2554. What’s Weight Got to Do with It? Prospective Pharmacokinetic/Pharmacodynamic Evaluation of Fixed-Dose Daptomycin

Abstract Background As daptomycin (DAP) CL does not scale proportionally with weight, fixed-dose DAP has been proposed to optimize efficacy and mitigate toxicity. This study evaluated systemic exposure of a fixed dose (750 mg) of DAP in patients with Staphylococcus aureus infections. Methods Adult non-ICU patients with CrCl ≥ 30 mL/min admitted to our academic medical center warranting DAP for a S. aureus infection were eligible for enrollment. DAP 750 mg was infused over 30 minutes every 24 hours. At steady state, concentrations were obtained pre-dose (0.5 hours) and 1, 12, and 24 hours after the start of infusion. Concentrations were measured using a validated LC-MS assay. Pharmacokinetic (PK) analysis was performed using first-order equations and stratified by weight: low (< 65 kg), normal (65-85 kg), and high ( > 85 kg). Therapeutic AUC24 (≥ 666 mg*hr/L) and elevated trough (Cmin > 24.3 mg/L) were the efficacy and safety targets, respectively. Results Overall, 22 patients (6 low weight, 8 normal weight, 8 high weight) were enrolled with no differences observed in baseline characteristics (median [IQR] age 49 [42.2, 56.5], CrCl 111 mL/min [79, 134]). PK parameters (median [IQR]) did not differ by weight with Vd 9.9 L [6.3, 17.2], Ke 0.078 h-1 [0.046, 0.098], CL 0.87 L/h [0.47, 1.34], AUC24 861 mg*hr/L [538, 1541], and Cmin 10.5 mg/L [7.3, 29.9]. Therapeutic AUC24 was achieved in 14/22 (64%) and elevated Cmin occurred in 7/22 (32%), with no differences seen among weight groups. However, differences were noted between males (n=10) and females (n=12) with significantly higher CL (median [IQR]) noted in males (1.26 L/h [0.92, 1.48]) vs. females (0.49 L/h [0.37, 0.86]) (p=0.027). Hence, median [IQR] AUC24 was significantly lower in males at 594 mg*hr/L [454, 736] vs. 1513 mg*hr/L [856, 1879] in females (p=0.021). Therapeutic AUC24 was achieved in 40% of males versus 83% of females, while elevated Cmin was seen in 20% of males and 32% of females. Conclusion DAP PK and exposure (AUC24 and Cmin) was not impacted by weight. These results support fixed, rather than weight-based, dosing of DAP in non-ICU patients with normal renal function. Notably, gender differences were observed with males having significantly higher CL, likely warranting higher doses of DAP to ensure optimal exposure. Disclosures Katie B. Olney, PharmD, BCIDP, The Society of Infectious Diseases Pharmacists (SIDP): Grant/Research Support