TABLE 3.
Population mean parameter estimates for the imipenem-plus-aminoglycoside (tobramycin or amikacin) combination models against three P. aeruginosa isolates
| Parameter | Abbreviation | Population mean value (SE [%]) for strain, treatment |
||
|---|---|---|---|---|
| FADDI-PA088, IPM + AGS | FADDI-PA001, IPM + AGS | FADDI-PA022, IPM + TOB | ||
| Log10 CFU, initial inoculum | LogCFU0 | 7.54 (3.8)a | 7.92 (1.2)a | 6.99 (1.3) |
| 7.46 (1.8)b | 7.78 (1.0)b | |||
| Log10 CFU, maximum population size | CFUmax | 9.56 (1.8) | 9.23 (0.7) | 9.54 (2.9) |
| Replication rate constant (h−1) | k21 | 50 (fixed) | 50 (fixed) | 50 (fixed) |
| Mean generation time (min) | ||||
| Population 1 (CFUSS) | k12S−1 | 26.9 (6.2) | 45.3 (10.9) | 63.8 (10.8) |
| Population 2 (CFURI) | k12I−1 | 873 (8.5) | 481 (15.2) | 565 (19.9) |
| Population 3 (CFUIR) | k12R−1 | 26.9 (6.2) | 45.3 (10.9) | 63.8 (10.8) |
| Log10 mutation frequencies | ||||
| IPM | LogMUT,IPM | −4.73 (5.8) | −4.99 (4.0) | −3.90 (9.4) |
| AGS | LogMUT,AGS | −7.00 (5.9)a | −7.33 (4.2)a | −7.55 (4.0) |
| −6.68 (3.4)b | −6.66 (4.0)b | |||
| Killing by IPM | ||||
| Maximum killing rate constant (h−1) | Kmax,IPM | 3.34 (5.5) | 3.21 (18.5) | 2.23 (10) |
| Imipenem concn causing 50% Kmax,IPM (mg/liter) | ||||
| Population 1 (CFUSS) | KC50,SS,IPM | 0.992 (33) | 33.2 (11.1) | 15.2 (25.7) |
| Population 2 (CFURI) | KC50,RI,IPM | 264 (9.7) | 118 (17.8) | 67.3 (24.2) |
| Population 3 (CFUIR) | KC50,IR,IPM | 23.5 (11) | 61.8 (9.0) | 52.7 (33.8) |
| Killing by AGS | ||||
| Maximum killing rate constants (h−1) | ||||
| Population 1 | Kmax,SS,AGS | 11.8 (7.9) | 2.84 (15.8) | 2.93 (11.8%) |
| Population 2 | Kmax,RI,AGS | 3.28 (26.3) | 3.14 (15.9) | 2.80 (21.2%) |
| Population 3 | Kmax,IR,AGS | 11.8 (7.9) | 2.84 (15.8) | 2.93 (11.8%) |
| AGS concn causing 50% Kmax,AGS (mg/liter) | ||||
| Population 1 | KC50,SS,AGS | 18.6 (39.6)a | 16.6 (17)a | 54.9 (8.1)a |
| 4.88 (25.3)b | 153 (12.7)b | |||
| Population 2 | KC50,RI,AGS | 849 (5.7)a | 228 (16.7)a | 568 (10.9)a |
| 280 (15.7)b | 738 (8.3)b | |||
| Population 3 | KC50,IR,AGS | 615 (4.1)a | 46.7 (9.9)a | 159 (34.7)a |
| 329 (10.8)b | 170 (10.5)b | |||
| Mean turnover time for hypothetical signal molecules (=1/kout,sig) (h) | MTTsig | 1 (fixed) | 1 (fixed) | 0.087 (31.3) |
| Maximum inhibition by hypothetical signal molecules | Imax,sig12 | 0.997 (13.7) | 0.996 (11.3) | 0.881 (56.2) |
| Log10 hypothetical signal molecule concn at 50% max effect | Log10,IC50,Sig | 10.2 (4.3) | 9.63 (2.3) | 8.95 (26) |
| Permeabilization of the outer membrane by AGS | ||||
| Maximum fractional decrease of KC50,IPM by AGS via outer membrane disruption | Imax,OM,AGS | 0.678c (31.8) | 0.130c (11.1) | 0.604c (126) |
| AGS concn causing 50% Imax,OM,AGS (mg/liter) | IC50,OM,AGS | 5.55 (29.3)a | 1.54 (17.5)a | 4.29 (21.6)a |
| 1.13 (49.0)b | 4.80 (14.2)b | |||
| Hill coefficient for bacterial killing | ||||
| IPM | HillIPM | 3.00 (13.8) | 3.09 (14.2) | 3.08 (27.4) |
| AGS | HillAGS | 1.11 (5.5) | 2.04 (10) | 0.998 (11.9)a |
| SD of residual error on log10 scale | SDCFU | 0.378 (6.0) | 0.290 (5.2) | 0.475 (10.4) |
a
Parameter estimates for tobramycin.
b
Parameter estimates for amikacin.
c
These estimates mean that the imipenem target site concentrations increased up to 3.11-fold for FADDI-PA088, 1.15-fold for FADDI-PA001, and 2.53-fold for FADDI-PA022 in the presence of high AGS concentrations (≫IC50,OM,AGS).