A review on antibiotic residue in foodstuffs from animal source: global health risk and alternatives

Abstract

The overuse and misuse of antibiotics to treat diseases and promote the growth of animals lead to the deposition of antibiotics in animal tissues, and subsequently, antibiotics come into the human body through the food chain. In this paper, comparative studies on antibiotic residue (AR) in foodstuffs from animal source and human health risks are reviewed in detail. The early part of this review is focused on the use of different veterinary antibiotics in animal farms and the marine environment as a reservoir of ARs. Later on, ARs in foodstuffs, including meat, milk, and marine foods have been comprehensively discussed. Review studies on human health issues associated with antibiotics show that people from poor and developing countries are the most vulnerable to infectious diseases caused by antibiotic-resistant bacteria. At the end of the review, some alternative approaches that include the use of phytogenic feed additive, organic acid, probiotic, prebiotic, and other substances are summarized, considering their potential exposure to replace antibiotics as growth promoters and mitigate the prevalence of antibiotic-resistant genes.

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A review on antibiotic residue in foodstuffs from
animal source: global health risk and alternatives
Ahmed Redwan Haque, Manobendro Sarker, Rana Das, Md. Abul Kalam
Azad & Md. Mehedi Hasan
To cite this article: Ahmed Redwan Haque, Manobendro Sarker, Rana Das, Md. Abul Kalam Azad
& Md. Mehedi Hasan (2021): A review on antibiotic residue in foodstuffs from animal source: global
health risk and alternatives, International Journal of Environmental Analytical Chemistry, DOI:
10.1080/03067319.2021.1912334
To link to this article: https://doi.org/10.1080/03067319.2021.1912334
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A review on antibiotic residue in foodstus from animal
source: global health risk and alternatives
Ahmed Redwan Haque
a
*, Manobendro Sarker
b
*, Rana Das
b
, Md. Abul Kalam Azad
c
and Md. Mehedi Hasan
a
a
Department of Food Processing and Preservation, Hajee Mohammad Danesh Science and Technology
University, Dinajpur, Bangladesh;
b
Department of Food Engineering and Technology, State University of
Bangladesh, Dhaka, Bangladesh;
c
Hunan Province Key Laboratory of Animal Nutritional Physiology and
Metabolic Process, CAS Key Laboratory of Agro-ecological Processes in Subtropical Region, National
Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production,
Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, Hunan, China
ABSTRACT
The overuse and misuse of antibiotics to treat diseases and pro-
mote the growth of animals lead to the deposition of antibiotics in
animal tissues, and subsequently, antibiotics come into the human
body through the food chain. In this paper, comparative studies on
antibiotic residue (AR) in foodstus from animal source and human
health risks are reviewed in detail. The early part of this review is
focused on the use of dierent veterinary antibiotics in animal
farms and the marine environment as a reservoir of ARs. Later on,
ARs in foodstus, including meat, milk, and marine foods have been
comprehensively discussed. Review studies on human health issues
associated with antibiotics show that people from poor and devel-
oping countries are the most vulnerable to infectious diseases
caused by antibiotic-resistant bacteria. At the end of the review,
some alternative approaches that include the use of phytogenic
feed additive, organic acid, probiotic, prebiotic, and other sub-
stances are summarized, considering their potential exposure to
replace antibiotics as growth promoters and mitigate the preva-
lence of antibiotic-resistant genes.
ARTICLE HISTORY
Received 23 January 2021
Accepted 26 March 2021
KEYWORDS
Antibiotic residue; foodstuff;
resistant bacteria; resistance
gene; toxicity
1. Introduction
Antibiotic is the most used veterinary drug for treating infectious diseases and growth
promoters in livestock farms [1]. The overuse and misuse of veterinary antibiotics lead to
the presence of residue in animal organs, body tissues, and milk [2]. It was found that
animals cannot absorb all antibiotics and approximately, 30–90% of veterinary antibiotics
can be transferred to the marine environment through urine, faces, and wastewater
euent [3,4]. Presently, veterinary AR is one of the dangerous pollutants in marine
ecosystems including marine animals. Among various antibiotics used in the livestock
farms, tetracycline, quinolones, streptomycin, and lincomycin are very common in milk,
CONTACT Manobendro Sarker manob08@gmail.com; Rana Das ranasust8@gmail.com
*These authors contributed equally to this work.
Supplemental data for this article can be accessed here.
INTERNATIONAL JOURNAL OF ENVIRONMENTAL ANALYTICAL CHEMISTRY
https://doi.org/10.1080/03067319.2021.1912334
© 2021 Informa UK Limited, trading as Taylor & Francis Group

