# Emergence of Antibiotic Residues and Antibiotic-Resistant Bacteria in Hospital Wastewater: A Potential Route of Spread to African Streams and Rivers, a Review

Wilfried Blandin Evoung Chandja, Richard Onanga, Pierre Philippe Mbehang Nguema, Roméo Wenceslas Lendamba, Yann Mouanga-Ndzime, Jacques François Mavoungou, Sylvain Godreuil

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Wilfried Blandin Evoung Chandja, Richard Onanga, Pierre Philippe Mbehang Nguema, Roméo Wenceslas Lendamba, Yann Mouanga-Ndzime, et al.. *Emergence of Antibiotic Residues and Antibiotic-Resistant Bacteria in Hospital Wastewater: A Potential Route of Spread to African Streams and Rivers, a Review*. Water, 2024, 16 (22), pp.3179. 10.3390/w16223179. hal-04933563

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Review

# Emergence of Antibiotic Residues and Antibiotic-Resistant Bacteria in Hospital Wastewater: A Potential Route of Spread to African Streams and Rivers, a Review

Wilfried Blandin Evoung Chandja <fnref n="1" />,* ID, Richard Onanga ¹ID, Pierre Philippe Mbehang Nguema <fnref n="2" />, Romeo Wenceslas Lendamba <fnref n="3" />, Yann Mouanga-Ndzime <fnref n="1" />, Jacques François Mavoungou <fnref n="2" /> and Sylvain Godreuil ⁴ID

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**Citation:** Evoung Chandja, W.B.; Onanga, R.; Mbehang Nguema, P.P.; Lendamba, R.W.; Mouanga-Ndzime, Y.; Mavoungou, J.F.; Godreuil, S. Emergence of Antibiotic Residues and Antibiotic-Resistant Bacteria in Hospital Wastewater: A Potential Route of Spread to African Streams and Rivers, a Review. *Water* **2024**, *16*, 3179. https://doi.org/10.3390/w16223179

Received: 9 May 2024

Revised: 26 July 2024

Accepted: 1 August 2024

Published: 6 November 2024

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**Copyright:** © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
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4.0/).

**Abstract:** Medicinal activities carried out within hospitals lead to high consumption of antibiotics and subsequently result in a high excretion rate of antibiotic residues. When consumed by humans, these antibiotics are not fully absorbed by the body and are often discharged into the environment along with biological waste from infected human patients. The significant water consumption in hospitals and the pharmaceutical impact on wastewater from healthcare facilities facilitate the emergence and spread of antibiotic-resistant bacteria (ARB) and antibiotic-resistant genes (ARGs) in the environment. Hospital effluents could be doubly involved in the dissemination of antibiotic molecules and multidrug-resistant bacteria in various ecosystems. The aim of this review is to characterize hospital effluents by assessing antibiotic concentrations and the diversity of antibiotic-resistant bacteria in these hospital wastewaters within the environment (aquatic environments; rivers) as well as to inventory the bacteria present and those carrying antibiotic resistance in both hospital wastewater and the environment.

**Keywords:** hospital effluents; antibiotic; antibiotic-resistant bacteria (ARB); environment

## 1. Introduction

The wastewaters generated by hospital activities can constitute a potential danger for humans and the environment due to the nature and quantity of specific substances and microorganisms it contains (pharmaceutical residues, chemical products and multiresistant pathogenic bacteria) [1]. These effluents are discharged into the municipal sewer system without prior treatment, similar to conventional urban wastewater [2].

On average, in healthcare facilities, the antibiotic consumption of a hospitalized patient is about 10 times higher than the average consumption per capita in households [3]. Furthermore, the significant use of antibiotics in hospitals exerts selective pressure that promotes the emergence of multidrug-resistant bacteria, including extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL) [4]. These multidrug-resistant bacteria are then eliminated in wastewater as antibiotic-resistant fecal bacteria (ARFB) and liquid waste [3,5,6]. In developing countries, wastewater treatment before discharge into the environment presents a major challenge due to a lack of resources, unplanned urbanization, and limited industrialization [7].

It is in this context that communal and hospital wastewater play an essential role in the dissemination of antibiotic-resistant bacteria (ARB), such as ESBL [4,8]. Multidrug-resistant

<footnote n="1">¹ Laboratory of Bacteriology, Interdisciplinary Medical Research Centre of Franceville (CIRMF), Franceville P.O. Box 769, Gabon; onangar@yahoo.com (R.O.); yann_mouangandzime@yahoo.fr (Y.M.-N.)</footnote>

<footnote n="2">² Microbiology Laboratory, Research Institute of Tropical Ecology (IRET), Libreville P.O. Box 13354, Gabon; mbehangphilippe@gmail.com (P.P.M.N.); mavoungoujacques@yahoo.fr (J.F.M.)</footnote>

<footnote n="3">³ Clinical Operations Department, Medical Research Centre of Lambarene (CERMEL), Lambarene P.O. Box. 242, Gabon; misterlemdamba@gmail.com</footnote>

<footnote n="4">⁴ Laboratory of Bacteriology, Montpellier University Hospital Centre, UMR MIVEGEC, IRD, CNRS, University of Montpellier, 34295 Montpellier, France; s-godreuil@chu-montpellier.fr</footnote>

<footnote>* Correspondence: evoungblandin@gmail.com</footnote>
microorganisms carried in these contaminated waters can induce the transfer and dissemi-
nation of antibiotic resistance genes (ARGs) to other bacteria, especially pathogenic bacteria,
posing a significant health risk to surrounding populations [9,10]. Infections stemming from
antibiotic-resistant bacteria (ARB) are projected to contribute to approximately 10 million
deaths worldwide by 2050 [11]. Matlou D. P. et al. [12] conducted a study to determine the
virulence profiles of vancomycin-resistant enterococci isolated from surface and ground-
water in the North West Province, South Africa. In total, 170 samples (119 groundwater
and 51 surface water) were analyzed. Of the enterococci identified, 38 were *E. faecium*,
17 were *E. faecalis*, and 1 was *E. saccharolyticus*, with the majority detected in boreholes
and dams and fewer in the river. [13]. This is a global public health problem, highlighting
the importance of a literature review on antibiotic-resistant bacteria (ARB) isolated from
hospital wastewater (HWw). This literature review will consist of drawing up a list of
antibiotic residues (AR) and antibiotic-resistant bacteria (ARB), both of which are present
in hospital effluent and in the environment.

