Available online at www.sciencedirect.

com Current Opinion in

ScienceDirect Environmental Science & Health

Pharmaceuticals, drugs, and resistant microorganisms —

environmental impact on population health
Tomás


Macku
lak1, Slavomír Cernanský 2
, Miroslav Fehér3,
Lucia Biro

sová4 and Miroslav Gál5

Abstract Edited by Yolanda Picó

Pharmaceuticals are indispensable for human and animal For a complete overview see the Issue and the Editorial
health. After use, the active agents and their metabolites are https://doi.org/10.1016/j.coesh.2019.04.002
excreted and impact the environment via different pathways.
2468-5844/© 2019 Published by Elsevier B.V.
They have been found in surface water, groundwater, drinking
water, sediment, sewage sludge, and manure. Monitoring in
the environment is still underway, but an impact on living or- Keywords
Pharmaceuticals, Illicit drugs, Resistant microorganism, Environment,
ganisms has already been detected.
Health.
Their primary sources are healthcare wastewaters, household
wastewater, sludge, and leakages from landfills. Because
wastewater treatment plants are unable to effectively degrade
Introduction
modern pharmaceuticals, drugs, and their metabolites and
Among more than 3000 various active pharmaceutical
remove antibiotic-resistant microorganisms, these compounds
substances, more than 200 compounds have been
are found in the wastewater treatment plant effluent and/or are
identified in the environment. The monitoring is
absorbed in the sludge, composted, and subsequently applied
focused mainly on psychoactive substances and drugs,
in the agriculture.
antibiotics, nonsteroidal antiinflammatory drugs, anti-
There is still a lack of knowledge concerning quantities of
epileptics, antidiabetics, hormones, antihistamines, and
pharmaceuticals entering the environment, the origin of the
cardiovascular drugs [1e5]. Their metabolites, degra-
pharmaceutical active agents, metabolism and transformation
dation products, and contrast agents also come to
pathways, the effects of the active substances, metabolites
attention [1e8]. Concentrations of drugs in the sewage
and transformation products on aquatic organisms, and their
system are affected by the offer of the pharmaceutical
persistence or degradability in the environment.
industry, the specific water consumption per capita, the
This short review summarizes the recent findings of studies
specific consumption of individual drugs, the season,
dealing with the impact of pharmaceuticals, illicit drugs, and
weather, and the type of sewage system involved [9e
resistant microorganisms present in wastewater on the envi-
12]. The precipitation can significantly reduce the
ronment and health of the population.
concentration of micropollutants (dilution effect), while
Addresses dry weather may cause an increase in their concentra-
1
Institute of Chemical and Environmental Engineering, Faculty of tions [13]. The occurrence of psychoactive drugs, anti-
Chemical and Food Technology, Slovak University of Technology in histamines, and antibiotics in wastewater is often
Bratislava, Radlinského 9, 812 37 Bratislava, Slovakia affected by the season [14e17]. However, the concen-
2
Department of Environmental Ecology, Faculty of Natural Sciences,
Comenius University in Bratislava, Mlynska dolina, Ilkovi

cova 6, 84215,
tration of other drugs, such as analgesics and antihy-
Bratislava, Slovakia pertensive agents, is more or less stable over the year
3
Department of Pharmacology, University of Veterinary Medicine and [17,18]. The occurrence of illicit drugs in sewage sys-
Pharmacy in Ko


sice, Srobárova 2, 041 80 Ko
sice, Slovakia
4
tems can be used as a complementary method, along
Department of Nutrition and Food Quality Assessment, Faculty of
with questionnaires, police reports, and medical data, to
Chemical and Food Technology, Slovak University of Technology in
Bratislava, Radlinského 9, 812 37 Bratislava, Slovakia form a comprehensive picture of drug usage in cities and
5
Department of Inorganic Technology, Faculty of Chemical and Food countries, as well as at music festivals [9e13,15,20e23].
Technology, Slovak University of Technology in Bratislava, Radlinského
9, 812 37 Bratislava, Slovakia
The behavior of drugs and pharmaceuticals
Corresponding author: Macku
lak, Tomá

s ([email protected]) in the sewage system and treatment plants
Municipal wastewater treatment plants (WWTPs) are
often referred to as permanent sources of micro-
Current Opinion in Environmental Science & Health 2019,
pollutants, which mainly reach the surface water
9:40–48
through the recipient [7,10e13,20,24e30]. Therefore,
This review comes from a themed issue on Environmental Chemistry:
recent studies start to examine not only their occurrence
Sewage Epidemiology

Current Opinion in Environmental Science & Health 2019, 9:40–48 www.sciencedirect.com

