ing
et
al.,
2007
Ger
man
yP
igN
AN
A23
NA
NA
13N
AN
A0
NA
NA
NA
NA
170
17.3
010
0N
Avo
n M
üffl
ing
et
al.,
2007
Spai
n (
O15
7)H
um
ans,
ca
ttle
, sh
eep
an
d fo
ods
NA
4114
1N
AN
A7
435
33
00
68
0.7
6N
A36
Mor
a et
al.,
20
05
Spai
n
(non
-O15
7)H
um
ans,
ca
ttle
, sh
eep
an
d fo
ods
NA
4158
1N
AN
A10
831
0.5
20
27
53
9N
A28
Mor
a et
al.,
20
05
Nig
eria
Mea
t25
028
70N
AN
AN
A72
.991
.411
.40
35.7
NA
NA
NA
NA
NA
NA
NA
NA
Olu
fem
i, 20
10A
lger
iaFr
ozen
b
ovin
e m
eat
2051
0.44
251
NA
NA
44.7
812
.35
71.4
37.8
3N
AN
AN
AN
AN
AN
A58
.3N
AN
AB
arka
an
d
Kih
al, 2
010
Rep
ub
lic o
f Tu
rkiy
eB
ovin
e an
d
shee
p30
6N
A48
NA
NA
12.5
NA
45.8
4.2
NA
04.
2N
AN
AN
A0
NA
8.3
Aks
oy e
t al.,
20
07Ir
elan
dC
attl
e fa
eces
an
d s
oil
128
NA
75
NA
7157
57N
A14
14N
A28
NA
NA
2871
100
Scot
t et a
l., 2
009
Ger
man
yFo
od: a
nim
al
and
hu
man
fa
eces
NA
NA
604
65
827
0N
AN
AN
AN
AN
A78
0N
AN
AK
lein
an
d B
ült
e,
2003
Gre
ece
(O15
7:H
7)Fo
od60
00.
53
00
00
0N
A0
NA
NA
0N
AN
A0
NA
0D
onto
rou
et a
l.,
2003
Gre
ece
(O15
7)B
ovin
e:
ovin
e an
d
cap
rin
e ra
w
milk
2005
1.45
2929
100
100
446
10N
AN
A75
NA
NA
NA
51N
A96
Solo
mak
os e
t al
., 20
09
Sou
th A
fric
a (O
157:
H7)
Mea
t18
02.
85
480
400
2080
20N
AN
AN
AN
AN
AN
AN
AN
AA
bon
g’o
and
M
omb
a, 2
009
Bel
giu
mA
nim
al a
nd
fo
odN
AN
A70
NA
NA
7.1
NA
5.7
NA
NA
NA
NA
2.9
NA
NA
4.3
15.7
17.1
Bu
ven
s et
al.,
20
10U
S (O
157:
H7)
Cat
tle:
gr
oun
d b
eef
and
hu
man
NA
NA
294
NA
140
930
00
NA
21N
A0
0N
A76
Zh
ao e
t al.,
20
01
US
(non
-O15
7)C
attl
e:
grou
nd
bee
f an
d h
um
an
NA
NA
214
NA
3329
430
00
NA
19N
A19
19N
A43
Zh
ao e
t al.,
20
01
AM
P, A
mp
icill
in; C
, Ch
lora
mp
hen
icol
; TE
T, T
etra
cycl
ine;
CN
, Cep
hal
oth
in; N
AD
, Nal
idix
ic A
cid
; CIP
, Cip
rofl
oxax
in; E
, Ery
thro
myc
in; A
MC
, Am
oxic
illin
Cla
vulo
nic
Aci
d; K
, Kan
amyc
in; N
, N
eom
ycin
; EN
R, E
nro
flox
acin
; ST
R, S
trep
tom
ycin
; ST
X, T
rim
eth
opri
m S
ulfa
xaxo
l; A
CA
, Am
pic
illin
Cla
vulo
nic
Aci
d; A
MX
, Am
oxic
illin
; SL
, Su
lph
onam
ide;
NA
, Not
Ava
ilab
le.
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tical
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iew
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66 A. Koluman and A. Dikici
Critical Reviews in Microbiology
be allowed to be added to animal feed for veterinary purposes. This decision was based on opinions from the Scientific Steering Committee, which recommended the progressive phasing out of antibiotics used for growth stimulation, while still preserving animal health.
