Article Figures & Data
Figures
- FIG 1
Single-dose plasma pharmacokinetics of fosfomycin after subcutaneous administration in groups of three infected mice per dose and time point. The error bars represent the standard deviation. Pharmacokinetic parameters listed in the box include maximum drug concentrations (Cmax), the AUC from 0 to infinity (AUC), and elimination half-life (T1/2) for each dose.
- FIG 2
Impact of pharmacodynamic regression of the in vivo dose fractionation study with fosfomycin against E. coli 1-741-1. Each symbol represents the mean from four thighs. The dose data are expressed as either AUC/MIC ratio (A), Cmax/MIC (B), or percent time that drug concentrations exceed the MIC over the dosing period (time above MIC [%]) (C). The R2 represents the coefficient of determination. The ED50 represents the PD index associated with 50% of the maximal effect (Emax), and N is the slope of the relationship or the Hill coefficient. The line drawn through the data points is the best-fit line based upon the sigmoid Emax formula. The horizontal dashed line at 0 represents the burden of organisms in the thighs of mice at the start of therapy. Data points below the line represent killing, and points above the line represent growth.
- FIG 3
Dose-response curves (A) and 24-h AUC/MIC ratio in relation to treatment effect (B) against five select E. coli strains using a neutropenic mouse thigh model. Each symbol represents the mean from four thighs. The horizontal dashed line at 0 represents the burden of organisms in the thighs of mice at the start of therapy. Data points below the line represent killing, and points above the line represent growth. The R2 represents the coefficient of determination. The ED50 represents the AUC/MIC ratio associated with 50% of the maximal effect (Emax), and N is the slope of the relationship or the Hill coefficient. The line drawn through the data points is the best-fit line based upon the sigmoid Emax formula.
- FIG 4
The dose-response curves (A) and 24-h AUC/MIC ratio in relation to treatment effect (B) against three select K. pneumoniae strains using a neutropenic mouse thigh model. Each symbol represents the mean from four thighs. The horizontal dashed line at 0 represents the burden of organisms in the thighs of mice at the start of therapy. Data points below the line represent killing, and points above the line represent growth. The R2 represents the coefficient of determination. The ED50 represents the AUC/MIC ratio associated with 50% of the maximal effect (Emax), and N is the slope of the relationship or the Hill coefficient. The line drawn through the data points is the best-fit line based upon the sigmoid Emax formula.
- FIG 5
The dose-response curves (A) and 24-h AUC/MIC ratio in relation to treatment effect (B) against two select P. aeruginosa strains using a neutropenic mouse thigh model. Each symbol represents the mean from four thighs. The horizontal dashed line at 0 represents the burden of organisms in the thighs of mice at the start of therapy. Data points below the line represent killing, and points above the line represent growth. The R2 represents the coefficient of determination. The ED50 represents the AUC/MIC ratio associated with 50% of the maximal effect (Emax), and N is the slope of the relationship or the Hill coefficient. The line drawn through the data points is the best-fit line based upon the sigmoid Emax formula.
- FIG 6
Relationship between the PD index AUC/MIC ratio and treatment efficacy of fosfomycin against all 10 isolates using a neutropenic mouse thigh model. The horizontal line at 0 represents the burden of organisms in the thighs of mice at the start of therapy. Data points below the line represent killing, and points above the line represent growth. The R2 represents the coefficient of determination. The ED50 represents 50% of the maximal effect (Emax), and N is the slope of the relationship or the Hill coefficient. The line drawn through the data points is the best-fit line based upon the sigmoid Emax formula.
Tables
- TABLE 1
In vitro activity of fosfomycin against select study strains
Strain Fosfomycin MIC by agar dilution (mg/liter) Resistance mechanism E. coli ATCC 25922 1 1-741-1 1 ESBL+ 681 16 ESBL+ 6042 8 ESBL+ 145 2 ESBL+ K. pneumoniae 7023 16 KPC-3 7068 8 7040 4 NDM-1 P. aeruginosa ATCC 27853 8 9002 16 - TABLE 2
In vitro and in vivo efficacy of fosfomycin against E. coli, K. pneumoniae, and P. aeruginosa
Organism group, strain, and/or parameter Control growth (log10 CFU/ml) MIC (mg/liter) Static dose (mg/kg/24 h) 24-h static dose AUC/MIC ratio Static dose time above MIC (%) 1-log kill dose (mg/kg/24 h) 24-h 1-log kill AUC/MIC ratio 1-log kill dose time above MIC (%) E. coli 145 2.31 2 97.2 19.3 41.4 348 27.5 51.9 681 2.52 16 3,305 18.9 37.7 NAa 6042 1.81 8 491 8.5 15.0 3,572 41.6 75.9 ATCC 25922 2.15 1 256 49.4 67.5 1,644 193 100 1-741-1 2.57 1 86.3 22.4 31.4 1,372 133 74.8 Mean 847 23.7 38.6 1,734 98.9 75.8 Median 256 19.3 37.7 1,508 87.5 75.3 SD 1,383 15.3 19.1 1,346 78.4 19.9 K. pneumoniae 7023 1.265 16 1,122 8.61 12.8 NA 7068 1.8,375 8 3,707 43.6 78.0 NA 7040 1.25 4 171 11.1 26.5 652 21.5 42.6 Mean 1,667 21.1 39.1 Median 1,122 11.1 26.5 SD 1,830 19.5 34.4 Enterobacteriaceae group Mean 1,154 22.7 38.8 1,518 83.3 69.0 Median 374 19.1 34.6 1,372 41.6 74.8 SD 1,494 15.6 23.4 1,262 76.1 22.5 P. aeruginosa ATCC 27853 3.42 8 692 11.3 22.5 1,004 15.6 30.9 9002 3.52 16 3,148 17.9 35.4 6,310 40.8 76.4 ↵a NA, not achieved.
