ABSTRACT

This work carried out an integrative review of scientific articles indexed between 2007 and 2017 in different databases on treatment and reuse of effluents from the antibiotic industry. Thirty-one articles were found and only four addressed effluent reuse, and one used a full-scale treatment system. Most of these studies were conducted in Asia, with emphasis on China. In Brazil, which is one of the largest producers and consumers of drugs in the world, this type of research is still incipient. The most commonly found processes were oxidative advanced processes that showed greater efficiency in removing antibiotics, but may generate by-products, which might pose an even greater risk depending on the substance formed. Biological processes must first be acclimated to antibiotics in order not to be impacted, however, the release of these resistant microorganisms into the water bodies also presents an environmental risk. Biological integrated membrane systems were also very efficient, but attention should be given to the risk in the final destination of these membranes that were able to retain those compounds. Overall, further studies on this approach are needed to reduce the risks of developing multi-resistant microorganisms in the environment.

KEYWORDS:
Drug industry. Anti-bacterial agents. Industrial effluent treatment. Drug resistance; bacterial. Wastewater use

Introduction

In the modern concept, sanitation includes water supply, waste management (solid, liquid and/or gaseous), urban drainage, rational use of the soil and control of communicable diseases. Such actions are essential for the physical, mental and social well-being of the population¹1 Brasil. Medida Provisória nº 868 de 27 de dezembro de 2018. Atualiza o marco legal do saneamento básico e altera a Lei nº 9.984, de 17 de julho de 2000, e dá outras providencias. [internet]. Diário Oficial da União. 28 Dez 2018. [acesso em 2019 jan 19]. Disponível em: http://www.planalto.gov.br/ccivil_03/_Ato2015-2018/2018/Mpv/mpv868.htm.
http://www.planalto.gov.br/ccivil_03/_At... . Thus, the non-accomplishment of any of these actions may result in damage to human and environmental health. An important component with direct effects on human health is the collection and treatment of effluents. Brazil has alarming values in relation to this component: in 2017, the Country collected 74% of the sewage generated and treated only 46%, which totals 4.2 billion m³ of untreated domestic sewage being discarded in the different water sources²2 Brasil. Ministério do Desenvolvimento Regional. Secretaria Nacional de Saneamento - SNS. Diagnóstico dos Serviços de Água e Esgoto 2017. [internet]. Brasília, DF: MDR; 2019. [acesso 2019 mar 11]. Disponível em: http://www.snis.gov.br/diagnostico-agua-e-esgotos/diagnostico-ae-2017.
http://www.snis.gov.br/diagnostico-agua-... .

The collection and treatment of domestic effluents is the responsibility of the public authorities, and may be granted to a private company, but supervised by the control agencies. A very critical type of effluent and that deserves attention is the industrial one, in which the responsibility for its collection and treatment lies with the generator. This effluent may be discharged into the public collection system or into receiving bodies as defined during the environmental licensing of the company³3 Hammer MJ. Water and wastewater technology. 3. ed. Englewood Cliffs: Prentice Hall; 1996.. It is noteworthy that effluents from the pharmaceutical industry may pose risks to human health⁴4 Monteiro SC, Boxal L. Occurrence and Fate of Human Pharmaceuticals in the Environment. In: Reviews of Environmental Contamination and Toxicology. Reviews of Environmental Contamination and Toxicology, vol 202. New York: Springer; 2010. p. 53-154.

5 Sangion A, Gramatica P. Hazard of pharmaceuticals for aquatic environment: Prioritization by structural approaches and prediction of ecotoxicity. Environ Int. 2016; (95):131-143.^-66 Wang J, Wang S. Removal of pharmaceuticals and personal care products (PPCPs) from wastewater: a review. J Environ Manage. 2016; (182):620-640.. The increased consumption of pharmaceutical products and the incentive to expand the pharmaceutical park lead to a greater generation of effluents with drug waste⁷7 Moraes DSL, Jordao BQ. Degradação de recursos hídricos e seus efeitos sobre a saúde humana. Rev Saúde Pública. 2002; 36(3):370-374.

8 Cordi L, Assalin MR, Diez MC, et al. Montagem, partida e operação de um sistema de lodos ativados para o tratamento de efluentes: parâmetros físico-químicos e biológicos. Rev Eng Ambiental. 2008; 5(1):97-115.^-99 Gadelha CAG, Vargas MA, Maldonado JMS, et al. O Complexo Econômico-Industrial da Saúde no Brasil: formas de articulação e implicações para o SNI em saúde. Rev Bras Inov. 2013; 12(2):251-282..

The Brazilian pharmaceutical industry presents financial profits superior to the other producing activities, having only the automobile industry ahead. The pharmaceutical sector obtained, in 2018, a 6.1% production growth compared to 2017¹⁰10 . Instituto Brasileiro de Geografia e Estatística. Indicadores. Pesquisa Industrial Mensal. Produção Física Brasil 2018. [internet]. Rio de Janeiro: IBGE; 2019. [acesso em 2019 mar 25]. Disponível em: https://biblioteca.ibge.gov.br/visualizacao/periodicos/228/pim_pfbr_2018_dez.pdf.
https://biblioteca.ibge.gov.br/visualiza... . Such a productive result is due to the fact that Brazil has recorded an accumulated increase of 10.8% in the consumption of pharmaceutical products between 2014 e 2018, with an estimated growth of 15% to 18% until 2023. This brings the Country from the seventh placing on the world drug market in 2018 to the fifth in the list of the 20 largest drug users in the world as shown in chart 1¹¹11 IQVIA Institute for Human Data Science. The Global Use of Medicine in 2019 and Outlook to 2023: Forecasts and Areas to Watch [internet]. EUA: IQVIA; 2019. [acesso em 2019 fev 25]. Disponível em: https://www.iqvia.com/institute/reports/the-global-use-of-medicine-in-2019-and-outlook-to-2023.
https://www.iqvia.com/institute/reports/... .