tissue, and marine animals [5–7]. ARs are relatively stable in the environment, and even
high heat treatment cannot destroy antibiotics completely. Eventually, these ARs can
come into contact with the human intestine through the food chain. Therefore, AR in
food-producing animals is a growing public health concern across the world.
AR in foods is one of the prime reasons for allergic problems, carcinogenic risk, toxicity,
and the development of antibiotic-resistant bacteria [8,9]. On the other hand, multidrug-
resistant bacteria are health risk issues that can spread from various environmental
settings, like livestock farm waste, sewage treatment euent, and aquatic environment
to the human body [10,11]. In addition, the antibiotic-resistant MCR-1 gene of E. coli found
in pork, while MCR-2 and MCR-3 are the most widespread colistin-resistance genes in the
environment [12]. Antibiotic-resistant infections cause almost 50,000 annual deaths in
Europe and the US alone [13]. It is a matter of concern that 23,137 gene records covering
380 species are resistant to 249 antibiotics while the sulphonamide resistance gene is
a more stabletotetracycline [14].
Considering the emerging health risk issues with AR in food-producing animals, research-
ers are devoted to nding alternatives for antibiotics to use in livestock farms. Recently, plants
and their extract having bioactive compounds, organic acids, probiotics, prebiotics, and other
natural materials have been studied to replace antibiotics in livestock farms [15–19]. Most of
the researchers have revealed the potentials of natural substances regarding antimicrobial
activity, immunity, blood prole, gut health, digestive enzyme activity, and growth rate.
Therefore, the purpose of this review article is to present the current situation of AR in
dierent food-producing animals and the residual eects on human health. Furthermore,
this review encompasses alternative options to the use of antibiotics in livestock farms.
2. Veterinary antibiotics used in animal farms
Antibiotics are eective to treat infectious diseases caused by bacteria, but not eective
against fungal and viral pathogens. The use of antibiotics as growth promoters in live-
stock farms started from the feeding of pharmaceutical wastes containing aureomycin in
the 1940s that results in a signicant weight gain of poultry. Following the incident,
subtherapeutic antibiotic treatment (STAT) was applied to chicken and swine from 1946
to 1950, and dramatically it enhances the weight gain (15–20%) of livestock. In 1951, Food
and Drug Administration (FDA) approved antibiotic use in livestock farms considering the
antibiotic eects on the weight gain of animals [20]. The mechanisms of antibiotic growth
promoters have been proposed in dierent ways as follows [21]: (1) reducing the inci-
dence and severity of infections caused by bacteria; (2) retarding the uptake of nutrients
by microorganisms; (3) reducing the secretion of growth-depressing metabolites by
gram-positive bacteria; and (4) enhancing the nutrient absorption by thinning the intest-
inal wall. At present, the overuse and misuse of antibiotics in livestock farming are not
xed and lies between 100,000 and 200,000 tons across the world. Antibiotics used in
food-producing animals can be classied into six major groups [22] (see Figure 1).
It is found that the sulphonamides group is the most used antibiotics in livestock farms
followed by uoroquinolones, aminoglycosides ≈ phenicols ≈ β-lactams, and tetracyclines
≈ oxazolidinones. Generally, antibiotics are administrated to livestock via feed, drinking
water, and injection to treat diseases and promote growth [23,24]. Salinomycin, tetracy-
cline, bacitracin, tylosin, virginiamycin, and bambermycin are very common antibiotics
2A. REDWAN HAQUE ET AL.

used in poultry farming in North America [25]. In the USA, two-thirds of antibiotics
administrated to food-producing animals are tetracyclines [26], whereas the amount in
the European Union (EU) is about 37%[27]. In 2014, approximately 1.22 million kg of
antibiotics were used in only poultry farms in Canada that represented 5% more than the
previous year. In Canada, bambermycin, bacitracin, salinomycin, β-lactam, streptogra-
mins, and tetracycline are very common antibiotics used in poultry farms for the preven-
tion of diseases and growth promotion [26,28].
It is important to note that countries enlisted in the European Surveillance of Veterinary
Antimicrobial Consumption (ESVAC) are not allowed to use antibiotics as animal growth
promoters [29]. Conversely, there are no strict rules like ESVAC for using antibiotics in animal
farms in Asian countries. As a result, the use of antibiotics in food-producing animal farms is
a matter of concern in developing countries in Asia. A survey of antibiotic use in dierent
poultry farms in Thailand revealed that the antibiotic regimen was used to raise 14,000
chickens of 3 kg in 41 days, which included amoxycillin, colistin, doxycycline, oxytetracycline
and tilmicosin [30]. A total of 4245 g of all antibiotics (303 mg/chicken) were used in the rst
1–4 post-receipt days followed by 9–12 days, 15–18 days, 21–24 days, and 28–31 days,
respectively. The authors concluded that roughly 161 tons of antibiotics prophylaxis were
administered in 1.4 billion chickens in 2016 [30]. Excessive use of antibiotics, especially the
same antibiotics used for human treatments, are being used in livestock farms because of
weak regulations on veterinary drugs in India [31]. The use of antibiotics for livestock in
China started in 1989 and the amount is increasing every year, where amoxycillin, orfeni-
col, lincomycin, penicillin, and enrooxacin are being used extensivly [32].
Despite having several rules for using antibiotics, the overuse and misuse in livestock
farms are prevalent in most of the countries around the world [33], and the average dose of
antibiotics is much greater in developing countries than any other developed countries [34].
However, China, the USA, Brazil, India, and Germany are the top ve countries using excess
veterinary drugs in livestock farms, and it is predicted that the share of global veterinary
antibiotics only in China will increase to 30% by 2030, which was only 23% back in 2010 [35].
Low cost and poor regulatory control are underlying reasons behind the abuse of veterinary
drugs on livestock [36].
Sulf onam ides
20%
Fluoroqui nolo nes
19%
Ami nogl ycosides
15%
Phenicols
15%
β-la ctams
15%
Tetracyclines
8%
Oxazolidino nes
8%
Figure 1. Classification of antibiotics used in food-producing animals (adapted) [22].
INTERNATIONAL JOURNAL OF ENVIRONMENTAL ANALYTICAL CHEMISTRY 3

