Antibiotic Pollution in the Environment: A Reviewdownload.xuebalib.com/xuebalib.com.42178.pdf ·...

Soil Air WaterCLEAN

CSAWAC 43 (4) 463-620 (2015) · Vol. 43 · No. 4 · April 2015

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Renewables

Sustainability

Environmental Monitoring

4 | 2015

Ritu GothwalThhatikkonda Shashidhar

Department of Civil Engineering,Indian Institute of TechnologyHyderabad, Ordnance Factory Estate,Yeddumailaram, Andhra Pradesh,India

Review

Antibiotic Pollution in the Environment: A Review

Antibiotics have been extensively and effectively used in human and veterinarymedicines. Their benefits have been recognized in agriculture, aquaculture, bee-keeping, and livestock as growth promoters. This paper collects information fromseveral investigations on the sources and occurrences of antibiotics in natural andartificial environmental systems. Several antibiotics were reported for theiroccurrences in water resources, effluent from industries, sludge, manure, soil, plants,and organisms across the globe. Sorption, photo-degradation, biodegradation, andoxidation were recognized as themain elimination pathways for these compounds andhave been discussed in detail. The adverse effects of the pollutants were alsohighlighted and necessary suggestions were made for effective monitoring andmitigating pollution, which may provide the scope for future research.

Keywords: Drugs; Elimination pathways; Occurrence; Resistance; Sources

Received: February 7, 2014; revised: April 23, 2014; accepted: May 24, 2014

DOI: 10.1002/clen.201300989

: Additional supporting information may be found in the online version of this article at thepublisher’s web-site.

1 Introduction

Antibiotics are the products of rapid innovations in the health sectorand their usage has changed the pattern of modern way of living.Ever since it has been recognized that they can be used as amedicineto treat and prevent infectious diseases, their market has beenexpanding out of bounds. They have been extensively and effectivelyused in human and veterinary medicines and their benefits havealso been recognized in agriculture, aquaculture, bee-keeping, andlivestock as growth promoters.Antibiotics can be defined as chemotherapeutic agents who

restrain or annul the growth of micro-organisms. There are severaldifferent kinds of antibiotics and they can be classified based ontheir chemical structure, action mechanism, action spectrum, andthe route of administration. Out of these classifications the mostpopular one is their mechanism of action and based on it the mostcommon groups are: b-lactams, sulfonamides, monobactams,carbapenems, aminoglycosides, glycopeptides, lincomycin, macro-lides, polypeptides, polyenes, rifamycin, tetracyclines, chloram-phenicol, quinolones, and fluoroquinolones. Table 1 containsfurther information on these groups with details on their modeof action, their representative drugs and infection cured.

2 Sources

In earlier periods the antibiotics were made up of common naturalproducts. They were discovered by laboratory screening and laterwere also used for deriving semi-synthetic antibiotics [1]. With the

beginning of the production of antibiotics, thus began the enteringof their effluents into the environment. Concentrations of severalmg/L of antibiotics were found in effluents in some Asian countries.Larsson et al. [2] investigated the effluent from a common treatmentplant serving bulk drug manufacturers near Hyderabad, India, andreported ciprofloxacin concentrations higher than that of maximaltherapeutic human plasma level. Sewage is another significantsource of antibiotics in the aquatic environment. Antibiotics enterinto the water cycle as parent compounds as well as theirmetabolites, when they are partially metabolized and subsequentlyexcreted. In general, 50–80% of total parent compounds is excretedthrough urine and partially through feces as amixture ofmetaboliteconjugated compounds [3–5]. Antibiotics are often eliminatedincompletely during sewage treatment and thus, are emitted intoreceiving surface water. Sometimes, mixing of untreated effluentwith storm water and accidental breakage of sewer or industrialeffluent pipes can also become non-routine episodes that can admitantibiotic contamination [6]. Land application of municipalbiosolids also results in admitting of antibiotics in soils, groundwa-ter, and subsurface drainage networks as well as in an artificiallyproduced surface runoff. Improper disposal of unused or expireddrugs, which are directly thrown into toilets or waste bins end up inwastewater treatment plants (WWTPs) and landfills [7] are alsoregarded as a significant local point of potential contamination.Minimization and mitigation are the best solution to reduce the

sources of antibiotics in the environment. Lower-dose prescribingfashioncouldplayan important role in reducingthe incidenceofdrugwastage. By targeting a lower dose, it can also reduce the entry ofantibiotics into the environment through excretion [8]. Impartingpropereducationandawarenessinpublicontheissuesofsafedrinkingcan be an effective tool for mitigation. Environmental problemsderived fromthehealth carepracticeshavebeenaddressed in thepast,but most of them failed to incorporate sustainable solutions becausehealth care and environmental professionals hardly interact andparticipate with each other. In these circumstances, technical

Correspondence: Dr. T. Shashidhar, Department of Civil Engineering,Indian Institute of Technology Hyderabad, Ordnance Factory Estate,Yeddumailaram 502205, Andhra Pradesh, IndiaE-mail: [email protected]

Abbreviations: ARG, antibiotic resistant gene; OECD, Organization forEconomic Cooperation and Development;WWTP, wastewater treatmentplant

479

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guidelines derived fromstudiesbasedonecotoxicity andenvironmen-tal risk assessment canhelp inprioritizing thedrug anddosage intakebehavior prior to its release into the market [8–10].

