Extended antibiotic prophylaxis in primary total knee arthroplasty: A narrative review of current evidence and controversies

Table 4 Evidence synthesis: Prophylaxis strategies, efficacy, and stewardship implications in primary total knee arthroplasty (restructured evidence synthesis comparing prophylaxis duration strategies – effect on infection outcomes and stewardship implications)

Ref.	Prophylaxis strategy	Typical regimen	Evidence sources in this review	Efficacy: Standard-risk primary TKA	Efficacy: High-risk subgroups	Harms and stewardship concerns	Practice interpretation (based on cited evidence)
Veltman et al[14]	Single pre-incision dose only	Cefazolin or equivalent within 60 minutes pre-incision; no postoperative doses	Registry comparisons; meta-analyses; guideline frameworks	No worse outcomes than longer courses in large registry and pooled analyses; single-dose performed as well or better than extended protocols in one meta-analysis (odds ratio = 0.78 favouring single-dose vs extended)	High-risk effects not established by randomised data; not specifically tested in defined high-risk subgroups in these analyses	Minimises antibiotic exposure; lowest selective pressure for resistance; lowest drug-related adverse event burden	Reasonable default in many guideline frameworks; strongest alignment with stewardship goals; supported by large-scale observational and registry evidence
Fernandes et al[19]	Standard prophylaxis ≤ 24 hours	Pre-incision dose plus limited postoperative dosing to complete 24 hours	Large observational datasets; orthopaedic society positions (American Academy of Orthopaedic Surgeons and American Association of Hip and Knee Surgeons-type frameworks as referenced in manuscript)	No consistent reduction beyond this window compared with single-dose in large observational datasets	No consistent evidence that extending past 24 hours adds benefit beyond perioperative coverage	Low but non-zero adverse event risk; still limited total exposure; modestly greater selective pressure than single-dose	Dominant orthopaedic standard; supported by society positions; appropriate for most primary TKA patients
Veltman et al[14]; Dhodapkar et al[18]	IV prophylaxis extended beyond 24 hours (multi-day IV)	Continued IV dosing for multiple postoperative days	Large registry and administrative analyses	No reduction in infection outcomes in population-level analyses	Not clearly beneficial; no data specifically supporting this approach in high-risk groups	Line-related risks if IV access prolonged; selection pressure; nursing and cost burden	Not supported for routine primary TKA; duration does not appear to be the modifiable driver relative to antibiotic choice and perioperative pathway optimisation
Inabathula et al[13]; Kheir et al[15]	Selective EOAs in high-risk patients	7 days of oral cephalexin or cefadroxil (typically 500 mg twice daily) after standard perioperative IV prophylaxis; applied only to defined high-risk patients	Two influential comparative cohort studies	Not intended for standard-risk patients in these studies; no data support routine use outside high-risk criteria	Reported reduction in early or 1-year PJI in study-defined high-risk cohorts; causality uncertain given non-randomised designs and confounding by indication	Potential for resistance selection; outpatient adherence variability; Clostridioides difficile risk biologically plausible even if not observed in these cohorts	Hypothesis-generating only; if used, should be restricted to protocolised, clearly defined high-risk criteria with stewardship oversight and robust surveillance; randomised evidence is absent
Flynn et al[9]; Bundschuh et al[17]	Universal EOA for all primary arthroplasty patients	7-10 days of oral antibiotics post-discharge for all patients regardless of risk	Large institutional policy-change cohort); universal single-surgeon protocol	No consistent reduction in 90-day or 1-year PJI when applied broadly	No benefit detected even in high-risk subgroup analyses in at least one large cohort; attribution problem compounded by co-interventions	Ecologic resistance risk at population scale; overtreatment of genuinely low-risk patients; adds unnecessary antibiotic exposure across the majority who would not benefit	Not supported by current evidence; routine universal EOA is difficult to justify given low baseline PJI rates and stewardship principles; should not be extrapolated from single-surgeon bundle studies
Bundschuh et al[17]	EOA plus co-interventions (e.g., intra-wound vancomycin powder)	Oral antibiotics paired with local antibiotic adjuncts; protocol varies by institution	Single-surgeon protocol combining cefdinir with vancomycin powder	Any observed reduction in infection rate cannot be attributed to EOA alone given the bundled design	Same attribution problem; high-risk-specific effect cannot be isolated from the bundle	Risk of confounding and inappropriate extrapolation to EOA as an independent intervention	Results should be interpreted as bundle effects only; not proof of EOA efficacy; co-intervention designs are insufficient to inform isolated EOA policy decisions
Kelly et al[12]	Prolonged antibiotics in non-primary TKA settings (resistance signal)	EOAs after two-stage exchange reimplantation	Reimplantation cohort; included for stewardship implications not primary prophylaxis efficacy	Not applicable to primary TKA prophylaxis efficacy	Not applicable	Strong signal for selection of resistant organisms among failures in prolonged-antibiotic group; clinically meaningful change in microbiology of recurrent PJI	Supports stewardship caution: Prolonged antibiotic exposure can meaningfully alter the microbial landscape; findings are generalisable as a harm signal even if not directly applicable to primary prophylaxis

EOA: Extended oral antibiotic; IV: Intravenous; PJI: Periprosthetic joint infection; TKA: Total knee arthroplasty.