3. Guidelines for judicious use of veterinary antibiotics
Organizations ascribe dierent guidelines for using veterinary antibiotics and all of them
are concerned to prevent antibiotic resistance. The major guidelines for using veterinary
antibiotics can be listed as follows: (1) the use of antibiotics could be suggested after
preliminary diagnosis of an ill animal; (2) antibiotics could be prescribed only to treat
diseases with bacterial aetiology; (3) antibiotics to treat the animals should be under the
supervision of a veterinarian; and (4) health status of an infected animal should be given
priority before using antibiotics [37]. The EU has established a maximum residue limit
(MRL) for permitted antibiotics in food-producing animals [38]. The veterinary antibiotics
and their maximum residue levels in dierent food specimens allowed by the EU are
presented in Table S1. Besides, the FAO/WHO has provided a guideline on MRLs for
veterinary antibiotics in food-producing animals (see Table S2) which is also supported
by the European Union, the United States and 70 other nationals [39]. However, Canada
has its own regulation on MRLs for veterinary drugs in foods from animal source [40],
which is stricter compared to the established limits by FAO/WHO. It is found that MRL of
an antibiotic largely depends on animal species and the target tissue. In additionn to MRL,
several other cosiderations for the consumption of foods from animal source is taken into
account to ensure food safety and minimize the health risk of humans. For instance, MRLs
of ampicillin in muscle, fat, liver, kidney and milk from all possible sources are 50, 50, 50,
50 and 4 μg/kg, respectively, while the egg containing ampicillinis is completely prohib-
ited for human consumption. Similarly, milk is prohibited for human consumption when
apramycin residue is found in muscle, fat, liver and kidney of bovine (see Table S1). It is
prominent that authorities of developed countries have proper guidelines for antibiotic
use and MRL in food samples. In case of developing and poor countries, guidelines for
judicious use of antibiotics are not clearly demonstrated to farmers, which could be
a major reason behind AR in foods from animal source [41].
4. Antibiotic residue in marine environment
The presence of AR in the marine environment is an increasing concern worldwide
[41]. In addition to the use of antibiotics in shery farms, there are several indirect
pathways of exposing veterinary antibiotics as well as human antibiotics to the
marine environment. Pathways of antibiotics discharging to the marine environment
are presented in Figure 2 [27].
Human antibiotics can come into contact with the aquatic environment via urine and
feces after consumption. Besides, dierent kinds of antibiotics can be transferred from the
production sources to the water bodies through direct disposal of euents from the
sewage treatment plant, landll leachate, leaking of sewers and manure storage tank,
runo, and leaching from elds fertilized with polluted manures [42,43]. Therefore, ARs
are likely to be found in surface water, groundwater, and even drinking water [44–48]. The
highest amount of AR can be found in the water bodies mixed with hospital euents,
sewage treatment euent, and manures polluted with antibiotics [49]. A high fraction of
ARs has been detected in sites adjacent to pig farms because of euents polluted with
veterinary drugs [50]. Many researchers observed several antibiotics in animal manure in
which oxytetracycline with the highest concentrations of 416.8 mg/kg in the chicken
4A. REDWAN HAQUE ET AL.

manure [51] and chlortetracycline with the highest concentrations of 764.4 mg/kg in
swine manure [52] were found in China. Another study revealed the presence of chlor-
amphenicol, sulphonamide, and tetracycline in the animal manure of 3.27–17.85 mg/kg,
5.85–33.37 mg/kg and 4.54–24.66 mg/kg, respectively.
However, quinolones, sulphonamides and trimethoprim are the most common anti-
biotics in water bodies. A wide range of antibiotics can be detected in the surface water
and sediments of rivers in China, where sulfamethoxazole, oxytetracycline, ciprooxacin,
noroxacin, ooxacin, clarithromycin, and erythromycin are the most common antibiotics.
Dierent types of environmental samples in Shandong province in China have been
found polluted with ARs. The maximum amount of antibiotics in river water, wastewater,
drinking water, river sediment, pig manure, outlet sediment was 3.90 μg/kg, 12.50 μg/kg,
21.40 μg/kg, 1.21 μg/kg, 1.91 μg/kg, and 11.68 μg/kg, respectively [53]. In north China,
maximum concentrations for sulphonamides (22 ng/g), macrolides (67 ng/g), uoroqui-
nolones (5770 ng/g), and tetracyclines (653 ng/g) have been detected in the sediments of
the Yellow River, Hai River and Liao River [54]. Extremely high concentrations of sulfa-
chloropyridazine (37,000 ng/L), sulfamethoxazole (3900 ng/L), tetracycline, and macro-
lides (1500 ng/L) were found in the Haihe River in China [55]. The study insinuates that the
untreated discharge of unused medicines and wastes with veterinary antibiotics in live-
stock farms are plausible explanations for drug residue in waterbody in suburban and
urban areas. A total of 14 ARs were found in the catchment sediments of Ningbo city in
east China where tetracyclines and uoroquinolones are dominant groups [56]. Sabri [57]
revealed the presence of antibiotics (macrolides, sulphonamides, and tetracyclines) in
both water and sediment samples of a river receiving euents within 20 km downstream
from the euent discharge point. It was also observed that ARs are absorbed on
suspended particles due to hydrophobicity, which leads to underwater sedimentation.
Finally, antibiotics and their byproducts can be absorbed by food-producing aquatic
animals and/or reach the drinking water of humans and other animals.
Figure 2. Possible exposure pathways of antibiotics to the marine environment (adapted) [27].
INTERNATIONAL JOURNAL OF ENVIRONMENTAL ANALYTICAL CHEMISTRY 5