3 Occurrence of antibiotics in theenvironment

The rampant usage of drugs hasmade their occurrence ubiquitous intheenvironmentandalmost thewholeof theworldhasacknowledgedtheir presence innatural andartificial systems. Soil, sediment, sludge,groundwater, wastewater, tap water, surface water (lakes, streams,rivers, sea), plants, and aquatic animals have been reported forcontamination of antibiotics. Kümmerer [11], Heberer [12], andHalling-Sarensen et al. [9] discussed about the sources, occurrence andfate of antibiotics, whereas Fatta-Kassinos et al. [13] includedmethodsof analysis and removal efficiencies of different treatment technolo-gies along with the occurrence of pharmaceuticals. A detaileddiscussion of studies related to occurrence of antibiotics in theenvironment around the world is presented in the followingsubsections and is also given in Supporting Information Table S1.

3.1 Occurrence in wastewater treatment plant

In sewage disposal systems, WWTPs are the last of the places whereantibiotics can be treated before entering into the natural systems.Unfortunately, none of themwere designed to target antibiotics andthus became main anthropogenic sites for the presence of

antibiotics. Detailed analysis of sewage sludge from WWTPs ofdifferent countries such as Canada, China, Spain, Sweden, and USAreported the accumulation of antibiotics [11, 13–24].Several studies have been done in China on the occurrence of

antibiotics in WWTPs. During the investigation of 45 WWTPs in 23cities in China, quinolones were found to be dominant andconcentrations were as high as 29 647mg/kg in the domestic sludgeof Shanxi Province [22]. Another study of a municipal wastewaterreclamation plant in Beijing reported the occurrence of quinolones,sulfonamide, and macrolides, and their mean concentrations werefound to be 4916, 2916, and 365ng/L, respectively [25]. A one-yearstudy on the fate of eleven classes of antibiotics in WWTPs ofGuangdong of South China showed varied removal from 21 to100% [24]. Occurrence and fate of quinolones and fluoroquinoloneswere investigated in sludge samples in a municipal sewagetreatment plant with anaerobic, anoxic, and aerobic treatmentprocesses. It was found in the study that antibiotics come incontact with biosolids during these treatment processes, whichare dense with bacterial population and they act as taxonomicbarriers to the horizontal transfer of genetic material and thus,WWTPs have become a prominent place for drug-resistantcultures [11, 26–28].

3.2 Occurrence in water

Natural, safe drinking water is becoming rare as the majority ofcountries is facing water quality issues. Even the tap water which

Table 1. Antibiotics classification with their representative drugs, mode of action, and infection cured by them

No. Class of antibiotic Representative drug Mode of action Infection cured

1 b–Lactam Phenoxypenicillin, oxacillin,amoxicillin, carbenicillin,piperacillin

Inhibits steps in cell wallsynthesis and mureinassembly

Hypersensitivity reaction,hemolytic anemia,interstitial nephritis

2 Sulfonamides Sulfamethoxazole, sulfamethazine Inhibitors of bacterialbeta lactamases

ThrombocytopeniaN4-AcetylsulfamethazineSulfdiazine, sulfadimethoxineSulfamethoxazole,sulfamethoxypyridazine,sulfapyridineSulfasalazine, sulfasoxazole, sulfathiazole

3 Aminoglycosides Gentamycin Inhibits translation(protein synthesis)

NephrotoxicityOtotoxicity

4 Glycopeptides Vancomycin Inhibits steps in mureinbiosynthesis andassembly

Red man syndromeNephrotoxicityOtotoxicity

5 Lincosamides Clindamycin, lincomycin Inhibits translation(protein synthesis)

NephrotoxicityOtotoxicity

6 Macrolides Clarithromycin, erythromycin-H2O Inhibits translation(protein synthesis)translation

Coumadin interactionOleandomycin, roxithromycinSpiramycin, tylosin

7 Rifamycins Rifamycin Inhibits transcription(bacterial RNApolymerase)

Body fluid discolorationHepatoxicity

8 Tetracyclines Chlortetracycline, demolocycline Inhibits translation(protein synthesis)

HepatotoxicityDoxycycline, oxytetracycline Tooth discolorationTetracycline Impaired growth

9 Chloramphenicol Chloramphenicol Inhibits translation(protein synthesis

Aplastic anemia gray babysyndrome

10 Quinolones Oxolinic acid, nalidixic acid,pipemidic acid, flumequine,pefloxacin

Inhibits DNA replication PhototoxicityAchilles tendon ruptureImpaired fracture healing

11 Fluoroquinolones Ciprofloxacin, norfloxacin,ofloxacin, enrofloxacin, enoxacin,sarafloxacin, danofloxacin,dofloxacin, lemofloxacin

Inhibits DNA replication PhototoxicityAchilles tendon ruptureImpaired fracture healing

480 R. Gothwal and T. Shashidhar


was trusted to be a safe drinkingwater source has not been spared bythe extent of antibiotic contamination. An investigation in Madrid,Spain, claimed contamination of tap water with macrolides,erythromycin, and clarithromycin among other pharmaceuticalresidues [29]. Guangzhou and Macao of China also reported fourfluoroquinolones (norfloxacin, ciprofloxacin, lomefloxacin, andenrofloxacin) in tap water ranging from 1.0 to 679.7 ng/L and 2.0to 37ng/L, respectively [30].

3.2.1 Rivers, streams, and lakes

Rivers named Jarma, Manzanares, Guadarrama, Henares, Tagus inSpain were reported for the presence of ciprofloxacin, clarithromy-cin, erythromycin, metronidazole, norfloxacin, ofloxacin, sulfa-methoxazole, tetracycline, and trimethoprim and theircorresponding median concentrations were found to be about 3,235, 320.5, 1195.5, 10, 179, 326, 23, and 424ng/L, respectively [29].The Ebro and Llobergat were also reported to possess concentrationsof all these antibiotics [31]. Similar studies of the Han river in SouthKorea, Ozark streams in USA, rivers Po and Arno in Italy, Sindian,Dahan and Gaoping rivers in Taiwan, Seine river in France, Hojeriver in Sweden also acknowledged the presence of antibiotics.Studies of rivers in China (Pearl river, Yellow river, Hai river, and Liaoriver) also reported norfloxacin, ofloxacin, ciprofloxacin, andoxytetracycline, with concentrations of 5770, 1290, 653, and652ng/g, respectively [5, 32, 33].