 Pharmaceuticals, drugs, and resistant microorganisms Macku
lak et al. 41

but also their behavior directly in sewerage Czech Republic. The increase in the contamination of
[24,25,29,30]. One of the main processes significantly banknotes by cocaine and methamphetamine used
affecting the results of the analyses is biotransformation during these festivals was observed [44]. Attention was
and biodegradation of drugs and pharmaceuticals, which also paid to the possible contamination of cashiers,
can be carried out directly in the sewerage [24,25,29]. particularly their hands. The study found that antibi-
Recent studies have also focused on the observation of otics d azithromycin (23 times) or erythromycin (up to
factors such as temperature, the impact of the seasons, 64 times) d were the most common hand contaminants
pH, hydraulic retention time, sewer length, oxidatione in cashiers compared to the normal sample of the pop-
reduction conditions, biofilm-to-wastewater-volume ulation. The occurrence of methamphetamine (5 fold)
ratio, and reduced sulfur forms [24e26,28e31]. and cocaine (up to 15 fold) was also observed. Hand-
Removal efficiency of drugs and other micropollutants in washing can, therefore, be one of several ways by which
a WWTP is affected by activated sludge age, physico- drugs and pharmaceuticals enter the wastewater [48].
chemical properties of the compounds in water entering
the plant, oxidationereduction conditions, sorption, The occurrence of drugs and
hydraulic retention time, organization of the individual pharmaceuticals in surface water and
biological stages (aerobic, anaerobic, and/or anoxic), seawater
temperature, season, or pH of the water [20,24,25,32e The contamination of surface water by drugs and phar-
36]. Stripping of pharmaceuticals and drugs, besides maceuticals depends on a number of different factors:
biotransformation and sorption onto activated sludge, the technology of the municipal WWTP, effluent water
can occur in the biological stage of wastewater treatment amount, season, water temperature, intensity of the
[24,25]. Considering a technological operation of the solar radiation, type of the river bed, river flow, and type
WWTP, sorption can be efficiently carried out at several of the river sediment. Most drugs and pharmaceuticals
places in the plant d in the mechanical stage (racks, in rivers are found in lower concentrations than in ef-
sand and grease traps, sedimentation tanks), biological fluents from WWTPs [17,20,25]. The main cause of this
stage, and then in the settling tank or directly in the phenomenon is the dilution by surface water. Degrada-
outflow. Sorption onto the sludge can also occur in tion of these compounds can be affected by microor-
anaerobic digestion processes in which biogas is pro- ganisms and their communities directly in water, river
duced [18,24,25]. Desorption is a much slower process sediment, abiotic pathways, or their various combina-
and can take place, for example, on sludge fields where tions. Microorganisms occurring in rivers are capable of
it results in the release of micropollutants into the effectively degrading some types of drugs and pharma-
environment [24,25,34e39]. Some WWTPs have ceuticals to smaller molecular fragments. In addition to
incorporated a tertiary treatment stage (membranes, biodegradation, direct and indirect photodegradation
biomembrane reactors, sand filters, UV radiation, and may also occur in surface water [6,24,25] (see Table 1).
chlorination) at the outflow, which may be one of the
factors in the different efficacy of micropollutant The contamination of surface waters by pharmaceuticals
removal. Application of a tertiary treatment in a WWTP and wastewater treatment plants also affects their
is limited, for example, when undissolved substances are occurrence in seawater, sediments, or animals. Illicit
present in the outflow [11,24,25]. Considering the drugs are found in seawater only in trace amounts, and
application of progressive technologies, a combination of their specific occurrence is mostly concentrated in the
ozonation and effective sorbents such as activated vicinity of the mainland copying the incidence of drugs
carbon or biochar seems to be one of the most effective among the population [50e53]. For example, Björlenius
technologies [36]. Besides WWTPs, their application is et al. [51] estimate the amount of carbamazepine in the
also perspective in smaller point sources such as Baltic Sea to be greater than 55 tons. It is assumed that
healthcare facilities. The need for degradation of the degradation of this drug may exceed 3.5 years. The
micropollutants and disinfection leads to a frequent presence of certain specific drugs, such as valsartan or
observation of advanced oxidation processes and their metoprolol; antibiotics, such as erythromycin, tetracy-
modifications [20,25,34,37]. cline, clarithromycin, and oxytetracycline; and
antibiotic-resistant microorganisms was also confirmed
Besides healthcare facilities, micropollutant concentra- in marine sediments [53].
tions in wastewater can be increased during festivals, in
discos, or during large open-air concerts [13,15,23,40e
43]. According to Macku
lak et al., [15] the influence The impact of pharmaceuticals on the
of dominant music on the occurrence of individual drugs environment
was observed. In addition to the analysis of wastewater, Some drugs in concentrations of 1e500 ng l 1 in the
analyses of banknote contamination by illicit drugs have environment can adversely affect the aquatic organisms
been conducted in the world for more than 20 years [6,24,39]. Contardo-Jaraa et al. [54] observed the effect
[44e47]. Banknote contamination by illicit drugs was of carbamazepine on a zebra mussel (Dreissena poly-
also observed during music festivals in Slovakia and the morpha) under laboratory conditions. They found that
www.sciencedirect.com Current Opinion in Environmental Science & Health 2019, 9:40–48
42 Environmental chemistry: sewage epidemiology