**2. Materials and Methods**

To carry out this literature review, we used the methodology of the systematic review on the contamination of the environment (rivers) by antibiotic residues and antibiotic-resistant bacteria and their resistance genes from hospital effluents. The search strategy for preparing this research review consisted of browsing the relevant articles on the subject in the Google Scholar, PubMed, and CrossRef databases. Articles or other scientific publications dealing mainly with the following keywords: such as antibiotics, antibiotic residues, antibiotic-resistant bacteria, bacterial population, water pollution, rivers and hospital effluents and combinations: such as “antibiotic residues in hospital wastewater”, “bacterial resistance to antibiotics in hospital wastewater”, “risks of hospital wastewater to human health”, “risks of hospital wastewater to the environment” and “ESBL in hospital effluent” (Figure 1) were all considered.

<figure><img src="image_5.png" /><figcaption>**Figure 1.** Flowchart of the process for selecting included studies.</figcaption></figure>
The articles included in this study were published between 2000 and 2023. The above-mentioned search method yielded very few scientific publications (articles) dealing specifically with the presence of antibiotic residues and the pollution of rivers and surface waters by hospital effluents in Africa. The search for documents in databases and other sources enabled us to obtain approximately 237 articles that corresponded to the keywords of our study. After examining the titles and abstracts, we found that there were duplicates (6) and that 93 articles were excluded—3 for the second exclusion. We obtained 138 (articles and other scientific documents), which were definitively included for the writing of this systematic review. This indicates that there is a real gap in knowledge when it comes to studies focusing on environmental protection. The aim was to identify recent trends in the bacteriology of hospital wastewater and the risks they represent for human health and aquatic ecosystems. In view of the above, a literature review was carried out on the basis of available information on water contamination by antibiotic residues and antibiotic resistance bacteria from hospital wastewater and their impact on the various receiving environments.

### 3. Hospital Waste Disposal

Hospitals are significant consumers of water. While the per capita daily water consumption in domestic settings ranges from 150 to 200 liters, the average water consumption in hospitals has increased from 400 to 1200 liters per day, and the production of liquid waste is estimated at 1 cubic meter per day per active bed [14,15]. Additionally, special waters used by the hospital, such as distilled water for irrigation, wound cleaning, tissue rinsing, or surgical equipment humidification, add to this water consumption [16]. The quantity of wastewater discharged by hospitals is estimated at 1000 liters per day in America [14,17].

In Africa, the situation regarding the disposal and treatment of liquid waste is dire [18]. Liquid waste generated by hospitals is continuously discharged into natural water reservoirs without any prior treatment, leading to the vulnerability of local flora and fauna in these natural environments [19,20].

### 4. Antibiotics and Pathogenic Bacteria in Hospital Wastewater

#### 4.1. *Origins of Antibiotic Residues Found in Wastewater*

Medical activities carried out within hospitals generally lead to high antibiotic consumption and a high excretion rate of antibiotic residues [10,21,22]. This consumption is believed to be the main source of antibiotic resistance in some patients and the environment, but it is difficult to assess [23,24]. Indeed, after ingestion, antibiotics undergo chemical modifications, and the resulting metabolites can be more or less toxic and may also have different—even antagonistic—properties compared to the initial medication [25]. Most of these antibiotics consumed in human and veterinary medicine are not fully absorbed by the body and are often released into the environment as biological waste (blood, urine, pus, etc.) from infected human and animal patients [18,26].

Furthermore, the portion of unused medications eliminated through wastewater discharge points can constitute a potential source of ecosystem pollution [27,28].

Additionally, healthcare facilities' discharges present a unique situation due to the number of patients treated, and the quantity and variety of drugs used, including anti-cancer drugs, anesthetics, antibiotics, diagnostic products, contrast agents, or radioactive materials [29,30]. In the external environment of hospitals, the quantitative and qualitative evolution of antibiotic and microorganism contamination occurs according to the gradient of anthropogenic activities [31,32] (Figure 2).
<figure><img src="image_6.png" /><figcaption>**Figure 2.** Dissemination of antibiotic residues and antibiotic-resistant micro-organisms in the four main ecosystems: humans, animals, soil, and rivers.</figcaption></figure>

## 4.2. Antibiotics in Hospital Wastewater, Their Dissemination in the Environment

Antibiotics are essential drugs used to combat bacterial infections in both humans and animals [33]. Intensive use of antibiotics in both of these medical fields has two serious consequences for environmental impact: the presence of residues of active molecules and the increase in the selection of resistant bacteria. The most commonly used antibiotic families in hospitals are beta-lactams (penicillin and cephalosporins), sulfonamides, tetracyclines (doxycycline, oxytetracycline), quinolones/fluoroquinolones (nalidixic acid, ciprofloxacin, ofloxacin, etc.) [34,35]. In fact, the antibiotics (30–90% of antibiotic doses) ingested by hospitalized patients are only partially metabolized by the body, so their residues [36], as well as antimicrobial-resistant bacteria, are excreted into the environment through urine and feces. [32]. Four antibiotics have been detected and quantified, with three of them regularly found in hospital effluents. These include amoxicillin (0.066 ± 0.08 µg/L), erythromycin (0.04 µg/L), sulfamethoxazole + trimethoprim (0.06 ± 0.21/0.08 ± 0.006 µg/L), and metronidazole (0.02 µg/L). Amoxicillin and sulfamethoxazole were detected and quantified at both points, while erythromycin and metronidazole were only found at the "G" Point of Bamako Teaching Hospital [37]. However, in the study by Senar Aydin et al. The total concentration of antibiotics in hospital effluents was ranged from 21.2 ± 0.13 to 4886 ± 3.80 ng/L in summer and from 497 ± 3.66 to 322.735 ± 4.58 ng/L in winter. Azithromycin, clarithromycin, and ciprofloxacin were detected in the highest concentrations among the investigated antibiotics [38] as shown in Table 1. Treated effluents from wastewater treatment plants (WWTPs) and soil runoff or leaching are the main sources of water and sediment contamination [39]. The total antibiotic contribution of hospitals to the influent of the WWTP was determined as 13% in summer and 28% in winter. The remaining 87% in summer and 72% in winter stem from households [38].
<table><caption>**Table 1.** Average concentrations measured in urban effluents (UWw) and hospital effluents (HWw) for commonly found pharmaceutical compounds [40].</caption><thead><tr><th>Antibiotics</th><th>Concentration in HWw (µg L<sup>-1</sup>)</th><th>Concentration in UWw (µg L<sup>-1</sup>)</th></tr></thead><tbody><tr><td>Ciprofloxacin</td><td>0.03–125</td><td>0.01–5.88</td></tr><tr><td>Clarithromycin</td><td>0.2–3</td><td>0.1–4.8</td></tr><tr><td>Ciprofloxacin</td><td>0.85–2</td><td>ND</td></tr><tr><td>Doxycycline</td><td>0.1–6.7</td><td>ND</td></tr><tr><td>Erythromycin</td><td>27–83</td><td>0.04–2.7</td></tr><tr><td>Lincomycin</td><td>0.3–2</td><td>ND</td></tr><tr><td>Metronidazole</td><td>0.1–90</td><td>ND</td></tr><tr><td>Norfloxacin</td><td>0.029–44</td><td>0.01–0.96</td></tr><tr><td>Ofloxacin</td><td>0.353–35.5</td><td>0.01–31.70</td></tr><tr><td>Oxytetracycline</td><td>0.01–3.75</td><td>ND</td></tr><tr><td>Penicillin G</td><td>0.85–5.2</td><td>0.03</td></tr><tr><td>Sulfamethoxazole</td><td>0.04–83</td><td>0.01–6.0</td></tr><tr><td>Tetracycline</td><td>0.01–4.2</td><td>0.01–1.30</td></tr><tr><td>Trimethoprim</td><td>0.01–15</td><td>0.02–7.90</td></tr></tbody></table>

