TABLE 2

Population mean parameter estimates for the mechanism-based model evaluation of the dynamic hollow-fiber infection model experiments assessing the meropenem with ciprofloxacin combination against hypermutable P. aeruginosa CW44a

ParameterSymbol (unit)Population mean value (SE [%])
Bacterial growth and subpopulations
    Initial inoculumLog10 CFU07.37 (2.53)
    Maximum population sizeLog10 CFUmax8.80 (0.796)
    Replication rate constantk21 (h−1)50.0 (fixed)b
    MGTc
        MEMs/CIPsk12,ss (min−1)181 (6.32)d
        MEMr/CIPik12,ri (min−1)86.3 (4.40)
        MEMi/CIPrk12,ir (min−1)121 (5.82)
    Log10 MFe
        MEMLog10 MFMEM−7.70 (1.39)
        CIPLog10 MFCIP−4.31 (3.78)
Killing by MEM
    Maximum killing rate constantKmax,MEM (h−1)0.975 (12.1)
    MEM concn causing 50% of Kmax,MEM
        MEMs/CIPsKC50,ss,MEM (mg/liter)2.08 (26.6)
        MEMr/CIPiKC50,ri,MEM (mg/liter)24.5 (13.0)
        MEMi/CIPrKC50,ir,MEM (mg/liter)5.48 (8.76)
    Hill coefficient for MEMHILLMEM1.60 (11.1)
Killing by CIP
    Maximum killing rate constantKmax,CIP (h−1)5.28 (6.58)
    CIP concn causing 50% of Kmax,CIP
        MEMs/CIPsKC50,ss,CIP (mg/liter)1.67 (13.9)
        MEMr/CIPiKC50,ri,CIP (mg/liter)14.5 (11.8)
        MEMi/CIPrKC50,ir,CIP (mg/liter)45.8 (10.3)
Mechanistic synergy
    Maximum fractional decrease of KC50,MEM via mechanistic synergyImax,SYN1 (fixed)
    CIP concn causing 50% of Imax,SYNIC50,SYN (mg/liter)0.914 (27.8)
    SD of residual error on log10 scaleSDCFU0.370 (6.97)
  • a All parameters were required for the MBM to achieve unbiased and precise curve fits.

  • b Bacterial replication was assumed to be fast as previously described (69).

  • c MGT, mean generation time.

  • d The relatively long estimated mean generation time for the susceptible population was likely due to slower bacterial growth at the tested high inoculum. While the MGT of the susceptible population was informed by the growth control at a high bacterial density, the MGT estimates for the two resistant populations were based on the faster regrowth from lower bacterial densities.

  • e MF, mutation frequency.