3.2.2 Seawater

Coasts are considered as ecologically sensitive areas, but very fewstudies have been carried out to analyze ocean water for antibioticcontamination. The Beibu gulf, coastal environment of Dalian,Bohai bay, offshore water of Yellow sea, and Bohai sea have beeninvestigated for the presence of antibiotics [34–37]. Concentrationsof antibiotics in seawater were very low (ng/L) as compared to riverwater and WWTPs sludge (mg/L and mg/kg). The expected sources ofantibiotic contamination in sea are direct discharge of sewage andthrough confluences of rivers. Coastal water of Bohai bay and sixrivers flowing into it have been investigated to understand theeffects of antibiotics on aquaculture. The study revealed that there isan ecological risk to the bay by the river discharge [37]. Erythromy-cin-H2O, sulfamethoxazole and trimethoprim were detected morefrequently in the Beibu gulf. The mean concentrations were in therange of 0.51–6.30 ng/L, which may pose a risk to algae species suchas Pseudokirchneriella subcapitata and Synechococcus leopoliensis [36].Offshore water of the Yellow sea and the Bohai sea has been reportedfor the presence of erythromycin, sulfamethoxazole, and trimetho-prim in the range of 0.10–16.6 ng/L, and these concentrations canpose risk to sensitive aquatic organisms [35]. Seawater, sediment,and aquatic organisms of Dalian province in China have beeninvestigated for the presence of antibiotics. Seawater showed about2.11–9.23 ng/L of tetracycline, whereas sulfonamides were dominantin both the sediments and aquatic organisms ranging between 1.42–71.32 and 2.18–63.87mg/kg, respectively. The study also proposed thepossibility of potential bioaccumulation of sulfamethazine, sulfa-methazole, sulfamonomethoxine, and doxycycline [34].

3.2.3 Groundwater

Anthropogenic activities have made urban aquifers vulnerable toantibiotic contamination. Although soil retards the movement of

contaminant into the subsurface water, but once contaminated, it isdifficult to subdue its effects. Natural bank filtrations, infiltration ofwastewater and water supply pipes, rainfall, etc., are considered assources of groundwater recharge and sometimes they act as sourcesof contamination too. Studies for the presence of emergingcontaminants in the groundwater of the rural and urban area ofSpain have been reviewed. Lopez-Serna et al. [31] have acknowledgedthe occurrence of 72 pharmaceuticals and 23 transformationproducts in groundwater underlying city of Barcelona, Spain. Thestudy stated that WWTPs are the most influencing sources ofgroundwater contamination. Groundwater from the deep confinedaquifer was monitored for three years at the Llobregat delta(Barcelona, Catalonia, Spain). Ciprofloxacin was found to be thehighest among all the antibiotics with a mean concentration of323.75ng/L due to agricultural activities and/or infiltration of poorlytreated water [38]. Eighteen types of sulfonamides ranging from 0.01to 3460.57ng/L were observed in groundwater of Catalonia, Spain.Manure was the main source of their contamination, sincesulfonamides are related to livestock veterinary practices [39, 40].In the United States, as part of continuing effort to collect baselineinformation on nation’s water resources, pharmaceuticals were alsodetected in a national reconnaissance survey. Groundwater samplesfrom 18 states of the USA in the year 2000 reported sulfamethoxa-zole as the most frequently detected veterinary and humanantibiotic [41]. The occurrence of veterinary antibiotics in ground-water located near swine and beef cattle facilities showed antibioticlevels similar to that of drinking water [42]. In groundwater,antibiotics have been reported along with many other organiccompounds such as pharmaceuticals, pesticides, industrial com-pounds, hormones, and personal care products, but the concen-trations are significantly lower than that in rivers and WWTPs [31,38, 40, 41, 43, 44].

3.3 Occurrence in soil and sediments

The natural occurrence of antibiotics is due to the biosynthesis bysoil microorganisms which dwells in soil and sediment habitats.However, sludge and manure constitute the major source for thedissemination of most of the pharmaceutical antibiotics into theland, due to repeated manure application antibiotics get accumu-lated in the soil. Kwon-Rae et al. [45] have estimated concentrationsof veterinary antibiotics in livestock manures from Korea byaccounting antibiotic production and its use, then considering theexcretion rate of each drug as reported in the literature. Macrolidesconcentration in cattle, pig and poultry manures were in the rangeof 0.07–0.14, 1.05–2.1, and 0.62–1.24mg/kg, respectively, whereassulfonamides and tetracyclines were observed as 0.49, 8.44, and1.39mg/kg and 1.65, 16.56, and 15.62mg/kg, respectively. Similarly,several other studies also documented the occurrence of antibioticsin manure, soil, and sediments [23, 34, 44, 46–49].Other significant sources of the antibiotics are their use in fish

culturing, flooding of surface water, dumping of industrial solidwaste on lands and the direct use as pesticides on vegetables, fruits,and ornamental plants [45]. Karci and Balcioglu [50] showed higherlevels of antibiotics in organic (manure applied) vegetable fields ascompared to traditional (chemical fertilizer applied) vegetablefields. In China, a study has been done to estimate the spatialdistribution of antibiotic residues in surface soils in a typicalintensive vegetable cultivation area. A new method called mean ofsurface with non-homogeneity was applied, which gives a smaller

Antibiotic Pollution in the Environment 481


standard error of the estimate. A spatial mean concentration ofantibiotic residues in the soil was suggested as the most importantindicator of environmental risk of a region to antibiotic residues [51].Lapen et al. [46] has applied pharmaceuticals with the fluorescentdye tracer rhodamine to tile drained fields for evaluation of thepersistence of antibiotics in the tile water. The relative benefits ofland application practice to reduce pharmaceuticals loading to thedrains were also studied with the same tracer. Application of sewagesludge onto agricultural land supposed to be a very desirabledisposal option, but the presence of persistent organic contami-nants in sludge has now raised questions on these ways of disposal.