### 4.3. Quantification of Antibiotic Residues Encountered in Samples from Certain Rivers Worldwide

According to a study conducted on irrigation water samples in Burkina Faso, the antibiogram showed that non-typhoid Salmonella was resistant to tetracycline (66.67%, 38/57), followed by ampicillin (66.67%, 38/57), amoxicillin + clavulanic acid, and amoxicillin (30%, 17/57) [41]. A Gabonese study highlighted resistance to antibiotics for ampicillin (91%, 32/35), cefotaxime (3%, 1/35), and cotrimoxazole (9%, 3/35) among the 35 coliforms (Enterobacteriales) found in 27 samples of river and stream waters. No resistance was detected against ciprofloxacin, imipenem, meropenem, and ertapenem, but the only resistance observed was against ampicillin and tetracycline in these waters [42].

The concentrations of antibiotic residues found in wastewater range from nanograms per liter to micrograms per liter [43] as in Table 2. In rivers, the range of antibiotic concentrations varies from a few nanograms to a few tens of nanograms per liter [44]. Among the main sources of surface water contamination, domestic effluents are primarily mentioned, as well as hospital effluents, and pharmaceutical manufacturing and packaging facilities [45].

<table><caption>**Table 2.** Susceptibilities to 12 antibiotics on bacterial isolates (Escherichia coli and Pseudomonas aeruginosa) isolated in WWE, WTP, and RW [46].</caption><thead><tr><th colspan="5">Activity on Isolates</th></tr><tr><th rowspan="2">Antibiotics</th><th rowspan="2">Resistance<br>Prevalence (%)</th><th colspan="3">MIC (mg L<sup>-1</sup>)</th></tr><tr><th>Rank</th><th>50%</th><th>90%</th></tr></thead><tbody><tr><td>Ampicillin (AMP)</td><td>100</td><td>64 to ≥1024</td><td>1024</td><td>1024</td></tr><tr><td>Amoxicillin (AMO)</td><td>100</td><td>1 to ≥1024</td><td>1024</td><td>1024</td></tr><tr><td>Chloramphenicol (CHL)</td><td>100</td><td>256 to ≥1024</td><td>1024</td><td>1024</td></tr><tr><td>Sulfonamide (SUL)</td><td>100</td><td>512 to ≥1024</td><td>1024</td><td>1024</td></tr><tr><td>Trimethoprim (TRI)</td><td>98</td><td>8 to ≥1024</td><td>1024</td><td>1024</td></tr><tr><td>Erythromycin (ERY)</td><td>92.5</td><td>4 to ≥1024</td><td>128</td><td>512</td></tr><tr><td>Streptomycin Sulfate (STR)</td><td>92.3</td><td>1 to ≥1024</td><td>128</td><td>52</td></tr><tr><td>Spiramycin (SPIRA)</td><td>90.6</td><td>2 to ≥1024</td><td>512</td><td>1024</td></tr><tr><td>Oxytetracycline (OXY)</td><td>90.6</td><td>1 to ≥1024</td><td>256</td><td>512</td></tr><tr><td>Tetracycline (OXY)</td><td>90.6</td><td>2 to ≥1024</td><td>128</td><td>256</td></tr><tr><td>Nalidixic Acid (NAL)</td><td>73.6</td><td>1 to ≥1024</td><td>512</td><td>1024</td></tr><tr><td>Kanamycin (KAN)</td><td>54.7</td><td>1 to ≥1024</td><td>128</td><td>1024</td></tr></tbody></table>

Note(s): WTP: wastewater treatment plant; WWE: wastewater effluent; RW: river water; MIC: Minimum Inhibitory Concentration. MICs for each antibiotic for all bacterial isolates tested wastewater, wastewater treatment plant, river water.
Matlou D. P., et al. [12], the highest resistance percentages were for nalidixic acid (83.9%), vancomycin (78.6%) and sulphamethoxazole (0–66.7%). In addition, 80.4% of enterococcal strains were MDR (guideline unspecified), 84.4% carried vanA, and 4% van-B genes. Virulence gene analysis revealed the presence of the gel gene in 36.4% of strains, asa1 in 27.3%, hyl in 6.8%, and esp in 4.5% [11,13].

### 4.4. Antibiotic Residues in Samples Taken from Certain Wastewater Treatment Plants

According to a study carried out in Kuwait by de Bondi Gevao et al., the average concentrations of various classes of antibiotics measured in water from dissolved influents and effluents from two wastewater treatment plants (Umm Al Hayman and Kabd). At the Umm Al Hayman wastewater treatment plant, the dominant compounds in the dissolved effluent were sulfamethoxazole (mean, 212 ng/L), ciprofloxacin (mean, 153 ng/L), ofloxacin (mean, 120 ng/L), dimetridazole (mean, 96 ng/L), and metronidazole (mean, 93 ng/L). At the Kabd treatment plant, however, the dominant compounds were sulfamethoxazole (mean, 338 ng/L), dimetridazole (mean, 274 ng/L), cefalexin (mean, 213 ng/L), ciprofloxacin (mean, 192 ng/L), and clarithromycin (189 ng/L) [47] (Table 3). Concentrations measured in dissolved aqueous effluent in this study were higher than those reported by Gros et al. [48] for the same antibiotics in effluent from the Girona wastewater treatment plant in Spain.

