Technology as a weapon against antibiotic resistance
The coronavirus pandemic has claimed more than a million lives. Though this is certainly dramatic, the rise of the silent killer antimicrobial resistance (AMR) in which bacteria are no longer susceptible for antibiotics is even more threatening and will claim many more victims. The expectation is that in the near future this number will ultimately climb to more than ten million a year worldwide. Researcher Chris Arts of Maastricht UMC+ is leading a major international study into alternatives to antibiotics, technological solutions and increased awareness of AMR. “We are heading for disaster if we do not recognize and address this problem.”
Chris Arts does understand that the last thing we all need is a new nightmare scenario. After all, the world already has its hands full with COVID-19. “Absolutely true,” he says, “but we’ll beat the virus, sooner or later. Resistance to antibiotics is even more serious, however. Bacteria are even more stubborn than viruses, they don’t weaken in strength and they also mutate. Currently, the only way to fight many serious infections is with antibiotics. If these drugs stop working, patients have to rely on their own immune systems. This often doesn’t end well, leaving patients with serious permanent damage or even causing their death. For years, we have been seeing more and more bacteria becoming resistant to antibiotics and we have been warning about the risk of an epidemic for a long time. I hate to have to say it, but this is no longer science-fiction and happening at an alarming rate.”
The orthopaedic researcher, who graduated as a human movement scientist in Maastricht and obtained his doctorate in Nijmegen, shows a map depicting the resistance to antibiotics for the life-threatening MRSA bacteria, among others. Several regions in Southern Europe and America in particular are turning an alarming shade of red. “This means that half the people who get infected can’t be treated successfully with antibiotics. The figures are a lot more encouraging in the Netherlands and Scandinavia. Firstly, because these countries are much more cautious about the use of antibiotics and we are very strict when it comes to adding antibiotics to our foodchain and drinking water. The cause of resistance is actually very simple: if very low levels of antibiotics enter the bidy, bacteria can develop resistance and the antibiotics can no longer kill the bacteria. In France, Spain and Portugal it’s easy to buy antibiotics. Six courses a year for a cold, diarrhea or other ailment; this is not an exception in these countries. People often don’t finish these courses of antibiotics and the wrong types are used. Put all of these bad stewardship factors together and you get an explosive increase in resistance, also because there are hardly any new antibiotic variants being developed anymore. And don’t assume we’re safe here in the Netherlands; resistant bacteria do not stop at borders.”
The consequences are becoming more dire by the day. “Take hospital patients who develop an infection after surgery; we see them in our practice in Maastricht as well. And their numbers are only rising. This isn’t immediately life-threatening, but it can be when antibiotics stop working. When this happens, a standard hip surgery, knee replacement or a thoracic procedure can prove fatal. At a minimum, it can lead to longer periods of care or admission to intensive care units and subsequent extended periods of rehabilitation. In Europe, 400,000 people are already ending up in intensive care because antibiotics aren’t working. Given the current growth rates, this number is likely to rapidly increase tenfold. Extrapolate this to the Netherlands, and there will be more pressure on IC units and hospital care than we’re now seeing from COVID-19. Now try to calculate how much this will cost. It’s in the billions.”
Despite these shocking figures, awareness of the problem is still not very widespread. People and also health care professionals still have a false sense of security. The use of antibiotics is only increasing. The Netherlands is an exception in this regard and we describe significantly less antibiotics compared to other European countries.. Last year, the now awarded a subsidy of 9.8 million Euro to the Dutch Antimicrobial Resistance Technology development and Biofilm Assessment Consortium, or DARTBAC for short. The objective of this international alliance of more than 26 scientific institutes, companies and entrepreneurs is to provide material technology solutions to the growing AMR problem. This is a consortium that includes Maastricht UMC+ as the lead partner, and Chris Arts as a project leader. “It’s no coincidence that we’re in the lead,” says the Brabant native, who co-directs a lab in Maastricht with 35 other orthopedic researchers and also conducts technical research at TU Eindhoven one day a week. “Here in South Limburg, we have a great ecosystem thanks to the Brightlands campuses. We have the best imaging facilities here, along with top researchers and institutes specializing in materials research. There are also crossovers with organizations in Germany, Finland and Belgium. We are able to conceive, develop and apply technological solutions here.”