3.4 Occurrence in plant and aquatic animals

The presence of antibiotics in surface water, groundwater, seawater,soil and sludge opened their entry into biota. Antibiotics can betaken up by vegetables, crops, aquatic plants, and animals [11, 23,34, 44, 49, 52, 53]. Their presence in vegetables and fishes haschallenged the standards of food safety. Eggen et al. [52] studied theuptake of ciprofloxacin in carrot (Daucus ssp. sativus cvs. Napoli) andbarley (Hordeum vulgare). In the study, a bioaccumulation factor wasfound to be <1 and the root concentration factor was found to behigher than the corresponding leaf concentration factor. Anotherstudy reported the distribution of antibiotics in the plants in thissequence: leaf> stem> root, and also, the winter season was foundto be more favorable than summer for bioaccumulation. In winter,coriander leaves accumulated high levels of oxytetracycline,tetracycline, and chlortetracycline which were in the range of78–330, 1.9–5.6, 92–481mg/kg, respectively; radish leaves accumu-lated sulfadoxine, sulfachloropyridazine, chloramphenicol, andsulfamethoxazole in the range of 0.2–0.6, 0.1–0.5, 8–30, and 0.9–2.7mg/kg, respectively; celery leaves accumulated ofloxacin, peflox-acin, and lincomycin in the range of 1.7–3.6, 1.1, and 5–20mg/kg,respectively [44]. Li et al. has reported predominant occurrence ofquinolone in aquatic plants (8.37–6532mg/kg). Aquatic animals andbirds were also detected with quinolones concentrations in therange of 17.8–167mg/kg and macrolides from non-detectable to182mg/kg in the Baiyangdian Lake of North China [49]. The octanol/water partition coefficient (logKow) is found to be the main factor forsuch uptake of antibiotics into biota through water transport andpassive absorption [44, 52]. The contaminant transfer usually takesplace from sludge-amended soils to the plants, via retention by rootsurfaces, root uptake, translocation, foliar uptake, and animalintake (soil and herbage ingestion) [54].

4 Elimination pathways of antibiotics in theenvironment

Elimination of antibiotics is the result of its fate and degradationpathways which ultimately depends on its physico-chemicalproperties. In a WWTP, antibiotics undergo mechanical, chemical,and biological processes. Removal efficiencies of conventionalsewage treatment are found to vary substantially and they arenot designed to deal with emerging pollutants like antibiotics.However, membrane bioreactor systems were reported to be slightlymore efficient than conventional activated sludge treatmentsystems. The fate of b-lactams, sulfonamides, trimethoprim,macrolides, fluoroquinolones, tetracyclines, and nitroimidazoleshas been studied in biological treatment, activated carbonadsorption treatment, and advanced oxidation processes. These

fate studies concluded that application of advanced treatment afterconventional biological process can improve the removal ofantibiotics, but operation and maintenance cost goes up [27, 55].Antibiotics enter into the natural aquatic environment mainly

through discharges fromWWTPs, they get mixed laterally as well asvertically and get transported downstream by advection anddispersion processes. During mixing and transportation, antibioticsmay get adsorbed to suspended matter, may accumulate ontosediments and may come back into the water column by re-suspension. The association of these compounds with the solidphase or the water column is answered by their sediment waterpartitioning coefficient. Antibiotics with small adsorption affinitystay in the water column and the rest will be retained in thesediments of water bodies. Weakly sorbing antibiotics that arepresent in soil get leached into surface run-off as well asgroundwater, while strongly sorbing antibiotics keep accumulatinginto soils or sediments [56]. The water partitioning coefficient is avery important factor as it affects adsorption, photodegradation,and as well as biodegradation of antibiotics.In comparison to the aquatic system, the soil environment ismore

complex. The toxic effects of contaminants can be mitigated by thebuffering capacity of soil; however, accumulation is easy in it as itoffers poor mobility. This poor mobility causes long exposures andcan cause increased toxic effects. The persistence of an antibiotic insediments or soil mostly depends on its photostability, binding/adsorption capability, degradation rate, and leaching in water.Kinetics of physical reactions (sedimentation, scour/resuspension,adsorption/desorption, and gas transfer), biological transformations(biological oxidation/reduction and co-metabolism), and chemicalreactions (hydrolysis, oxidation, photodegradation) are the factorswhich are crucial in the elimination of contaminants from theenvironment. However, sorption, photodegradation, biodegrada-tion, and oxidation appear to be more significant processes in theelimination of antibiotics [57, 58].

