976. Population Pharmacokinetic/Pharmacodynamic (PK/PD) Target Attainment Analysis of Intravenous Fosfomycin for Treatment of Multidrug-Resistant Gram-Negative Bacterial Infections

BACKGROUND: Intravenous (IV) fosfomycin is increasingly used globally for treatment of infections due to multidrug-resistant Gram-negative bacteria (GNB). This study aimed to determine the optimal dosage of IV fosfomycin for patients with varying degrees of kidney function. METHODS: Eligible patients were adults ≥ 18 years who were treated with IV fosfomycin 2-4 g every 6-8 hours. Five serial blood samples were collected after the 4(th) dose of fosfomycin and concentrations were measured and modeled by population PK analysis. Monte Carlo simulations were conducted to evaluate the probability of target attainment (PTA) of different dosages using species-specific 1-log(10) kill targets (AUC(24h)/MIC of 98.9, 21.5, and 28.2 for E. coli, K. pneumoniae, and P. aeruginosa, respectively). The kidney function adjusted dosing regimens for E. coli are proposed by using the lowest dose that can achieve ≥ 90% PTA at an MIC of 32 (EUCAST breakpoint) and 64 µg/mL. The highest MIC values at which selected doses provide ≥ 90% PTA for K. pneumoniae and P. aeruginosa were also analyzed. RESULTS: A total of 138 plasma samples from 28 patients were included. The model was best described by a 1-compartment model with linear elimination. Significant covariates in final model were creatinine clearance and male sex on clearance (CL), and body weight on volume of distribution (V). The parameter estimates were CL of 0.65 ± 0.1 L/h, and V of 12.59 ± 0.8 L. The PTA of simulated dosages for E. coli are shown in Figure 1. For MIC ≤ 32 mcg/mL, a dosage of 12 g/day achieved ≥ 90% PTA for CL(CR) 90-120 ml/min. For MIC ≤ 64 µg/mL, a dosage of 24 g/day was needed. The proposed kidney function adjusted dosing regimens for E. coli are shown in Table 1. The highest MIC values of K. pneumoniae and P. aeruginosa where these doses provide ≥ 90% PTA were 128 and 256 µg/mL, respectively. [Figure: see text] [Figure: see text] CONCLUSION: A dosage of 12 g/day of fosfomycin is required for E. coli at EUCAST susceptible breakpoint in patients with normal renal clearance and dose adjustments are needed for patients with renal insufficiency. DISCLOSURES: jason M. Pogue, PharmD, AbbVie: Advisor/Consultant|Entasis: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Qpex: Advisor/Consultant|Shionogi: Advisor/Consultant