Periprosthetic knee infection (PKI) remains one of the most challenging complications after total knee replacement, especially if caused by multidrug-resistant (MDR) or extensively drug-resistant (XDR) organisms. Multiple treatment options are available, such as long-term antibiotic suppression, surgical debridement with retention of the prosthesis, definitive resection arthroplasty, arthrodesis, one-stage or two-stage revision procedures, amputation. We present a rare case of a PKI caused by a XDR Klebsiella pneumoniae in a young patient who underwent a prosthetic reconstruction due to an osteosarcoma of the tibia. In this patient, the PKI has been treated using intravenous administration of Amikacin and an Amikacin-impregnated PMMA custom-made spacer. To our knowledge, only two cases that successfully used hand-mixed antibiotic-loaded spacer based on antibiotic sensitivity for the treatment of PKI caused by MDR and XDR microorganisms have been reported in the literature.