Technological solutions for antimicrobial resistance. So the goal isn’t new antibiotics? “No it is not!, At DARTBAC, short-term we’re looking at combinations using antibiotics and other substances such as metals to improve therapy potency. We are also trying to create broad Societal AMR awareness. The focus here in Maastricht and the local area is on the development of materialtechnology not based on antibiotics that repel bacterial attachment and biofilm formation or that destroy bacteria. Examples include hip and knee implants, plates used for fractures, but also materials for IVs, catheters, pacemakers, stents, and so on. There’s always a chance of infection with any surgery, but we hope to minimize that risk and prevent the need for antibiotics. Prevention is always better than cure. We are developing coatings with antibiotics that attack the bacteria very locally; we are looking for materials that bacteria cannot affect, with a specific focus on biological materials. The developments at the campuses and MUMC+ are promising. For example, they’re working on a coating with minuscule dots which make it impossible for bacteria to adhere to the surface and thus adversely affect bone or tissue. We use the M4I scanners, the best in Europe, to test whether or not this works and what the molecular mechanisms behind these processes are to determine how best to disrupt them.”
Diagnosis and treatment
A major complication after arthroplasty surgery or trauma is bacterial infection or periprosthetic joint infection (PJI). The treatment of PJI is difficult, time-consuming and costly and almost always involves surgery. Despite aggressive antibiotic treatment, it often results in diminished quality of life. Our aim in the Dartbac project is therefore also to optimize diagnostic strategies that allow faster and more accurate pathogen detection, so antimicrobial treatment can be started or switched to the appropriate drug. We will evaluate different strategies to diagnose PJI. With respect to detection of bacterial causes of PJI bacterial culture techniques will be evaluated retrospectively. Further in prospective studies novel molecular diagnostic methods will be compared to standard bacterial culture e.g. IS-PRO technology (Inbiome) and 16S sequencing (Nanopore sequencing) and application of Raman Spectroscopy device (Nostics) to perform label-free identification of bacterial species. To optimize antibacterial treatment, we will use static and dynamic biofilm models to screen for successful antimicrobial coating compounds. These models will be used to investigate optimal methods for measuring antibiotic susceptibility in biofilm settings. By combining these data, we aim to optimize patient care for patients with various infection types.
Over the next six years, the duration of the DARTBAC project, Chris Arts wants to clinically validate at least three groundbreaking technological solutions. At least ten more researchers will be hired in Maastricht to accelerate the research. “This definitely does not mean the danger has been averted. Material technology is only part of the solution. We’ll be very happy if we can minimize the AMR effect in the Netherlands.” In addition to groundbreaking technological solutions, it is therefore imperative to increase awareness about AMR. Especially in the Netherlands this topic needs attention, as in contrast to most other European countries the level of antimicrobial resistant bacteria is still very low. As a result, important target groups, such as general health professional, patients, and citizens, tend to underestimate the threat and to overestimate their sense of security. One of the pillars of DARTBAC is therefore solely focused on using expertise from the field of health promotion and communication to increase awareness among these three important target groups. Ultimately, we hope that the creation of awareness and a sense of urgency will catalyze future acceptance of new antimicrobial technologies.
Source: Website Brightlands Maastricht Health Campus
Principal Investigator: Dr. Chris Arts
DARTBAC is an interdisciplinary, 23 partner consortium consisting of:
Academic partners: Maastricht University, Maastricht UMC+, Amsterdam UMC, Leiden UMC, the National Institute for Public Health and the Environment (RIVM), Delft University of Technology, Eindhoven University of Technology, UMC Groningen, UMC Utrecht and the University of Amsterdam.
Industry partners: B. Braun Aesculap (Germany), BiosparQ (Netherlands), Bonalive (Finland), CAM Bioceramics (Netherlands), DSM (Netherlands), MadamTherapeutics (Netherlands), OS-1 (Netherlands), PCI Biotech (Norway) and Healthcare Innovations Netherlands (Netherlands).
Other partners: AMR-Insights, Federation Medical Specialists Knowledge Institute, Dutch Orthopaedic Association and ReumaNederland.
"By involving social sciences, communication sciences, materials sciences, medical sciences as well as medical specialist organizations, the RIVM, communication experts, health funds and industrial partners straight from the start of the project, we create the opportunity to raise awareness around AMR and to develop and clinically apply possible material technical solutions more quickly."
Research team (Maastricht UMC+)
Involved research lines
- Functioning, Participation and Rehabilitation
- Promoting Health and Personalised Care
• From a material perspective, develop new antimicrobial technologies that are not based on antibiotics to target infection prevention and eradication on implant surfaces, in hard tissues, and in soft tissues.
