## 4 Discussion
### Seasonal Differences in Concentrations of Pharmaceuticals  
To assess if it is possible to define potential seasonal differences in the PRs levels in sewage water in both influent and effluent, it is crucial to understand what sampling campaigns were carried out in the eighteen studies. However, here too, some criticisms may be levied, as nearly 50% of the works focused their research of PRs on a period shorter than one week, a time that can only provide a punciform view of the situation. Conversely, ten studies out of eighteen have investigated a more extended period, and three carried on annual campaigns [10; 35; 50], although only a few works provided accurate information on the efforts made to assess potential correlation between seasons and levels of antimicrobial substances in WWTPs [10; 17; 37; 50]. From the analysis of these latter four studies, it is not realistic to obtain statistical results applicable to a worldwide context, especially considering the extremely high degree of variability in climate conditions across countries; however, the data collected in this study are particularly beneficial in estimating the potential modifiers for seasonal PR concentrations. What emerged from this scrutiny is the contradictory nature of outcomes, perfectly exemplified by the study of [PERSON] and colleagues on the presence of antibiotic residues in the effluents of 13 European WWTPs [10]. Although the authors of this comprehensive monitoring observed in WW samples from Finland, Ireland and Spain higher concentrations of antibiotics in early spring (March 2015 and 2016) than in early autumn (September 2015 and October 2016), no clear seasonal trend was detected for Germany, Norway or Portugal and an inverse trend was observed in one treatment facility in Cyprus, with higher levels in autumn than in spring. On the other hand, the investigation of [PERSON] et al. on the seasonal variation of 23 pharmaceutical compounds in two WWTPs in Gran Canaria did not exhibit significant variance in their sampling campaigns [37]. In contrast, [PERSON] and colleagues showed that the concentrations of 25 PRs detected in the effluent of a Polish treatment facility were higher in winter than in warmer seasons [50]. Finally, as emphasised by [PERSON] et al. [17], the contribution of tourism may lead to an increase in the concentrations and loads of PRs during the high season. The discrepancies between the studies are accentuated when looking at the seasonal differences for individual pharmaceutical compounds. For example, ciprofloxacin was detected at higher concentrations both in a Norwegian WWTP during autumn and in a Finnish WWTP during spring. The same trend was observed for metronidazole at higher concentrations in Germany and Finland during the cold months and in Spain and Norway during warmer months [10]. Levels of erythromycin during winter and spring in Poland were two-thirds higher than the levels during summer and autumn [50]; conversely, in other countries, macrolides did not show significant seasonal variations [10; 37]. Statistical analyses were performed to assess seasonal differences in influent and effluent concentrations among the 14 PRs occurring in more than a quarter of the studies (Supplementary Material Tables). Figure 5 shows the only two significant seasonal differences identified in this study regarding levels of ofloxacin and sulfamethoxazole in influents. The concentration of ofloxacin was significantly higher during autumn than winter (\(p\)-value: 0.006), spring (\(p\)-value: 0.001) or summer (\(p\)-value: 0.001). A different trend was observed for sulfamethoxazole, which was significantly higher during winter than in spring (\(p\)-value: 0.04). Seasonal variations were also investigated in the effluents of WWTPs. In this case, significant differences in effluent concentrations across seasons were observed for azithromycin and ciprofloxacin. The azithromycin concentration was significantly higher during winter than in summer (\(p\)-value: 0.019).