5. Antibiotic residue in foodstus from animal source
Whenever an animal is treated with antibiotic without proper guidelines, ARs can remain
in the animal tissues. Table S3 shows the occurrence of ARs in dierent food stus from
animal source [58–65]. It has found that the amount of AR varies in dierent parts of the
animal body. The highest amount of AR was found in the kidney of chicken, pork and cow
compared to other body parts. Although the deposition of antibiotic residue in dierent
organs of food producing animals varies with the type of the antibiotic, Tables S1 and S2
containing MRLs for antibiotics in edible portions of animals also insinuate that on an
average kidney and liver of food producing animal source contain a higher percentage of
antibiotic residues compared to muscle, skin, and fat. Among organs of sh, the liver
contains the highest amount of AR. Incase of milk, raw milk contains a higher amount of
AR than pasteurized milk because thermal heat decreases the concentration of AR [66].
5.1. Antibiotic residue in meat
The distribution of antibiotics in livestock and poultry meats largely depends on their
application to treat diseases in animal husbandry. Methenamine is an antibiotic used to
treat the urinary tract infection or prevent the bladder infection which is banned in several
countries, like the USA, Russia, Australia, and New Zealand. The mechanism of this
antibiotic is the generation of formaldehyde under acidic condition and formaldehyde
possesses antimicrobial activity. Nowadays, methenamine residue in meat is an arising
concern because of its potentially harmful eects on human health. Edible tissues of
swine, namely muscle, kidney, and liver collected from a local market in China were
studied for methenamine content by high-performance liquid chromatography coupled
with tandem mass spectrometry (HPLC-MS/MS) [67]. Methenamine was not prevalent in
muscle and liver, whereas two kidney samples were found with methenamine of
18.20 μg/kg and 41.70 μg/kg. This study also validated the application of HPLC-MS/MS
to determine the methenamine in edible tissues. Furthermore, the AR has been detected
in 35.30% for pork and 22.20% for chicken among 35 fresh samples in Shanghai. The
majority of the detected antibiotics in meat were tetracyclines and uoroquinolones,
while the residue content of noroxacin was 27 ng/g in pork and 49.60 ng/g in chicken
followed by oxytetracycline (16.90 ng/g) in chicken [7].
Three analytical methods (ELISA, TLC, and HPLC) were studied for the detection of four
ARs in the 150 fresh meat samples of chicken, beef, and pork in South Africa [59]. All
methods showed the dierent fractions of ARs in samples. The concentration of sulpha-
nilamide, tetracycline, streptomycin, and ciprooxacin ranged from 19.80–92.80 µg/kg,
26.6–489.10 µg/kg, 14.20–1280.80 µg/kg and 42.60–355.60 µg/kg were revealed with
ELISA, whereas concentration ranged from2 0.7–82.1 µg/kg, 41.8–320.8 µg/kg, 65.2–-
952.2 µg/kg, and 32.8–95.6 µg/kg were detected by HPLC method, respectively.
However, mean value of ciprooxacin and streptomycin residue levels exceeded the
Codex/SA MRL recommended limit, where the MRLs are 100 µg/kg for both ciprooxacin
[68] and streptomycin [69]. The Premi test was applied for residual antibiotic study in pork
in Madagascar [70]. Incidence rates of AR were 34.42% in urban abattoirs and 42.20% in
provincial abattoirs among 360 samples. Authors reported that animals under treatment
or sick are the underlying reason for drug residue in the meat. Similarly, Shahbazi et al.
6A. REDWAN HAQUE ET AL.

[71] observed that 25% of poultry carcasses were polluted with tetracycline residue
among 120 samples, including liver, thigh and breast. The mean values of tetracycline
residue in the samples ranged from 45–247.32 µg/kg to 31.40–889 µg/kg with ELISA and
HPLC, respectively. Recently, Timofeeva et al. [72] developed a cheap approach based on
deep eutectic solvent (DES) pretreatment to extract uoroquinolones in meat samples.
Results showed a highly eective approach for ooxacin and eroxacin separation with
extraction recovery of 98–100% for meat samples from chicken and beef.
A dose of minocycline (7 mg/kg) was administrated orally into the stomach of chicken
to estimate the withdrawal time of antibiotics in poultry tissue [73]. Widespread distribu-
tion of minocycline in dierent tissue samples was observed and the detected amount
was 49.20–135.20 μg/kg in all types of tissue samples till the 3
rd
day following the oral
administration of the drug. Furthermore, 11.80 μg/kg of minocycline was detected in
kidneys till the 7
th
day after the drug administration. Beyene [74] studied the risk factors of
veterinary drug residue and noted that the residual eect of antibiotics in meat would be
negligible for a longer withdrawal time before animals are sacriced for sale. Therefore, it
is important to note that the proper withdrawal period needs to get attention before the
marketing of animals for safe human consumption.
5.2. Antibiotic residue in milk
Veterinary drugs, mainly antibiotics are used in dairy farms to prevent and treat various
diseases. Tetracycline, quinolone, lincomycin, streptomycin, and chloramphenicol are
common antibiotics to be used for its therapeutic and antibiotic properties against
diseases, especially mastitis, respiratory and digestive infections [75]. Farmers are also
suspected of using the antibiotics in milk directly to increase the shelf-life by hindering
the growth and development of microorganisms. The presence of AR in the milk of
dierent animals due to the overuse and misuse of antibiotics has been discussed below:
In China, pasteurized and ultra-high temperature milk are most consumed dairy
products as per capita consumption of milk which increased from 4.89 kg in 1997 to
36.20 kg in 2016 [76], but it is a matter of concern that 15 screened antibiotics including
human antibiotics with dierent fractions have been found in dairy products in China. The
detection frequency of human antibiotics only, chloramphenicol and cefradine,were
found 10.60% of abovementioned antibiotics. An early study revealed the presence of
uoroquinolones (47.20%) and sulphonamides (20.10%) in milk collected from 10 pro-
vinces in China [77]. Another study revealed that the detection rate of streptomycin was
relatively higher (15.50%) than that of tetracycline (4.70%), quinolone (3.30%), and
lincomycin (2.70%) in UHT milk available in China. The maximum levels of streptomycin,
tetracycline, quinolone, and lincomycin have been found at 8.92 µg/kg, 9.06 µg/kg,
4.06 µg/kg and 7.66 µg/kg, respectively, which are within the safety limits of AR in milk
[6]. Some other studies [65,78] revealed the presence of antibiotics, like tetracycline,
sulphonamide and quinolone with a maximum residue value of 47.70 µg/kg, 20.24 µg/
kg, and 20.49 µg/kg, respectively.
It can be noted that the heating process cannot destroy the drug residues completely
in milk and thus, AR remains in processed milk and dairy products [79,80]. Among 100
pasteurized milk samples, three samples were found with AR at dierent fractions, like
oxytetracycline (121.80 µg/kg), tetracycline (93.50 µg/kg), chlortetracycline (61.60 µg/kg)
INTERNATIONAL JOURNAL OF ENVIRONMENTAL ANALYTICAL CHEMISTRY 7