Harmonization of national regulations with EU con-cerning additives in feeding stuffs aimed the establish-ment and functioning of the common market for animal feeds. Since national regulations of each member state differs, as regards to their basic principles, some changes in applications may occur. Council Directive 70/524 published in the Official Journal L 270 on 14 December 1970 determined the main principle of regulation: application of biotics in poultry feeds. Since the first harmonization with Directive 70/524 until publication of regulation 1831/2003 which deleted these additives per-mitted in feeds from the European Register. EU supports the specific recommendations of the WHO, Food and Agriculture Organization (FAO) and World Organization for Animal Health (WOAH) to ban antimicrobial used in animal feeds. This is expected to favor other countries also phase these substances out. The member states, within 2 year following notification, brought into force the laws regulations and administrative provisions necessary to comply with this Directive and from 25 November 1972 additives feeding stuffs containing additives and human foods from livestock feed additives were subject only to the marketing restrictions. This regulation also applied to other countries of the European Economic Area (Iceland, Norway), Recently, Directive 70/524 was replaced by Regulation 1831/2003 of the European Parliament and of the Council on additives for use in animal nutrition. Regulation 1831/2003 stated that antibiotics, other than coccidiostats and histomonostats, might be marketed and used as feed additives only until 31 December 2005. Anticoccidial substances, such as antibiotics ionophores, also will be prohibited as feed additives before 2013. After this date, medical substances in animal feeds will be limited to therapeutic use by veterinary prescription.
In the European Union, the legal use of antibiotic or chemotherapeutic (synthetically produced substances) feed additives requires an approval by a Community pro-cedure as laid down in the Council Directive 70/524/EEC and its amendments. Feed additives are included into Annex I of this Directive can be used in all Member States according to the provisions outlined. Additives included in Annex II may be the subject of national provisional authorizations. For inclusion into Annex, available data on efficacy and safety have to be evaluated by different independent and official scientific boards of the EU. Only those substances which have been proved being efficient in growth-enhancing and being safe for the consumers of food of animal origin, for the target animals the work-ers handling the feed additives and for the environment will be approved under Annex I. This Council Directive has been modified by the Council Directive 96/51/EEC amendment of the EU Council Directive 70/524/EEC. The approved additives are classified as follows: Annex
A (Part A including antibiotics, coccidiostats and other medicinal substances, growth promoters; and PaBrt including trace elements: copper and selenium and vitamins, pro-vitamins and well-defined substances with similar effects: vitamins A and D); Annex B (Chapter I, additives linked to a person responsible for putting them into circulation, inserted in Annex l before 1 January 1988; Chapter II, additives linked to a person responsible for putting them into circulation, inserted in Annex I after 31 December 1987; Chapter III, additives linked to a person responsible for marketing, inserted in Annex II before 1 April 1998); Annex C (Part I, additives subject to authorization linked to the person responsible for putting them into circulation, antibiotics, coccidiostats, and other medicinal substances and growth promoters; Part II, other additives: antioxidant substances, flavoring, and appetizing substances, emulsifying and stabilizing agents, thickeners and gelling agents, colorants, includ-ing pigments, preservatives, vitamins, pro-vitamins, and chemically well-defined substances having similar effect, trace elements, binders, anticaking agents, and coagu-lants, acidity regulators, enzymes, and micro-organisms).
The EU has already banned antibiotics used in human medicine from being added to animal feed. The new Feed Additives Regulation 1 completed measure with the total ban on antibiotics as growth promoters from 1 January 2006 on that date, the following 4 substances will be removed from the EU Register of permitted feed additives:
– Monensin sodium used for cattle for fattening.– Salinomycin sodium used for piglets and pigs fatten-
ing.– Avilamycin used for piglets, pigs for fattening, chick-
ens for fattening and turkeys.– Flavophospholipol used for rabbits laying hens, chick-
ens for fattening, turkeys, piglets, pigs, calves, and cattle for fattening.
This measure is in line with the Commission’s overall Strategy to combat the threat to human, animal and plant health posed by antimicrobial resistance.
The risk concerning residues of antibiotics in edible tissues and products that can produce allergic or toxic reactions in consumers is known to be negligible (Donoghue, 2003) because only antibiotics that are not absorbed in the digestive tract are authorized as growth promoters. However, the wider use of antibiotics as feed additives in the long run can contribute to the development of resistant bacteria to drugs used to treat infections. These bugs with resistant genes pose a potential risk for humans if they are transferred to persons. For this reason, the WHO (1997) and the Economic and Social Committee of the European Union (1998) concluded that the use of antimicrobials in food animals is a public health issue. As soon as the 1970s, antibiotics from classes which were or might be used in human or veterinary medicine were transferred from Annex I to Annex II to stop usage after a certain period. It was the case of tetracycline (Directive 73/264), penicillin
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Antimicrobial resistance of emerging foodborne pathogens 67
© 2013 Informa Healthcare USA, Inc.