4.1 Sorption

The evaluation of the fate and transport of antibiotics in theenvironment is handicapped by the limited knowledge of thesorption mechanism toward solids. The main phenomena whichexplain the sorption mechanisms are cation exchange, surfacecomplexation, cation bridging, and hydrogen bonding. The sorptionaffinity of antibiotics onto sludge is defined by the constant Kd,solid(L/kg) and the accumulation in sludge can also be assessed by Kow(octanol/water partition coefficient). The efficiency of WWTP is alsolimited by the adsorption of antibiotics onto dissolved organicmatter which may decrease the bioavailability by complexation.Based on Kow, compounds can be characterized in three log-classes ofthe n-octanol/water distribution coefficient: logKow< 2.5 is charac-terized as low sorption, logKow between 2.5 and 4 is mediumsorption, and logKow> 4 is characterized as high sorption [59].The sorption phenomenon has been exploited for the removal of

antibiotics in advanced WWTPs. Activated carbon can be used forremoving hydrophobic and charged particles from the wastewa-ter [55]. Activated carbon is also used in drug manufacturingindustries for purification of antibiotics [60]. Nitroimidazoles onactivated carbon was reported with a capacity of 1–2mmol/g [61].Several antibiotics with dosages between 10 and 20mg/L have beenremoved from river water by 49–99% after 4 h contact time withpowdered activated carbon [62, 63]. Macrolides, fluoroquinolones,



trimethoprim, and clindamycin were also removed from hospitalwastewater with powdered activated carbon at dosages of 20–40mg/L(http://tinyurl.com/eawag-spitalabwasser) [64]. Sulfonamide andtetracycline have also been removed from river water after 24hcontact time with 1mg/L activated carbon [65]. Adsorption byclays [66], carbon nanotubes [67], ion exchange [68], sewage sludge,andwaste oil sludge-derived adsorbents [69] has been investigated forthe removal of antibiotics. Tolls [70] has reviewed sorption ofveterinary pharmaceuticals in soils and compiled their sorptioncoefficients. The study showed that these chemicals have a widerange ofmobility and a Kd,solid range between 0.2 and 6000 L/kg. It hasbeen stated that based on Kow, the prediction of Koc (soil organiccarbon/water partition coefficient) is not accurately possible.The sorption of antibiotics to soil is fast as it reaches equilibrium

in few hours and is significantly governed by pH, organic matter,and mineral content in soil. It is weakly sorbed to minerals ascompared to organic matter. Strong adsorption for fluoroquino-lones, tetracyclines, aminoglycosides, and tylosins has beenreported toward clay than to minerals like montmorillonite, illite,and kaolinite. Adsorption of tetracyclines toward humic substanceand clay minerals is influenced by pH and ionic strength of themedium [71]. Thiele-Bruhn [71] has elaborately discussed thesorption mechanisms of antibiotics to soils and also summarizedsorption coefficients of different antibiotics in soils, sediments, andslurry. Schauss et al. [72] discussed the fate of sulfonamides in soils.The transport and transformation of sulfonamides are a function ofsorption, which again depends on the pH of soil. Sulfonamides arepresent in soils in neutral form, but as pH increases their anionicform becomes abundant. Ciprofloxacin, ofloxacin, enrofloxacin, andoxalinid acid showed a high value of Kd in the range of 70–5000 L/kg,which can be interpreted as high affinity toward solids. Inves-tigations have been going on to elucidate the sorption behavior ofdifferent antibiotic classes to different solids (soils, sediments,sludge, humus, animal manure, minerals) present in the environ-ment. In sewage sludge and sediments, the mineral content is lowand aerobic/anaerobic conditions vary with depth. Lipid contentsare very high in sludge when compared to sediments, therefore, theconcentration of non-polar/less polar and cationic materials arehigh with respect to sediments [73]. Uptake and degradation ofantibiotics occur over the reaches of streams as they are notconservative and are very much susceptible to getting adsorbed tothe bed material. The sorption behavior of antibiotics is dependenton their molecular structure, functional groups as well as pH and aparticle size fraction of the sediment. True sediment/waterpartitioning coefficient Kd values are difficult to estimate in streamreaches as thewater column and sedimentwill not be at equilibriumat the time of study. Therefore, pseudo-partitioning coefficients areusually calculated to compare sorption characteristics ofantibiotics [73].

4.2 Photodegradation

Photodegradation is one of the important factors which influencethe environmental fate of fluoroquinolones. In the photodegrada-tion process, parameters such as light source, pH, temperature,time, type of matrix, and the type/amount of impurities in thematrix (salts, organic compounds, soils, etc.) are important, whichcan produce stable and toxic compounds or vice versa [11]. Amongfluoroquinolones, enrofloxacin, and ciprofloxacin are highlyphotodegradable, their half-lives are dependent on light

intensity, pH, concentration level, phosphorus level, and thepresence of organic matter. Half-lives of enrofloxacin were 0.8,3.7, and 72 days for 100% (full light exposure), 28% (partial shading),and 0.5% (near complete shading) light exposure conditions typicalof upper epilimnion, lower epilimnion, and hypolimnion, respec-tively. In the presence of light enrofloxacin rapidly degrades tociprofloxacin and keeps degrading further, it lasts for longer timesunder lower light conditions [57]. At an acidic pH, the photo-degradation of ciprofloxacin forms 7-[(2-amino ethyl) amino]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid,which further degrades to 7-amino-1-cyclopropyl-6-fluoro-1,4-dihy-dro-4-oxo-3-quinoline carboxylic acid [74].The cleavage of the sulfonamide bond and the aromatic ring

rearrangement are the main pathways for sulfamethoxazole andsulfapyridine photo-Fenton and ozone degradation. It involves theattack of hydroxyl radicals on the benzenic or aromatic rings [75].The degradation of trimethoprim is slow but the reaction rate can bealtered by TiO2 acting as a catalyst [76]. The mechanism for thedegradation of trimethoprim involves a slow reaction by directirradiation and is followed by a faster mechanism induced by theformation of a photoreactive intermediate causing an autocatalyticeffect [77].