and doxycycline (73 µg/kg) in Brazil [81]. The presence of tetracycline in Brazilian milk is
only 3%, where 2% of milk samples containing residue of tetracycline exceeds the MRL
(100 µg/kg) [82]. In a study, Abbasi [83] evaluated the tetracycline content in a total of 90
pasteurized, 10 sterilized, and 14 raw milk samples in Iran. The mean of the total tetra-
cycline residues for all samples was 97.60 ng/g, whereas pasteurized and sterilized milk
contained a relatively low amount of tetracycline of 87.10 ng/g and 112 ng/g, respectively,
than found in raw milk (154 ng/g). The comparative analysis of AR in milk samples of
dierent countries showed that the detection rate of tetracycline in milk was higher in
Croatia (76%) than Brazil (14%) and China (2.80%) [6,63,78,84]. The highest residue was
found in China (47.70 µg/kg), followed by Brazil (11.40 µg/kg) and Croatia (4.26 µg/kg).
The detected rate of quinolone was similar in Mexico and China, but the total residue level
(5047.30 µg/kg) observed in milk samples from Mexico was 200 times higher than that
detected in China (4.06 µg/kg). Therefore, it can be noted that the occurrence of ARs in
milk and dairy products is worldwide which is a growing concern to all because of
possible antibiotic resistance to humans.
5.3. Antibiotic residue in marine food
Antibiotics can enter the marine environment as well as food chain from its application
source via the aquaculture farm, contaminated manures used as feed for aquatic animals,
and sewage treatment plant connected to the water bodies and indirectly threaten
human health. On the other hand, sh farming has become competitive, and farmers
are using antibiotics as growth regulators to maintain maximum sh density within
a single tank [85]. AR in marine animals is a growing concern, particularly when banned
antibiotics are identied [86–88]. It has been found that 91.70% of snakeheads are
polluted with veterinary and human antibiotics collected in Shanghai, followed by loa-
ches (81.80%), carps (76.90%), yellow-head catshes (40%), and shrimps (16.70%) [7]. It is
a matter of concern that 50% of snakeheads and 5.10% of loaches contain a human
antibiotic named azithromycin. Furthermore, the residue levels of enrooxacin and
trimethoprim in one sample exceeded the maximum limit of 1 μg/kg/day [7]. In Taiwan,
bivalves including hard and freshwater clams are most cultured shellsh, which are
contaminated with antibiotics. Among 42 samples of hard clams, freshwater clams, and
oysters, 19.10% of samples were found with banned antibiotics and pesticides, while the
maximum concentration of chloramphenicol in hard clam was 3.80 ng/g [89]. In a study,
50 sh and 50 shrimp samples collected from the local market in Vietnam were analyzed
for AR in which 25% of samples were contaminated with AR [90]. Two antibiotics,
uoroquinolone and tetracycline were found in most of the contaminated samples that
indicated the lack of adequate withdrawal times before harvesting aquatic animals.
According to the survey analysis, a considerable number of aquaculture farms (23.40%)
used antibiotics up to harvesting time to maintain a healthy appearance of the sh and
shrimps. The authors also stated that the lack of knowledge about the proper use of
antibiotics in aquaculture is the underlying reason for drug residue in the aquatic animal
that should be emphasized on a priority basis.
8A. REDWAN HAQUE ET AL.

