TABLE 2.

Estimates of model D for P. aeruginosa PAO1 and ATCC 27853

ParameterSymbolUnitEstimate for P. aeruginosa PAO1Estimate for P. aeruginosa ATCC 27853 (NONMEM)
Estimate (%SE) byRange from case deletionf (NONMEM)
NONMEMS-ADAPT
Parameters describing bacterial growth and inoculum size
    Log10 IC for 106 CFU/ml, 107 CFU/ml, and 108 CFU/mlLog10 CFUo6.01 (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, 8.08-8.11Read from observed CFU data at 0 h
    Log10 fraction of resistant population at time zeroLog10 FrR−3.54 (4.8)−4.05 (2.8)−4.09-−3.27−3.15
    Generation time at low CFUoMTT12 = k12−1min28.3 (7.3)31.9 (1.3)23.4-34.324.8f
    Doubling rate constant k 21 h−150 (fixed)a50 (fixed)a50 (fixed)a
    Maximum population sizeLog10 CFUmax9.78 (5.3)10.1 (7.4)8.98-10.39.06
Parameters describing phenotypic change due to signal molecules
    MTT for elimination and synthesisMTTS10 = kS10−1min2.33 (40.8)1.90 (77)1.58-14.72.33 (fixed)
    MTT for transfer from central to peripheral compartmentMTTS12 = kS12−1min1 (fixed)b1 (fixed)b1 (fixed)
    MTT for transfer from peripheral to central compartmentMTTS21 = kS21−1h24 (fixed)c24 (fixed)c24 (fixed)
Parameters describing effects of drug and signal molecules
    Maximum stimulation of autolysin effect for susceptible population S max, S 1 (fixed)e1 (fixed)e1 (fixed)
    Maximum stimulation of autolysin effect for resistant population S max, R0.560 (1.3)0.541 (4.1)0.542-0.5710.526
    Drug concn causing 50% stimulation of autolysin effectSC50mg/liter0.294 (9.3)0.262 (15.3)0.237-0.3810.294 (fixed)h
    Ratio of elimination rate constant of autolysin effect and k12 k out/k120.438 (20.3)0.521 (3.3)0.333-0.5731.57
    Log10 of signal molecule concn at 50% of maximum effectLog10C50, Sig7.24 (1.4)7.25 (0.6)7.16-7.637.60
    Maximum stimulation of loss of autolysin effect by signal molecules S max, loss 1.18 (7.9)1.24 (6.1)1.09-1.900.630
    Ceftazidime concn causing 50% of stimulation for prolonging generation timeEC50, drugmg/liter35.3 (41.9)320 (32.2)15.7-78.4
    Maximum stimulation of prolonging generation time S max, k12 10 (fixed)d10 (fixed)d0 (fixed)g
    SD of residual error on log10 scaleσ0.224 (8.5)0.186 (5.7)0.208-0.2280.378
  • 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 MTT12 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 MTT12 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 SC50 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 SC50, which does not support a precise estimation of SC50.