Pharmacology

Dose Optimization of Colistin Combinations against Carbapenem-Resistant Acinetobacter baumannii from Patients with Hospital-Acquired Pneumonia in China by Using an In Vitro Pharmacokinetic/Pharmacodynamic Model

Xingchen Bian, Xiaofen Liu, Yuancheng Chen, Daijie Chen, Jian Li, Jing Zhang
DOI: 10.1128/AAC.01989-18

Article Figures & Data

Figures

  • FIG 1
    FIG 1

    Static time-kill curves show the bactericidal effect of colistin (blue), meropenem (orange), and their combination (green) against carbapenem-resistant A. baumannii isolates (mean ± SD, n = 3). CST, colistin; MEM, meropenem.

  • FIG 2
    FIG 2

    Dynamic in vitro PK/PD killing kinetics of ATCC 19606 (A), AB1845 (B), and AB2092 (C) in different dosage regimens. Meropenem dose of 0.5 g is infused for 0.5 h, and 1 or 2 g is for 3-h infusion. CST, colistin; MEM, meropenem.

  • FIG 3
    FIG 3

    The values of ΔlogCFU0–24 for ATCC 19606, AB1845, and AB2092 after each monotherapy and the combination.

  • FIG 4
    FIG 4

    Observed (symbols) and model fitted (lines) viable counts for the dynamic in vitro PK/PD model experiments with colistin or meropenem alone and the combination against A. baumannii ATCC 19606 (A), AB1845 (B), and AB2092 (C). Meropenem dose of 0.5 g is infused for 0.5 h, and 1 or 2 g is for 3-h infusion. CST, colistin; MEM, meropenem.

  • FIG 5
    FIG 5

    Diagnostic plots of fitting results for ATCC 19606, AB1845, and AB2092 and validation results for AB2092. Meropenem was dosed at 2 g every 8 h with 8-h infusion.

  • FIG 6
    FIG 6

    Validation of the PK/PD modeling for the regimen of 1 mg/liter colistin in combination with 2 g meropenem every 8 h with 8-h infusion.

  • FIG 7
    FIG 7

    Pharmacodynamic predictions of colistin and meropenem mono- and combination therapy against A. baumannii AB1845(A) and AB2092(B). The units for colistin and meropenem are mg/liter at steady state and g with 3-h infusion, respectively. LOD, 1 log10 CFU/ml.

Tables

  • TABLE 1

    Δ logCFU0–24 values of colistin and meropenem as monotherapy and in combination

    Strain (MICCST/MICMEM)ΔlogCFU0–24 by antibiotic therapy (mean ± SD) (n = 3)
    No drugColistinMeropenemCombination
    050111 (0.5/128)2.62 ± 0.121.13 ± 1.502.69 ± 0.24−5.25 ± 1.93
    AB1845 (0.5/32)1.81 ± 0.082.19 ± 0.171.86 ± 0.09−6.1 ± 0.92
    AB2092 (1/128)2.11 ± 0.101.58 ± 0.302.04 ± 0.14−6.52 ± 0.24
  • TABLE 2

    Values of %T>MIC, %T>2MIC, and %T>3MIC for AB2092 with different dosing regimensa

    Meropenem dosage (g)Infusion value (mg/liter)MIC at an infusion duration (h) of:
    1238
    1%T>MIC (8)2532380
    %T>2MIC (16)16183.60
    %T>3MIC (24)9.4000
    2%T>MIC (8)37445190
    %T>2MIC (16)2632380
    %T>3MIC (24)2025270

    • ↵a MIC values refer to those in the checkerboard assay.

  • TABLE 3

    Parameter estimates for the in vitro PK/PD model

    ParameterExplanationValue for strain:
    ATCC 19606A. baumannii 1845A. baumannii 2092
    kgrowth (h−1)Rate constant of bacterial net growth0.2501.010.640
    Bmax (log10CFU/ml)Bacterial count in the stationary phase8.568.028.03
    Emax_CST (h−1)Maximum achievable kill rate constant by colistin7.210.9984.66
    EC50_CST (mg/liter)Colistin concentration that results in 50% of Emax0.07150.3740.730
    Emax_MEM (h−1)Maximum achievable kill rate constant by meropenem1.110.9470.095
    EC50_MEM (mg/liter)Meropenem concentration that results in 50% of Emax15.514.813.5
    γCSTHill factor for colistin1.271.051.55
    γMEMHill factor for meropenem0.3060.7737.30
    fMaximal adaptation factor2903.609.54
    kRate of adaptation1.060.1560.444
    IntParameter describing drug interaction0.1900.01180.0117
    fval (%)Residual error fraction5.993.772.23

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KEYWORDS

Acinetobacter baumannii
PK/PD modeling
carbapenem resistance
colistin
combination therapy
meropenem

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