Among the most commonly used drugs, antibiotics stand out. According to the World Health Organization (WHO) report, in 2016 alone the Brazilian population consumed 22.75 daily doses of antibiotics per thousand inhabitants¹²12 World Health Organization. Report on surveillance of antibiotic consumption: 2016-2018 early implementation [internet]. Geneva:WHO; 2018. [acesso em 2019 fev 22]. Disponível em: https://apps.who.int/iris/bitstream/handle/10665/277359/9789241514880-eng.pdf.
https://apps.who.int/iris/bitstream/hand... . The WHO also points out that among the 65 countries in the world, Brazil is ranked 19th in the antibiotic consumption ranking and the highest among the countries of the Americas¹²12 World Health Organization. Report on surveillance of antibiotic consumption: 2016-2018 early implementation [internet]. Geneva:WHO; 2018. [acesso em 2019 fev 22]. Disponível em: https://apps.who.int/iris/bitstream/handle/10665/277359/9789241514880-eng.pdf.
https://apps.who.int/iris/bitstream/hand... .

The high consumption of antibiotics is due to the fact that this medicine has given the population a new hope against various diseases. However, microorganisms can adapt to environmental conditions, developing some resistance to antibiotics, requiring the development of new substances or their combined use¹³13 García-Rey C, Martín-Herrero J E, Baquero F. Antibiotic consumption and generation of resistance in Streptococcus pneumoniae: the paradoxical impact of quinolones in a complex selective landscape. Clin. Microbiol Infect. 2006; 12(3):55-66.

14 Collignon C, Uroz S, Turpault MP, et al. Seasons differently impact the structure of mineral weathering bacterial communities in beech and spruce stands. Soil Biol Biochem. 2011; 43(10):2012-2022.^-1515 Walsh CT, Timothy WA. Prospects for new antibiotics: a molecule-centered perspective. J Antibiot. 2014; 67(1):7-22.. There is also a warning about the development of multi-resistant microorganisms that has become a concern today. As a result, WHO has been searching for new antibiotics to prevent populations from dying again from previously controlled infections¹⁶16 World Health Organization. Antimicrobial resistance: global report on surveillance. [internet]. Geneva: WHO; 2014. [acesso em 2019 jan 21]. Disponível em: https://www.who.int/drugresistance/documents/surveillancereport/en/.
https://www.who.int/drugresistance/docum... . If nothing is done, it is estimated that 10 million people could die from a disease caused by multi-resistant microorganisms by 2050¹⁷17 O'Neill J, Davies S, Rex J, et al. Review on antimicrobial resistance, tackling drug-resistant infections globally: final report and recommendations. [internet]. London:Wellcome Open Res; 2016. [acesso em 2019 jan 4]. Disponível em: https://amr-review.org/sites/default/files/160518_Final%20paper_with%20cover.pdf.
https://amr-review.org/sites/default/fil... . Environmental studies have been raising evidence of increased antimicrobial resistance by microorganisms found in rivers, seas and coastal areas that may have been developed by the presence of antibiotics from effluent disposal¹⁸18 Halling-Sorensen B, Nielsen N S, Lanzky PF, et al. Occurrence, fate and effects of pharmaceutical substances in the environment - A review. Chemosphere.1998; 36(2):357-394.

19 Sanderson H, Johnson DJ, Reitsma T, et al. Ranking and prioritization of environmental risks of pharmaceuticals in surface waters. Regul Toxicol Pharmacol. 2004; 39(2):158-183.^-2020 Baquero F, Martínez JL, Cantón R. Antibiotics and antibiotic resistance in water environments. Curr Opin Biotechnol. 2008; 19(3):260-5..

The effluent of the pharmaceutical industry is normally composed of wastewater from the production lines, waste from production and leftovers of substances removed from machinery and equipment. It has specific characteristics that can vary depending on the products that are manufactured by the industrial unit. The effluent generated by the production of antibiotics may carry residues of the active substance. In this way, this residue must first go through a process of inactivation or elimination of this active principle to prevent it from being carried into the environment.

Different processes may be used for the treatment of pharmaceutical industrial effluents. Among the most widespread and least expensive technologies, biological processes stand out²²22 Guimarães JR, Maniero MG. Tratamento de água e efluentes líquidos. In: Rosa AH. Fraceto LF, Moschini-Carlos V. Meio ambiente e sustentabilidade. Porto Alegre: Bookmam; 2009. p. 322-345., but the efficiency of these processes in degrading these compounds may be questionable. In some cases, it is necessary to use other processes combined with biological processes, such as physical and chemical processes. Chemical and physicochemical processes are more efficient than biological processes in the removal of refractory substances such as drugs²³23 Almeida E, Assalin MR, Rosa MA. Tratamento de efluentes industriais por processos oxidativos na presença de ozônio. Quím Nova. 2004; 27(5):818-824.. Activated charcoal adsorption, acid or alkaline hydrolysis and ozone oxidation are examples of promising processes in the removal and/or degradation of drug wastes²⁴24 Caldwell DJ, Mertens B, Kappler K, et al. A risk-based approach to managing active pharmaceutical ingredients in manufacturing effluent. Environ Toxicol Chem. 2016; 35(4):813-822..

