domain: sdv sde

text:
Amine Ezzariai

Mohamed Hafidi

Ahmed Khadra

Quentin Aemig

Loubna El Fels

Maialen Barret

Georges Merlina

Dominique Patureau

Eric Pinelli
email: pinelli@ensat.fr

Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes

Keywords: Sludge, Manure, Composting, Antibiotics, Antibiotic resistance genes

Highlights

 Sludge and manure present high range and level of antibiotics.  Composting is a solution to partially remove some antibiotics.  The transformation pathways are barely known.  The fate of antibiotic resistance genes during composting still remains inconsistent.  Authorized levels of antibiotics in sludge, manure and compost should be considered.

Introduction

Prior to the beginning of the 20 th Century, infectious diseases (cholera, typhoid fever, etc) were expanded worldwide. Thereby, the average life expectancy was 47 years [START_REF] Pinelli | The treasure called antibiotics[END_REF]. Since the discovery of penicillin in 1928, the increase of antibiotic use reduced significantly the mortality rate. Today, antibiotics are widely used in human and veterinary medicine [START_REF] Rice | Use of animal drugs in livestock management[END_REF] (Table 1). The annual use of antibiotics was estimated to be between 100,000 and 200,000 t worldwide [START_REF] Jeong | Degradation of tetracycline antibiotics: Mechanisms and kinetic studies for advanced oxidation/reduction processes[END_REF]. In Europe, 2/3 of antibiotics are used in human medicine and 1/3 for veterinary use [START_REF] Fedesa | Antibiotic use in farm animals does not threaten human health[END_REF]. In the United States, 16,000 t of antimicrobial compounds are used annually, 70% are used for non-therapeutic purposes [START_REF]Hogging it: Estimates of antimicrobial abuse in livestock[END_REF]. The intensive use of antibiotics for human purposes leads to their continuous release into wastewater treatment plants. Moreover, most of the wastewater treatment plants, based on biological aerated systems for example [START_REF] Lester | Integrative Advanced Oxidation and Biofiltration for Treating Pharmaceuticals in Wastewater[END_REF],

were not designed to treat such compounds and present limited performances regarding their elimination [START_REF] Rizzo | Urban wastewater treatment plants as hotspots for antibiotic resistant bacteria and genes spread into the environment : A review[END_REF][START_REF] Polesel | Removal of Antibiotics in Biological Wastewater Treatment Systems -A Critical Assessment Using the Activated Sludge Modeling Framework for Xenobiotics (ASM-X)[END_REF]. So, a part of these molecules is discharged by the wastewater treatment plant effluent toward the aquatic environment and the other part, adsorbed on sludge, could reach the soil according to the sludge use state rules [START_REF] Michael | Urban wastewater treatment plants as hotspots for the release of antibiotics in the environment: A review[END_REF][START_REF] Xu | Occurrence of antibiotics and antibiotic resistance genes in a sewage treatment plant and its effluent-receiving river[END_REF]. Hence, wastewater treatment plants are considered as an anthropogenic source for the environmental contamination by antibiotics [START_REF] Mao | Prevalence and proliferation of antibiotic resistance genes in two municipal wastewater treatment plants[END_REF]. Another hotspot of antibiotic dissemination in the environment is the veterinary use [START_REF] Heuer | Antibiotic resistance gene spread due to manure application on agricultural fields[END_REF][START_REF] Wegst-Uhrich | Assessing antibiotic sorption in soil : a literature review and new case studies on sulfonamides and macrolides[END_REF]. Very high antibiotic concentrations varying from 91 to 136 mg kg -1 of dry matter of sulfonamides [START_REF] Martínez-Carballo | Environmental monitoring study of selected veterinary antibiotics in animal manure and soils in Austria[END_REF] and tetracyclines [START_REF] Winckler | Verhalten von Tetracyclinen und anderen Veterina ¨rantibiotika in Wirtschaftsdu ¨nger und Boden[END_REF], and other molecules were found in manure. As a consequence of these massive discharges into the environment, antibiotics were found in each environmental compartment, in soil [START_REF] Pawelzick | A survey of the occurrence of various tetracyclines and sulfamethazine in sandy soils in northwestern Germany fertilized with liquid manure[END_REF], sediment [START_REF] Rico | Use , fate and ecological risks of antibiotics applied in tilapia cage farming in Thailand[END_REF], surface and groundwater [START_REF] Hirsch | Occurrence of antibiotics in the aquatic environment[END_REF]. Such presence is one of the factors contributing to the spread of antibiotic resistance [19]. Thus, it is necessary to propose strategies to manage and reduce the dissemination of antibiotics [START_REF] Vikesland | Towards a Comprehensive Strategy to Mitigate Dissemination of Environmental Sources of Antibiotic Resistance[END_REF].

Composting is a bioremediation technology able to reduce or eliminate the residual concentrations of antibiotics present in sludge or manure before their application to agricultural fields. The presence of antibiotics and consequently antibiotics resistance genes in sludge and manure and their fate during composting are up to date research topics, particularly since 2009 (Fig. 1). After 2009, the number of publications increased up to 100 publications between 2016 and 2017. The assessment of composting efficiency toward the elimination of antibiotics and their antibiotic resistance genes is still in progress, and needs more knowledge. In the light of the recent researches, providing a global vision and perspectives about the fate of antibiotics and antibiotic resistance genes during composting is highly valuable. In this context, the authors have been worked during 2 years in this review to explore the sources, the dissemination routes and the impacts of antibiotics and their associated antibiotic resistance genes. In addition, the fate of antibiotics and antibiotic resistance genes during composting of sludge or manure was reviewed to assess the potentiality of composting as a strategy to mitigate the dissemination of antibiotics and antibiotic resistance genes.

The occurrence of antibiotics in raw and composted sludge or manure and their impact on the environment after soil application

In the European Union, 53% of the sludge produced by wastewater treatment plants is used in agriculture [START_REF] Kelessidis | Comparative study of the methods used for treatment and final disposal of sewage sludge in European countries[END_REF]. Many antibiotics end up in sewage sludge as shown on the Figure-1a with concentration varying between few nano-grams and 100 mg kg -1 dry matter. The four main families (tetracyclines, sulfonamides, macrolides and fluoroquinolones) have been quantified in raw sludge, including primary, secondary, mixed and dehydrated sludge (Figure . 2a).

In raw sludge, ciprofloxacin, norfloxacin, and tylosine are present at the highest concentration with a median value superior to 1000 µg kg -1 dry matter. Tetracyclines present a high range of concentrations, particularly tetracycline and oxytetracycline, with medians above 10 µg kg -1 dry matter. Macrolides present also medians above 10 µg kg -1 dry matter but with a lower range of concentrations. Sulfonamides present medians around 10 µg kg -1 dry matter. In composted sludge (Fig. 2b), ciprofloxacin and norfloxacin present lower medians than in raw sludge (near 100 µg kg -1 dry matter). For the other compounds, reported values are quite similar between raw and composted sludge. It emphasizes that some compounds are recalcitrant to the biological and physico-chemical transformations occurring during composting. The comparison between Fig. 2a and Fig. 2b revealed that sludge produced on wastewater treatment plants is more studied than the sludge compost, underlying the need to investigate the fate of such compounds during this sludge treatment process and to quantify their presence in the produced organic waste often used as fertilizers on agricultural soil. In the United States, 130 million tons of pig, bovine and chicken manure are produced annually.

In Canada, 177.5 million tons are produced per year [START_REF] Hofmann | A geographical profile of Manure production in Canada-2001[END_REF], in France in 2012, over 274 million tons of livestock wastes were generated and applied on soil [START_REF] Bourdat-Deschamps | Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes[END_REF]. Considering the high use of antibiotics in veterinary medicine and depending on pharmacokinetics and specific transformation processes in the animals, large proportions of antibiotics are usually excreted (30-90%) by urine or faeces [START_REF] Elmund | Role of excreted chlortetracycline in modifying the decomposition process in feedlot waste[END_REF]. Therefore, antibiotics could be released into the environment when urine [START_REF] Mullen | Optimizing extraction and analysis of pharmaceuticals in human urine, struvite, food crops, soil, and lysimeter water by liquid chromatography-tandem mass spectrometry[END_REF] and manure (Fig. 2c) were used directly as fertilizers. A very high range of concentrations was found from µg to g kg -1 dry matter due to the various practices in livestock industries, e.g. use of antibiotics as growth promoters in many developing countries [START_REF] Sarmah | A global perspective on the use, sales, exposure pathways, occurrence, fate and effects of veterinary antibiotics (VAs) in the environment[END_REF]. As it was observed in the Fig. 2a, the Fig. 2c showed that the four main families have been quantified in raw manure. Medians are around 100 and 1000 µg kg -1 dry matter. Nevertheless, the Fig. 2d showed that only one paper reported tetracyclines value on composted manure with also a wide range of concentrations [START_REF] Qiao | Fate of tetracyclines in swine manure of three selected swine farms in China[END_REF]. The fluoroquinolones were not studied after manure composting although they may persist. As previously mentioned for sludge composting, the fate of antibiotics in different composted manures must be studied.

