Table 2.

Studies of an antibiotic concentration–response (SSI) relationship in SAP.

Study	Study Design	Antibiotic 1	Surgery	Measured Antibiotic Concs (Analytical Assay)	Number of SSI Cases and Comparators or Controls 2	Key Findings Regarding Antibiotic Concentration and SSI
Zelenitsky et al., 2002 [31]	PKPD subgroup analysis in a prospective double-blinded trial of a single-dose vs. multiple-dose regimen of gentamicin and metronidazole prophylaxis (n = 146) [32]. 3	Gentamicin	Colorectal surgery	Total serum concs at least 30 min after the preoperative dose and postsurgery in recovery (fluorescence immunoassay)	33 superficial SSIs and 10 deep SSI within 30 days vs. 91 without infection	-Lower serum conc at closure (p = 0.02), diabetes (p = 0.02), stoma (p = 0.04), and older age (p = 0.05) were independently associated with SSI; 4 -Serum conc at closure <1.6 mg/L was a significant threshold for SSI (p = 0.002, sensitivity = 70.8%, specificity = 65.9%). 5
Zelenitsky et al., 2018 [33]	PKPD subgroup analysis in a prospective non-interventional PK study of cefazolin prophylaxis (n = 55) [34]. 6	Cefazolin	CABG, cardiac valve repair or replacement 7	Total and unbound plasma concs 30 min after the preoperative dose, prior to redosing, and within 15 min of wound closure (HPLC-tandem mass spectrometry)	8 superficial SSIs within 30 days vs. 32 without infection	-Lower total plasma conc at closure (OR = 1.3 per 10% decrease, p = 0.038) and longer surgery (OR = 2.9 per 1 h increase, p = 0.027) were independently associated with SSI; 4 -Total plasma conc at closure <104 mg/L and surgery >346 min were significant thresholds for SSI. 8
Albacker et al., 2022 [35]	Prospective PK study of cefuroxime prophylaxis. 9	Cefuroxime	CABG 7	Total serum concs immediately before incision, before and 1 h after starting CPB, and before skin closure (analytical assay not described)	14 SSIs (superficial within 30 days and deep/organ space within 90 days) vs. 64 without infection	-Serum concs were not different in patients with SSI compared to those without infection; -Longer durations from the preoperative dose to starting CPB (p = 0.01) and to skin closure (p = 0.03) were associated with SSI. 10
Takayama et al., 2022 [36]	Prospective PK study of cefmetazole prophylaxis. 11	Cefmetazole	Colectomy (laparoscopic), proctectomy	Total serum concs at the time of incision, intestinal resection, redosing, and skin closure, and whole adipose tissue concs at the time of incision and skin closure (HPLC)	7 superficial SSIs, 2 deep SSIs, and 4 organ space SSIs within 30 days vs. 92 without infection	-Lower tissue conc at closure (1.0 vs. 2.2 mg/g, p = 0.09), not redosing during surgery (p = 0.09), lower creatinine clearance (p = 0.09), and older age (p = 0.02) were associated with SSI (α = 0.1). 10
Sheikh et al., 2022 [40]	Prospective PK study of ceftriaxone prophylaxis in pediatrics (mean 6.1 years, range 2–12 years). 12	Ceftriaxone	Pediatric clean or clean-contaminated surgery (multiple)	Total serum and whole adipose tissue concs simultaneously at the time of incision, mid surgery, and wound closure (HPLC)	3 SSIs vs. 47 without infection (surveillance period not described)	-Lower tissue concs at closure (p = 0.04) but higher tissue concs at incision (p = 0.02) were correlated with SSI; -Longer surgery (p = 0.02), higher wound classification (p = 0.035), urinary catheter (p = 0.029), and implantation were associated with SSI (p = 0.002). 13
Sheikh et al., 2023 [41]	Prospective PK study of ceftriaxone prophylaxis. 14	Ceftriaxone	Spinal surgery	Total serum and whole adipose tissue concs simultaneously at the time of incision, mid surgery, and wound closure (HPLC)	4 SSIs vs. 46 without SSI (surveillance period not described)	-Lower serum conc at closure (64.25 vs. 84.46 mg/L, p = 0.003) and lower tissue conc at closure (6.90 vs. 8.82 mg/L, p = 0.008) were correlated with SSI; -Lower serum (p = 0.003) and tissue (p = 0.008) concs at closure, longer surgery (p = 0.003), and implantation (p = 0.049) were associated with SSI. 13
Byers et al., 2022 [42]	PK subgroup analysis in a retrospective study of extended courses of antimicrobial prophylaxis postsurgery (n = 184). 15	Cefazolin	Megaprosthetic reconstruction	Whole tissue concs in cortical bone and adjacent skeletal muscle from punch biopsies collected during surgery (HPLC-tandem mass spectrometry)	5 PJIs within 1 year vs. 5 procedure-matched controls without infection	-Tissue concs during surgery in cortical bone (0.065 vs. 0.42 ng/mL, p < 0.01) and adjacent skeletal muscle (0.20 vs. 1.95 ng/mL, p = 0.03) were lower in patients with PJI compared to controls.

CABG is coronary artery bypass grafting, Conc is concentration, CPB is cardiopulmonary bypass, HPLC is high-performance liquid chromatography, OR is odds ratio, PJI is prosthetic joint infection, PK is pharmacokinetic, PD is pharmacodynamic, SAP is surgical antimicrobial prophylaxis, SSI is surgical site infection, vs. is versus. ¹ Intravenous administration. ² Number of cases included in the analysis of a concentration–response relationship. ³ Serum creatinine <150 umol/L for inclusion. Single-dose regimen of gentamicin 4.5 mg/kg and metronidazole 500 mg preoperatively compared to multiple-dose regimen of gentamicin 1.5 mg/kg and metronidazole 500 mg preoperatively and at 8, 16, and 24 h postsurgery. ⁴ Multivariable logistic regression analysis. ⁵ Receiver operating characteristic (ROC) curve. ⁶ Creatinine clearance ≥50 mL/min for inclusion. Cefazolin by protocol, i.e., 1–2 g preoperatively within 1 h, repeated every 4 h during surgery, and every 8 h for 2 days postsurgery. ⁷ Surgery involving cardiopulmonary bypass. ⁸ Classification and regression tree (CART) analysis. ⁹ Cefuroxime dosing described as “according to the Society of Thoracic Surgeons Practice Guideline Series”. ¹⁰ Univariate analysis,. ¹¹ Cefmetazole by protocol, i.e., 1–2 g preoperatively within 1 h, repeated every 3 h during surgery. ¹² Ceftriaxone by protocol, i.e., 75 mg/kg preoperatively to a maximum of 1 g after induction. ¹³ Correlation test with ceftriaxone serum and tissue concentration and patient characteristics as independent variables, and SSI as the dependent variable. Binary logistic regression analysis of associations between SSI with each individual predictable variable and various concentrations. ¹⁴ Ceftriaxone by protocol, i.e., 1 g preoperatively after induction. ¹⁵ Cefazolin by protocol, i.e., 1–3 g preoperatively within 1 h, repeated every 4 h during surgery, and for a median of 3 days postsurgery.