The level of treatment to be adopted by the industry is associated with the legal release requirements and the desired quality standard of the treated effluent²⁴24 Caldwell DJ, Mertens B, Kappler K, et al. A risk-based approach to managing active pharmaceutical ingredients in manufacturing effluent. Environ Toxicol Chem. 2016; 35(4):813-822.. In relation to the Brazilian regulation regarding the launch of drugs in the environment, there is a need for its suitability, mainly due to new evidences of effects on wild biota and men²⁵25 Blair BD, Crago JP, Hedman CJ, et al. Evaluation of a model for the removal of pharmaceuticals, personal care product, and hormones from wastewater. Sci Total Environ. 2013; 444:515-21.^,2626 Cunha DL, Silva SMC, Bila DM, et al. Regulamentação do estrogênio sintético 17α-etinilestradiol em matrizes aquáticas na Europa, Estados Unidos e Brasil. Cad. Saúde Pública. 2016; 32(3):1-13.. However, the countries of the European Union already have standardization for the subject²⁷27 European Commission. Directive 2000/60/EC of the European Parliament and of the Council of 23 October 2000. Establishing a Framework for Community Action in the Field of Water Policy [internet]. Oficial Journal European Union. 22 Dez 2000. [acesso em 2018 fev 20]. Disponível em: http://data.europa.eu/eli/dir/2000/60/oj.
http://data.europa.eu/eli/dir/2000/60/oj...

28 European Commission. Directive 2013/39/EU of the European Parliament and of the Council of 12 August 2013 amending Directives 2000/60/EC and 2008/105/EC as regards priority substances in the field of water policy [internet]. Official Journal of the European Union. 24 Dez 2013. [acesso em 2018 fev 20]. Disponível em: https://eur-lex.europa.eu/eli/dir/2013/39/oj.
https://eur-lex.europa.eu/eli/dir/2013/3... ^-2929 European Commission. Decision 2015/495/EC of 20 March 2015 establishing a watch list of substances for Union-wide monitoring in the field of water policy pursuant to Directive 2008/105/EC of the European Parliament and of the Council [internet]. Official Journal of the European Union. 24 Mar 2015. [acesso em 2018 fev 20]. Disponível em: http://data.europa.eu/eli/dec_impl/2015/495/oj.
http://data.europa.eu/eli/dec_impl/2015/... .

Another important component in sanitation actions is water supply. Scarcity and low water availability represent the challenges of modern humanity. It is noteworthy that, among human activities, the industrial sector is considered the third largest consumer of water resources in the world³⁰30 Andrade BAS, Lacerda PSB, Oliveira JLM. Viabilidade técnica de reúso de efluente gerado do sistema de osmose reversa em uma indústria farmacêutica. Rev Ambient Água [internet]. 2017 [acesso em 2019 fev 19]; 12(5):694-707. Disponível em: http://dx.doi.org/10.4136/ambi-agua.1980.
http://dx.doi.org/10.4136/ambi-agua.1980... .

In the pharmaceutical industry, water must have purity levels appropriate to its multiple uses. Water used in production, for example, must be treated at the level of purified water; while other support sectors, such as utility units, control laboratories, and research and development sectors, require different levels of water quality³⁰30 Andrade BAS, Lacerda PSB, Oliveira JLM. Viabilidade técnica de reúso de efluente gerado do sistema de osmose reversa em uma indústria farmacêutica. Rev Ambient Água [internet]. 2017 [acesso em 2019 fev 19]; 12(5):694-707. Disponível em: http://dx.doi.org/10.4136/ambi-agua.1980.
http://dx.doi.org/10.4136/ambi-agua.1980... ^,3131 Franco L, Bilotta P. Implantação de um Laboratório de Análise da Qualidade da Água e Efluentes de uma Indústria Farmacêutica. Rev Gest Indus. 2014; 10(2):393-405.. Therefore, the importance of water resources management in the pharmaceutical industry is highlighted.

Effective integrated water management (water consumed and effluent generated) in the industry can reduce the risk of environmental pollution and contribute to lower water consumption. One way to reduce water consumption in the industrial sector is to reuse treated effluents. While the petrochemical and food sectors are already doing a lot of work on this topic, little is known about this practice in the pharmaceutical industry³⁰30 Andrade BAS, Lacerda PSB, Oliveira JLM. Viabilidade técnica de reúso de efluente gerado do sistema de osmose reversa em uma indústria farmacêutica. Rev Ambient Água [internet]. 2017 [acesso em 2019 fev 19]; 12(5):694-707. Disponível em: http://dx.doi.org/10.4136/ambi-agua.1980.
http://dx.doi.org/10.4136/ambi-agua.1980... . On the other hand, the pharmaceutical industry must be aware of the risk of this reuse to public health and productive activity.

Reuse modalities may be adopted according to the need of the industry. Indirect reuse is the most common, in which treated effluents are thrown into rivers and lakes and, subsequently, captured, treated and used. Direct reuse is related to the use of effluents from one particular activity in another with lower requirements. In general, it is very common the reuse of industrial effluents in towers of cooling, gardening, washing of patios and sidewalks, water for toilets and in the activities of civil construction. For more specific uses of the industry, as in the manufacturing process itself, such effluents shall undergo treatment appropriate to the quality required for their application, observing the risks that this practice may have³²32 Sindicato da Indústria da Construção Civil no Estado de São Paulo. Manual de Conservação e reúso de Água em Edificações. São Paulo: SINDUSCON; 2005.