<table><caption>**Table 3.** Average, maximum and median antibiotic concentrations, measured in ng/L, in effluent from two wastewater treatment plants (WWTPs) in Kuwait [47].</caption><thead><tr><th rowspan="2">Antibiotics</th><th colspan="3">Kabd WWTP (ng/L)</th><th colspan="3">Umm Al Hayman WWTP (ng/L)</th></tr><tr><th>Average</th><th>Maximum</th><th>Median</th><th>Average</th><th>Maximum</th><th>Median</th></tr></thead><tbody><tr><td>Sulfamethoxazole</td><td>338</td><td>649</td><td>264</td><td>212</td><td>272</td><td>236</td></tr><tr><td>Dimetridazole</td><td>274</td><td>527</td><td>246</td><td>96</td><td>237</td><td>48</td></tr><tr><td>Cefalexin</td><td>213</td><td>444</td><td>192</td><td>69</td><td>203</td><td>2</td></tr><tr><td>Ciprofloxacin</td><td>192</td><td>535</td><td>115</td><td>153</td><td>533</td><td>40</td></tr><tr><td>Clarithromycin</td><td>189</td><td>420</td><td>134</td><td>39</td><td>80</td><td>35</td></tr><tr><td>Ofloxacin</td><td>127</td><td>311</td><td>98</td><td>120</td><td>324</td><td>76</td></tr><tr><td>Tetracycline</td><td>112</td><td>307</td><td>27</td><td>75</td><td>126</td><td>75</td></tr><tr><td>Metronidazole</td><td>93</td><td>182</td><td>64</td><td>93</td><td>157</td><td>93</td></tr><tr><td>Ronidazole</td><td>78</td><td>153</td><td>78</td><td>80</td><td>156</td><td>80</td></tr><tr><td>Erythromycin</td><td>57</td><td>118</td><td>28</td><td>34</td><td>66</td><td>34</td></tr><tr><td>Azithromycin</td><td>48</td><td>119</td><td>32</td><td>26</td><td>74</td><td>14</td></tr></tbody></table>

In effluents, nitroimidazole concentrations were dominant, particularly at Kabd, followed by sulfonamides, fluoroquinolones, beta-lactams, macrolides, and tetracycline. The difference in antibiotic concentrations between the two treatment plants was not statistically significant (*p* > 0.05). Higher mean concentrations of clarithromycin were measured in the Kabd treatment plant, and higher mean concentrations of sulfamethoxazole were found in the Umm Al Hayman treatment plant.

### 5. Bacteria Found in Hospital

Wastewater typically contains 107 to 108 bacterial organisms per liter, with a concentration of pathogenic bacteria on the order of 104 organisms per liter [49]. The most common bacteria found in hospital wastewater can be those originating from biological waste (feces, urine, surgical instruments, etc.) of hospitalized patients (*Acinetobacter* spp., *Klebsiella pneumoniae*, *Proteus mirabilis*, *Enterobacter cloacae*, *Bacillus cereus*, *Salmonella* spp., *Shigella* spp., and *Staphylococcus aureus*, among others), or bacteria responsible for nosocomial infections (*Escherichia coli*, *Staphylococcus* spp., *Streptococcus* spp., *Pseudomonas* spp., etc.). Pathogenic bacteria such as *Salmonella*, especially *Salmonella typhi* and *paratyphi* species, are generally more prevalent in hospital-origin urban wastewater and can be harmful to human health while potentially harboring antibiotic resistance genes (ARGs) [50,51].
The concentrations of identified bacteria are 10 times higher in hospital effluents than in community wastewater [16,51,52] (Table 4).

<table><caption>**Table 4.** Main bacteria found in bathing waters [38,39].</caption><thead><tr><th>Pathogenic Species</th><th>Load of Bacteria Detected in 100 mL Water Effluent</th><th>Estimated Minimal Infecting Dose</th></tr></thead><tbody><tr><td><em>Campylobacter</em> spp.</td><td>10<sup>4</sup>–10<sup>5</sup></td><td>1 × 10<sup>3</sup></td></tr><tr><td><em>Clostridium perfringens</em></td><td>6 × 10<sup>4</sup>–8 × 10<sup>4</sup></td><td>10<sup>3</sup>–10<sup>5</sup> spores</td></tr><tr><td><em>Escherichia coli</em></td><td>10<sup>4</sup>–10<sup>7</sup></td><td>10<sup>6</sup>–10<sup>7</sup>; 10–10<sup>2</sup></td></tr><tr><td><em>Intestinal Enterococci</em></td><td>4.7 × 10<sup>3</sup>–10<sup>8</sup></td><td>60–10<sup>2</sup></td></tr><tr><td><em>Salmonella</em> spp.</td><td>0.2–8 × 10<sup>3</sup></td><td>10<sup>4</sup>–10<sup>10</sup></td></tr><tr><td><em>Vibrio</em> spp.</td><td>NA</td><td>1 × 10<sup>6</sup></td></tr><tr><td><em>Shigella</em> spp.</td><td>0.1–10<sup>3</sup></td><td>10–10<sup>4</sup></td></tr></tbody></table>

Note: NA = not applicable.

## 5.1. Bacteria Isolated in Community Wastewater and Rivers

In developing countries, poverty and a lack of awareness about health risks lead populations to use wastewater as their primary choice for irrigating vegetable gardens [47]. These practices expose vegetable growers to health risks and also lead to the introduction of various contaminants from these waters into the food chain [53]. In most African countries (Table 5), there are numerous issues related to the quantity and quality of hospital wastewater. In Burkina Faso, Somda et al. reported that hospital wastewater was responsible for the contamination of certain lettuces and other garden products, as they were contaminated with certain antibiotics and bacteria (*Salmonella paratyphi* B and *Salmonella spp.*) generated by hospital activities, and these various impacts were identified in the surrounding water bodies [54]. Furthermore, it has been reported in some countries like Benin, Morocco, and Kenya, hospital wastewater is discharged into community septic tanks due to inappropriate drainage systems [55,56].