(Directive 73/275), and oleandomycin (Directive 78/743), which were placed in Annex II to be used only at a national scale in feeds for poultry. This national authorization was limited until 30 June 1976 (tetracyclines and penicillins) or 30 September 1979 (oleandomycin).
A member state which, as a result of new information or of a reassessment of existing information made since the provisions in question were adopted, had detailed grounds for establishing that the use of one of the addi-tives authorized at the Community scale constituted a danger to animal or human health or the environment could temporarily suspend the authorization to use that additive in its territory, and it should forthwith inform the Commission; member states should not. However, be able to have recourse to that power to hinder the free movement of the products. According the information provided by the state, a decision on the additive was taken. Sweden prohibited in 1986 the use in feeding stuffs of additives belonging to the groups of antibiotics. When Sweden accessed in 1995 as a member of the European Union, it was authorized to maintain in force until 31 December 1998, its legisla-tion before accession, before that date, Sweden submit-ted applications, accompanied by detailed scientific grounds, for adjustments for the antibiotics authorized in the Community. Also, other member states prohib-ited on their territories the use of some antibiotics in animal feedstuffs. Avoparcin was banned in Denmark (20 May 1995) and Germany (19 January 1996) arguing that this glycopeptide antibiotic produces resistance to glycopeptides used in human medicine, spiramycin was prohibited in Finland (1 January 1998) because this product was used in human medicine, and virgin-iamycin was prohibited in Denmark (15 January 1998) because 2 streptogramins were clinically important in human medicine. As results of these national initiatives, Directive 97/6 withdrew approval for Avoparcin from 1 April 1997, and Regulation 2821/1998 banned spiramy-cin and virginiamycin from 30 June 1999. Regulation 2821/1998 also banned bacitracin zinc because its use in human medicine as treatment of infections of the skin. On 1 January 1999, Sweden applied the safeguard clause for the antibiotics still authorized as feed additives, including those still permitted in poultry feeds: flavophospholipol and avilamycin. The scientific ground submitted by Sweden, as well as the conclusions of the WHO (1997) and of the Economic and Social Committee of the European Union (1998), led to no longer to authorize the use of antibiotics as growth promoters: Regulation 1831/2003 stated that antibiotics, other than coccidiostats and histomonos-tats, might be marketed and used as feed additives only until 31 December 2005; as from 1 January 2006, those substances would be deleted from the Community Register of authorized feed additives. Finally, the ban of antibiotics in animal feeds will have consequences in the international trade of poultry meat because the European Union only imports foods obtained from
animals that were not fed with antibiotics, in applica-tion of the precaution principle allowed by the World Trade Organization. However, because concern is ris-ing that drug-resistant pathogens could be transmitted to humans via the food chain (WHO, 2003, 2004), it is expected that the use of antimicrobials in animal pro-duction will decrease in further years, at least in those farms with better hygiene conditions.
conclusion
The safety of food sources from farm to fork became main subject for a safer food. The contaminations of foodborne pathogens on public health have been more significant as the demand increases. On the other hand the increase in demand triggers an increase in sup-ply but the supplies are limited. The producers have been taking additional measures in farm level, which includes antibiotic application as growth promoter. The growth promoter administration of antibiotics has been leading resistance in microflora of animals and this microflora contains pathogens. These pathogens can contaminate the food during process. The contami-nation with resistant bacteria leads major problems in treatment of gastroenteritis. As this became clearer, many countries published regulations and use of antibiotics as growth promoters banned. The ban lead lesser antibiotic residue in food but the resistance in bacteria remains.
Antibiotic administration is still widespread in many under developed and developing countries some of which are accepted as global food source. Additionally, it became more significant that the globalization of food consumption habits arise of some foodborne patho-gens in developed countries that infection has not been reported before. This phenomenon can be explained by increase in both exportation of artisanal products and touristic activities. This leads spread of different strains to different countries. The food safety aspect must be taken into account in every country.
European Union banned antibiotic administration for promoting the growth in farm animals. In many devel-oped country, antibiotic application is a question of concern. There is an awareness rising about the antibi-otic-resistant bacteria and their effects on public health.
The scientists turn their face to the organic compounds for combating food pathogens that are known to trigger no resistance in bacteria. Global counter measures for combating the antibiotic-resistant bacteria must be taken and new regulations must be designed in countries for this purpose.
The science and regulation must support each other for a safer and reliable food. Global measures must be taken for administration of antibiotics at farm level.
Declaration of interest
The authors declare no conflicts of interest.
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