Local antibiotic delivery using different carriers plays an important role in both infection prophylaxis and treatment. Besides dead space management, these carriers have the advantage of providing a high concentration of local antibiotics with a lower risk of systemic toxicity. Few studies have reported on systemic toxicity associated with antibiotic-impregnated carriers. The present study investigates the systemic tobramycin concentration at 24, 48 and 72 h postoperatively after using tobramycin-loaded polymethyl methacrylate (PMMA) and calcium sulfate (CS) as local antibiotic carriers. Additionally, this work assesses the renal function postoperatively for indications of acute kidney injury (AKI). Fifty-two patients were treated in 58 procedures with tobramycin and vancomycin-loaded PMMA, CS, or both. All systemic tobramycin levels were <2 mcg/mL at 72 h, and the resulting rate of AKI was 12% (7/58). In conclusion, local tobramycin antibiotic delivery using PMMA, CS, or both remains a safe and effective modality in the treatment of osteomyelitis as long as the surgeon is aware of its possible nephrotoxic effect.