6. Emerging public health issues associated with antibiotic residue
Based on earlier sections in this review, ARs are likely to be found in foodstus from
domestic animals to sea animals and subsequently, antibiotic residue, antibiotic-resistant
bacteria and resistance gene can be transfered into human body through food chain (See
Figure 3). Besides, AR in dierent animal foods is an ultimate threat to human health,
although thermal processing leads to the degradation of antibiotics to byproducts lead-
ing to a decrease in the concentration [66].
6.1. Antibiotic-resistant bacteria and reistance gene
According to the World Health Organization (WHO), the resistance of bacteria to anti-
biotics in food-producing animals is one of the vital public health issues of the 21
st
century [91]. Antibiotic-resistant bacteria, like Salmonella spp., Campylobacter spp.,
Staphylococcus spp. and enterotoxigenic E. coli are common in animals that can be
transmitted to people causing gastrointestinal diseases [92,93]. Approximately, 78%
broiler and laying hens have been found with tetracycline resistance in Ecuador [94].
Similarly, Salmonella enterica isolated from egg and chicken carcasses exerted resistance
against several antibiotics, like penicillin, streptomycin, tetracycline, quinolone, and sul-
phisoxazole [95].
Methicillin-resistant Staphylococciconfers resistance to the β-lactam antibiotics due to
the mecA gene with the production of an altered penicillin-binding protein (PBP) and
causes both hospital- and community-acquired infections in human [96]. Enterococcus
faecium and Enterococcus faecalis are common species of Enterococci for a wide range of
infections including sepsis. Six types of vancomycin resistance genes are found in
Enterococci in which vanA and vanB are widespread. On the other hand, E. coli,
Klebsiella spp., Enterobacter spp., and Salmonella spp. under Enterobacteriaceae are com-
mensals of the gastrointestinal tract of humans, whereas E. coli is found resistant to 11
antibiotics [97]. Increasing antibiotic resistance of Enterobacteriaceaespecies is a public
health concern. Consumption of antibiotic administered livestock can be the underlying
reason for antibiotic resistance genes in the human body. In India, approximately 95% of
Figure 3. Human health concerns of ARs in foodstuffs from animal source.
INTERNATIONAL JOURNAL OF ENVIRONMENTAL ANALYTICAL CHEMISTRY 9

adults carry β-lactam antibiotic-resistant bacteria in the intestine that can be considered
as ‘last resort’ antibiotics. Interestingly, antibiotic resistance is relatively lower in organic
livestock farms [98]. Therefore, legislation for antibiotic use to the food-producing animals
should be strict, and scientic study for the risk assessment of antibiotics residue in foods
for human health should be undertaken on an urgent basis.
6.2. Toxic eects of antibiotic residues
The long term eects of antibiotics on human health are not fully understood yet
probably due to the technical challenges of analyzing the unknown metabolites in the
highly heterogeneous gastrointestinal system. Nonetheless, a few researchers have tried
to nd the possible outcome of long term exposure to antibiotics and chronic toxicity,
such as gut-microbiota disruption, carcinogenicity, mutagenicity, inammation, hepato-
toxicity, reproductive disorderand bone marrow toxicity [99,100]. The accumulation of
antibiotics in the human body causes chronic toxicity. Quinolones and tetracyclines used
in aquaculture can aect the development of children’s teeth [101]. Moreover, the
residual eects of tetracycline have been found to cause poorer development of the
foetus, gastrointestinal disorders, pro-inammatory, cytotoxic, and immune-pathological
eects on the human health [102]. The residual amount of tilmicosin used for the
prevention of pneumonia in cattle, sheep, pigs aects the haematological and biochem-
ical parameters of human [103]. On the other hand, the presence of sulphamethazine,
oxytetracycline, and furazolidone residues is supposed to have immune-pathological
eects on humans (e.g. carcinogenicity), and the combination of gentamicin and chlor-
amphenicol may pose threat to reproductive abnormalities or bone marrow toxicity [104].
A study indicated that the overuse of antioxidants in animals may increase the risk of the
development of resistant bacteria [105], while these resistant bacteria including resistant
factors may transfer from animals to humans [106]. Furthermore, the eects of antibiotics
used as growth promoter have pejorative impact on fat digestion and utilization by the
host due to the excretion of enzyme by intestinal bacteria [107].
On the other hand, allergic reaction due to AR in food is not very common [108]. But
some antibiotics can cause allergic reaction in human body. For instance, tetracyclines
resulted in idiosyncratic reactions, like rash, phototoxic dermatitis and allergy [109].
Besides, Β-lactams leads to the allergic reactions in the human body [110].
7. Alternative approaches to the use of antibiotics
Considering the health risks of AR in food-producing animals, researchers are thinking
alternatives to antibiotics for livestock farming. The main objectives of using alternatives
are to improve gut-microbiota, maintain growth, lower mortality, and preserve consumer
health [28]. Bioactive components, probiotics, prebiotics, organic acids, amino acids, and
enzymes have been used to livestock as an alternative to antibiotics.
7.1. Phytogenic feed additive
Phytogenic feed additives, like black seed, cinnamon, and their extracts have been found
eective to reduce the stress, improve the immune system, and nally enhance the
10 A. REDWAN HAQUE ET AL.

