Parameter | Symbol | Unit | Estimate for P. aeruginosa PAO1 | Estimate for P. aeruginosa ATCC 27853 (NONMEM) | ||
---|---|---|---|---|---|---|

Estimate (%SE) by | Range from case deletion^{f} (NONMEM) | |||||

NONMEM | S-ADAPT | |||||

Parameters describing bacterial growth and inoculum size | ||||||

Log_{10} IC for 10^{6} CFU/ml, 10^{7} CFU/ml, and 10^{8} CFU/ml | Log_{10} CFUo | 6.01 (1.7), 7.37 (1.1), 8.10 (0.6) | 6.06 (0.4), 7.37 (0.1), 8.07 (0.1) | 5.99-6.04, 7.35-7.38, 8.08-8.11 | Read from observed CFU data at 0 h | |

Log_{10} fraction of resistant population at time zero | Log_{10} Fr_{R} | −3.54 (4.8) | −4.05 (2.8) | −4.09-−3.27 | −3.15 | |

Generation time at low CFUo | MTT_{12} = k_{12}^{−1} | min | 28.3 (7.3) | 31.9 (1.3) | 23.4-34.3 | 24.8^{f} |

Doubling rate constant |
k
_{21}
| h^{−1} | 50 (fixed)^{a} | 50 (fixed)^{a} | 50 (fixed)^{a} | |

Maximum population size | Log_{10} CFU_{max} | 9.78 (5.3) | 10.1 (7.4) | 8.98-10.3 | 9.06 | |

Parameters describing phenotypic change due to signal molecules | ||||||

MTT for elimination and synthesis | MTT_{S10} = k_{S10}^{−1} | min | 2.33 (40.8) | 1.90 (77) | 1.58-14.7 | 2.33 (fixed) |

MTT for transfer from central to peripheral compartment | MTT_{S12} = k_{S12}^{−1} | min | 1 (fixed)^{b} | 1 (fixed)^{b} | 1 (fixed) | |

MTT for transfer from peripheral to central compartment | MTT_{S21} = k_{S21}^{−1} | h | 24 (fixed)^{c} | 24 (fixed)^{c} | 24 (fixed) | |

Parameters describing effects of drug and signal molecules | ||||||

Maximum stimulation of autolysin effect for susceptible population |
S
_{max, S}
| 1 (fixed)^{e} | 1 (fixed)^{e} | 1 (fixed) | ||

Maximum stimulation of autolysin effect for resistant population |
S
_{max}, _{R} | 0.560 (1.3) | 0.541 (4.1) | 0.542-0.571 | 0.526 | |

Drug concn causing 50% stimulation of autolysin effect | SC_{50} | mg/liter | 0.294 (9.3) | 0.262 (15.3) | 0.237-0.381 | 0.294 (fixed)^{h} |

Ratio of elimination rate constant of autolysin effect and k_{12} |
k
_{out}/k_{12} | 0.438 (20.3) | 0.521 (3.3) | 0.333-0.573 | 1.57 | |

Log_{10} of signal molecule concn at 50% of maximum effect | Log_{10}C_{50, Sig} | 7.24 (1.4) | 7.25 (0.6) | 7.16-7.63 | 7.60 | |

Maximum stimulation of loss of autolysin effect by signal molecules |
S
_{max, loss}
| 1.18 (7.9) | 1.24 (6.1) | 1.09-1.90 | 0.630 | |

Ceftazidime concn causing 50% of stimulation for prolonging generation time | EC_{50, drug} | mg/liter | 35.3 (41.9) | 320 (32.2) | 15.7-78.4 | |

Maximum stimulation of prolonging generation time |
S
_{max, k12}
| 10 (fixed)^{d} | 10 (fixed)^{d} | 0 (fixed)^{g} | ||

SD of residual error on log_{10} scale | σ | 0.224 (8.5) | 0.186 (5.7) | 0.208-0.228 | 0.378 |

↵

*a*Assumed to be very fast (i.e., not rate limiting).↵

*b*As there is a very limited amount of information on this parameter available in the current data set, the onset of the signal molecule effect was assumed to be very fast according to data from starvation experiments and since cell-to-cell communication is tightly controlled.↵

*c*The parameter was estimated to be greater than 48 h. As the sensitivity of bacterial count curves toward this parameter was low, it was fixed to 24 h.↵

*d*The parameter was fixed to 10, since there was only limited information available in the data set.↵

*e*The parameter was estimated to be between 0.99 and 1 and therefore was fixed to 1.↵

*f*Estimate for the McGrath study. For the in vitro model studies, the estimated MTT_{12}was 24.0 min for the study by Barclay et al. (1) and 78.2 min for the study by Cappelletty et al. (9). For the time-kill experiments by Shalit et al. (55), Barclay et al. (2), and Tam et al. (61), the estimated MTT_{12}was 36.6 min.↵

*g*The estimate was fixed to zero, since the modeling of the in vitro PD model data on PAO1 and on ATCC 27853 resulted in values very close to zero, suggesting no effect.↵

*h*The SC_{50}was fixed to the estimate for PAO1, since the MIC for both strains was the same and since ceftazidime concentrations for strain ATCC 27853 were almost fivefold higher than the SC_{50}, which does not support a precise estimation of SC_{50}.