In Gabon, studies conducted by Jonas Ehrhardt et al. [57] and Yala et al. [58] showed a high population of enterobacteria in the rivers bordering certain provinces of Gabon. In the first study, they were able to isolate *Citrobacter freundii* (25.9%, 7/27), *Enterobacter* spp. (25.9%, 7/27), *Escherichia coli* (3.7%, 1/27), *Klebsiella pneumoniae* (22.2%, 6/27), *Kluyvera ascorbata* (3.7%, 1/27), *Leclercia adecarboxylata* (3.7%, 1/27), *Pantoea dispersa* (3.7%, 1/27), *Serratia marcescens* (37%, 10/27), and *Yokenella regensburgei* (3.7%, 1/27). This corresponds to an overall contamination rate of 13.5% by coliforms. Additionally, a strain of *Klebsiella pneumoniae* producing extended-spectrum beta-lactamase (ESBL) was found in one of the collected samples (i.e., the river "Petit Odavo", a rural sampling site with 1000 CFU/100 mL) [57]. In the second study, the authors were able to isolate the following enterobacteria: *Enterobacter sakazakii* (9.67%, 3/31), *Escherichia coli* (6.45%, 2/31), *Enterobacter cloacae* (3.2%, 1/31), *Klebsiella ozaenae* (3.2%, 1/31), and *Klebsiella pneumoniae* (3.2%, 1/31) [58].

<table><caption>**Table 5.** Transmission of pathogenic bacteria between household effluents and environmental effluents.</caption><thead><tr><th>Country</th><th>Source</th><th>Host (s)</th><th>Reference</th></tr></thead><tbody><tr><td>Benin</td><td>Urban wastewater</td><td><em>Escherichia coli</em></td><td>[59]</td></tr><tr><td>RC</td><td>Household Wastewater</td><td><em>Escherichia coli</em>, <em>Salmonella</em> spp., <em>Shigella</em> spp., <em>Klebsiella</em> spp., <em>Enterobacter aerogenes</em>, <em>Enterobacter cloacae</em>, <em>Arizona</em> spp., <em>Proteus</em> spp.</td><td>[60]</td></tr><tr><td>Gabon</td><td>River</td><td><em>Citrobacter freundii</em>, <em>Enterobacter sp.</em>, <em>Escherichia coli</em>, <em>Klebsiella pneumoniae</em>, <em>Kluyvera ascorbata</em>, <em>Leclercia adecarboxylata</em>, <em>Pantoea dispersa</em>; <em>Serratia marcescens</em>; and <em>Yokenella regensburgei</em>, <em>Salmonella enterica</em></td><td>[57]</td></tr><tr><td>Tunisia</td><td>Urban wastewater</td><td><em>Escherichia coli</em>, <em>Salmonella</em> spp.</td><td>[61]</td></tr><tr><td>Ethiopia</td><td>Hospital sewage</td><td><em>Klebsiella</em> spp., <em>P. aeruginosa</em></td><td>[62]</td></tr><tr><td>DRC</td><td>River</td><td><em>Escherichia coli</em></td><td>[63]</td></tr></tbody></table>

Note(s): RC: Republic of Congo, DRC: Democratic Republic of Congo.
In estuarine environments or rivers, antibiotic-resistant bacteria and the most stable drug molecules are deposited in mudflats [23]. Sediments then become an environment in which sub-inhibitory concentrations of antibiotics can be reached. A potential transfer of resistance genes to environmental bacteria (*Acinobacter baumannii*, *Aeromonas* spp., *E. coli*), followed by a retrotransfer to strains pathogenic to humans, although the probability is low [32].

## 5.2. *The Bacteria Isolated from Both Hospital Effluents and Rivers*

The number of microorganisms can multiply by a thousand in river waters after urban waste discharge and stagnant waters provide a favorable environment for the development of bacterial biofilms conducive to the contamination of numerous ecosystems [40,42] (Table 6). However, antibiotic-resistant bacteria naturally exist in many water sources, even in geographical areas without significant antibiotic selection pressure [64,65].

<table><caption>**Table 6.** List of bacteria found in hospital wastewater and some rivers in Africa.</caption><thead><tr><td>Species</td><td>Country</td><td>Water Source</td><td>Reference</td></tr></thead><tbody><tr><td>Pseudomonas aeruginosa, salmonella spp.</td><td>Ivory Coast</td><td>Hospital sewage</td><td>[66]</td></tr><tr><td>Escherichia coli</td><td>DRC</td><td>Hospital sewage, river</td><td>[67]</td></tr><tr><td>Klebsiella spp.</td><td>South Africa</td><td>Hospital sewage</td><td>[68]</td></tr><tr><td>Salmonella spp., Pseudomonas spp., and Escherichia coli</td><td>Burkina Faso</td><td>Hospital sewage</td><td>[69]</td></tr><tr><td>Klebsiella pneumoniae, Aeromonas spp. and Escherichia coli</td><td>Benin</td><td>Hospital sewage</td><td>[70]</td></tr><tr><td>Escherichia coli, Enterococcus faecium, Enterobacter cloacae and Pseudomonas aeruginosa, Acinetobacter townii</td><td>Benin and Burkina Faso</td><td>Hospital sewage</td><td>[71]</td></tr><tr><td>E. coli, Klebsiella spp., Salmonella spp., Shigella spp., Citrobacter spp.; Bacillus spp., Proteus spp.</td><td>Ethiopia</td><td>Hospital sewage</td><td>[72]</td></tr><tr><td>Klebsiella spp., Pseudomonas spp., E. coli, Citrobacter spp.</td><td>Ethiopia</td><td>Hospital sewage</td><td>[73]</td></tr><tr><td>Klebsiella oxytoca, K. pneumoniae, Enterobacter amnigenus, E. asburiae, E. hormaechei, Citrobacter freundii, E. coli</td><td>South Africa</td><td>Hospital sewage</td><td>[26]</td></tr></tbody></table>

Note(s): DRC: Democratic Republic of Congo.

## 5.3. *Antibiotic-Resistant Bacteria Found in Rivers Surrounding Hospitals*

Microbial pollutants can also serve as indicators of water quality [74]. Untreated effluents generated by hospital activities can significantly contribute to the spread of microbial pollutants in the environment, particularly multidrug-resistant bacteria (MDR) originating from patient pathological products [75,76]. MDR from effluents primarily stem from either colonized patient biological fluids [26] or horizontal transfer of resistance genes between multidrug-resistant infectious strains and environmental strains [77].