33 Mierzwa JC, Rodrigues LB, Silva M. Manual de Conservação e Reúso de Água na Indústria [internet]. Rio de Janeiro: Sistema FIRJAN; 2015. [acesso em 2018 fev 20]. Disponível em: http://www.firjan.org.br/data/pages/2C908CE9215B0DC4012164A77509221B.htm.
http://www.firjan.org.br/data/pages/2C90... ^-3434 Eslamian A, Eslamian F, Eslamian S. Water Reuse Guidelines for Industry. In: Eslamian S. Urban Water Reuse Handbook, Boca Raton, Flórida: CRC Press. 2016. p. 187-194.. Therefore, effluent treatment efficiency should be evaluated for different types of reuse, especially those containing drug wastes³⁵35 Melo SAS, Trovó AG, Bautitz IR, et al. Degradação de fármacos residuais por processos oxidativos avançados. Quím Nova. 2009; 32(1):188-197..

In view of this, this article brings an integrative literature review on the studies performed in the treatment of effluents in the pharmaceutical industry of antibiotics and on the possibility of reuse of this treated effluent.

Methodology

This article was elaborated through an integrative literature review³⁶36 Cooper HM. Integrating research: Applied social research methods series. A guide for literature reviews. 2. ed. Thousand Oaks, CA, US: Sage Publications; 1989.

37 Souza MT, Silva MD, Carvalho R. Revisão Integrativa: o que é e como fazer. Einstein. 2010; 8(supl1):102-106.^-3838 Dyniewicz AM. Metodologia da pesquisa em saúde para iniciantes. 2. ed. São Caetano do Sul: Difusão; 2009.. Inclusion criteria for this review were indexed articles written in Portuguese, English or Spanish, from 2007 to 2017, retrieved from the search for descriptors and keywords in the Science Direct, Scopus, Web of Science, PubMed and Virtual Health Library (VHL) databases through the website of the Journal of the Coordination for the Improvement of Higher Education Personnel (Capes).

From the selection of descriptors and keywords, the retrieval of references in the indexed databases was performed by two forms of search. The first was composed of the terms 'antibiotic' AND 'wastewater treatment' OR 'industrial effluents treatment' OR 'industrial waste' AND 'recycling' OR 'reuse' which are vocabularies controlled by DeCS and MeSH. These indices were used in all search bases except PubMed, where the term 'reuse' was excluded as it did not aggregate any results.

After the recovery of the publications, a screening process was performed from the reading of the title and the summary, adopting as inclusion criterion the presence of data on 'treatment of industrial effluents from the production of antibiotics'. Despite the use of the filters offered by the databases, books, opinion articles and patent were observed, which were also removed after detailed reading of the title and the summary. A second evaluation was performed with the help of the Zotero Program Standalone(r) for the exclusion of duplicate references. At the end of this screening, the articles were fully read, being excluded, restricted or paid access articles or, still, that presented divergent information to the object of this study.

Results

From the search criteria and the filters used in the databases, 400 references were cataloged as shown in figure 1. By reading the title and the summary of these articles, 341 articles that had divergent themes from the one proposed in this paper were excluded. Of the remaining 59, 15 were in duplicate and were excluded (figure 1B), thus, leaving 44 articles. Finally, with the full reading, only 31 articles were selected (figure 1C).

Of the works found on this subject, most were carried out in China (17 articles), followed by India (4), France and Iran (2 each); and Brazil, Spain, Finland, Israel, Malaysia and Portugal (1 each), as shown in figure 2. From the categorization of effluent treatment processes, 9 articles that addressed biological processes were found: where 4 referred to strictly biological processes - 3 for activated sludge and 1 for anaerobic reactors; 4 integrated the biological with the physical using membranes; and 1 associated the biological system with the chemical by biocatalysis, as shown in figure 3.

Of the other works, only 1 article used exclusively physical process by reverse osmosis, 10 articles used physicochemical processes, 8 of adsorption, 1 of separation by foaming agent and adsorption and 1 of separation using ionic solution. Of the articles found that used the oxidative processes, 1 was by the potassium ferrate oxidation method with ultrasound and 1 by the polychromatic UV oxidation. Among the 13 articles that tested Advanced Oxidative Processes (POA) in their work, 11 were exclusive to POA, of these, 2 by the Fenton method, 4 by photo-Fenton, 1 by hydrogen peroxide and 4 by photocatalysis. In addition, 2 articles used POA associated with other types of processes: one used Fenton associated with coagulation/sedimentation and the other applied photo-Fenton with immobilized biomass biological reactor.

It is also noteworthy that only four studies were obtained that addressed the possibility of reuse of these effluents. All of these studies found used POA as an alternative treatment.

Discussion

Most of the work on treating effluent from antibiotic production occurred in China. This result may express a marked economic expansion after its commercial opening, besides the need to adapt to patent laws that allowed the reproduction of various industrialized products, including drugs. This economic evolution covered the pharmaceutical sector, mainly in the field of active pharmaceutical production⁴⁰40 Ding J, Xue Y, Liang H, et al. From imitation to innovation: A study of China's drug R&D and relevant national policies. J. Technol. Manag Innov. 2011; 6(2):1-13.

