Chronic degenerative diseases including osteoarthritis are on the rise leading to a growing demand for joint replacement surgery in elderly and often multimorbid patients. Periprosthetic joint infections (PJIs) constitute serious complications following endoprosthetic surgery. Increasing prevalences of PJIs by multi-drug resistant and/or biofilm-producing bacteria hinder sufficient anti-infectious treatment especially in vulnerable patients. Hence, alternative and/or adjunct therapeutic approaches appear crucial in the combat of difficult-to-treat PJIs. In our review we summarize recent evidence for changes in the spectrum of PJI-associated pathogens over time and elucidate treatment concepts beyond established standard therapies. Our literature search revealed that the spectrum of bacterial pathogens can vary considerably depending on the time course post-surgery, the geographical region, and the patient population. While standard antibiotic therapy besides surgical revision remains the corner stone of treatment, alternative/adjunct antibiotics-independent methods are increasingly coming to the fore. These include the targeted dissolution of bacterial biofilms, enzyme-based approaches, and enhanced infection prevention measures upon risk assessment of the patient. Despite promising methodological approaches clinical evidence of their therapeutic value in everyday care is scarce. Hence, optimized early pathogen detection measures, individually tailored treatment concepts and their application in interdisciplinary settings will be important in the combat of difficult-to-treat PJIs.  Kulcsszavak: periprosthetic joint infections, multidrug-resistant (MDR) bacteria, biofilm-producing pathogens, shift in pathogen spectrum, alternative antibiotics-independent treatment options