In China, a study by Zhang L et al. (2020) demonstrated that the most frequently identified bacteria in the river water receiving hospital effluents were *E. coli* (37.9%, 25/66), followed by *K. pneumoniae* (16.7%, 11/66) and *Acinetobacter* spp. (16.7%, 11/66) [78], but the resistant strains identified in the effluent samples were dominated by *Pseudomonas* spp. (29.4%, 5/17), *Acinetobacter* spp. (29.4%, 5/17), and *E. coli* (23.5%, 4/17). In another study, researchers characterized bacterial populations present in surface waters (Xiao River) receiving effluents from an oxytetracycline (OTC) production plant. In this water from the upstream Xiao river, only *Stenotrophomonas maltophilia* isolates showed a significantly higher prevalence of resistance compared to *Pseudomonas fragi*, *Pseudomonas fluorescens*, *Bacillus cereus*, and *Pseudomonas putida* (paired Wilcoxon test, all 'p' values were <0.009) [79].

In France, multidisciplinary FLASH project (Fate of Antibiotics, Gene and Antibiotic-Resistant Bacteria Fluxes in Surface Hydrosystems) aimed to study the relationship between antibiotic prescription (both veterinary and human use), antibiotic resistance, and antibiotic molecules in water on the scale of a rural hydrological continuum and a hospital continuum discharging into a Seine tributary (the Risle). The study's results show the presence of antibiotic-resistant strains of *E. coli* and *Enterococcus* spp. circulating in these waters. This
antibiotic resistance selection pressure results from both medical prescriptions in human clinics and veterinary clinics [31].

### 5.4. Antibiotic-Resistant Bacteria in Water

Compared to Enterobacterales, few published reports have documented the isolation of class A carbapenemase-producing glucose-non-fermenting Gram-negative bacteria (GNB) from aqueous ecosystems [80], KPC (*Klebsiella pneumoniae* carbapenemase), KPC-2-, GES variants (for Guiana extended spectrum). The GES-5 enzyme has been detected in *K. pneumoniae* isolated from stream water [54]; in *R. ornithinolytica* and *Citrobacter* sp. recovered from river water [47,79,80]; in *Enterobacter* spp. isolates obtained from seawater [33,70]; in *Citrobacter* spp., *E. coli*, *K. pneumoniae*, *K. oxytoca*, and *E. cloacae* obtained from hospital sewage [55,74]; and in *E. cloacae* complex, *K. pneumoniae*, and *R. ornithinolytica* isolated from wastewater treatment plants (WWTPs) [74,79–81]. GES-16-producing *Acinetobacter* spp. and *Aeromonas* spp. isolates were recovered from WWTPs, hospital sewage, and river and seawater samples in the USA, Brazil, and China [80,82–84]. In addition, the GES-31 carbapenemase was first described in an *Aeromonas punctata* isolate recovered from a Brazilian river [85,86], and de Araujo et al. and Xu et al. have reported the isolation of KPC-2-producing *Aeromonas hydrophila* from rivers in Brazil and China, respectively [87,88]. Recently, KPC-2-producing *A. hydrophilia* and *Aeromonas caviae* were recovered from river water and WWTP effluents, respectively [89,90].

### 5.5. Characterization of ESBLs in Wastewater

Numerous studies (Table 7) have found significant quantities of bacteria producing extended-spectrum beta-lactamases (ESBL-producing *E. coli*) [78] in community and hospital effluents as well as in bathing waters, with more ESBL-producing *E. coli* in hospital wastewater than in community wastewater [4]. This can be explained, in part, by a higher frequency and density of carriage among hospitalized patients compared to healthy community carriers [91]. On the other hand, the high consumption of antibiotics in hospitals leads to their elimination in the form of compounds that are still active in wastewater. These compounds exert a selection pressure that favors resistant bacteria, including extended spectrum β-lactamases (ESBLs) [92]. These enzymes that hydrolyze broad-spectrum penicillins and cephalosporins were initially derived from narrow-spectrum plasmidic penicillinases and were mainly found in hospital strains of *Klebsiella pneumoniae* [93,94] and *Klebsiella oxytoca* [51].

In a study by Hassen B. et al., ESBL-producing *E. coli* and *K. pneumoniae* were isolated from 105 wastewater samples and 15 river samples in Tunisia. The water samples contained 2 g/mL of cefotaxime. The study showed that 25% of the wastewater treatment plants (WWTPs) and 12% of the river water samples tested positive for ESBL-producing Enterobacteriaceae (ESBL-E) strains, with 33 strains of *E. coli* and 4 strains of *K. pneumoniae* identified. Of these strains, 30 out of 37 were considered to be MDR [13,95].

<table><caption>**Table 7.** Bacteria capable of producing ESBLs encountered in effluents (hospitals and rivers).</caption><thead><tr><td>Country</td><td>Source</td><td>Host</td><td>ESBLs</td><td>Reference</td></tr></thead><tbody><tr><td>Ghana</td><td>River waters</td><td><i>Escherichia coli</i></td><td>P, <i>E. coli</i></td><td>[96]</td></tr><tr><td>South Africa</td><td>Sewage</td><td><i>Escherichia coli</i></td><td>P, <i>E. coli</i></td><td>[97]</td></tr><tr><td>Burkina Faso</td><td>Sewage</td><td><i>Klebsiella oxytoca</i>, <i>Serratia</i> spp., <i>Citrobacter</i> spp.</td><td>P, <i>K. oxytoca</i></td><td>[98]</td></tr><tr><td>Cameroun</td><td>Well water</td><td><i>E. coli</i>, <i>Salmonella</i> spp., <i>P. aeruginosa</i>, <i>Klebsiella pneumoniae</i> and <i>Bulkholderia cepaciae</i></td><td>P, <i>E. coli</i></td><td>[99]</td></tr><tr><td>Ivory Coast</td><td>Hospital sewage</td><td><i>E. coli</i>, <i>K. pneumoniae</i>, <i>P. aeruginosa</i> and <i>Acinetobacter baumanii</i></td><td>P, <i>Acinetobacter baumanii</i></td><td>[100]</td></tr></tbody></table>
<table><caption>**Table 7. Cont.**</caption><thead><tr><th>Country</th><th>Source</th><th>Host</th><th>ESBLs</th><th>Reference</th></tr></thead><tbody><tr><td>Nigeria</td><td>Hospital sewage</td><td><i>E. coli</i>, <i>Klebsiella pneumoniae</i>, <i>E. coli</i>, <i>K. pneumoniae</i></td><td>P, <i>E. coli</i> and <i>K. pneumoniae</i></td><td>[101]</td></tr><tr><td>Ethiopia</td><td>Sewage</td><td><i>E. coli</i>, <i>Salmonella</i>, <i>Klebsiella pneumonia</i>, <i>Enterobacter aerogenes</i>, <i>Citrobacter</i>, <i>Klebsiella oxytoca</i> and <i>Enterobacter cloacae</i></td><td>P, <i>K. pneumonia</i> &amp; <i>E. coli</i></td><td>[102]</td></tr><tr><td>Tunisia</td><td>Sewage</td><td><i>Escherichia coli</i>, <i>K. pneumoniae</i></td><td>P, <i>K. pneumoniae</i> &amp; <i>E. coli</i></td><td>[96]</td></tr></tbody></table>

Note(s): P: Positive at ESBL.