4.3 Biodegradation

Transformation of organic compounds can be intracellular orextracellular of microbes; it is themajor pathway of the degradationby enzymatic transformation under aerobic and anaerobic con-ditions by bacteria, algae, or fungi. However, the biodegradation ofantibiotics under aerobic conditions assisted by bacteria is found tobe rare [28, 58, 78]. Alexy et al. [79] assessed the biodegradability inthe closed bottle test according to the test guidelines of theOrganization for Economic Cooperation and Development (OECD)“301 D” for 18 antibiotics. Out of these only a few were slightlydegraded in 28 days. Benzylpenicillin sodium salt was degraded by27%, amoxicillin by 5%, nystatin and trimethoprim by 4%, and therest was reported to be <4%. Kümmerer et al. [78] reported noreduction for ciprofloxacin and ofloxacin showed only 5% reductionin the OECD 301 D test even after 40 days. Gartiser et al. [80] alsostudied the inherent biodegradability of 17 antibiotics in acombined test, the Zahn-Wellens test and CO2-evolution test (OECD301 B and OECD 302 B, 1992). Benzylpenicillin G was the onlybiodegradable compound to the extent of 78–87% of ThCO2

degradation. Amoxicillin, imipenem, and nystatin were regardedas partially biodegradable with the formation of stable metabolites.Ciprofloxacin, ofloxacin, metronidazole, and lincomycin were notbiodegraded and hence, genotoxicity caused by these compoundswas also not eliminated [78, 81]. An extremely low mass change wasreported during biodegradation of quinolones and fluoroquinolonein a municipal sewage treatment plant, which again confirmed thefact that biodegradation is of minor importance in its removal inWWTPs [9, 28]. Elimination of sulfadiazine by biodegradation is alsonegligible in soils. A transformation process was assessed for 14C-labeled sulfadiazine in manure-amended soil and only de-acetyla-tion of the biologically-inactive N-acetyl-sulfadiazine happened tothe parent compound [72]. However, Li and Zhang [58] claimed thatin activated sludge processes, cefalexin, sulfamethazole, andsulfadiazine are the only antibiotics, which have been reported tobe predominantly removed by biodegradation in both freshwaterand saline sewage systems.



Degradation of antibiotics by fungus has been reported byRodriguez-Rodriguez et al. [82]. Trametes versicolor, a white rot fungus,has potential to degrade a diverse range of xenobiotics fromcomplex matrices like sludge. It uses extracellular and non-specificlignin-mineralizing enzymes (i.e., laccases and peroxidases) andintracellular enzymatic complexes. One of the most commonly usedveterinary antibiotic, sulfamethazine, was observed in a definedliquid medium at high concentrations. Laccase seemed to play animportant role in the transformation process and its metaboliteswere identified from enzymatic degradation assays [83]. Degradationof sulfapyridine and sulfathiazole was also assessed by T. versicolor. Itwas found that despite the high concentrations, sulfapyridine wascompletely degraded and degradation products were elucidated.Sulfathiazole showed resilience toward degradation; after 96h ofincubation, 12% of the initial concentration was still remaining. Acontinuous fluidized bed reactor with fungal pellets was alsoemployed to check the feasibility of the simultaneous elimination ofa mixture of sulfapyridine, sulfamethazine and sulfathiazole. 72 hhydraulic retention time successfully eliminated the compoundsand their metabolites at the end of the batch experiment. Hence,efficient degradation capability of T. versicolor can be utilized forbioremediation purposes, but toxicity assessmentmust be employedbefore its field application [82].

4.4 Oxidation

The process of oxidation involves the use of strong oxidizing agentsuch as hydroxyl radicals [84, 85], ozone [86], potassium permanga-nate [87, 88], and chlorine [89]. The processes which enhance theformation of free radicals is known as advanced oxidation processessuch as ozonation, Fenton oxidation, heterogeneous photocatalysiswith TiO2 and sonolysis. Advanced oxidation treatment processes areefficient to treat wastewater which is found biologically recalcitrantand rejected by membranes. Several advanced oxidation processeshave been employed for the removal of antibiotics in wastewatereffluents [62, 90–93]. Ozonation is very effective in the removal ofsulfonamides and trimethoprim. The ratio of molecular ozone andhydroxyl radicals, concentration of organic matter, and thecorresponding reaction kinetics actually decides the oxidativepathways of antibiotics. More than 95% removal was observed inriver water within 1.3min at an ozone dosage of 7.1mg/L. More than2mg/Lofozone in secondarywastewater effluentseffectively removedmacrolides by 90–99%, whereas 99% of b-lactams, macrolides,quinolones, and trimethoprim were removed by using 5–10mg/Lozone and a hydroxyl radicals dosage fromwastewater containing 5–23mg/L dissolved organic carbon. Oxidative degradation can occur bydirect reaction with the applied oxidant or by producing highlyreactive secondary species [55]. The solar photo-Fenton system is alsoeffective for the degradation of ofloxacin and trimethoprim. Theresults demonstrated the complete elimination of antibiotics using5mg/L of Fe2þ with 75mg/L of H2O2 within 180min (texp) of solarirradiation in a pilot treatment plant [94]. Degradation of oxytetracy-cline in aqueous solution at different pHvalues by ozonationhasbeenobserved by Li et al. [95]. Pharmaceutical industrial effluentscontaining high concentrations of oxytetracycline was treated withozone for 60min at pH 11 and the results confirmed that ozonationimproves the biodegradability of the effluent. Furthermore, theresults indicated that thefirst by-product of oxytetracyclinewasmoretoxic thantheparentcompoundafterpartialozonation [95]. Similarly,Dantas et al. studied the ozonation of sulfamethoxazole at

different pH values and observed complete abatement with 10% ofmineralization of antibiotic at 200mg/L in 15min with 0.4g/Lozone. [96]. Degradation of metronidazole was observed by Shemeret al. using photochemical oxidation treatments in differentcombinations as UV, H2O2, Fe

