Antimicrobial prophylaxis regimens in joint replacement surgery: susceptibility and PK/PD target attainment

BACKGROUND: Effective surgical antimicrobial prophylaxis requires activity against likely pathogens and antibiotic concentrations above the minimum inhibitory concentration (MIC) throughout surgery. We compared microbiological coverage and PK/PD target attainment of cefazolin, cefuroxime or vancomycin, alone or with gentamicin, for primary total knee or hip arthroplasty. METHODS: We linked two datasets: archived prosthetic joint infection (PJI) isolates after primary total knee or hip arthroplasty, used for susceptibility testing and MIC determination; and plasma antibiotic concentrations at closure from a 135-patient prospective cohort receiving a study regimen. We assessed microbiological coverage (percentage of isolates susceptible to ≥1 antibiotic) and PK/PD target attainment (percentage with isolate-specific MICs below the free plasma concentration at closure of ≥1 antibiotic, irrespective of categorical susceptibility). RESULTS: Among 75 isolates, coagulase-negative staphylococci (CoNS) (27; 36%) and Staphylococcus aureus (26; 35%) predominated. Single-agent coverage and PK/PD attainment were 49.3% and 72.0% for cefazolin, 52.0% and 64.0% for cefuroxime, and 81.3% and 81.3% for vancomycin. Only cefazolin showed a significant discrepancy between microbiological coverage and PK/PD attainment (p=0.004), mainly due to methicillin-resistant CoNS: 13/19 (68.4%) had MICs below the free concentration at closure despite categorical non-susceptibility. Gentamicin increased coverage (to 80.0%, 81.3% and 96.0%) and PK/PD attainment (to 89.3%, 82.7% and 96.0%), mainly through improved Gram-negative activity. Vancomycin-containing regimens outperformed cefuroxime-containing, but not cefazolin-containing, regimens in PK/PD attainment. CONCLUSIONS: Cefazolin may retain prophylactic activity against methicillin-resistant CoNS despite categorical non-susceptibility. Vancomycin-containing regimens had the highest PK/PD performance but were not significantly superior to cefazolin-based regimens. Gentamicin improved Gram-negative activity.