growth rate of animals [111–113]. The use of cinnamon 2 g/kg in the diet exerted the
positive eect on growth as the weight was 974 g vs. 850 g at 28 days of age and 2111 g
vs. 1931 g at 42 days of age compared to the control diet [112]. A diet supplemented with
black seed of 10 g/kg resulted in decreased plasma cholesterol, whereas the diet supple-
mented with 20 g/kg black seed didn’t exert any additional eect on growth performance
[111]. Furthermore, volatile components of black seed, like thymoquinone, dithymoqui-
none, thymohydroquinone, and thymol have been reported to reduce the activity of
3-hydroxy-3-methyl-glutaryl-CoA reductase in the liver that is a key enzyme for choles-
terol prole in blood [111]. The dried power of marigold (Calendula ocinalis) was studied
as an antibiotic growth promoter to broiler chickens [114]. This study revealed that
marigold powder has no signicant inuence on the immunity and growth performance
of poultry birds. A product named Alquernat Nebsui L, composed of bioactive com-
pounds, such as ellagic acid, cimenol, and allilin extracted from Punicagranatum,
Thymus vulgaris, and Allium sativum, respectively, is found to be benecial for laying
hens when it is added to the drinking water at the rate of 0.5 mL/L. It increases the hen day
egg production, improves feed conversion ratio and decreases feed intake [115]. Antother
study showed that a supplementation of a processed phytogenic feed additive reduced
the core body temperature of broiler chicken and increased feed intake and water
consumption, which thereby result in higher body weight compared to the control
chicken [116].
7.2. Organic acid
The organic acids, such as acetic acid, formic acid, butyric acid, and propionic acid
have been reported with antimicrobial properties, and also used as substitutes for
antibiotics in the livestock farm. Supplementation of organic acids to the poultry
birds revealed a positive eect on the prevention of enteric diseases, nutrient
digestibility, improved blood prole, and immunity [117]. The supplementation of
2% citric acid improved cell proliferation and increased the villi height of the
gastrointestinal tract of broiler chickens [118]. Supplementation of organic acids
resulted in an increased Immunoglobulin G (IgG)-Sheep Red Blood Cells (SRBC)
antibodies, IgG and IgM antibodies, Cutaneous Basophil Hypersensitivity (CBH)
response, and CD4-expressing of E. coli challenged broilers. Broilers treated with
organic acid supplementation had a higher benecial Lactobacilli spp. and a lower
faecal E. coli [119]. In a study, a blending of organic acids (sorbic acid, and fumaric
acid) and essential oil (thymol) was found to increase the crypt depth of the jejunum
and ileum during the nishing period of 42 days. Furthermore, this supplementation
increased digestive ecacy through a higher activity of lipase, trypsin, and chymo-
trypsin in the jejunum [120]. The marine sh olive ounder (Paralichthys olivaceus) is
found to have better gut health, improved serological characteristics and disease
resistance performance when blended with dietary organic acids [121]. Interestingly,
these blends could be suggested as analternative to oxytetracycline. A recent study
suggested the combination of organic acids and medium chain fatty acids as
a promising antibiotic growth promotor which improves immune function and
intestinal morphology in weaning piglets [122].
INTERNATIONAL JOURNAL OF ENVIRONMENTAL ANALYTICAL CHEMISTRY 11

7.3. Probiotic
The application of probiotics in the livestock farm is promising, and Bacillus, Lactobacillus,
Bidobacterium, Enterococcus, Pediococcus, and Streptococcus are the most common
probiotic bacteria [123,124]. The administration of probiotics shows antimicrobial activity
and a positive eect on growth and meat quality [125–128]. Typically, spore-forming
bacteria used as probiotics produce several extracellular enzymes, like cellulose, α-
amylase, proteases and metalloproteases, and consequently improve the gut micro-
ecosystem of pigs [129]. The reduction of diarrhoea by administering probiotics has
been frequently studied and most of the studies revealed positive eects of probiotics
in reducing the diarrhoea incidence of piglets [130]. The application of various
Lactobacillus spp. in swine husbandry has found to be benecial to enhance immune
status and intestinal morphology of pigs [131]. The application of Bacillus subtilis H4 or
together with S. boulardii Sb to the lactic acid bacteria strains (E. faecium 6H2,
L. acidophilus C3, P. pentosaceus D7, and L. fermentum NC1) was found eective against
diarrhoea [132–134]. However, a multi-strain probiotic containing B. safensis,
B. megaterium, B. subtilis, and Cupriavidus metallidurans with a total bacteria number of
1.4 × 108 CFU/mL exerted signicant inuences on gizzard, spleen and small intestine of
chicken, similar to other antibiotic groups [135]. Probiotics administration of 5 mL/L
drinking water (PROB50) promoted the breast weights than any other treatments, but
there were no signicant dierences in wing weight, thigh weights, and meat quality
between PROB50 and antibiotic group. Another study concluded with the health, produc-
tion and immunomodulatory benets of poultry when using probiotics instead of anti-
biotics [136].It has been found that both probiotics and antibiotics has positive eects on
digestive system of the food producing animals [137]. However, the symbiotic eects of
probiotic and antibiotics on the animal health and afterwards its antibiotic residual limits
are yet to be unearthed completely. Hence, there is a future scope to determine how
probiotics can partially supplement antibiotics and reduce the residual eects in animals.
Therefore, probiotic supplementation can be suggested in the place of antibiotic use as
a growth promoter in livestock farms.
7.4. Prebiotic
Supplementation of prebiotic to a mammalian animal is a prominent strategy to regulate
the immune system of host by selectively boosting the growth and activity of benecial
gastrointestinal microbiota, while prebiotic is a non-digestible bre and only fermented
by gastrointestinal microbiota [138–140]. Dierent types of saccharides (e.g. fructooligo-
saccharides, inulin, mannanoligosaccharides, and ranose) and chitosan extracted from
shrimp or crab are commonly used prebiotics [15], which are eective to enhance the
antibacterial, antifungal, and antioxidant activity, mineral absorption and the concentra-
tion of short-chain fatty acid [141–143]. In a clinical study, the eects of prebiotic included
a high concentration of Secretory Immunoglobulin A (sIgA) in the intestinal lumen,
increased number of B cell in Peyer’s patches and intestinal tissues, high IL-10 protein
secretion, decreased mRNA expression and low concentration of protein of pro-
inammatory cytokines [144,145].
12 A. REDWAN HAQUE ET AL.