41 Chitour H-L. Big Pharma in China - the driving forces behind their success - A qualitative analysis. Chinese Stud. 2013; 2(4):169-1773.^-4242 Delgado IG. Política industrial para os setores farmacêutico, automotivo e têxtil na China, Índia e Brasil. Brasília, DF: Instituto de Pesquisa Econômica Aplicada; 2015.. Other data that draw attention refer to the fact that 25 works were developed in Asia, 5 in Europe and only 1 in the Americas. Considering the level of production and consumption of drugs that has been reflected worldwide, there should be more studies on this approach, especially in Brazil and the United States. On the other hand, studies on the occurrence of drugs in surface water and drinking water in Europe and the United States have shown the importance of monitoring these residues²⁶26 Cunha DL, Silva SMC, Bila DM, et al. Regulamentação do estrogênio sintético 17α-etinilestradiol em matrizes aquáticas na Europa, Estados Unidos e Brasil. Cad. Saúde Pública. 2016; 32(3):1-13.. In addition, rules and procedures reinforce the care these nations require to prevent their water resources from containing these types of waste⁴³43 Bila DM, Dezotti M. Fármacos no meio ambiente. Quím. Nova. 2003; 26(4):523-530.^,4444 Oliveira NB, Kligerman DC, Lacerda P, et al. Revisão dos dispositivos legais e normativos internacionais e nacionais sobre gestão de medicamentos e de seus resíduos. Ciênc. Saúde Colet. [internet]. [acesso em 2019 abr 15]. Disponível em: http://www.cienciaesaudecoletiva.com.br/artigos/revisao-dos-dispositivos-legais-e-normativos-internacionais-e-nacionais-sobre-gestao-de-medicamentos-e-de-seus-residuos/16331?id=16331.
http://www.cienciaesaudecoletiva.com.br/... . However, even on this subject, there is little research in Brazil²⁶26 Cunha DL, Silva SMC, Bila DM, et al. Regulamentação do estrogênio sintético 17α-etinilestradiol em matrizes aquáticas na Europa, Estados Unidos e Brasil. Cad. Saúde Pública. 2016; 32(3):1-13..

The POA, followed by membranes isolated or integrated to biological systems (Membrane Bioreactors - MBR), were the most cited in the articles found. The purely biological processes appeared in four works found. In fact, the most widely used treatment processes, whether for domestic or industrial wastewater, are biological ones. While the activated sludge system serves most of the Brazilian population, anaerobic reactors are the most used in the industrial sector. However, there is doubt as to whether the biological process is effective in removing/degrading antibiotics. Mechanisms for the elimination/removal of effluent antibiotic residues by biological processes may occur by incorporation of the compounds into the sludge biomass (sorption) or by biodegradation⁴⁵45 De Cazes M, Abejón R, Belleville M-P, et al. Membrane Bioprocesses for Pharmaceutical Micropollutant Removal from Waters. Membranes. 2014; 4(4):692-729..

Abassi et al.⁴⁶46 Abbassi BE, Saleem MA, Zytner RG, et al. Antibiotics in wastewater: Their degradation and effect on wastewater treatment efficiency. J Food Agric Environ. 2016; 14(3-4):95-9. observed that the presence of ampicillin, amoxicillin and ciprofloxacin wastes in the industrial effluent caused a reduction in the concentration of microorganisms in the activated sludge process.

The acclimatization or prolonged exposure of antibiotic residues to microorganisms may increase their resistance to these compounds, improving their ability to degrade these substances, as compared to Industrial and Sanitary Effluent Treatment Plants containing fluoroquinolone-based antibiotics⁴⁵45 De Cazes M, Abejón R, Belleville M-P, et al. Membrane Bioprocesses for Pharmaceutical Micropollutant Removal from Waters. Membranes. 2014; 4(4):692-729.

46 Abbassi BE, Saleem MA, Zytner RG, et al. Antibiotics in wastewater: Their degradation and effect on wastewater treatment efficiency. J Food Agric Environ. 2016; 14(3-4):95-9.^-4747 Marathe NP, Shetty SA, Shouche YS, et al. Limited Bacterial Diversity within a Treatment Plant Receiving Antibiotic-Containing Waste from Bulk Drug Production. PLoS ONE. 2016; 11(11):e0165914.. However, this procedure can be a risk, as these microorganisms present in this sludge can carry this resistance to the environment. It is also emphasized that this acclimatization is not a guarantee that these microorganisms can develop the biodegradability of these compounds. Saravanne and Sundararaman⁴⁸48 Saravanane R, Sundararaman S. Effect of loading rate and HRT on the removal of cephalosporin and their intermediates during the operation of a membrane bioreactor treating pharmaceutical wastewater. Environ Technol. 2009; 30(10):1017-22. used MBR with acclimatized biomass to treat cephalexin residues, and this resulted in the generation of 7 7-amino-3-desacetoxy cephalosporanic acid and phenylacetic acid metabolites. Another alternative tested in the MBR study was the addition of enzymes to favor the degradation of antibiotics. However, besides the high cost, this procedure may not be effective for a broad spectrum of antibiotics⁴⁵45 De Cazes M, Abejón R, Belleville M-P, et al. Membrane Bioprocesses for Pharmaceutical Micropollutant Removal from Waters. Membranes. 2014; 4(4):692-729..

The degradation of drug wastes by biological processes presents better performance when associated with other processes, such as oxidative or physical. Sistori et al.⁴⁹49 Sirtori C, Zapata A, Oller I, et al. Decontamination industrial pharmaceutical wastewater by combining solar photo-Fenton and biological treatment. Water Res. 2009; 43(3):661-8. had an effective reduction in the concentration of nalidixic acid of the effluent using Immobilized Biomass Reactors associated with photo-Fenton. However, this process generated metabolites compounds with higher toxic potential and could be a risk to aquatic ecosystems. Wang et al.⁵⁰50 Wang J, Li K, Wei Y, et al. Performance and fate of organics in a pilot MBR-NF for treating antibiotic production wastewater with recycling NF concentrate. Chemosphere. 2015; 121:92-100. used MBR with nanofiltration and observed a decrease in the concentration of spiramycin, being related to the mass transfer from the liquid phase to solid phase retained in the membrane, which also occurs in the osmosis treatment system. Despite the good efficiency observed by studies using membrane processes, a transfer of these wastes is observed, so, there is a demand for the proper treatment of these membranes⁵⁰50 Wang J, Li K, Wei Y, et al. Performance and fate of organics in a pilot MBR-NF for treating antibiotic production wastewater with recycling NF concentrate. Chemosphere. 2015; 121:92-100.