Table 1 found that diclofenac in the food chain of the vultures

caused their gradual extinction [61]. Subsequently,
The amount of drugs and metabolites in surface waters of
diclofenac was intensively studied in other species of
Slovakia in 2017 [49].
birds (pigeons and chickens), with mortality observed
Compound ng/l at 0.25 for pigeons and 2.5 mg kg 1 for chickens [62].
It is believed that the toxicity of diclofenac leads to
Diclofenac Nd - 110 increased production of reactive oxygen species and a
Carbamazepine Nd - 340 subsequent change in the metabolism (production and
Dihydrocarbamazepine Nd - 3.3 removal) of uric acid [63]. The predicted acute
Carbamazepine Nd - 430
toxicity values for fish are at 100 mg l 1. However,
Codeine Nd -13
Tramadol Nd - 82 during a 28-day test, it was found that toxic effects in
Atenolol Nd -3.6 the rainbow trout may already occur at a concentration
Caffeine Nd - 850 of 1 mg l 1. Damage to these organisms has been
Erythromycin Nd - 25 confirmed, for example, in the case of river trouts at
Clarithromycin Nd -41
concentrations of about 50 mg l 1 [64]. The meta-
Clindamycin Nd - 46
Sulfamethoxazole Nd -240 bolism of these types of drugs to compounds that
O-Desmethylvenlafaxine Nd -160 exhibit similar properties to their maternal molecules
Venlafaxine Nd - 55 and are capable of good bioaccumulation in the tissues
Fexofenadine Nd -130 is also an environmental problem.
Valsartan Nd -120
Telmisartan Nd - 340
Metoprolol Nd -76
Metoprolol acid Nd - 430 The penetration of pharmaceuticals into the
food chain
Nd: not detected (under the limit of detection); rivers: Danube, Morava, Sludge and its application on agricultural land is one of
Váh, Hron, Hornád, Bebrava, Uh, Turiec, Torysa, Myjava, Chvojnica, the dominant sources if one talks about the penetration


Nitra, Zitava,

Kysuca, Cierna Orava. of micropollutants, antibiotic-resistant microorganisms,
and environmental resistance genes into the food chain
[38,65e67]. About 40% of the sludge produced in
exposure of the mussel to concentrations similar to European Union (EU) countries is spread directly on
those in sewage can cause changes in mRNA in this agricultural lands and another 12% indirectly in the form
animal [54]. One of the most recent studies conducted of compost. In Slovakia, 65% of the sludge is spread on
in surface water in the United States connects changes agricultural lands as compost, and the direct application
in the structure and growth of macrozoobenthos with to the soil has been reduced (5e10%) [38,65]. Several
the presence of carbamazepine [55]. Brodin et al. [56] studies confirm the transformation and penetration of
studied the effect of benzodiazepines on the behavior pharmaceuticals from surface water and soils into
of freshwater fish (river shrike). They found that at a aquatic plants and agricultural crops [68e70].
certain concentration, the pharmaceutical can signifi-
cantly affect its self-preservation instinct [56]. By 2016, It was found that when wastewater from WWTP efflu-
several studies have been published to address the ef- ents is used for plant irrigation, there is a gradual in-
fects of commonly prescribed psychoactive pharma- crease in the concentration of certain groups of
ceuticals on fish and various aquatic animals. These pharmaceuticals such as antibiotics and analgesics [71].
pharmaceuticals may not exhibit toxic effects directly, The examined groups of pharmaceuticals were able to
but their amount in surface fluxes may affect the levels penetrate up to a depth of more than 150 cm. The
of neurotransmitters (serotonin, dopamine) in the penetration of pharmaceuticals into plants takes place
brains of aquatic animals [24,57e60]. Schult et al. [60] mainly through the root system. Pharmaceuticals or
observed the effect of various antidepressants on the drugs reach the root by diffusion, which depends on
anatomy of the reproductive organ, physiological func- their chemical properties (log Kow coefficient, molar
tions, and male pattern variations of the common mass below 300, number of H-donors below 3, H-ac-
minnow [60]. The authors also emphasize that antide- ceptors under 6 or hydrophobicity) [68e70].
pressants, and in particular the reuptake inhibitors of
serotonin and norepinephrine (fluoxetine, sertraline), It is difficult to tell whether elevated concentrations of
are capable of adversely affecting the morphology of the certain drug metabolites in agricultural plants can ulti-
reproductive organs of fish in concentrations of several mately cause a health hazard to humans. Nonetheless, the
nanograms per liter. presence of pharmaceuticals or their metabolites in a
plant may adversely affect the development of the plant.
Diclofenac came into awareness in the 1990s, when Although plants have certain mechanisms that are
the population of white-rumped vultures (Gyps benga- designed to digest micropollutants, these mechanisms are
lensis) dramatically decreased (by 95%). It has been not always sufficiently effective [68,70] (see Scheme 1).
Current Opinion in Environmental Science & Health 2019, 9:40–48 www.sciencedirect.com
 Pharmaceuticals, drugs, and resistant microorganisms Macku
lak et al. 43

