Background <p>Retaining the native bilateral kidneys after transplantation is a common treatment for patients with end-stage autosomal dominant polycystic kidney disease. However, this strategy poses the risks of potential complications from polycystic kidney infection. The efficiency of antibiotic therapy and the optimal time for native nephrectomy in managing these infections remain uncertain.</p> Case presentation <p>We report a case of a kidney transplant recipient with retained bilateral polycystic kidneys who experienced recurrent cyst and bloodstream infections, accompanied by antibiotic-driven pathogen replacement. After multiple failed attempts at antibiotic therapy, the patient subsequently underwent unilateral polycystic kidney resection. Subsequently, a new infection episode occurred, leading to the other native nephrectomy. Cystic tissue and fluid samples were collected from both shallow and deep layers of the polycystic kidneys, along with peripheral blood and urine samples. These samples were analyzed using microbial culture, metagenome sequencing, and digital polymerase chain reaction to identify infectious pathogens. Pathogen replacement occurred across different infection episodes, with the dominant bacterial species being <i>Escherichia coli</i>, <i>Klebsiella aerogenes</i>, and <i>Enterococcus faecium</i>, in succession.</p> Conclusions <p>This case highlights the replacement of dominant pathogens under antibiotic selection pressure in polycystic kidney infections, primarily involving gram-negative bacilli. When initial and subsequent antibiotic therapy fail, re-evaluation of the cyst infection definition is necessary, and preemptive native nephrectomy should be considered.</p>