2þ (photo-Fenton). Photolysis is foundto be less effective compared toUV/H2O2, andoxidation can further beenhanced in the process by increasing the concentration of hydrogenperoxide. Treatment carried out in combination of UV/H2O2/Fe

2þ andH2O2/Fe

2þ for oxidation of metronidazole follows second orderreaction kinetics, here, oxidation can be enhanced by increasing theconcentration of the ferrous ions [97].The conversion of antibiotics can be more effective at applied

increased power densities, acidic conditions, and in the presence ofdissolved air. Municipal wastewater and surface water are usuallytreated with chlorination; hence, aqueous chlorination of trimeth-oprim has been studied by Dodd and Huang. They observed thattrimethoprim rapidly reacts with freely available chlorine at pH andoxidant concentration conditions, which are usually present inWWTPs, but the reaction is slow in case of surface water treatmentconditions. Another observation has been derived by analyzing theby-products that there is no substantial degradation of the parentcompound after the reaction of trimethoprim and chlorine [98].Except few, most of the studies are devoid of any information onbyproducts, which are formed during oxidation and their antibioticactions. However, by-products can also be ecotoxic and hence, it isessential to monitor the entire processes carefully. The oxidationreaction also helps in increasing the biodegradability of compounds,but optimization of the advanced oxidation process should be donethrough toxicity tests along with the analytical determination ofproduct forming during the processes [93]. Hence, proper ecotoxico-logical investigation should be conducted tomonitor the generationof potentially toxic transformation products before applying thesefacilities for practical use [99, 100].

5 Issues related to the presence of antibioticsin the environment

5.1 Development of antibiotic resistance

Themost important issueof antibiotic release into the environment isrelated to the development of antibiotic resistancewhich has resultedin the reduction of therapeutic potential against human and animalpathogens. It is not the fact that the presence of antibiotic resistancewas never seen before in the natural environment, but it wasassociated only with some bacterial strains, as resistance is animportant process of evolutionary conservation. The resistance isinherited by organisms of the same species through cell division(vertical resistance transfer), which is known as primary resistance,while the secondary resistance is developed during therapy/contact ofmicro-organisms with an antibiotic. Plasmid-mediated resistance istransferable between micro-organisms and in such cases, extra-chromosomal genetic material is transferred between differentbacterial species by conjugation (horizontal resistance transfer) [11].Horizontal gene transfer is associated with three primary mecha-nisms: (a) Conjugation, plasmid transfer from one bacterium toanother; (b) transduction, viralmediated (phage) gene transfer; and (c)transformation, the uptake of naked DNA via the cell wall, and theincorporation of thatDNA into the existing genome or plasmids [101].Traditional culturing techniques, quantitative real time polymer-

ase chain reaction, metagenomics, and functional metagenomics



are employed by several studies for resistance gene quantification.Such quantification can be useful to investigate distribution ofantibiotic resistance genes in different environmental compart-ments, to correlate the antibiotic concentration and correspondingantibiotic resistance genes (ARG). ARG and their relationship withantibiotics in the Huangpu River and drinking water sources(Shanghai, China) has been investigated by Jiang et al. [102].Occurrence of sulfonamide and corresponding resistant bacteriaand resistance genes has been investigated in the aquacultureenvironment of Tianjin, northern China [103]. Similarly, tetracy-cline resistant bacteria were observed in the Drweca River water innatural reserves (Poland) as the potential indicator of drugresistance [104]. The occurrence of pollution indicators andantibiotic resistant bacterial isolates from water and sedimentsamples of three eco-regions have been investigated at the Chennaicoast, India [105]. Another study in Shanghai, China, correlated thepresence of ARG with the presence of corresponding antibiotics andheavymetals, such as Cu, Zn, and As. A weak positive correlation wasfound between ARGs and corresponding antibiotics, whereassignificant positive correlations was found between ARGs and heavymetals [106]. One study in Spain collected samples from aman-madereservoir as they play an important role in the water supply,irrigation and recreational uses. The links between the occurrenceof antibiotics, its resistance and composition of bacterial communi-ty has been investigated. The study suggested the conformation ofbacterial communities in reservoir and questioned the potentialeffects of polluted lakes and reservoirs on bacterial-relatedecosystems [107]. A relationship between antibiotic residues,bacterial community structure, and composition with antibioticresistance is demonstrated by Novo et al. [108]. This studyhypothesized the correlation between the occurrence of antimicro-bial residues and ARG in sewage with the structure, composition ofbacterial communities, and the antibiotic resistance loads of thefinal effluent. A positive correlation was found between antibioticresistance, tetracycline residues, and temperature. For members ofthe class Epsilonproteobacteria, a negative correlation was foundbetween beta-lactam, Gammaproteobacteria, and Firmicutes withantimicrobials [108].Anthropogenic activities such as manure/biosolid application,

wastewater irrigation, and agricultural application of antibioticcompounds are supposed to be responsible in transmittingantibiotic resistance to the environment. However, studies foundthat highly diverse and abundant levels of antibiotic resistantbacteria are already present in soils. A wide array of clinically-associated and novel antibiotic resistance genes are harboring inun-impacted and pristine soils. Hence, speculations were madethat many pathogens-associated antibiotic resistance genes maybe originated in antibiotic-producing bacteria and reachedpathogens via horizontal gene transfer [101]. Kristianssonet al. [109] also confirmed that antibiotic contamination ispromoting the genetic resistance and its mobilization can occurfrom environmental microbes to pathogens. The study conductedculture independent shotgun metagenomics and found severalelements of horizontal gene transfer. Among several resistanceresidues, two were found to be resistant plasmids, which werenever characterized before. Hence, it can be concluded that withthe increasing incidences of antibiotic resistance in the environ-ment, the microbes that were once susceptible to antibiotics arebecoming more and more difficult to treat and pose a globalthreat to humankind [1].