Scheme 1

Pathways and fate of pharmaceuticals/drugs/antibiotic resistance in the environment and its possible impact on public health. WWTP, wastewater
treatment plant.

Antibiotic-resistant bacteria in WWTPs and ever list of antibiotic-resistant ‘priority pathogens’ d a

their effect on the public health catalog of 12 families of bacteria that pose the greatest
An increase in the number of antibiotic-resistant bac- threat to human health.
teria (ARBs) and antibiotic-resistant genes (ARGs)
complicating the treatment of both human and animal Wastewater is the main vector of pollutants and serves as
pathogens is recently observed [72,73]. Some strains are an inflow channel for ARBs and environmental resistance
resistant to more than 100 different types of antibiotics genes. Discharges from sewage treatment plants, anti-
[74]. Antibiotic-resistant infections require extended biotic production plants, livestock farms, and aquacul-
hospital stays, additional follow-up doctor visits, and ture contribute to the ARBs and ARGs reported in
costly and toxic alternatives [75]. aquatic environment [78]. Antibiotics at subinhibitory
concentrations have been shown to act as signaling
The European Centre for Prevention and Control Dis- molecules and can lead to the development of sponta-
eases estimated that the number of fatal cases associ- neous mutations in bacterial DNA with a much higher
ated with resistant microorganisms in the EU increased frequency. These subinhibitory concentrations can also
up to 25 000/year and the total amount of costs incurred induce horizontal gene transfer, mutagenesis, and code
to health care up to 1.5 trillion euros [76]. The USA signal of extreme distress (SOS) response in bacteria,
recorded that at least 2 million people get an antibiotic- leading to the selection of ARBs [79]. However, antibi-
resistant infection with at least 23 000 deaths [77]. In otics also flow into the sewerage together with human
2017, the World Health Organization published its first- pathogenic and potentially pathogenic ARBs because of
www.sciencedirect.com Current Opinion in Environmental Science & Health 2019, 9:40–48
44 Environmental chemistry: sewage epidemiology

the horizontal transfer gene propagating its resistance category of wastewater is hospital wastewater, which is a
genes to sensitive species of microorganisms via plas- significant source of multidrug-resistant (MDR) bacte-
mids and integrins [78,80]. Studies also point to the fact ria, ARGs, and antibiotics [91]. ARBs leave medical fa-
that biocides and heavy metals act together with residual cilities via colonized patients and the sewer system. The
amounts of antibiotics on present microorganisms and number of antibiotic-resistant fecal indicator bacteria in
stimulate the horizontal transfer of ARGs [78,81]. Ac- the hospital effluent in Slovakia is about one logarithmic
cording to this knowledge, municipal WWTPs belong to order higher than that in the influent WWTP waste-
main hot spots of antibiotic resistance in both environ- water [44,93]. Moreover, the majority of these bacteria
mentally and medically significant bacterial strains that show MDR phenotype [88,92]. This situation increases
can be disseminated by discharging inadequately puri- the probability of ARG transfer conferring to higher
fied wastewater into the environment or food chain [82]. dissemination of antibiotic resistance.