• Assess safety and efficacy of these newly developed antimicrobial technologies.
• Enhance the therapeutic efficacy of current antibiotics by combination therapy.
• Develop a new workflow based on AOPs (see grey box at the right) of predictive in vitro and in vivo models to test safety and efficacy of newly developed antimicrobial technology in order to shorten the time to market.
• Maintain awareness of the emerging AMR problem in the Netherlands by informing the general public and HCPs.
An Adverse Outcome Pathway (AOP) is a structured representation of biological events leading to adverse effects and is considered relevant to risk assessment. Identifying adverse outcomes caused by the implanted biomaterial as a starting point from which AOP frameworks can be build allows us to structure essential information on biocompatibility. Therefore, to assess/predict implant safety and biocompatibility besides chemical material-derived stimuli, research efforts at RIVM focus on the physical and mechanical properties of biomaterials and their impact on human cells and tissues.
Our most important scientific output
- Geurts JA, van Vugt TAG, Arts JJ. Use of contemporary biomaterials in chronic osteomyelitis treatment: Clinical lessons learned and literature review. J Orthop Res. 2021 Feb;39(2):258-264 doi: 10.1002/jor.24896.
- Schwarz EM, Arts JJC, Chen AF. Introduction for the Journal of Orthopaedic Research Special Issue on musculoskeletal infection. J Orthop Res. 2021 Feb;39(2):225-226. doi: 10.1002/jor.24981.
- van Vugt TAG, Heidotting J, Arts JJ, Ploegmakers JJW, Jutte PC, Geurts JAP. Mid-term clinical results of chronic cavitary long bone osteomyelitis treatment using S53P4 bioactive glass: a multi-center study. J Bone Jt Infect. 2021 Nov 12;6(9):413-421. doi: 10.5194/jbji-6-413-2021. eCollection 2021.
- Bevers RTJ, van de Voort MHM, van Loo IHM, Geurts JA, Arts JJ. The Role of Material Technologies Targeting P. Aeruginosa and S. Aureus Quorum Sensing in Biofilm Formation. Medical Research Archives,2022, 10(10). https://doi.org/10.18103/mra.
- Vazquez-Rodriguez JA, Shaqour B, Guarch-Pérez C, Choińska E, Riool M, Verleije B, Beyers K, Costantini VJA, Święszkowski W, Zaat SAJ, Cos P, Felici A, Ferrari L. A. Niclosamide-releasing hot-melt extruded catheter prevents Staphylococcus aureus experimental biomaterial-associated infection. Sci Rep. 2022 Jul 19;12(1):12329. doi: 10.1038/s41598-022-16107-4. PMID: 35854044; PMCID: PMC9296466.
- Pijls BG, Sanders IMJG, Kuijper EJ, Nelissen RGHH. Effectiveness of mechanical cleaning, antibiotics, and induction heating on eradication of Staphylococcus aureus in mature biofilms. Bone Joint Res. 2022 Sep;11(9):629-638. doi: 10.1302/2046-3758.119.BJR-2022-0010.R1. PMID: 36047617; PMCID: PMC9533241.
- Van Dijk B, Hooning van Duyvenbode JFF, de Vor L, Nurmohamed FRHA, Lam MGEH, Poot AJ, Ramakers RM, Koustoulidou S, Beekman FJ, van Strijp J, Rooijakkers SHM, Dadachova E, Vogely HC, Weinans H, van der Wal BCH. Evaluating the Targeting of a Staphylococcus-aureus-Infected Implant with a Radiolabeled Antibody In Vivo. Int J Mol Sci. 2023 Feb 22;24(5):4374. Doi: 10.3390/ijms24054374. PMID: 36901805; PMCID: PMC10002501.
- Warmink K, Vinod P, Korthagen NM, Weinans H, Rios JL. Macrophage-Driven Inflammation in Metabolic Osteoarthritis: Implications for Biomarker and Therapy Development. Int J Mol Sci. 2023 Mar 24;24(7):6112. doi: 10.3390/ijms24076112. PMID: 37047082.
- Valentin JDP, Altenried S, Varadarajan AR, Ahrens CH, Schreiber F, Webb JS, van der Mei HC, Ren Q. Identification of Potential Antimicrobial Targets of Pseudomonas aeruginosa Biofilms through a Novel Screening Approach. Microbiol Spectr. 2023 Feb 13:e0309922. doi: 10.1128/spectrum.03099-22. Epub ahead of print. PMID: 36779712.