A high proportion of antibiotics and potentially bioactive transformation products reach agriculture fields or soil throughout the direct discharge or application of sludge and manure [START_REF] Bourdat-Deschamps | Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes[END_REF][START_REF] Golet | Determination of Fluoroquinolone Antibacterial Agents in Sewage Sludge and Sludge-Treated Soil Using Accelerated Solvent Extraction Followed by Solid-Phase Extraction[END_REF][START_REF] Sabourin | Runoff of pharmaceuticals and personal care products following application of dewatered municipal biosolids to an agricultural field[END_REF][START_REF] Wu | Plant uptake of pharmaceutical and personal care products from recycled water and biosolids: A review[END_REF][START_REF] Ho | Simultaneous determination of veterinary antibiotics and hormone in broiler manure , soil and manure compost by liquid chromatographytandem mass spectrometry[END_REF]. Concentrations in soil compartment vary according to the history of the field. In soils amended with raw or composted sludge, Bourdat-Deschamps et al. [START_REF] Bourdat-Deschamps | Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes[END_REF] have measured 4-10 µg kg -1 dry matter of fluoroquinolones. Hu et al. [START_REF] Hu | Occurrence and source analysis of typical veterinary antibiotics in manure , soil , vegetables and groundwater from organic vegetable bases , northern China[END_REF] mentioned 2.5-105 µg kg -1 dry matter for tetracylines and 33.1-1079 µg kg -1 dry matter for chortetracycline in soils amended with organic pig manure. Karci and Balcioglu [START_REF] Karci | Investigation of the tetracycline, sulfonamide, and fluoroquinolone antimicrobial compounds in animal manure and agricultural soils in Turkey[END_REF] have quantified sulfonamides (40-400 µg kg -1 dry matter) in soils amended with cattle or chicken manure. Very few papers studied the long-term impact of several spreading on soil concentration. One recent paper emphasized that even if high concentration of antibiotics were found in amended fertilizers, no accumulation in soil and few transfer to soil leachates were observed [START_REF] Bourdat-Deschamps | Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes[END_REF]. These results may be explained by the various dissipation mechanisms occurring in soils according to the physical and chemical proprieties of antibiotics (Table 1). Indeed, the majority of antibiotics have low to moderate persistency in the soil with half-lives comprised between days and months (Table 3). In addition, low (sulfamethoxazole, sulfamethazine log Koc<3) [34,35] or high sorption (fluoroquinolones, log Koc>3) [START_REF] Bourdat-Deschamps | Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes[END_REF] contributes in rendering antibiotics more or less available for water and plant transfer. Indeed, under specific conditions plant uptake have been reported but under field conditions the concentration level of antibiotics in crops has been found to be very low [START_REF] Wu | Plant uptake of pharmaceutical and personal care products from recycled water and biosolids: A review[END_REF]36]. Prosser and Sibley [START_REF] Prosser | Human health risk assessment of pharmaceuticals and personal care products in plant tissue due to biosolids and manure amendments, and wastewater irrigation[END_REF] assessing the human health risk of antibiotics in plant tissues due to sludge or manure amendment concluded to a de minimis risk to human health for individual compound, but consider the existence of a risk in the presence of mixtures. [36,[START_REF] Prosser | Human health risk assessment of pharmaceuticals and personal care products in plant tissue due to biosolids and manure amendments, and wastewater irrigation[END_REF]. Whatever their behavior (persistence, mobility, transfert), their presence in the soil may impact organisms and biodiversity. Batchelder et al. [START_REF] Batchelder | Chlortetracycline and oxytetracycline effects on plant growth and development in liquid cultures[END_REF] tested the effect of showed that a low antibiotic concentration can influence the plant growth. Khadra et al. [START_REF] Khadra | Assessment of the genotoxicity of quinolone and fluoroquinolones contaminated soil with the Vicia faba micronucleus test[END_REF] showed an important genotoxic effect of the quinolones and fluoroquinolones on Vicia faba root tip, even at low concentrations of antibiotic mixtures. Antibiotics release was also shown to contribute to the dissemination of the antimicrobial resistance thanks to a concomitant release of antibiotic resistant bacteria and antibiotic resistance genes implying an enrichment of the environmental resistome [START_REF] Chen | Development and application of real-time PCR assays for quantification of erm genes conferring resistance to macrolides-lincosamides-streptogramin B in livestock manure and manure management systems[END_REF].

The development of antibiotic resistance still remains a very complex process, and even more with antibiotic concentrations below the inhibitory threshold. Bacteria can be intrinsically resistant to certain antibiotics but can also acquire resistance to antibiotics via horizontal gene transfer [START_REF] Wright | Molecular mechanisms of antibiotic resistance[END_REF]. Many researchers have demonstrated that sewage sludge contained large amounts of resistant genes [START_REF] Munir | Release of antibiotic resistant bacteria and genes in the effluent and biosolids of five wastewater utilities in Michigan[END_REF][START_REF] Naquin | Presence of antibiotic resistance genes in a sewage treatment plant in Thibodaux, Louisiana, USA[END_REF] to tetracyclines [START_REF] Guillaume | PCR typing of tetracycline resistance determinants ( Tet A-E ) in Salmonella enterica serotype Hadar and in the microbial community of activated sludges from hospital and urban wastewater treatment facilities in Belgium[END_REF][START_REF] Auerbach | Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes[END_REF][START_REF] Diehl | Effect of Temperature on the Fate of Genes Encoding Tetracycline Resistance and the Integrase of Class 1 Integrons Within Anaerobic and Aerobic Digesters Treating Municipal Wastewater solids[END_REF][START_REF] Zhang | Tetracycline resistance genes and tetracycline resistant lactose-fermenting Enterobacteriaceae in activated sludge of sewage treatment plants[END_REF][START_REF] Zhang | Occurrence, abundance, and diversity of tetracycline resistance genes in 15 sewage treatment plants across china and other global locations[END_REF][START_REF] Gao | Antibiotic resistance of Streptococcus agalactiae from cows with mastitis[END_REF], sulfonamides [START_REF] Gao | Antibiotic resistance of Streptococcus agalactiae from cows with mastitis[END_REF], macrolides [START_REF] Zhang | Occurrence, abundance, and diversity of tetracycline resistance genes in 15 sewage treatment plants across china and other global locations[END_REF] and antibiotic resistant bacteria that are usually multi-resistant (Escherichia coli or Enterobacteriaceae [START_REF] Olańczuk-Neyman | Identification and antimicrobial resistance of Enterococcus spp. isolated from surface water[END_REF][START_REF] Moura | Novel gene cassettes and integrons in antibiotic-resistant bacteria isolated from urban wastewaters[END_REF][START_REF] Reinthaler | ESBL-producing E. coli in Austrian sewage sludge[END_REF][START_REF] Kaplan | Characterization of fluoroquinolone resistance and qnr diversity in Enterobacteriaceae from municipal biosolids[END_REF], Enterococcus [START_REF] Martins Da Costa | Antimicrobial resistance in Enterococcus spp. isolated in inflow, effluent and sludge from municipal sewage water treatment plants[END_REF], Peudomonas sp [START_REF] Kaszab | Antibiotic resistance profiles and virulence markers of Pseudomonas aeruginosa strains isolated from composts[END_REF], Staphylococcus aureus [START_REF] Börjesson | A seasonal study of the mecA gene and Staphylococcus aureus including methicillin-resistant S. aureus in a municipal wastewater treatment plant[END_REF] and Salmonella sp [START_REF] Sahlström | Salmonella isolated in sewage sludge traced back to human cases of salmonellosis[END_REF]). Antibiotic resistance genes and antibiotic resistant bacteria are also present in livestock manure [START_REF] Koike | Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes[END_REF][START_REF] Whitehead | Stored swine manure and swine faeces as reservoirs of antibiotic resistance genes[END_REF][START_REF] Zhang | Impacts of addition of natural zeolite or a nitri fi cation inhibitor on antibiotic resistance genes during sludge composting[END_REF][START_REF] Chambers | Metagenomic analysis of antibiotic resistance genes in dairy cow feces following therapeutic administration of third generation cephalosporin[END_REF][START_REF] Glaeser | Cultivation of vancomycin-resistant enterococci and methicillin-resistant staphylococci from input and output samples of German biogas plants[END_REF]. Antibiotic resistance genes can be readily disseminated via bacterial division and horizontal gene transfer among bacteria in the environment [START_REF] Binh | Piggery manure used for soil fertilization is a reservoir for transferable antibiotic resistance plasmids[END_REF]. Therefore, a transfer of antibiotics resistance determinant toward bacteria of human beings including pathogens is established [START_REF] Binh | Piggery manure used for soil fertilization is a reservoir for transferable antibiotic resistance plasmids[END_REF]. It has been estimated that antibiotic resistance is responsible for more than 25,000 and 23,000 deaths every year in the European Union and the United States respectively [START_REF] Berglund | Environmental dissemination of antibiotic resistance genes and correlation to anthropogenic contamination with antibiotics[END_REF]. Infections by antibiotic resistant bacteria have an annual cost of 1.5 billion dollars in the European Union [START_REF] Wright | Molecular mechanisms of antibiotic resistance[END_REF]. Antibiotics and antibiotic resistance genes are considered as new contaminants and may pose a potential worldwide human health risk [START_REF] Vikesland | Towards a Comprehensive Strategy to Mitigate Dissemination of Environmental Sources of Antibiotic Resistance[END_REF][START_REF] Zhu | Diverse and abundant antibiotic resistance genes in Chinese swine farms[END_REF][START_REF] Franklin | Antibiotics in Agroecosystems: Introduction to the Special Section[END_REF]. Therefore, improving the removal of antibiotics and antibiotic resistance genes from sewage sludge or manure before their application to soil is necessary.

