Evaluating the potential of novel antimicrobial strategies in a multimodal treatment model for implant-related infections: antibiotics, antimicrobial peptides, bacteriophages, induction heating

Verheul, M. (2026)

Doctoral Thesis

Prosthetic joint infections are a devastating complication of total joint replacement surgery. These infections are difficult to treat because bacteria form a protective biofilm on the implant, shielding them from the effects of antibiotics and the immune system. As a result, current treatments frequently fail, requiring multiple invasive surgeries and prolonged antibiotic therapy. New therapeutic approaches are therefore urgently needed.

This thesis investigated three innovative treatment strategies: bacteriophages (viruses that kill bacteria), induction heating of metal implants, and the antimicrobial peptide SAAP-148. To evaluate these approaches, bacterial biofilms were cultured in the laboratory on metal discs made from the same material as joint prostheses. This model was used to assess the individual treatments and their combinations.

Although bacteriophages penetrated biofilms, they were less effective against biofilm-associated bacteria than against free-floating bacteria. Bacteria released from biofilms temporarily survived bacteriophage exposure, likely due to their enhanced cell-wall organization and altered metabolism. Repeated exposure to bacteriophage-antibiotic combinations for three consecutive days improved the treatment efficacy compared to one-day exposure. Importantly, induction heating effectively eradicated biofilms, including antibiotic-tolerant bacteria, and enhanced the efficacy of antibiotics and SAAP-148.

Overall, this research demonstrates that combining treatment strategies may provide a promising approach to improve the eradication of implant-associated infections.

• Prosthetic joint infections
• Fracture-related infections
• Bacterial biofilm
• Non-contact induction heating
• Bacteriophages
• Antimicrobial peptides
• Antibiotics
• Multimodality treatment
• Staphylococcus aureus
• In vitro

• All authors: Verheul, M.
• Supervisor: Nelissen, R.G.H.H.
• Co-supervisor: Nibbering, P.H.; Pijls, B.G.C.W.
• Committee: Boer, M.G.J. de; Smits, H.H.; Brouns, S.J.J.; Wouthuyzen-Bakker, M.
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2026-09-02
• ISBN (print): 9789465344829
• Sponsorship: This work was supported by the project DARTBAC (with project number NWA.1292.19.354) of the research program NWA-ORC, which is (partly) financed by the Dutch Research Council (NWO).