## 5.6. Characterization of Antibiotic Resistance Genes in Bacteria Isolated from Wastewater

In South Africa, among the 31 bacterial species isolated in a study by Fadare F. T. et al. [18], genes encoding for beta-lactamases were detected in 20 species (64.5%, 20/31), while resistance genes to other antibiotic families were detected in 27 species (87.1%, 27/31) [18]. The most commonly detected beta-lactam resistance genes belonged to the *bla*<sub>CTX-M</sub> group (including Groups 1, 2, and 3), which were detected in isolates at a rate of 51.6% (16/31) [17]. In China, on the other hand, other authors were able to determine (66.3%, 69/104) the *bla*<sub>CTX-M</sub>-type gene in water samples [8]. In the same study, Fadare F. T et al. [18] showed that among resistance genes to other antibiotic families, the most frequently detected were CatII (79.2%, 19/24) (acting against phenicol), followed by the tetA gene (46.7%, 14/30) (against tetracyclines). Frequencies of other non-beta-lactam genes include sull and sullII (35.5%, 11/31) (against sulfonamides), tetB (23.3%, 7/30), aadA (12.9%, 4/31) (against aminoglycosides), tetC (10%, 3/30), and tetD (3.3%, 1/30) [18].

The aforementioned studies by Hassen B. et al. [13] and Hosu M. C. et al. [103] indicate that wastewater treatment plants are favored reservoirs for strains of the ES-KAPE group of pathogens. This group includes vancomycin-resistant *Enterococcus faecium* and methicillin-vancomycin-resistant *Staphylococcus aureus*—which are classified as high-priority pathogens—as well as carbapenem-resistant *Klebsiella pneumoniae*, *Acinetobacter baumannii*, *Pseudomonas aeruginosa*, and *Enterobacter* spp. These are by the World Health Organization as critical-priority pathogens [104], especially those with multidrug resistance (MDR) profiles and carrying ESBL-associated genes such as *bla*<sub>CTX-M</sub>, *bla*<sub>SHV</sub>, and *bla*<sub>TEM</sub>. ESBL genes are more prevalent than class B metallo-beta-lactamases (MBL) and MBL genes for carbapenemase in wastewater than in surface water sources [13].

A study by Ehi-Ebomah K. et al. [105] assessed the presence of carbapenem-resistant Enterobacter species harboring the *bla*<sub>NDM-1</sub>, *bla*<sub>KPC</sub> and *bla*<sub>OXA-48</sub>-like genes in various environmental sources in South Africa, including hospital wastewater effluent, final effluent from wastewater treatment plants, surface water (rivers and canals) and irrigation water. Of the samples analyzed (257), 142 isolates were identified as *Enterobacter* spp. and only 115 as *E. cloacae*. Antibiotic susceptibility testing revealed that 85 isolates of *E. cloacae* were resistant to a panel of four carbapenems (with resistance percentages of 80% for doripenem, 75% for meropenem, 72% for imipenem, and 66% for ertapenem). Out of 85 bacterial isolates, 41 harbored carbapenem resistance genes: 29 isolates harbored the *bla*<sub>NDM-1</sub> gene, 9 isolates harbored the *bla*<sub>KPC</sub> gene, and 6 isolates harbored the *bla*<sub>OXA-48</sub>-like gene. The highest increase in ARG in *E. cloacae* was detected in hospital wastewater effluents (29%), followed by irrigation water and surface water (17%) and final effluents from wastewater treatment plants (10%) [13,105].

## 6. Fate of Hospital Antibiotics in Natural Environments

The danger of pharmaceutical substances in the environment lies in the fact that they can behave from a physicochemical perspective like substances secreted by the host organism, thus retaining their effectiveness [106]. They can also substitute for molecules or bind to specific receptors within the recipient organism. Furthermore, these substances
may follow the path of bioaccumulation of antibiotics in organisms and affect ecosystem functioning [107].

Additionally, the low concentrations of drugs and their metabolites, generally lower than those encountered in therapy, do not allow for an accurate estimation of the actual presence of these substances in the environment [65].

Fecal bacteria and chemical contaminants associated with suspended matter in the water column settle in the mudflats, and sediment accumulation zones [105]. In these sediments, it has been shown that antibiotics persist for more than 30 years at concentrations reaching 32 mg/kg for quinolones, 15 mg/kg for sulfamides, and 20 mg/kg for nalidixic acid [105]. The risk associated with certain antibiotics such as doxycycline, oxytetracycline, and levofloxacin lies in their elimination by the organism in an active form (bioactive molecules), potentially dangerous for the environment [65,108].

Iva Buriánková et al. conducted a study in which they demonstrated that there was an increase in the concentrations of ARG and ARB (resistance rate of *Escherichia coli* ranged from 51.4% (±16.3%) in raw wastewater to 33.7% (±9.7%) in treated wastewater) in the river water and in the sediments sampled downstream of the WWTP discharge point. The discovery of ARGs and ARBs in the river downstream of the WWTP discharge point was rather expected, but the detectable levels of all the analyzed ARGs and ARBs found in the upstream samples suggest that some antibiotic resistance may be occurring naturally in the river environment. Many factors may be responsible for the maintenance of this resistance in the Svratka River and in the samples taken, including agricultural runoff and soil leaching [54]. In the case of the Svratka river, they assumed that the ARGs and ARBs found upstream of the discharge point of the Brno-Modrice WWTP most probably come from the effluent of the University Hospital WWTP [109].