The majority of microbiome and resistome present in Some bacteria are able to attach to the surface and form
wastewater come from human gut microbiota. Nowa- a biofilm. High bacterial density and diversity are found
days, ubiquitous representatives of gut microbiota are of in biofilms from wastewater systems, especially from
interest because some groups emerge as multidrug- activated sludge of sewage treatment plants and hospital
resistant nosocomial pathogens of major importance in effluents [94,95]. Microorganisms attached to a surface
the last few decades [83]. Gut microbiota of healthy in the form of a biofilm exhibit remarkable resistance to
individuals also contains ARBs and ARGs [84e87], all types of antimicrobial challenge, compared with mi-
which can be disseminated to the environment along croorganisms grown as freely suspended cells [96]. In
with the treated wastewater. Monitoring of Slovak Slovakia, bacteria in biofilm from effluent sewerage were
WWTPs showed also a high prevalence of ciprofloxacin- more resistant to all tested antibiotics than microor-
and gentamicin-resistant strains [25,84,88]. Tetracy- ganisms from influent biofilm [31]. Bacteria from
cline resistants were observed in a smaller rate, but their sewerage biofilm can release into wastewater and
occurrence in wastewater correlates with their high therefore increase the number of ARB effluent, re-
prevalence in gut microbiota. However, the use of cipients, and surface water. This phenomenon is docu-
chloramphenicol is limited or forbidden in many coun- mented by many studies, which confirmed the presence
tries; coliform bacteria resistant to this antibiotic are also of ARGs and ARBs in rivers, lakes, sea, and water sedi-
detected in wastewater because of cross-resistance [84]. ments [80,93,97e104]. Lépesová [93] observed
Compared to coliform bacteria, an abundance of antibiotic-resistant coliform bacteria and enterococci in
antibiotic-resistant enterococci and staphylococci in samples of rivers and sediments in Slovakia. Water and
Slovak WWTPs is lower. The majority of these gram- sediment samples collected downstream from WWTP
positive bacteria found in WWTPs were resistant to effluents contained a higher number of ARBs. Moreover,
ampicillin, penicillin, or methicillin. This phenomenon these bacteria were resistant to more antibiotics than
reflects frequent prescription of b-lactam antibiotics those present in samples taken upstream from WWTPs
[89,90]. In the case of enterococci, vancomycin resis- [93]. This also strengthens the fact that WWTPs
tance is also observed. Nowadays, vancomycin-resistant contribute to the dissemination of antibiotic resistance
enterococci represent a huge problem in treatment; into the environment.
however, data from European Antimicrobial Resistance
Surveillance Network (EARS-Net) indicate that van- Municipal WWTPs also produce large amounts of
comycin-resistant enterococci are becoming a cause for sewage sludge, which contains different pharmaceuti-
concern in Europe [76]. cals and biocides in subinhibitory concentration, thus
creating selective pressure on bacteria. Combination of
Monitoring of antibiotics and resistant coliform bacteria this pressure with enough nutrients forms a suitable
occurrence in individual stages of WWTP during condition for development, growth, and propagation of
wastewater treatment showed high levels of these bac- ARBs [105]. Most of the sewage sludge in Slovakia is
teria after mechanical cleaning [25]. The whole waste- transferred to the composting plant where it is mixed
water treating process reduces the number of ARBs, but with compost and applied to the soil [19,38]. Studies
in many cases, they are still present at the effluent water show that sewage sludge contains a high number of
and spread to the environment. According to Slovak ARBs with MDR phenotype [19,84,88,93]. During
monitoring, the number of resistant fecal indicator composting, ARBs may be released in the form of bio-
bacteria was reduced by more than two logarithmic aerosols and impact occupational health of the public
orders [25,84,88]. living in close proximity to such facilities. Such bio-
aerosols can contain different microorganisms and be
Sewerage systems collect wastewater not only from typical for composting plants operating in the open
households but also from hospitals, psychiatric clinics, because their bioaerosols are released directly into the
homes for retirees, and other healthcare facilities, which surrounding environment without any pretreatment
are a significant source of drugs [44,91,92]. A particular using biofilters or bioscrubbers [106]. The use of sewage
Current Opinion in Environmental Science & Health 2019, 9:40–48 www.sciencedirect.com
 Pharmaceuticals, drugs, and resistant microorganisms Macku
lak et al. 45

sludge is preferred in the field of agriculture for its high APVV-17-0183 and the Scientific Grant Agency of the Ministry of Educa-
tion of the Slovak Republic (ME SR) and of Slovak Academy of Sciences
content of valuable forms of some elements, which are (SAS) VEGA 1/0343/19, VEGA 1/0096/17, VEGA 1/0424/18 and VEGA 1/
useful for composting materials. Wang et al. [107] have 0658/19.
documented that human pathogens are able to share
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