51 Wang J, Wei Y, Li K, et al. Fate of organic pollutants in a pilot-scale membrane bioreactor-nanofiltration membrane system at high water yield in antibiotic wastewater treatment. Water Sci Technol. 2014; 69(4):876-81.^-5252 Gholami M, Mirzaei R, Kalantary RR, et al. Performance evaluation of reverse osmosis technology for selected antibiotics removal from synthetic pharmaceutical wastewater. Iranian J Environ Health Sci Eng. 2012; 9(1):19..

Extraction processes adopting nonpolar or foam phases that favor the removal by liquid-liquid processes were also found in this search. Almeida et al.⁵³53 Almeida HFD, Freire MG, Marrucho IM. Improved extraction of fluoroquinolones with recyclable ionic-liquid-based aqueous biphasic systems. Green Chem. 2016; 18(9):2717-2725. analyzed the potential for removal of fluoroquinolones from the addition of an ionic solution to the effluent. The difference in polarity between these solutions (extractor and effluent) caused antibiotic residues to be removed from the effluent to the extractor solution. Kou et al.⁵⁴54 Kou Q-Y, Li J, Zhao B, et al. Recovery of streptomycin sulfate from the wastewater using foam fractionation coupled with adsorption separation for reusing sodium dodecyl sulfate. J Chem Technol Biotechnol. 2015; 90(5):874-879. used flotation coupled with adsorption separation for streptomycin removal (recovery). Other authors have also tested adsorption processes for the removal of antibiotic residues such as dioxicycline⁵⁵55 Li J, Ng DHL, Ma R, et al. Eggshell membrane-derived MgFe2O4 for pharmaceutical antibiotics removal and recovery from water. Chem Eng Res Des. 2017; 126:123-133.; amoxicillin⁵⁶56 Pachauri P, Falwariya R, Vyas S, et al. Removal of amoxicillin in wastewater using adsorption by powdered and granular activated carbon and oxidation with hydrogen peroxide. Nat Environ Pollut Technol. 2009; 8(3):481-488.; gatifloxacin⁵⁷57 Yao H, Lv Z, Zhou Y, et al. Experiment of gatifloxacin adsorption by sludge activated carbon. J Residuals Sci Technol. 2009; 6(4):171-177.; cephalexin, cephradine⁵⁸58 Li S, Yang Q, Ye Y. Preparation of activated carbon from herbal residues and kinetics of cephalosporin antibiotic adsorption in wastewater. Bio Resources. 2017; 12(2):2768-2779., sulfamethoxazole⁵⁹59 Han X, Liang C, Li T, et al. Simultaneous removal of cadmium and sulfamethoxazole from aqueous solution by rice straw biochar*. J Zhejiang Univ Sci B. 2013; 14(7):640-649.; tetracycline⁶⁰60 Acosta R, Fierro V, Martinez de Yuso A, et al. Tetracycline adsorption onto activated carbons produced by KOH activation of tyre pyrolysis char. Chemosphere. 2016; (149):168-176.^,6161 Liu M, Hou L, Yu S, et al. MCM-41 impregnated with A zeolite precursor: Synthesis, characterization and tetracycline antibiotics removal from aqueous solution. Chem Eng J. 2013; 223(100):678-87. and ciprofloxacin⁶²62 Wang F, Yang B, Wang H, et al. Removal of ciprofloxacin from aqueous solution by a magnetic chitosan grafted graphene oxide composite. J Mol Liq. 2016; (222):188-194.. The environmental and financial cost of transferring phase contaminants can be extremely high due to the need for other processes that effectively degrade waste in these new matrices.

The phase transfer of the contaminant can also be observed in oxidation processes using medium support, such as in the application of photocatalysis in support medium for the removal of oxytetracycline⁶³63 Priya B, Shandilya P, Raizada P, et al. Photocatalytic mineralization and degradation kinetics of ampicillin and oxytetracycline antibiotics using graphene sand composite and chitosan supported BiOCl. J Mol Catal Chem. 2016; (423):400-413., tetracycline⁶⁴64 Li W, Li T, Li G, et al. Electrospun H4SiW12O40/cellulose acetate composite nanofibrous membrane for photocatalytic degradation of tetracycline and methyl orange with different mechanism. Carbohydr Polym. 2017; 168:153-162. and deoxytetracycline⁶⁵65 Chen M, Chu W. Degradation of antibiotic norfloxacin in aqueous solution by visible-light-mediated C-TiO2 photocatalysis. J Hazard Mater. 2012; 15(219-220):183-189.. This process did not present the complete elimination of antibiotics, however, photocatalysis without medium support has degraded 100% of antibiotic residues⁶⁵65 Chen M, Chu W. Degradation of antibiotic norfloxacin in aqueous solution by visible-light-mediated C-TiO2 photocatalysis. J Hazard Mater. 2012; 15(219-220):183-189.. On the other hand, the protolithic oxidation requiring only the light source was not efficient for sulfamethoxazole, oxytetracycline and ciprofloxacina⁶⁶66 Avisar D, Lester Y, Mamane H. pH induced polychromatic UV treatment for the removal of a mixture of SMX, OTC and CIP from water. J Hazard Mater. 2010; 175(1-3):1068-1074. elimination.