The fate of antibiotics during composting

Several processes used to treat sludge or manure may impact the fate of antibiotics.

Incineration was used to dispose of sludge [START_REF] Pruden | Management options for reducing the release of antibiotics and antibiotic resistance genes to the environment[END_REF]. However, a large quantity of energy is required. In addition, high amounts of nutrients are transformed into nitrogen oxides, and even dioxins are produced during the process. Pasteurization, thermal hydrolysis, advanced oxidation processes and ammonia treatment can also be used [START_REF] Malmborg | Pharmaceutical residues in sewage sludge : Effect of sanitization and anaerobic digestion[END_REF]. But the elevated costs of these processes limit their application. manure management, anaerobic digestion was also tested in several researches [START_REF] Lallai | The effects of certain antibiotics on biogas production in the anaerobic digestion of pig waste slurry[END_REF][START_REF] Arikan | Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes[END_REF]. On one hand, a significant inhibition of anaerobic digestion was shown at very high antibiotic concentrations (up to 100 mg L -1 ), for example, by affecting the methane production [START_REF] Mitchell | The effects of the antibiotics ampicillin, florfenicol, sulfamethazine, and tylosin on biogas production and their degradation efficiency during anaerobic digestion[END_REF][START_REF] Sara | Effect of veterinary antibiotics on biogas and bio-methane production[END_REF][START_REF] Shi | Effect of antibiotics on methane arising from anaerobic digestion of pig manure[END_REF],

and on the other hand, a lower antibiotic degrading ability was also observed [START_REF] Álvarez | The effect and fate of antibiotics during the anaerobic digestion of pig manure[END_REF].

Since aerobic system like composting is one of the promising options to manage contaminated sludge and manure, an overview of the fate of antibiotics and antibiotic resistance genes during this process is presented below.

a. Composting

Composting is an aerobic biological decomposition process where pH, C/N ratio, and moisture are controlled in the initial mixture to be composted. These key factors determine the microbial development and the organic matter stabilization. Microorganisms growing during composting reflect the evolution and the performance of the process. The different communities occurring during composting are: bacteria, Actinobacteria, fungi, protozoa or algae [START_REF] Hassen | Microbial characterization during composting of municipal solid waste[END_REF]. Composting consists of two main stages. During the thermophilic stage, the organic matter undergoes firstly a microbial decomposition which liberates CO2 and ammonia. The organic matter degradation is accompanied by a heat release involved in the elimination of pathogens [START_REF] Tuomela | Biodegradation of lignin in a compost environment: A review[END_REF]. At the end of the thermophilic stage, the easily biodegradable part (sugars, amino acids) is completely mineralized. During the maturation stage, another part of the less biodegradable organic matter such as lignin serves as a new material to build molecules leading to humic substances [START_REF] Tiquia | Carbon, nutrient, and mass loss during composting[END_REF][START_REF] Kögel-Knabner | Analytical approaches for characterizing soil organic matter[END_REF]. Regarding the agronomical value of the final product, composting has been widely used for producing soil amendments [START_REF] Li | Characteristics of dairy manure composting with rice straw[END_REF][START_REF] Himanen | Composting of bio-waste, aerobic and anaerobic sludges -Effect of feedstock on the process and quality of compost[END_REF].

b. The efficiency of antibiotics removal during composting

Composting is an effective approach for stabilizing sludge and manure via the biological degradation of organic matter. It has also been shown to be effective in reducing the levels of persistent organic pollutants [START_REF] Poulsen | Organic micropollutant degradation in sewage sludge during composting under thermophilic conditions[END_REF][START_REF] Sadef | Uncertainty in degradation rates for organic micro-pollutants during full-scale sewage sludge composting[END_REF] and certain antibiotics [START_REF] Liu | Effects of composting process on the dissipation of extractable sulfonamides in swine manure[END_REF][START_REF] Youngquist | Fate of Antibiotics and Antibiotic Resistance during Digestion and Composting: A Review[END_REF][START_REF] Ray | Fate and Effect of Antibiotics in Beef and Dairy Manure during Static and Turned Composting[END_REF][START_REF] Cessna | Veterinary Antimicrobials in Feedlot Manure: Dissipation during Composting and Effects on Composting Processes[END_REF][START_REF] Dolliver | Antibiotic Losses in Leaching and Surface Runoff from Manure-Amended Agricultural Land[END_REF][START_REF] Mitchell | Antibiotic degradation during thermophilic composting[END_REF]. Indeed, the fate of antibiotics during composting was followed in several studies as summarized in the Table 2.

The main findings on recent studies are summarized hereafter:

 The tetracyclines family is the most studied one followed by sulfonamides, macrolides and fluoroquinolones;

 82% of these studies were conducted at laboratory scale using a reactor and only 18%

were carried out by windrowing the compost mixture; High antibiotics concentrations are often used during these experiments, showing no inhibition on the organic matter degradation [START_REF] Hu | Characterization of organic matter degradation during composting of manure-straw mixtures spiked with tetracyclines[END_REF][START_REF] Bao | Depletion of chlortetracycline during composting of aged and spiked manures[END_REF] and thus underlying that composting biomasses are either tolerant to such level or develop resistance mechanisms including degradation ability. In some cases, the antibiotic removal was correlated to several parameters such as total organic carbon, total nitrogen, phosphorus, total organic carbon / total nitrogen, total organic carbon / phosphorus and metallic trace elements [START_REF] Bao | Depletion of chlortetracycline during composting of aged and spiked manures[END_REF]. However, some authors showed also that the heat release and organic matter degradation can be delayed by increasing antibiotic concentration. The effect of antibiotics on composting performances depends on the type of antibiotic and the level of concentrations. At 35 mg kg -1 dry matter, erythromycin affected the peak temperature while oxytetracycline, norfloxacin and tylosine did not [START_REF] Eguchi | Establishment of evaluation method to determine effects of veterinary medicinal products on manure fermentation using small-scale composting apparatus[END_REF]. In addition, it was shown that high antibiotics mixture concentrations (50 mg kg -1 chortetracycline + 10 mg kg -1 sulfadiazine + 5 mg kg -1 ciprofloxacin), delayed the organic matter decomposition and affected the removal of ciprofloxacin by comparison to the complete chortetracycline and sulfadiazine removals [START_REF] Selvam | Composting of swine manure spiked with sulfadiazine, chlortetracycline and ciprofloxacin[END_REF]. In a more recent study [START_REF] Ezzariai | Evaluation of the antibiotics effects on the physical and chemical parameters during the co-composting of sewage sludge with palm wastes in a bioreactor[END_REF], high antibiotics concentrations (50-250, 20-100 and 10-50 mg kg -1 dry matter for tetracyclines, macrolides and fluoroquinolones respectively) decreased the thermophilic stage duration, temperature increase and decrease as well as the heat release. Additionally, the efficiency of the composting system and the compost quality (organic matter degradation and C/N ratio)

were altered for the highest antibiotic concentrations. The thermophilic conditions occurring during composting seemed to have a huge impact on the tetracyclines elimination [START_REF] Arikan | Management of antibiotic residues from agricultural sources: Use of composting to reduce chlortetracycline residues in beef manure from treated animals[END_REF][START_REF] Wu | The behavior of tetracyclines and their degradation products during swine manure composting[END_REF]. Arikan et al. [START_REF] Arikan | Management of antibiotic residues from agricultural sources: Use of composting to reduce chlortetracycline residues in beef manure from treated animals[END_REF] showed a very fast removal of chortetracycline at 55°C by comparison to 25°C. It was confirmed by Wu et al. [START_REF] Wu | The behavior of tetracyclines and their degradation products during swine manure composting[END_REF] with chortetracycline, oxytetracycline and tetracycline removals of 74%, 92% and 70% respectively during the thermophilic phase. The degradation kinetics of these three antibiotics fitted with a first order model and allowed to calculate half-live for chortetracycline, tetracycline and oxytetracycline of 8.2, 11 and 10 days, respectively, indicating that chortetracycline was the more degraded compound [START_REF] Wu | The behavior of tetracyclines and their degradation products during swine manure composting[END_REF]. Liu et al. [START_REF] Liu | Effects of composting process on the dissipation of extractable sulfonamides in swine manure[END_REF] showed similar results

for sulfonamides with highest dissipation rate at high temperature. The effect of thermophilic condition on antibiotics removal could be enhanced by the type of the substrate. For example, sulfonamide removal is more important in swine manure than chicken manure. In addition, sulfonamide transformation could be more pronounced in chicken manure at 30°C rather than 60°C [START_REF] Lin | Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes[END_REF]. These results suggested that the microbial community composition, related to the used substrate, played a crucial role in removing antibiotics. The microbial intensity regarding antibiotic removal is not conditioned, in all times, to high temperature. The microbial intensity could be enhanced on the basis of other parameter than temperature. The acclimatized sludge could play an important role in the biodegradation of antibiotics in the microbial fuel cell. The faster oxidation of the co-substrate to produce more electrons for sulfamethoxazole leading to their accelerated degradation [START_REF] Miran | Biodegradation of the sulfonamide antibiotic sulfamethoxazole by sulfamethoxazole acclimatized cultures in microbial fuel cells[END_REF].

