Title

Ninety-Day Adverse Events Following Systemic Antibiotic Treatment for Early, Delayed, and Late Periprosthetic Joint Infection After Total Knee Arthroplasty

Background

• Systemic antibiotics are essential for the treatment of periprosthetic joint infection (PJI) following total knee arthroplasty (TKA), but their short-term adverse-event burden remains incompletely characterized.
• Most PJI literature focuses on infection eradication, reoperation, and implant retention, while antibiotic-associated renal, hepatic, hematologic, gastrointestinal, allergic, and cardiac complications receive less attention.
• This study evaluated 90-day adverse events following systemic antibiotic treatment for TKA PJI and compared adverse-event profiles according to infection timing. 

Methods

• A retrospective descriptive cohort study was performed using a federated, de-identified global electronic health record network.
• Adults undergoing TKA who subsequently developed PJI were identified using procedural and diagnosis codes.
• To improve diagnostic specificity, inclusion required:
  • ≥2 PJI diagnosis codes
  • Systemic antibiotic exposure within 1 month of the first PJI diagnosis.
• PJI was stratified by timing after the index TKA:
  • Early: <3 months
  • Delayed: 3 months to 1 year
  • Late: >1 year
• The primary analysis assessed 90-day adverse events after systemic antibiotic exposure, including:
  • C. difficile testing and diagnosis-coded infection
  • Acute kidney injury
  • Elevated AST/ALT
  • Elevated BUN/creatinine
  • Hematologic abnormalities
  • Allergic reactions
  • Toxic liver disease
  • Cardiac events including long-QT syndrome/torsades de pointes
• For each outcome, patients with that event before systemic antibiotic use were excluded from the corresponding at-risk population.
• As a secondary analysis, adverse-event rates were compared across early, delayed, and late PJI groups using Pearson chi-square testing. 

Results

• 4,128 patients met inclusion criteria:
  • 1,443 early PJI
  • 997 delayed PJI
  • 1,688 late PJI. 
• Renal and hepatic laboratory abnormalities were the most common adverse events.
  • Elevated BUN/creatinine: 19.6% early, 23.5% delayed, 25.4% late
  • Elevated AST/ALT: 16.2%, 18.9%, and 17.0%, respectively.
• Acute kidney injury occurred in 5.5%, 5.5%, and 6.2% of early, delayed, and late PJI patients, respectively.
• C. difficile testing occurred in 4.8%, 4.0%, and 5.2%, while hematologic abnormalities occurred in 2.0%, 2.9%, and 3.1%.
• Most adverse events did not differ significantly by PJI timing.
• Allergic reactions were significantly more frequent in early PJI compared with delayed and late PJI (4.8% vs 3.0% vs 2.9%; p=0.044).
• Diagnosis-coded C. difficile infection, toxic liver disease, and cardiac events were infrequent or not reportable because of small cell counts. 

Conclusion

• Among patients receiving systemic antibiotics for TKA PJI, renal and hepatic laboratory abnormalities were the most frequently recorded 90-day adverse events.
• Overall adverse-event profiles were generally similar across early, delayed, and late PJI, although allergic reactions were more frequent in early PJI.
• These findings demonstrate a measurable short-term morbidity associated with systemic antibiotic therapy and support consideration of treatment-related toxicity alongside infection control.
• This is particularly relevant because antibiotic treatment duration for PJI remains guided by limited high-quality evidence, reinforcing the need to balance efficacy with potential adverse effects.