Oxidative processes may also be integrated with physical or chemical agents, such as the study by Zhang et al.⁶⁷67 Zhang Y, Marrs CF, Simon C, et al. Wastewater treatment contributes to selective increase of antibiotic resistance among Acinetobacter spp. Sci Total Environ. 2009; 407(12):3702-3706. who tested potassium ferrate with ultrasound for the degradation of sulfadiazine, sulfamazine and sulfamethoxazole. However, this process was not as effective for the complete elimination of these compounds.

Many authors cite that POA are the most promising for drug waste degradation because they are capable of generating free radicals (●OH) that have high oxidative potential. However, many of the articles found in this search show that these processes and their associations did not achieve a 100% reduction in antibiotic concentration. The following methods were found: Fenton for removal of amoxicillin⁵⁶56 Pachauri P, Falwariya R, Vyas S, et al. Removal of amoxicillin in wastewater using adsorption by powdered and granular activated carbon and oxidation with hydrogen peroxide. Nat Environ Pollut Technol. 2009; 8(3):481-488., cefpirome, latamofex, aztreonam, cefoperazone, cefatrizine, propylene glycol, ceftazidime⁶⁸68 Xing Z-P, Sun D-Z. Treatment of antibiotic fermentation wastewater by combined polyferric sulfate coagulation, Fenton and sedimentation process. J Hazard Mater. 2009; 168(2-3):1264-1268. and sulfamethoxazole⁶⁹69 Dehghani S, Jonidi Jafari A, Farzadkia M, et al. Sulfonamide antibiotic reduction in aquatic environment by application of fenton oxidation process. Iranian J Environ Health Sci Eng. 2013; 10(1):29.; photo-Fenton associated with an iron and cerium heterogeneous catalyst in the presence of hydrogen peroxide under the irradiation of ultraviolet light for the removal of tetracycline in effluent⁷⁰70 Ya-ping Z, Cheng-guang J, Ran P, et al. Heterogeneous photo-assisted Fenton catalytic removal of tetracycline using Fe-Ce pillared bentonite. J Cent South Univ. 2014; 21(1):310-316.; and electro-photo-Fenton, electro-Fenton ultraviolet irradiation to degrade tetracycline⁷¹71 Liu S, Zhao X, Sun H, et al. The degradation of tetracycline in a photo-electro-Fenton system. Chem Eng J. 2013; (231):441-448.. It is also worth mentioning the application of Fenton associated with hydrogen peroxide and ozone that contributed to the complete degradation of sulfamethoxazole, sulfadimethoxine, sulfamethazine, erythromycin and tylosin tartrate⁷²72 Lin AY-C, Lin C-F, Chiou J-M, et al. O3 and O3/H2O2 treatment of sulfonamide and macrolide antibiotics in wastewater. J Hazard Mater. 2009; 171(1-3):452-458.. All these processes, in addition to not completing the complete mineralization of antibiotics, cite the formation of other compounds (degradation by-products) that may have toxic characteristics or express similar resistance to the original compound⁷³73 Deschamps E, Vasconcelos O, Lange L, et al. Management of effluents and waste from pharmaceutical industry in Minas Gerais, Brazil. Braz J Pharm Sci. 2012; 48(4):727-736..

Of the 31 articles recovered, only 2 presented techniques capable of completely eliminating the antibiotic residues tested⁵⁶56 Pachauri P, Falwariya R, Vyas S, et al. Removal of amoxicillin in wastewater using adsorption by powdered and granular activated carbon and oxidation with hydrogen peroxide. Nat Environ Pollut Technol. 2009; 8(3):481-488.^,7373 Deschamps E, Vasconcelos O, Lange L, et al. Management of effluents and waste from pharmaceutical industry in Minas Gerais, Brazil. Braz J Pharm Sci. 2012; 48(4):727-736., 27 demonstrated some level of removal and 2 were not efficient. The studies that carried out the association between the biological system by sludge activated with other processes presented good efficiency in the removal of antibiotics, which shows that this path can be quite promising.

One noteworthy observation is that only one article was performed in a full-scale treatment system, demonstrating that some of the methods tested by other studies may undergo considerable variations when submitted to larger scales.

From the analysis of these results, there is a need for urgent standardization measures for the release of effluents containing antibiotics. In addition, greater encouragement should be given to research and implementation of effective methods to reduce the risk of environmental contamination by these wastes in alignment with the emergency situation presented by WHO.

It is noteworthy that, in 2015, the WHO called on all countries to draw up National Action Plans to Contain Antimicrobial Resistance; and, in 2018, Brazil published its plan with the collaboration of the Ministry of Health and Welfare. It is emphasized that this plan is close to the current environmental demand of the implementation of reverse logistics for antibiotics, not addressing the problem of liquid effluent from industrial pharmaceutical production⁷⁴74 Brasil. Ministério da Saúde. Agência Nacional de Vigilância Samitária. Plano de Ação da Vigilância Sanitária em Resistência aos Antimicrobianos [internet]. Brasília, DF: Anvisa; 2018. [acesso em 2019 mar 3]. Disponível em http://portal.anvisa.gov.br/documents/3487091/3697444/Plano+de+a%C3%A7%C3%A3o+da+vigil%C3%A2ncia+sanit%C3%A1ria/09f85d62-bc23-4ccf-8c86-0a6431a355f9.
http://portal.anvisa.gov.br/documents/34... .