The substrates used during composting play an important role regarding antibiotics elimination. The fate of chortetracycline, sulfamethazine and tylosine at 3 concentrations (2, 10 and 20 mg kg -1 dry matter) showed that chortetracycline and sulfamethazine removal depends on the presence of straw but tylosine removal did not [START_REF] Kim | Decline in extractable antibiotics in manure-based composts during composting[END_REF]. At high temperature, straw provides a wide range of additional biding sites favorable for the chortetracycline and sulfamethazine adsorption. Antibiotics adsorption on co-substrates (palm rachis matrix for example) could reduce the bioavailability of antibiotics towards the microorganism involved during composting, and then explain why composting process was not entirely inhibited by high antibiotic concentration [START_REF] Ezzariai | Evaluation of the antibiotics effects on the physical and chemical parameters during the co-composting of sewage sludge with palm wastes in a bioreactor[END_REF].

The coexistence of other pollutants with antibiotics and their influence on the elimination of antibiotics during composting was the object of a study carried out by Liu et al. [START_REF] Liu | Effects of composting process on the dissipation of extractable sulfonamides in swine manure[END_REF]. Indeed, these authors showed that the dissipation of sulfonamides was slightly delayed in the presence of 2000 mg kg -1 of copper. This inhibitory effect could be explained by the toxicity of copper to microorganisms involved in the sulfonamides degradation. The reported data in the Table 2 showed that the tetracycline family is the most studied.

Generally, the most of tetracycline molecules are degradable after composting. Then, the compost could be used safely in soil as it was reported in several studies [START_REF] Selvam | Composting of swine manure spiked with sulfadiazine, chlortetracycline and ciprofloxacin[END_REF][START_REF] Arikan | Management of antibiotic residues from agricultural sources: Use of composting to reduce chlortetracycline residues in beef manure from treated animals[END_REF][START_REF] Arikan | Composting rapidly reduces levels of extractable oxytetracycline in manure from therapeutically treated beef calves[END_REF]. The recalcitrant molecules to the degradation (fluoroquinolone) are less studied, probably due to several analytical challenges that we have revealed in some of our current studies. So, the future studies need to focus on recalcitrant antibiotics and how the composting process could be optimized to improve their removal. Extensive studies including the role of temperature and time could provide more interesting data on the removal of recalcitrant antibiotics. In the same way, the potential risks of recalcitrant antibiotic after the use of composts in the agriculture soil (fauna and flora) must be investigated. A lot of studies reported in the Table 2 focused on the removal on extractible parent forms of antibiotics and concluded that compost could be safely used in the soil. However, the elimination of parent compounds are not sufficient. The presence of transformation products (metabolites) with active forms need to be investigated to ensure the safety of the final products. Antibiotics, and more particularly fluoroquinolone family and their transformation products represent an important environmental concern, and must be the subject of the future regulation dealing with sludge or compost valorization.

c. The mechanisms of elimination of antibiotics during composting

The physicochemical properties of antibiotics (Table 1) drive their fate (persistence, mobility) during composting. Moreover the physicochemical conditions and the degradation of organic matter occurring during the composting process may influence the fate of these molecules by changing their availability, i.e., their chemical form and their interactions with the organomineral matrix. Indeed, several processes could be implied in their removal, i.e., volatilization, abiotic and biotic transformation, mineralization, sequestration (formation of bound residues, non-extractible by the analytical methods). On the described literature in demeclocycline) were quantified and their removal also assessed. In the experiment of Kim et al. [START_REF] Kim | Decline in extractable antibiotics in manure-based composts during composting[END_REF], the addition of sawdust to manure composting had a significantly positive effect on the removal of chortetracycline; the authors hypothesized that sorption plays a main role in this removal due to great quantity of divalent cations present in these organic matrices and the possible formation of chelates complexes with organic substances. In counterpart, tyosine do not form complexes with metal ions, but can form strong chemical bonds with negatively charged compounds in manure [START_REF] Kim | Decline in extractable antibiotics in manure-based composts during composting[END_REF], accelerating the decline of the extractible antibiotic levels. Paesen et al. [START_REF] Paesen | Study of the stability of tylosin A in aqueous solutions[END_REF] described the hydrolysis of A-Tylosine to B-Tylosine under acid conditions. Under neutral and alkaline conditions, the compound produces Tylosine-A-aldol at the same time as other polar decomposition products. The hydrolysis of tylosine is reported to be high over the whole pH range from 2 to 13. For the sulfonamides, the decline in concentration of these molecules could be linked to the presence of organic substances, which generate adsorption sites at high temperatures during the composting process rendering them less extractible [START_REF] Hartlieb | Mineralization, metabolism and formation of non-extractable residues of 14C-labelled organic contaminants during pilot-scale composting of municipal biowaste[END_REF]. Humic substances play also an important role in the elimination of antibiotics. The production of humic substances leads to the sequestration of antibiotics within organic and inorganic matter that render them less extractable as hypothesized by Ho et al. [START_REF] Ho | Degradation of veterinary antibiotics and hormone during broiler manure composting[END_REF] for various antibiotics during 40 days broiler manure composting.

The processes involved in antibiotics removal still remained not elucidated. Biodegradation could be responsible of the antibiotics decrease. Elsewhere, there is no study highlighting the real antibiotics biotransformation as a result of organic matter mineralization. Some abiotic processes could be also implied such as sequestration and/or chemical transformation. Indeed, biotic and abiotic processes are two concomitant removal pathways that have to be elucidated to gain better understanding and propose process optimization strategies.

The fate of antibiotics resistance genes during composting

Several researches investigated the fate of antibiotic resistance genes during composting (Table 4).These studies focused on the most important parameters involved in the antibiotic resistance genes removal during the composting of sludge or manure. A brief resume of the studied conditions is presented hereafter:

 4 studies were conducted on sewage sludge whereas 20 studies were focused on different types of manure (swine, chicken, cattle, poultry, pig, cow, duck, bovine and dairy manure);  To assess the fate of antibiotic resistance genes during composting, their removals are expressed in percentage (%) or by calculating the absolute or relative abundance (logs units, copies/16S rRNA, copies/g Total Solid or copies/g dry matter);

The main outcomes are:

 The addition of antibiotics, surfactants (biological or chemical), natural zeolite, biochar or metallic trace-elements are able to control the antibiotic resistance genes abundance and removal during composting;

 The bacterial communities, the abundance of transposons and horizontal gene transfer are some keys parameters implied in the antibiotic resistance genes removal.

 The composting stages (mesophilic, thermophilic and cooling phases) and their duration as well as physicochemical parameters (pH, moisture, ammonium nitrogen, and water-soluble carbon contents) play a crucial role regarding the antibiotic resistance genes removal.

 Some studies showed the effectiveness of composting on the antibiotic resistance genes removal but other ones showed the persistence and the increase of the concentrations of some antibiotic resistance genes after composting.