## 6.1. Risk of Contaminated Water in Aquatic Animals

Aquatic environments constitute important reservoirs of antibiotic-resistance genes. They also serve as a vehicle through which antibiotic resistance genes (ARGs) or antibiotic-resistant bacteria (ARB) can be disseminated from one ecosystem to another [110]. The effects of these anthropogenic inputs on the bacterial flora of the aquatic environment are still poorly understood. However, the genomes of aquatic bacteria are particularly rich in mobile genetic elements involved in the selection and dissemination of resistance genes [108]. For example, qnrA and qnrS, plasmidic resistance genes to quinolones, have been mobilized from the genomes of Shewanella algae and Vibrio splendidus [111].

The bioaccumulation of antibiotics in wild fish species has been observed by Valdés et al. [111]. Erythromycin was the most commonly observed antibiotic in the crustacean Fenneropenaeus penicillatus at the adult stage and was found in concentrations ranging from 2498 to 15,090 ng/g⁻¹ [86]. When the aquatic environment receives inputs from animal or anthropogenic sources, the number and type of bacteria present can render the water unfit for human and animal use [112,113].

## 6.2. Consequences of Contamination Related to Hospital Wastewater

Most diseases resulting from contact with wastewater are caused by pathogenic germs such as bacteria. These pathogens can cause severe illnesses, especially in particularly vulnerable groups (children, the elderly, and individuals with weakened immune systems), and workers in contact with such waters, such as sewage workers and wastewater treatment plant employees [108].

## 6.3. Consuming Untreated Water Can Lead to Waterborne Illnesses

Water, vital for existence, can also be a source of water-related diseases [113]. According to the World Health Organization (WHO), 361,000 children under the age of 5 die each year from diarrheal diseases due to inadequate access to clean water and sanitation [87]. Human health is seriously affected by water-related diseases as well as by pollution from chemical discharges into water from various human activities. According to UNICEF,
60% of child mortality worldwide is due to infectious or parasitic diseases, mostly related to water pollution [114,115]. Moreover, if measures are not taken to combat antibiotic resistance, it is estimated that by 2050, antibiotic-resistant bacteria could be responsible for the deaths of 10 million people annually worldwide, including 390,000 people in Europe. Global economic losses would amount to EUR 100 trillion [116].

# 7. Solutions to Combat Antibiotic-Resistant Bacteria in Surface Water

## 7.1. Influence of Wastewater Treatment Plants on Surface Water Protection

A study conducted in the town of Sneek (The Netherlands) by Ilse Verburg et al. showed that ARGs decreased after wastewater treatment in wastewater treatment plants. Almost all antimicrobial concentrations decreased by 50% after treatment at the WWTP. Although none of the antimicrobials were observed above the detection limit in surface water, human markers (gabapentin concentration) were found in the receiving streams. These results show that the WWTP often discharges contaminants and resistant bacteria into surface water, albeit in low concentrations. No significant difference was observed between the percentage of resistant species in upstream and downstream waters, but bacterial counts showed that the WWTP had a significant effect on the concentrations of certain bacteria such as *E. coli* in surface waters (p > 0.05) [117].

In the study by Klaudia Kulik et al., they showed that wastewater treatment plants are not specifically designed to completely reduce the levels of antibiotics, antibiotic-resistant bacteria, and ARGs. The elimination of different antibiotics occurs at different stages of the wastewater treatment process, and the efficiency of their elimination varies depending on the antibiotic. Removal efficiency depends on the physical and chemical properties of the antibiotics and the conditions of the treatment process. However, previous studies have concluded that conventional secondary treatment processes are unable to completely remove antibiotics from wastewater. Advanced wastewater treatment techniques, such as membrane processes, activated carbon adsorption, and UV radiation, may increase the percentage of antibiotic removal from wastewater and are presented later in this review [118].

## 7.2. Influence of Bioremediation Bacteria in Wastewater Treatment

In a study carried out by Yousra Turki et al., they identified bacteria in wastewater samples that have a significant activity in wastewater purification. These bacteria could play an essential and important role in the process of degrading various chemical and organic pollutants likely to be present in wastewater. These bacterial species (e.g., *Cronobacter sakazakii*, *Chromobacterium violaceum*, *Fluviicola taffensis*) represent a relatively stable population that adapts to the different stages of treatment because they form and adhere to the biofilm matrix [119] and have been found in the majority of wastewater treatment stages. Various studies have shown that Chromobacterium species are known to be very active denitrifying bacteria [120] and are involved in the detoxification of cyanate, for example. In addition, *Fluviicola taffensis*, represented by the weak band, was also found in all wastewater and biofilm samples. This species has been shown to consume and degrade low- and high-molecular-weight dissolved organic matter [121].

Indeed, in the process of large-scale wastewater treatment, several species—such as *Enterobacter agglomerans*, *Cronobacter sakazakii*, and *Pantoea agglomerans*—well known for their bioremediation activities were found in the majority of biofilm samples. Numerous studies have shown the role of these bacteria in the degradation process of certain organic pollutants such as paraffin, olive oil, and sodium dodecyl sulphate (SDS) [122] as well as in the production of enzymes and antibiotics and as antagonistic organisms against numerous plant pathogens [123,124].

# 8. Conclusions

This review has highlighted the potential link between hospital effluents and environmental contamination by antibiotic-resistant bacteria and antibiotic residues. It is therefore
essential to consider the whole chain of the problem in order to effectively study preventive measures and better implement solutions to protect environmental waters from antibiotic-resistant bacteria. The genetic diversity of bacteria naturally present in the environment makes it a natural reservoir of resistance genes. The spread of antibiotic-resistant bacteria and their genes in hospital wastewater could, in turn, worsen their presence in the environment. Further studies are needed to assess the impact of antibiotic-resistant bacteria and their genes in watercourses. Ensuring good water quality before discharge helps to maintain a minimally polluted or unpolluted environment while protecting public health.

**Author Contributions:** Conceptualization, W.B.E.C. and R.O.; methodology, W.B.E.C.; validation, W.B.E.C., R.O. and P.P.M.N.; formal analysis, R.W.L.; investigation, W.B.E.C.; resources, J.F.M., S.G., R.O., P.P.M.N.; writing—original draft preparation, W.B.E.C., R.O, P.P.M.N., Y.M.-N. and J.F.M.; writing—review and editing, W.B.E.C., R.O. and S.G.; visualization, W.B.E.C., R.O., R.W.L. and Y.M.-N.; supervision, R.O. and S.G.; project administration, W.B.E.C. and R.O. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Data Availability Statement:** Data are contained within the article.

**Acknowledgments:** The authors would like to thank CIRMF for administrating the project, and for funding acquisition.

**Conflicts of Interest:** The authors declare no conflict of interest.

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