Background & Challenges

One of the greatest challenges facing mankind in this century is the management of multidrug resistant pathogens and clinically relevant antibiotic resistance genes (ARGs). 

In the clinical-medical sense, resistant pathogens are infectious microorganisms (bacteria, fungi, parasites, viruses) that are insensitive to certain antibiotics (bacteria) / antimycotics (fungi) / antivirals (viruses). 

Multi-resistant organisms (MROs) are resistant to several different classes of antibiotics and pose a challenge in the event of an infection, as they are difficult to treat.

Resistance is initially caused by random mutations (changes in the genetic material of microorganisms), which can lead in different ways to microorganisms no longer being killed or inhibited in their growth by certain antibiotics. The sections of the genetic material of these microorganisms responsible for resistance are also called resistance factors and consist of linear sections of genetic material (transposons) or small circular sections of genetic material (plasmids). The spread and transfer of resistance factors can occur vertically (reproduction of microorganisms by division) or horizontally between different species of microorganisms.

The inappropriate use of antibiotics on a large scale for decades has led to the continuous formation of resistant microorganisms, which colonize humans and animals and enter the environment largely unfiltered, where they can be further distributed or even reabsorbed by humans. In addition, the uncontrolled release of antibiotics into the environment (e.g. via wastewater) also leads to the formation of resistant microorganisms outside of humans and animals. Resistance creates a selection advantage for microorganisms, as they become insensitive to antibiotics, allowing them to reproduce and spread without hindrance. This situation would become serious if an infection by MROs occurred that could not be successfully treated due to a lack of backup drugs. 

In 2019, approximately 4.95 million people worldwide died directly or indirectly from MRO infections, with no improvement in sight [1]. It is predicted that by 2050, more people worldwide will die from MRO infections than from cancer (10 million vs. 8.2 million), resulting in immense economic losses in addition to the personal fate of relatives [2]. 

In 2024, the WHO’s Bacterial Priority Pathogens List (BPPL) identified a total of 15 bacterial families with diverse and overlapping resistance that should be prioritized for intense research focus, drug development, and preventive measures in science and industry, as therapeutic options are sometimes extremely limited [3]. 

In order to minimize the global spread of multi-resistant microorganisms, the Global Action Plan (GAP) was proclaimed in 2015, which should include all influences, including human health, food production, animal husbandry and environmental sectors. Another important aspect is wastewater.  

The Robert Koch Institute (RKI) and the Commission for Hospital Hygiene and Infection Prevention (KRINKO) classify both municipal and hospital wastewater as potentially infectious. Persistent outbreaks of hospital-acquired infections have been attributed to sewage systems as reservoirs of pathogens [4]. Increasingly, hospital wastewater has shown a correlation between antibiotic concentrations and resistant microorganisms. 

Of particular concern are the so-called 4 MRGN pathogens (multi-resistant gram-negative bacteria), which are resistant to up to four of the most important clinical antibiotic classes (piperacillin, third-generation cephalosporins, fluoroquinolones and carbapenems) [5].  Apart from the high contamination of hospital wastewater with MROs, it also contains other critical substances such as absorbable organic halogen compounds (AOX), drug residues and degradation products, for example from antibiotics and cytostatic. 

The effect and presence of chemical contaminants is reduced over time by dilution, absorption and degradation. On the other hand, MROs can multiply and ARGs can spread across species through horizontal gene transfer, so that antibiotic-resistant strains can be found in distant lakes, rivers or shorelines. Water systems are a critical factor in the spread of MROs and ARGs, as they are used both for sewage disposal and as a lifeline for various (human) needs. This is confirmed by a recent publication by Leopold et al. who were able to trace MROs along the Danube River over a distance of 2300 km [6]. 

Current wastewater treatment processes in Germany and the Netherlands are not designed to remove MROs, mobile ARGs or critical drug residues, which means that these risk factors are released into the environment with insufficient reduction. The resulting threats are not yet calculable [5].

Most of the wastewater treatment plants currently in operation in Germany consist of three stages of water treatment [7]. According to the EU, all municipal wastewater treatment plants for >150,000 PE should be equipped with treatment stage 4, adsorptive treatment, by 2045 [8]. Here, the remaining organic suspended solids and micropollutants such as antibiotics and other drug residues, coolant lubricants or other chemical compounds are removed from the water by: i) nanofiltration, ii) reverse osmosis, or iii) precipitation. The impact on the removal of MROs remains to be seen, although this can in principle be achieved by adding oxidants (e.g. H₂O₂, O₃) through additional technical processes.

This is the starting point of the INTERREG Germany-Netherlands project SPOWAR (Sustainable Protection of WAter Resources). The aim of SPOWAR is to develop, characterize, establish and introduce new resource-saving and efficient processes for the treatment of waste and process water in order to prevent the emission and spread of MROs and other pathogens, resistance genes and ecotoxicologically critical organic compounds (drug residues, substances with hormone-like effects, etc.) in the environment.

With its developments, the SPOWAR project is currently focusing on the first item of the “Global Research Agenda for Antimicrobial Resistance in Human Health“, which is concerned, among other things, with investigating the influences and efficacy to ensure the safe handling of water, sanitary facilities, hygiene and waste / wastewater in order to reduce the environmental burden caused by resistance to antimicrobial agents [9].

[1] Antimicrobial Resistance Collaborators. (2022). Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. The Lancet; 399(10325): P629-655. DOI: 10.1016/S0140-6736(21)02724-0.

[2] J. O’Neill. (2014). Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations. The Review on Antimicrobial Resistance. 

[3] WHO. (2024). Bacterial Priority Pathogens List (BPPL). ISBN 978-92-4-009346-1.

[4] Federal Health Gazette – Health Research – Health Protection. (2020). Hygiene requirements for drainage systems in medical facilities. Bundesgesundheitsbl 63: P484-501. DOI: 10.1007/s00103-020-03118-7.

[5] M. Exner, et al. (2020). HyReKA: Hygienic-medical relevance and control of antibiotic-resistant pathogens in clinical, agricultural and municipal wastewater and their significance in raw water” Preliminary final report as of 07.2020; Interinstitutional file: 2022/0345(COD) http://www.hyreka.net/. Accessed: 30.07.2024.

[6] M. Leopold, et al. (2024). A comparative study on antibiotic resistant Escherichia coli isolates from Austrian patients and wastewater-influenced Danube River water and biofilms. J.Hyg.Environ, Volume 258(114361). DOI: 10.1016/j.ijheh.2024.114361. 

[7] Federal Environment Agency. (2023). Public wastewater disposal. https://www.umweltbundesamt.de/daten/wasser/wasserwirtschaft/oeffentliche-abwasserentsorgung#rund-10-milliarden-kubikmeter-abwasser-jahrlich. Accessed: 30.07.2024.

[8] EU General Secretariat of the Council. (2024). Proposal for a Directive of the European Parliament and of the Council concentring urban wastewater treatment (recast).

[9] WHO. (2023). Global research agenda for antimicrobial resistance in human health, policy brief.  https://cdn.who.int/media/docs/default-source/antimicrobial-resistance/amr-spc-npm/who-global-research-agenda-for-amr-in-human-health—policy-brief.pdf?sfvrsn=f86aa073_4&download=true. Zugriff: 30.07.2024.