In the study of Selvam et al. [START_REF] Selvam | Fate of tetracycline, sulfonamide and fluoroquinolone resistance genes and the changes in bacterial diversity during composting of swine manure[END_REF], sulfonamides, tetracyclines and fluoroquinolones resistance genes represented respectively 10.28, 1.91 and 0.00022% of the 16S rDNA copies in the initial compost. After 42 days of composting, no antibiotic resistance genes were detected for the studied antibiotics. Yu et al. [START_REF] Yu | Development and Application of Real-Time PCR Assays for Quantification of Genes Encoding Tetracycline Resistance[END_REF] found also a complete removal of tetracycline antibiotic resistance genes for the ribosomal protection protein groups in swine manure compost, and a reduction of 6 logs for others belonging to the ''efflux" group. In the same way, Chen et al. [START_REF] Chen | Development and application of real-time PCR assays for quantification of erm genes conferring resistance to macrolides-lincosamides-streptogramin B in livestock manure and manure management systems[END_REF] reported a reduction (7.3 logs) in the abundance of erythromycin antibiotic resistance genes during swine manure. Wang et al. [START_REF] Wang | Effect of red mud addition on tetracycline and copper resistance genes and microbial community during the full scale swine manure composting[END_REF] reported a partial removal of the tetracyclines antibiotic resistance genes (2.4 log copies/g dry matter) especially in the parameter related to the transfer of a mobile plasmid (pIE732) [START_REF] Guan | Influence of temperature on survival and conjugative transfer of multiple antibiotic-resistant plasmids in chicken manure and compost microcosms[END_REF]. In this study, chicken manure and compost were incubated separately at 23 and 50°C. The plasmid transfer from E.

coli occurred in manure and compost at 23°C. At 50°C, plasmid transfer was not confirmed.

High temperature is a main contributor in reducing (i) antibiotic resistance genes transfer and

(ii) pathogen bacteria's [START_REF] Wu | Influence of two-phase anaerobic digestion on fate of selected antibiotic resistance genes and class I integrons in municipal wastewater sludge[END_REF].

Other studies showed contradictory results. Indeed, while a removal of 100% for oxytetracycline and sulfamethazine was reached during swine manure composting, a proliferation of the corresponding antibiotic resistance genes was observed by Wang et al. [START_REF] Wang | Effects of thermophilic composting on oxytetracycline, sulfamethazine, and their corresponding resistance genes in swine manure[END_REF]. Another recent study conducted by Kang et al. [START_REF] Kang | Short-term thermophilic treatment cannot remove tetracycline resistance genes in pig manures but exhibits controlling effects on their accumulation and spread in soil[END_REF] showed that the short-term thermophilic compost treatment could not remove the tetracycline resistance genes in pig manure.

The presence of heavy metals in sludge or manure at high level [START_REF] Amir | Sequential extraction of heavy metals during composting of sewage sludge[END_REF][START_REF] Fels | Efficiency of co-composting process to remove genotoxicity from sewage sludge contaminated with hexavalent chromium[END_REF] is considered as a co-selection factor for antibiotic resistance genes reduction [START_REF] Stepanauskas | Elevated microbial tolerance to metals and antibiotics in metalcontaminated industrial environments[END_REF][START_REF] Baker-Austin | Co-selection of antibiotic and metal resistance[END_REF][START_REF] Ji | Antibiotic resistance gene abundances associated with antibiotics and heavy metals in animal manures and agricultural soils adjacent to feedlots in Shanghai ; China[END_REF][START_REF] Cui | Effect of different biochars on antibiotic resistance genes and bacterial community during chicken manure composting[END_REF]. Antibiotic resistance genes come into contact with heavy metals which could drive the selection and the evolution (increase/decrease) of antibiotic resistance bacteria [START_REF] Becerra-Castro | Assessment of copper and zinc salts as selectors of antibiotic resistance in Gram-negative bacteria[END_REF]. The bioavailable fraction of heavy metals acts as a selective pressure on microbes [START_REF] Seiler | Heavy metal driven co-selection of antibiotic resistance in soil and water bodies impacted by agriculture and aquaculture[END_REF]. Using a co-substrate such as biochar or superabsorbent polymers (sodium poly-acrylate) during composting could help to adsorb heavy metals, decreasing their availability and then contributing to reduce the selective pressure on antibiotic resistance bacteria [START_REF] Li | Effects of bamboo charcoal on antibiotic resistance genes during chicken manure composting[END_REF][START_REF] Hofmann | A geographical profile of Manure production in Canada-2001[END_REF]. Nevertheless, the mechanisms involved on the dynamics of antibiotic resistance genes in the presence of heavy metals during composting are still unclear.

Basing on the reported data in the table 4, several studies confirmed that some antibiotic resistance genes were partially eliminated after composting and clearly demonstrated the contribution of high temperature, microbial community composition/changes and composting duration. Other studies revealed that the presence and the availability of other pollutants, such as heavy metals, could affect either the increase or the reduction of antibiotic resistance genes.

Specific research on removal of these antibiotics resistance genes, including the role of temperature during extended periods of time are needed. In addition, very few information about the microbial mechanisms involved on antibiotic resistance genes transfer are reported. In the same way, the associated risks of antibiotic resistance genes transfer after compost utilization are also very scarce. Hence, the fate of antibiotic resistance genes during sludge or manure composting still remains unclear and needs more detailed researches to determine optimizing removal strategies.

Conclusions and perspectives

The use of antibiotics in human or veterinary medicine is continuously increasing and leads to the emergence of these molecules as well as antibiotic resistance genes and antibiotic resistant bacteria on the whole environment compartments. The consequences on human health can involve countless deaths. The research on the mobility, the persistence, and the mechanisms of antibiotics elimination is still in progress. Although, developing common tools to assess the environmental proliferation or attenuation of antibiotic resistances and their impact on the environment and health is recommended.

Composting is a promising solution to eliminate or reduce the discharge of antibiotics and antibiotic resistance genes. However, lots of the studies were conducted at lab-scale under controlled conditions with very high antibiotics concentration (often spiked) and none of them elucidate the real mechanisms behind the removal performances, i.e., biotic or abiotic transformations, bound residues formation. This literature review highlighted the importance of process management (temperature, co-composting substrates) regarding the fate of antibiotics and antibiotic resistance genes. More research is still needed to better understand the driving mechanisms during antibiotics and antibiotic resistance genes removal as well as their interactions. This better understanding is a prerequisite for identifying better but compromised process management practices that simultaneously target antibiotics and antibiotic resistance genes, in order to reduce their load to the environment. The increase of the composting period can leave more time for antibiotics degradation especially during the maturation stage but may lead to proliferation of antibiotic resistance genes. Regarding the major role of sludge and manure land application in the dissemination of antibiotics and antibiotic resistance genes and the related environment and health issues, the establishment of standards regarding the authorized levels of antibiotics in sludge, manure and compost before the direct land application should be considered. Table 1. Selected examples of commonly used human and veterinary antibiotics and their physical and chemical properties -The relative abundance of antibiotic resistance genes were of 0.05 and 0.14 copies/16S rRNA genes respectively after hyperthermophilic and conventional composting.

-Hyperthermophilic condition.

[105] -The enrichment of antibiotic resistance genes was observed during composting.

-Bacterial phylogenetic; compositions. [START_REF] Su | Antibiotic Resistome and Its Association with Bacterial Communities during Sewage Sludge Composting[END_REF] Tetracycline (tetM, tetO, tetQ, tetS, tetT, tetWtetB/P; tetC, tetE, tetG, tetH, tetYandtetZ) Sulfonamide (sul1, sul2, sul3, dfrA1, drfA2 and drfA7) Fluoroquinolone (gyrA and parC)

-Swine manure and sawdust mixed at a ratio of 1:1 (v/v).

-Lab-scale reactor -Composting duration: 56 days Yes (Spiking at two levels)

-Resistance genes of tetracycline, sulfonamide and fluoroquinolone represented 0.02-1.91, 0.67-10.28 and 0.00005-0.0002%, respectively, of the total 16S rDNA copies in the initial compost mass.

No detection of antibiotic resistance genes except parC -Thermophilic stage; -The addition of antibiotics; -The bacterial diversity. [START_REF] Selvam | Fate of tetracycline, sulfonamide and fluoroquinolone resistance genes and the changes in bacterial diversity during composting of swine manure[END_REF] Tetracycline (tetA, tetB, tetC, tetL, tetO, tetM, tetW and tetX).

-Swine manure mushroom and red mud.

-The windrow size is about 27 m 3 .

-Two windrows by adding the red mud (RM) and a control (CK) without adding the red mud.

No

--antibiotic resistance genes in swine manure were removed after composting (by 2.4 log copies/g TS), especially during the -Bacterial community; -The addition of red mud. -Temperature; -Adding biochar.

[121]

Tetracycline (tetC, tetG, tetQ, tetW, and tetX), Sulfonamide (sul1, sul2, and dfrA7) Macrolide (ermF, ermQ, and ermX) Quinolone (qnrS, qnrD, and aac(6′)-ib-cr).

-Swine manure and wheat straw mixture at a ratio of 1:1 (v/v).

-Lab-scale composting reactor.

-Sodium polyacrylate (SP) was added at two levels + control without SP (CK).

-Composting duration: 35 days No -Absolute abundance of antibiotic resistance genes in the initial material were ranged from 10 7 to 10 10 copies g -1 DW.

-The absolute abundance of all the antibiotic resistance genes detected in the CK decreased by 8.12-96.70%. -Greater reductions in the absolute abundance of antibiotic resistance genes were obtained in the H treatment than the other two treatments.

