Medical devices made of polymers are often protected against infection-relevant biofilm formation by embedding nanoparticles as a source of bioactive metal ion release. Safe application of such nanocomposites requires finding the optimal ion dose and identifying the cross-effects caused by material mixtures. This study investigated the safety and antimicrobial efficacy of thermoplastic polyurethane (TPU), which is widely used for medical devices, e.g., catheters containing zinc, silver, copper and magnesium nanoparticles, respectively, and combinations thereof. Nanoparticles were generated by using pulsed laser ablation in polymer solution. We found that the composites embedded with nanosilver were noncytotoxic to cells but toxic to bacteria, with an optimal effect at 0.5 wt\%. In contrast, zinc, copper, and magnesium nanoparticle composites did not inhibit bacteria growth. Interestingly, by combining the antibacterial metals (Ag, Cu) with nanoparticles made of elements required in biological systems (Zn, Mg), we observed an altered ion release and corresponding changes to their antibacterial efficacy and biocompatibility. The combination of silver with magnesium in the nanocomposites did increase both the amount and rate of silver ion release, and resulted in an increased antimicrobial effect of this Ag-Mg-TPU composite material. The therapeutic window of silver could not be changed quantitatively by the Ag-Mg combination, but less wt\% silver was required for achieving antimicrobial efficacy because of faster ion release in the clinically relevant, critical initial phase of immersion. According to our observations, the mechanism of Mg increasing the mass-specific bio-effectivity of silver is possibly nonelectrochemical but volumetric. A fine-tuning of the Mg to Ag ratio and the overall load would be required to test whether a larger therapeutic window compared with Ag composites can be gained by the mixed Mg-Ag nanocomposites. Overall, the addition of Mg to Ag reduces the lag phase of bioactivity by increasing the Ag ion release in the critical first days after application of the medical device.