Of the 31 references retrieved by the integrative review, only 4 evaluated the possibility of reuse of treated effluents from antibiotic production. These studies used as a treatment method the Fenton/coagulation/sedimentation⁶⁸68 Xing Z-P, Sun D-Z. Treatment of antibiotic fermentation wastewater by combined polyferric sulfate coagulation, Fenton and sedimentation process. J Hazard Mater. 2009; 168(2-3):1264-1268. association, photolysis⁶⁶66 Avisar D, Lester Y, Mamane H. pH induced polychromatic UV treatment for the removal of a mixture of SMX, OTC and CIP from water. J Hazard Mater. 2010; 175(1-3):1068-1074. and MBR with nanofiltration⁵⁰50 Wang J, Li K, Wei Y, et al. Performance and fate of organics in a pilot MBR-NF for treating antibiotic production wastewater with recycling NF concentrate. Chemosphere. 2015; 121:92-100.^,5151 Wang J, Wei Y, Li K, et al. Fate of organic pollutants in a pilot-scale membrane bioreactor-nanofiltration membrane system at high water yield in antibiotic wastewater treatment. Water Sci Technol. 2014; 69(4):876-81.. Therefore, there are a small number of works seeking the reuse of effluents treated by the pharmaceutical industry. This fact may be related to the sanitary requirements for water use in this industrial typology⁷⁵75 Linninger AA, Chakraborty A, Colberg RD. Planning of waste reduction strategies under uncertainty, Comp. Chem. Eng. 2000; 24(2-7):1043-1048.. However, other studies that apply the reuse of effluents in various industrial types are observed, being at the discretion of each manufacturing unit the best way to apply the reuse practice. Effluent reuse is reported in industrial activities that, due to quality criteria, are not incorporated into the product, and effluent reuse is more frequent after specific treatment in cooling towers and boilers⁷⁶76 Asano T. Planning and implementation of water reuse projects. Water Sci. and Techn. 1991; 24(9):1-10.

77 Crook J, Surampalli RY. Water reclamation and reuse criteria in the U.S. Water Sci. and Techn. 1996; 33(10-11):451-462.

78 Mujeriego R, Asano T. Tratamento avançado em esgotos, água recuperada e reúso. Water Sci. and Techn. 1999; 40:1-9.^-79.79 Mancuso PC, Santos HF. Reúso de água. São Paulo: Manole; 2003.

The plastic recycling industry is able to reuse 100% of the generated effluents. These effluents from the prewash and washing of plastics and sanitary sewage are directed to the wastewater treatment system, and the treated effluent is added to rainwater precipitated over the industry, which feeds the production process⁸⁰80 Bordonalli ACO, Mendes CGN. Reúso de água em indústria de reciclagem de plástico tipo PEAD. Eng Sanit Ambient. 2009; 14(2):235-244.. Likewise, the textile industry is also able to reuse its effluents from the effluent aftertreatment by advanced oxidative process⁸¹81 Nagel-Hassemer M, Coral LA, Lapolli FR, et al. Processo UV/H2O2 como pós-tratamento para remoção de cor e polimento final em efluentes têxteis. Quím Nova. 2012; 35(5):900-9004.. Effluent reuse is already practiced even in the food production industry⁸²82 Casani S, Rouhany M, Knochel S. A discussion paper on challenges and limitations to water reuse and hygiene in the food industry. Water Res. 2005; 39(6):1134-46.

83 Vourch M, Alannec B, Chaufer B, et al. Treatment of dairy industry wastewater by reverse osmosis for water reuse. Desalination. 2008; 219(1-3):190-202.^-8484 Suárez A, Fidalgo T, Riera FA. Recovery of dairy industry wastewaters by reverse osmosis. Production of boiler water, Sep Purif Technol. 2014; (133):204-211.. In addition to industrial processes, other segments also already perform the practice of reuse, as the International Airport of Rio de Janeiro, in which the treated effluents are directed to the cooling towers, reducing monthly consumption of up to 33 thousand m³ of water. Therefore, further studies are needed on the reuse of effluents mainly treated in the pharmaceutical industry.

Final considerations

From this review, it can be concluded that, in these ten years of research, few studies have been found on treatment of effluents from the antibiotic industry, especially in countries with higher drug consumption and production. While China is emerging in research on this subject, Brazil, which rises in the ranking of pharmaceutical industries, generated little knowledge with this approach.

It is noteworthy that less than 5% of the studies found were developed in full-scale systems, which is a negative result since only in this way it is possible to understand the behavior of antibiotics in treatment systems already installed.

The most tested processes for antibiotic removal/degradation were the advanced oxidative processes (35%) followed by the physical-chemical processes (32%) and, lastly, the strictly biological ones (13%). It is noteworthy that many works used combined processes, including obtaining good efficiencies in relation to the isolated systems. The systems with the worst performance were strictly biological, while the advanced oxidative processes were the best. Few works used systems strictly of membranes (3%), but, yes, with the combination to the biological system (MBR) in which they had good removal efficiencies.

One of the problems for biological systems is the impact of these pollutants on sludge microfauna, because, once acclimatized, they can carry this resistance to antibiotics to the environment. When well adjusted, advanced oxidative processes promote good efficiency in the degradation of antibiotics, however, they can generate unknown byproducts or even with higher toxic potential than the original pollutant. Thus, an assessment of the toxicity and possible effects of these by-products on aquatic ecosystems is required. On the other hand, membrane systems are efficient in removing these compounds that are retained in the membrane; with this, a transfer of these pollutants is observed, which are then discarded as solid residues in the membranes. This same observation should be made to the processes of adsorption by activated carbon.

This review shows that research on the use of effluents in pharmaceutical industries is still in its infancy; especially on antibiotic producers. The 21st century will be marked by the challenge of water scarcity; and one of the ways to alleviate this problem is the reuse of water and effluent in producing activities such as industrial.

Finally, in Brazil, there are no legal limits for the release of effluents with antibiotic residues in the environment. However, this practice poses a risk to environmental health and may favor the development of multi-resistant bacteria.

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