-pH, moisture and bacterial community; -Addition of sodium polyacrylate. [START_REF] Guo | Effects of superabsorbent polymers on the abundances of antibiotic resistance genes, mobile genetic elements, and the bacterial community during swine manure composting[END_REF] 144 antibiotic resistance genes encoding potential resistance to macrolide, lincosamide, streptogramin B, aminoglycoside, multidrug, tetracycline, and β-lactam.

-Cattle manure and sawdust.

-Conventional composting by windrow. -MHRs; -Changes in the microbial communities.

No

[134]

ARGs conferring resistance to multidrug, aminoglycoside, betalactam, tetracycline, vancomycin, macrolide, lincosamide and streptogramin B, fluoroquinolone, chloramphenicol and sulfonamides.

-Cattle, poultry, and swine manure mixed with rice straw.

-Large-scale commercial composting.

No

-Abundance of antibiotic resistance genes in raw cattle and poultry manure: 1.9 and 5.5 copies/cell.

-Abundances in the final cattle and poultry mature composts : 0.2 and 1.8 copies -Thermophilic composting ; -Some antibiotic resistance genes persist after composting; -Optimal conditions and composting duration.

[106]

Tetracycline (tetA, tetB, tetC, tetE, tetG, tetK, tetL, tetM, tetO, tetQ, tetW and tetX) Sulfonamide (sulI, sulII and sulⅢ) Fluoroquinolone (gyrA, gyrB,parC and parE) Macrolides (ermB, ermC,ermEandermF).

-Pig manure and sawdust (ratio of 5 :1 (v/v)).

-Compost mixture quantity: 8. -Temperature and ammonium nitrogen. -The Microbial community ; -The bio-availability of heavy metals. [START_REF] Cui | Effect of different biochars on antibiotic resistance genes and bacterial community during chicken manure composting[END_REF] Tetracycline (tetA, tetB, tetC, tetE, tetG, tetM, tetO, tetQ, tetT, tetW, and tetX) Sulfonamide (sul1, sul2, sulA, dfrA1, and dfrA7).

-Cow manure and straw mixed at a ratio of 4:1 (v/v).

-Conventional composting by windrow.

-Composting duration: 40 days

Yes

The cow manure was spiked by oxytetracycline at 3 levels --The RAs of tetC, tetX, sul1, sul2, and intI1 increased 2-43 times, while those of tetQ, tetM, and tetW decreased by 44-99%.

-The oxytetracycline addition increased the absolute abundance and RAs of tetC and intI1, while the highest concentration (200 mg/kg) of oxytetracycline also enhanced those of tetM, tetQ, and drfA7.

-The bacterial community; -Composting was not effective in reducing most of the ARGs.

[137]

Tetracycline (tetC, tetG, tetM, tetQ, tetW, and tetX), Sulfonamide (sul1, sul2, and dfrA7) Macrolide (ermB, ermF, and ermX) Quinolone (aac(60)-Ib-cr).

- -Temperature and the water-soluble carbon contents; -RL and Tw. [START_REF] Zhang | Effects of adding different surfactants on antibiotic resistance genes and intI1 during chicken manure composting[END_REF] 12 ARGS (tetB, tetL, tetM, tetW, tetQ, tetX; sul1, sul2,cfr, cmlA, fexA, andfloR) -Pig and duck manure, sawdust, rice straw biochar (RSB) and mushroom biochar (MB).

-Rectangular foam container.

-Composting duration: 42 days Yes Animal feeding operations -Total abundance of antibiotic resistance genes was 3.75×10 - 1 copies/g (duck manure) which is 3.7 times higher than in pig manure.

-The average removal of antibiotic resistance genes was 2.56 and 2.09 log units in duck and pig manure compost.

-Biochar addition; -The type of biochar and manure. [START_REF] Cui | The behavior of antibiotic resistance genes and arsenic influenced by biochar during different manure composting[END_REF] Tetracycline (tetB, tetC, tetM, tetO, tetT, and tetZ) -Pig manure -Petri dishes were incubated at 60°C -Thermophilic composting duration: 4 days Yes Animal feeding operations ---Thermophilic composting cannot remove tetracycline resistance genes in pig manures. [START_REF] Kang | Short-term thermophilic treatment cannot remove tetracycline resistance genes in pig manures but exhibits controlling effects on their accumulation and spread in soil[END_REF] blatem, tet(M), sul1, sul2, ermB -Chicken manure -Composting heap -Composting duration: 6 weeks

Yes

Animal feeding operations ---Colistin administration had no impact on the antibiotic resistance genes; -Composting is insufficient to eliminate ARGs.

[140]

109 antibiotic resistance genes conferring resistance to aminoglycoside, MLSB, tetracycline, -lactame, multidrug, vancomycin, chloramphenicol, sulfonamide.

-Bovine, chicken and pig manure -Industrial composting using 12 different composting mixtures -Composting duration: 15-90 days --The total abundances (copies/16S rRNA) in bovine, chicken, and pig manure were 0.08-0.28, 1.71-3.07, and 0.54-1.49 respectively -The total abundances (copies/16S rRNA) were 0.06-0.52, 0.08-0.36,and 0.11-1.17 in bovine, chicken, and pig composts respectively -Animal species, the abundance of transposons, heavy metal concentration, total nitrogen level, dosage and duration of exposure to antibiotics; -Some antibiotic resistance genes were reduced after composting, but other antibiotic resistance genes were inconsistently influenced. [START_REF] Qian | Diversity , abundance , and persistence of antibiotic resistance genes in various types of animal manure following industrial composting[END_REF] Tetracycline (tetA, tetB/P, tetC, tetE, tetG, tetM, tetO, tetQ, tetT, tetW, and tetX) Sulfonamide (sul1, sul2, sulA, dfrA1, and dfrA7) Fluoroquinolone (gyrA, parC, qnrA, qnrC, qnrS, and aac( 6 -Temperature; -Bacterial community; -Copper addition.

[144]

  I P T 1. Introduction ......................................................................................................................... 2. The occurrence of antibiotics in raw and composted sludge or manure and their impact on the environment after soil application ........................................................................................ 3. The fate of antibiotics during composting .......................................................................... a. Composting ..................................................................................................................... b. The efficiency of antibiotics removal during composting .............................................. c. The mechanisms of elimination of antibiotics during composting ............................... 4. The fate of antibiotics resistance genes during composting ............................................. 5. Conclusions and perspectives ........................................................................................... Acknowledgement .................................................................................................................... References ................................................................................................................................

  Comment citer ce document : Ezzariai, A., Hafidi, M.,Khadra, A., Aemig, Q., El Fels, L., Barret, M., Merlina, G., Patureau, D., Pinelli, E. (Auteur de correspondance) (2018). Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes. Journal of Hazardous Materials, 359, 465-481. , DOI : 10.1016/j.jhazmat.2018.07.092 6

  Comment citer ce document : Ezzariai, A., Hafidi, M.,Khadra, A., Aemig, Q., El Fels, L., Barret, M., Merlina, G., Patureau, D., Pinelli, E. (Auteur de correspondance) (2018). Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes. Journal of Hazardous Materials, 359, 465-481. , DOI : 10.1016/j.jhazmat.2018.07.092 7

  Comment citer ce document : Ezzariai, A., Hafidi, M., Khadra, A., Aemig, Q., El Fels, L., Barret, M., Merlina, G., Patureau, D., Pinelli, E. (Auteur de correspondance) (2018). Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes. Journal of Hazardous Materials, 359, 465-481. , DOI : 10.1016/j.jhazmat.2018.07.092 8 chortetracycline and oxytetracycline on the apricot plants growth in aerated medium. They

10 

 10 Comment citer ce document : Ezzariai, A., Hafidi, M., Khadra, A., Aemig, Q., El Fels, L.,Barret, M., Merlina, G., Patureau, D., Pinelli, E. (Auteur de correspondance) (2018). Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes. Journal of Hazardous Materials, 359, 465-481. , DOI : 10.1016/j.jhazmat.2018.07.092 Only 3 studies were conducted without spiking sludge or manure and the rest was conducted by spiking sludge before composting at high concentrations varying between 1 and 150 mg kg -1 dry matter;  The removal rates were calculated by referring to the initial and final concentrations (expressed in mg or g per kg of dry matter) without taking into account the compost mass or ash content evolution during composting; Composting showed very high removal for the molecules belonging to the tetracyclines, sulfonamides and macrolides families with an elimination rate of 70-99%. For the fluoroquinolone family, some studies reported an elimination rates up to 99% for the enrofloxacin and norfloxacin. In contrast, other studies showed the persistence of norfloxacin, ciprofloxacin and ofloxacin in the final compost product;  The half-lives in days, are calculated on the basis of first order kinetic model and they varied according to each antibiotic family from 1-105, 2-105, 1-17 and 200-2500 respectively for tetracyclines, macrolides, sulfonamides and fluoroquinolones;