Considering the health benets of prebiotics, several researchers have studied the
eects of dierent doses of prebiotics on the food-producing animal. For instance,
Bednarczyk et al. [146] administrated three types of prebiotics, e.g. DN (DiNovo®, an
extract of beta-glucans), BI (Bi2tos, trans-galactooligosaccharides), and ranose in-ovo,
in-water supplementation and in a combined way (in-ovo+in-water) as alternatives to
antibiotic growth promoters on broiler chicken. All prebiotics signicantly increased the
bodyweight of chicken compared to the control group, but in ovo combined with in-
water supplementation had no signicant eect on growth performance compared to
mere in ovo injection. The optimal dose of DN and BI in ovo was 0.88 mg/embryo and
3.5 mg/embryo, respectively, and found to increase the number of Lactobacillusand
Bidobacterium in chicken faeces [146]. Similarly, commercial prebiotics at a dose of
3.5 mg/embryo (BI) and 0.88 mg/embryo (DN), were studied in ovo method to evaluate
the eects on growth performance and oxidative stability of chicken meat [147]. The
slaughtered chickens at the age of 42 days showed that BI and DN-treated groups had
signicantly higher body weight, carcass yield and breast muscle weight than that of
the control group. Furthermore, lipid oxidation of breast meat was relatively higher in
the prebiotic-treated group and signicantly higher from the fourth day of storage
which might be due to a high amount of intramuscular fat though the thiobarbituric
acid value which was within the range (2.0 mgMDA/Kg) formeat acceptance [148].
Somewhat greater diameter of muscle bre in prebiotic-treated chicken has also been
observed in a previous study [149]. It is a contradictory nding that combine-eects of
microencapsulated Enterococcus faecalis CG1.0007 (PRO) (probiotic) and chitosan oligo-
saccharide (COS) were not signicant on growth and prevention of diarrhoea incidence
of enterotoxigenic E. coli (ETEC) K88+ challenged piglets [150]. This discrepancy might
be attributed to dierence in age, breed, genetic factors, and anti-nutritive factors in
diets. It is obvious that the ecacy of merely applied prebiotics has received much
attention in poultry farming. Therefore, research on the application of prebiotics on
food-producing animals could be a scope of the study for further development of
prebiotics as a growth promoter as well as an alternative to in-feed antibiotics [151].
7.5. Other substances
Several studies evaluated other substances as growth promoters for livestock. For instance,
butyrate and its derivatives are found to be eective to improve and modulate the gut-
microbiota, control enteric pathogens and inammation, and enhance the growth rate of food-
producing animals, especially young animals [152]. Besides, octacosanol extracted from rice
bran was studied for piglets and found to promote the secretion of triiodothyronine (T3),
growth hormone (GH), glucagon (GU), and adrenaline (AD) in blood and regulates the gene
expressions of glucose transporter protein (GLUT-4) and adenosine monophosphate protein
kinase (AMPK) in muscle and liver tissues of weaning piglets [153]. Extracted octacosanol also
plays a vital role to reduce the diarrhoea incident because of its higher antioxidant and energy
metabolism capacity in the animal body [153]. On the other hand, bioactive peptide (casein
glycomacropeptide-CGMP) derived from milk was applied to E. coli K88 challenged piglets as
a growth promoter [154]. Serum sialic acid concentration increased serum DAO and D-lactate
levels of CGMP treated piglets. CGMP supplementation also ameliorated inammation
responses induced by specic pathogen invasion and thus it is found very eective against
INTERNATIONAL JOURNAL OF ENVIRONMENTAL ANALYTICAL CHEMISTRY 13

E. coli K88 infection. In another study, broiler chicken fed with 10 g/kg anise seed (Pimpinella
anisumL.) was found to have more carcass yield compared to the antibiotic treated groups and
also showed increased resistance against avian inuenza virus compared with other
groups [155].
8. Conclusion
The use of antibiotics in animal farms is prescribed to treat ill animals with bacterial aetiology.
However, over doss leads to the deposition of antibiotics in organs and body tissues of food-
producing animals that have been a growing health risk issue for humans across the world. It has
been reviewed that processing methods, like heat treatment, reduce the AR level but cannot
completely degrade in food specimens. On the other hand, several antibiotic-resistant bacteria can
be found in which Salmonella spp., Campylobacter spp., Staphylococcus spp. and enterotoxigenic
E. coli are very common in the animal body. For instance, Salmonella enterica isolated from egg and
chicken carcass is resistant against penicillin, streptomycin, tetracycline, quinolone, and sulphisox-
azole which nally inltrate to people causing gastrointestinal diseases. The consumption of
antibiotic administered animals can be the underlying reason for antibiotic-resistant genes in
the human body. The antibiotic-resistant genes could be lower in organic farming and therefore,
the present study suggests applying bioactive components, such as probiotics, organic acids,
amino acids, and enzymes as alternative approaches to the use of antibiotics in animal farms.
Disclosure statement
No potential conict of interest was reported by the author(s).
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