Antimicrobial Adverse Events in Periprosthetic Joint Infections: A Narrative Review of Incidence, Drug Class-Specific Toxicities, and Risk Factors

Periprosthetic joint infection (PJI) is a severe complication of arthroplasty, frequently requiring prolonged antimicrobial therapy. Despite being essential for infection control, extended antibiotic exposure predisposes patients to adverse drug events (ADEs), which may compromise treatment efficacy and patient safety. This review aims to synthesize current evidence on the incidence, spectrum, and risk factors of antimicrobial-related ADEs in PJI, with an emphasis on drug class-specific toxicities and their therapeutic implications. A narrative literature search was conducted in PubMed, Embase, and the Cochrane Library from January 2010 to September 2025. Eligible studies included randomized trials, prospective and retrospective cohort studies, and systematic reviews evaluating ADEs associated with antimicrobial therapy for PJI. Data were extracted on incidence, severity, drug classes, treatment modifications, and identified risk factors. A narrative synthesis was performed because of methodological heterogeneity. Across the analyzed literature, the reported incidence of ADEs ranged from 7.8% to 46%, with approximately 7.8% to 20.4% classified as severe events. Vancomycin and piperacillin–tazobactam combinations showed the highest rates of nephrotoxicity, whereas rifampin and linezolid were commonly associated with hepatotoxicity and hematologic toxicity, respectively. Prolonged treatment duration, intravenous administration, advanced age, obesity, and comorbidities significantly increased the risk of ADEs. Emerging evidence suggests that oral step-down therapy and shorter antimicrobial regimens may provide comparable efficacy while offering improved safety profiles. Overall, antimicrobial-related ADEs are common and clinically significant in PJI management, often leading to treatment modification or discontinuation. Optimizing regimen selection, treatment duration, and monitoring, along with adopting standardized ADE reporting frameworks, remains essential to enhancing safety and therapeutic outcomes in PJI care.