  Comment citer ce document : Ezzariai, A., Hafidi, M.,Khadra, A., Aemig, Q., El Fels, L., Barret, M., Merlina, G., Patureau, D., Pinelli, E. (Auteur de correspondance) (2018). Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes. Journal of Hazardous Materials, 359, 465-481. , DOI : 10.1016/j.jhazmat.2018.07.092 11

  Comment citer ce document : Ezzariai, A., Hafidi, M.,Khadra, A., Aemig, Q., El Fels, L., Barret, M., Merlina, G., Patureau, D., Pinelli, E. (Auteur de correspondance) (2018). Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes. Journal of Hazardous Materials, 359, 465-481. , DOI : 10.1016/j.jhazmat.2018.07.092 12

14 

 14 Comment citer ce document : Ezzariai, A., Hafidi, M.,Khadra, A., Aemig, Q., El Fels, L., Barret, M., Merlina, G., Patureau, D., Pinelli, E. (Auteur de correspondance) (2018). Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes. Journal of Hazardous Materials, 359, 465-481. , DOI : 10.1016/j.jhazmat.2018.07.092 The composting experiments were mainly conducted with lab-scale reactors and a duration ranging between 4 and 183 days; The most used co-substrates during the composting of sludge or manure are mushrooms, composting end-products, sawdust, rice straw, wheat stalks, wheat straw, medicinal herbal residues and cotton stalks; Antibiotic resistance genes conferring resistance to tetracyclines, sulfonamides, macrolides, fluoroquinolones and -lactam are the most studied;

  Comment citer ce document : Ezzariai, A., Hafidi, M.,Khadra, A., Aemig, Q., El Fels, L., Barret, M., Merlina, G., Patureau, D., Pinelli, E. (Auteur de correspondance) (2018). Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes. Journal of Hazardous Materials, 359, 465-481. , DOI : 10.1016/j.jhazmat.2018.07.092 15thermophilic stage (1.5 log copies/g dry matter). In these papers, a positive correlation was found between the antibiotic resistance genes reduction during composting and the temperature[START_REF] Selvam | Fate of tetracycline, sulfonamide and fluoroquinolone resistance genes and the changes in bacterial diversity during composting of swine manure[END_REF][START_REF] Wang | Effect of red mud addition on tetracycline and copper resistance genes and microbial community during the full scale swine manure composting[END_REF][START_REF] Liao | Hyperthermophilic Composting Accelerates the Removal of Antibiotic Resistance Genes and Mobile Genetic Elements in Sewage Sludge[END_REF][START_REF] Xie | Changes in antibiotic concentrations and antibiotic resistome during commercial composting of animal manures[END_REF][START_REF] Duan | Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes[END_REF][START_REF] Jang | Fate of antibiotic resistance genes and metal resistance genes during thermophilic aerobic digestion of sewage sludge[END_REF]. Additionally, temperature was identified as an important

  Comment citer ce document : Ezzariai, A., Hafidi, M.,Khadra, A., Aemig, Q., El Fels, L., Barret, M., Merlina, G., Patureau, D., Pinelli, E. (Auteur de correspondance) (2018). Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes. Journal of Hazardous Materials, 359, 465-481. , DOI : 10.1016/j.jhazmat.2018.07.092 16

AAAA 30 List of tables and figuresFigure 1 .Figure 2 .

 3012 Figure 1. The evolution of the number of publication in the studied topic from 2009 to 2017 (the keywords used in Web of Science are: antibiotic, antibiotic resistance gene, sludge, manure, composting)

31 Table 1 .

 311 Comment citer ce document : Ezzariai, A., Hafidi, M., Khadra, A., Aemig, Q., El Fels, L., Barret, M., Merlina, G., Patureau, D., Pinelli, E. (Auteur de correspondance) (2018). Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes. Journal of Hazardous Materials, 359, 465-481. , DOI : 10.1016/j.jhazmat.2018.07.092 Selected examples of commonly used human and veterinary antibiotics and their physical and chemical Comment citer ce document : Ezzariai, A., Hafidi, M., Khadra, A., Aemig, Q., El Fels, L., Barret, M., Merlina, G., Patureau, D., Pinelli, E. (Auteur de correspondance) (2018). Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes. Journal of Hazardous Materials, 359, 465-481. , DOI : 10.1016/j.jhazmat.2018.07.092 Comment citer ce document : Ezzariai, A., Hafidi, M., Khadra, A., Aemig, Q., El Fels, L., Barret, M., Merlina, G., Patureau, D., Pinelli, E. (Auteur de correspondance) (2018). Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes. Journal of Hazardous Materials, 359, 465-481. , DOI : 10.1016/j.jhazmat.2018.07.092 Comment citer ce document : Ezzariai, A., Hafidi, M., Khadra, A., Aemig, Q., El Fels, L., Barret, M., Merlina, G., Patureau, D., Pinelli, E. (Auteur de correspondance) (2018). Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes. Journal of Hazardous Materials, 359, 465-481. , DOI : 10.1016/j.jhazmat.2018.07.092 34

37 Table 3 .

 373 Comment citer ce document : Ezzariai, A., Hafidi, M., Khadra, A., Aemig, Q., El Fels, L.,Barret, M., Merlina, G., Patureau, D., Pinelli, E. (Auteur de correspondance) (2018). Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes. Journal of Hazardous Materials, 359, 465-481. , DOI : 10.1016/j.jhazmat.2018.07.092 in sludge before composting; b : concentrations expressed by g/kg dry matter. Comment citer ce document : Ezzariai, A., Hafidi, M., Khadra, A., Aemig, Q., El Fels, L., Barret, M., Merlina, G., Patureau, D., Pinelli, E. (Auteur de correspondance) (2018). Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes. Journal of Hazardous Materials, 359, 465-481. , DOI : 10.1016/j.jhazmat.2018.07.092 Antibiotics half-live during composting of sludge or manure Comment citer ce document : Ezzariai, A., Hafidi, M., Khadra, A., Aemig, Q., El Fels, L., Barret, M., Merlina, G., Patureau, D., Pinelli, E. (Auteur de correspondance) (2018). Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes. Journal of Hazardous Materials, 359, 465-481. , DOI : 10.1016/j.jhazmat.2018.07.092 38

39 -

 39 Comment citer ce document : Ezzariai, A., Hafidi, M., Khadra, A., Aemig, Q., El Fels, L.,Barret, M., Merlina, G., Patureau, D., Pinelli, E. (Auteur de correspondance) (2018). Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes. Journal of Hazardous Materials, 359, 465-481. , DOI : 10.1016/j.jhazmat.2018.07.092 Composting duration: 53 days thermophilic stage (by 1.5 log copies/g TS) Tetracycline (tetC, tetG, tetW, and tetX), sulfonamide ( sul1, sul2, dfrA1, and dfrA7) Macrolide (ermB, ermF, ermQ, and ermX). -Chicken manure (C), wheat stalks (K) and bamboo charcoal (BC). -Compost mixture quantity: 3 kg -Lab-scale reactor. -3 different proportions of BC -Composting duration: 26 days No --Relative abundance of tetC, tetG, tetW, tetX, sul2, drfA1, drfA7, ermB, ermF, ermQ, and ermX decreased by 21.6-99.5%, while the relative abundance of sul1 increased by 7.5-17.7 times. -Relative abundance of antibiotic resistance genes (except sul1) in the mixture CK showed an elimination of 0.85 logs. -Adding 5, 10 and 20% of BC in the CK mixture increased the average reductions in the relative abundance of antibiotic resistance genes by 1.05, 1.08, and 1.15 logs, respectively.

  Comment citer ce document : Ezzariai, A., Hafidi, M.,Khadra, A., Aemig, Q., El Fels, L., Barret, M., Merlina, G., Patureau, D., Pinelli, E. (Auteur de correspondance) (2018). Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes. Journal of Hazardous Materials, 359, 465-481. , DOI : 10.1016/j.jhazmat.2018.07.092 40 Tetracyclines (tetA, tetB, tetL, tetM, tetW, tetQ, tetO and tetX), sulfonamide (sul1 and sul2) and chloramphenicol (fexA, floR,cmlA, cfr and fexB) -Rice straw biochar (RSB), mushroom biochar (MB) and chicken manure -Compost mixture quantity: 5 kg -Lab-scale composting reactor -Three composting experiments were carried out: composting with RSB, MB and a control without biochar (CM) -Composting duration: 42 days No --The average removal rate of antibiotic resistance genes was 0.86 log units in CM. -The average removal rate was 0.61 and 1.49 log units in (CM + RSB) and (CM + MB) respectively.

  ')-ib-cr) Macrolide (ermB and ermQ)

  Comment citer ce document : Ezzariai, A., Hafidi, M.,Khadra, A., Aemig, Q., El Fels, L., Barret, M., Merlina, G., Patureau, D., Pinelli, E. (Auteur de correspondance) (2018). Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes. Journal of Hazardous Materials, 359, 465-481. , DOI : 10.1016/j.jhazmat.2018.07.092 41 tetC, tetL, tetM, tetW, ermA, ermB, ermF, ermX, sul1 and sul2. (concentration of 16S rDNA) ermA, ermB, ermF, ermX, sul1 and sul2. (concentration of 16S rDNA) tetM, tetO, tetQ, tetW, tetA, tetC, tetG, tetL, tetX, sul1 and sul2. abundance were decreased for ermA (0.4-1.2 logs) and ermB (1.2-1.6 logs).