5.2 Other effects of antibiotics

Antibiotics are regarded as persistent or “pseudo-persistent” becausethe rate of entering into the environment is more than the rate ofelimination. Therefore, due to their persistence, ecological risks tothe environment have been assessed in several studies. Theemergence of antibiotic pollution in the environment is causingpotential toxic effects on micro-organisms, plants, animals, andultimately humans.One way of assessing the hazards caused by antibiotics is on the

basis of risk quotients. The risk quotients can be calculated throughthe predicted environmental concentration or measured environ-mental concentration divided by the predicted non-effect concen-tration, which can be obtained by the ratio of the half maximaleffective concentration (EC50) and the half maximal lethalconcentration (LC50) divided by an assessment factor [35]. Thegeneral indicators of toxicity LC50, EC50, and mean inhibitoryconcentration (IC50) have been reported by many studies forantibiotics with respect to non-target sensitive organisms such aszebra fish, Daphina, algae, mussels, and other aquatic organisms [35,110–112]. However, some studies claim that LC50, EC50, IC50 indexesare inappropriate to evaluate the low toxicity and low concentrationof antibiotics as the synergistic toxic effects of antibiotics iscompletely ignored [53, 112].There is a common claim that toxicity acts first at the molecular

level, then it reaches to the cellular level, subsequently organismlevel, individual level, population level, community level, andeventually ecosystem level. Keeping this in mind, the susceptibilityat the DNA level has been used as a more sensitive and effectivebiomarker for detecting toxicity of contaminants in the soil. Thus,DNA damage and change in enzyme activities were used asbiomarker tools to find out the antibiotic stress and genotoxicityon various organisms. The comet assay test has been conducted onearthworm (Eisenia fetida) and the results showed that chlortetracy-cline and tetracycline could induce DNA chain breakage. These twoantibiotics also caused changes in enzymatic activities on theirexposure to earthworm (E. fetida) [53].Antibiotics such as tetracyclines, fluoroquinolones, and macro-

lides affect the chloroplastic and mitochondrial protein synthesis inplants [11, 113]. Flouoroquinolones inhibit DNA synthesis ineukaryotic cells, plastid replication, and have negative influenceson plants morphology and photosynthesis. Streptomycin inhibitschlorophyll synthesis in Hordeum vulgare; sulfadimethoxine andenrofloxacin reduce growth significantly; ciprofloxacin reducesphotosynthesis and hence, growth in plants. Tetracyclines also havephytotoxic effects which may cause chromosomal aberrations andinhibition of plant growth. b-Lactams have been considered to beless toxic, but they also affect the plastid division in lower plants [11,113–124]. Tetracyclines, ciprofloxacin, and erythromycin reduce thecontent of photosynthetic pigments, chlorophylls, and carotenoidsin plants. Penicillins, cephalosporins, and tetracyclines affect thephotosynthetic electron transport rate. Opris et al. [125] studied theeffect of nine antibiotics on foliage photosynthesis and found thatciprofloxacin and cephalosporins strongly inhibit the net assimila-tion rate because of the reduction in stomatal conductance.

6 Concluding remarks and future prospects

Antibiotic pollution has been detected around the world in almostall compartments of the environment. Until now, the majority of



research studies and regulatory developments happened signifi-cantly in North America, Europe, and China. Therefore, much lessinformation is available from other parts of the world such asOceania, Africa, and South America and parts of Asia other thanChina. So, a development of a world database with a wider range ofclimate conditions ranging from tropical to arctic is essential to setup standards and guidelines to reduce risk and mitigate thepollution.WWTPs are considered as the most common source and pathway

of antibiotic transport to surface water, drinking water, groundwa-ter, seawater, soil, plants, and aquatic organisms. Drug manufactur-ing plant and hospital effluent is also amajor source of antibiotics inlocal scenarios. Land application of WWTPs sludge, sewage, andmanure has become a rather contentious issue as this activity offersan important source of antibiotics entering into the food chain viagrazing animals and agricultural practices.The behavior of antibiotics in conventional as well as advanced

WWTPs is not completely understood despite identifying sorption,biodegradation photo-degradation, and oxidation as major process-es of elimination. Currently, very little information is available withregards to metabolites excreted by humans and transformationproducts in WWTPs. Identification of metabolites, transformationproducts, and their potential formation of pharmacologically activeor more toxic products is still an open question. A mixture of parentcompounds, their metabolites and transformation products withother toxic organic and inorganic compounds that are present inWWTPs and their biological potency of these mixtures is still amystery as compositions always vary. Hence, synergistic effects ofthese compounds altogether with other environmental conditionswill have entirely different toxic effects on non-target organisms.The impact of antibiotics and antibiotic resistance gene pollution

has become a major concern lately and it is essential to understandthe interaction of antibiotics with ecosystems. Most of these studiesconclude that non-target organisms would be exposed to such sub-lethal concentrations which can unlikely cause any acute toxicity,but may induce toxicity at cellular/DNA level. Hence, effects ofantibiotic stress on non-target organisms should be detected byusing biomarker tools. The release of antibiotics into the environ-ment resulted in developing its resistance gene and other resistancegenetic material (integrons, transposons, etc.). These resistancegenes were also found in human pathogens and pristine environ-ment, and now these genes can persist and spread even in theabsence of antibiotics.

The authors have declared no conflict of interest.

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