42 Figure 1

 421 Figure 1.

Table 2 ,

 2 very few papers provide information on the mechanisms of antibiotics elimination,

			U S C R I P T
			N
		A
		M
	for example by using abiotic controlled reactors (to assess abiotic transformation or C C E P T E D
	sequestration), or radiolabeled compounds (mineralization proved by production of A
	radiolabeled carbon dioxide, quantification of non-extractible residues), by quantifying
	transformation products. For Wu et al. [95], the removal of tetracyclines, which are
	(4-epichlortetracycline,	4-epioxytetracycline,	4-epitetracycline,	anhydrotetracycline

considered unstable because of their chemical structure, could be linked to abiotic transformations like epimerization or dehydration. In this work, the transformation products Comment citer ce document : Ezzariai, A., Hafidi, M., Khadra, A., Aemig, Q., El Fels, L., Barret, M., Merlina, G., Patureau, D., Pinelli, E. (Auteur de correspondance) (2018). Human and veterinary antibiotics during composting of sludge or manure: Global perspectives on persistence, degradation, and resistance genes. Journal of Hazardous Materials, 359, 465-481. , DOI : 10.1016/j.jhazmat.2018.07.092 13

Table 2 .

 2 The fate of antibiotics during composting

Table 3 .

 3 Antibiotics half-live during co-composting of sludge and manure

Table 4 .

 4 Synthesis on recent studies on the fate of antibiotic resistance genes during composting of sludge or manure

Table 2 .

 2 The fate of antibiotics during composting Molecules

Disposal of composting Compost mixture Moisture % (M) and C/N ratio before composting Compost quantities Spiking of the initial mixture before composting Initial antibiotics concentration (mg/kg DW)

							Maximal	Duration of	Elimination	Parameters related in antibiotics	References
							temperature	composting	(%)	removal
							(°C)		(days)
	Oxytetracycline	Self-heating	Beef manure,	M : 72.4	3.3 kg	Beefs were	115	60	35	99.8	The basis on the oxytetracycline	[123]
		laboratory	sawdust	C:N= 29		medicated by					removal is not known.
		composting				22mg/kg/day for 5 days					After composting, oxytetracycline residues have been rendered biologically inactive or unavailable.
	Chlortetracycline	Pile and	Turkey	M : 40%		Yes	1.5	60	35	>99	Thermophilic temperature resulted in	[129]
	Monensin	vessel	manure, blend	C:N=12.-12.9			11.9			54	a reduction in chlortetracycline,
	Sulfamethazine	composting	of aspen,				3.7			No	monensin and TYL concentration.
			shavings and							degradation	Biotic and abiotic factors contributed
	Tylosine		sunflower				10.8			76	to antibiotic degradation during
											composting.
	Chlortetracycline	self-heating	Manure-	M :68.3	3.5 kg	Beefs were	-	55	30	98	Abiotic process is responsible of	[94]
		laboratory	Straw-	C/N=25.5		medicated by					chlortetracycline elimination.
		composter	Woodchips			22mg/kg/day for
						5 days
	Chlortetracycline	Lab vessel	Broiler and	M= 50-60	4 kg	No	94.72 (Broiler	55	42	92.59	Antibiotics depletion is depending on	[90]
		composter	Hog manure				Manure)				carbon, nitrogen and phosphorus.
							879.6 (Hug	58		27.33
							manure)
			Layer-Hen			Yes	50	55		100
			manure				100			94.92
							150			94.51
	Chlortetracycline		Hen manure	M= 65		Yes		55	45	98.5	Not indicated		[89]
			and straw	C/N=13.2
		Self-heating composter	Pig manure and straw	M= 65 C/N=17.7	45 kg		60	62		95.7 97.3
		(60L)								96.2
	OTC		Hen manure	M= 65%				55		97.2
	Tetracycline		and straw	C/N=13.2				55		93.8
	Chlortetracycline	Pilot scale	Manure-	M : 56.9	5m 3	No	2.9	55-60	52	74	Antibiotics	elimination	[95]
		composting	mushroom	C/N=11.02							predominately took place in the
	OTC		residues				1.6			92	thermophilic stage.
	Tetracycline	Open-air					0.4			70	Transformation	products
		windrow									indentification
		manually
		turned
	Chlortetracycline Bench-scale	Swine	M : 55	7 kg	Yes	50	60-64	56	100	High level of antibiotics delayed the	[92]
		composting	manure-	C/N=29			5			100	initial decomposition that also
	Sulfadiazine	conducted	Sawdust	Aeration rate: 0.5			10			100	affected the nitrogen mineralization
		in computer		L/kg DW/min			1
	Ciprofloxacin	controlled					10			83
		20-L					1			69
		reactors
	Chlortetracycline	lab-scale	Manure-	M : 70	30 kg	Yes	2	50	40	96	Binding sites resulted in the reduction	[98]

Table 4 .

 4 Synthesis on recent studies on the fate of antibiotic resistance genes during composting of sludge or manure Antibiotic

resistance genes Compost mixture Composting conditions Antibiotics Spiking of the initial mixture Initial concentrations of antibiotic resistance genes Fate of antibiotic resistance genes after composting Key parameters implied in the antibiotic resistance genes removal References

	Tetracycline (tetG, tetW and tetX)	-Dewatered sewage sludge and	-Lab-scale composting reactor	No	-		-The total antibiotic resistance genes copies	-Addition of natural zeolite;	[60]
	Sulfonamide (sulI and sulII)	mushrooms	-Three composting experiments:				were enriched 2.04 and 1.95 times in reactors	-The thermophilic and cooling stages;
	Fluoroquinolone (aac(60)-Ib-cr)	-Compost mixture quantity: 45kg	the control (A), natural zeolite				A and C.	-The bacterial community structure and
	B-lactam (blaCTX-M and blaTEM)	(at a ratio of 1 :3 (v/v))	addition (B) and nitrification				-The total antibiotic resistance genes copies	changes.
	Macrolide (ereA, ermB, ermF and		inhibitor addition (C).				were reduced by 1.5% in the reactor B.
	mefA).		-Composting duration: 183 days				-Some antibiotic resistance genes were
							reduced by 0.3-2 logs, while others increased
							by 0.3-1.3 logs after composting.
	Tetracycline (tetA, tetB, tetC, tetG, tetL, tetM, tetQ,	-Dewatered sewage sludge mixed	-Industrial hyperthermophilic and	No	-Tetracycline		and
	tetO, tetW, and tetX)	with composting end-products at	conventional composting in piles.		sulfonamide	(the	most
	Macrolide (ermB, ermF, ermT, ermX, mefA, and ereA)	a ratio of 1:3 (v/v).	-Composting duration: 45 days		dominant antibiotic resistance
	Aminoglycoside (aacA4, aadA, aadB, aadE, aphA1,	-Compost mixture quantity: 200			genes):
	strA, and strB) Sulfonamide (sul1, sul2, and sul3).	tons			5.1×10 11 and 1.1×10 10 gene
					copies per gram (dry weight)
					in the initial raw sludge.

  .39, 8.14, 7.68, 9.23, 9.63, 8.63, 7.42, 8.01, 8.25, 9.31 and 9.38 Log10 copies g dry matter respectively for tetB, -10.58, 7.60, 10.92, 5.43, 8.12, 6.61, 7.95, 10.06, 8.87, 8.80 and 8.64 Log10 copies g dry matter respectively for tetB, tetC, tetL, tetM, tetW,

						-Thermophilic and mature phase of	[142]
						composting;
					11 copies per gram dry	-Bacterial succession and horizontal gene
					compost	transfer.
	Tetracycline (tetB, tetC, tetL, tetM, tetW)	-Cattle manure	-Lab-scale composter	Feed and fortified	-7-Oral administration;	[143]
	Erythromycin( ermA, ermB, ermF, ermX)		-Composting duration: 30 days	treatments		-Antimicrobial concentrations;
	Sulfamethazine( sul1, sul2)					-Mesophilic and thermophilic temperatures;
						-Longer thermophilic composting period.

Acknowledgement

This research was supported by a Franco-Moroccan project (Toubkal: TBK/16/33) and Centre National de Recherche Scientifique et Technique in Morocco (Bourse d'excellence, Edition 2015). We would like to thank for their financial support the French Environment and Energy Management Agency-ADEME (convention n°1706C0023) and the French Agency for Food, Environmental and Occupational Health & Safety-ANSES (Call 2017/3 ABR/008).

Comment citer ce document : Ezzariai, A., Hafidi, M., Khadra, A., Aemig, Q., El Fels, L., Barret The degradation of antibiotics depends on the compost mixture.