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Pharmacology

Antibacterial Activity of Human Simulated Epithelial Lining Fluid Concentrations of Ceftazidime-Avibactam Alone or in Combination with Amikacin Inhale (BAY41-6551) against Carbapenem-Resistant Pseudomonas aeruginosa and Klebsiella pneumoniae

Safa S. Almarzoky Abuhussain, Joseph L. Kuti, David P. Nicolau
Safa S. Almarzoky Abuhussain
aCenter for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA
bUmm Al-Qura University, Makkah, Saudi Arabia
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Joseph L. Kuti
aCenter for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA
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David P. Nicolau
aCenter for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA
cDivision of Infectious Diseases, Hartford Hospital, Hartford, Connecticut, USA
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DOI: 10.1128/AAC.00113-18
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  • FIG 1
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    FIG 1

    Observed versus predicted ceftazidime (a) and amikacin (b) concentrations in the in vitro pharmacodynamic model.

  • FIG 2
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    FIG 2

    Mean bacterial densities over 72 h for ceftazidime-avibactam (CZA) alone and CZA plus amikacin (AMK) combination therapy against P. aeruginosa C42-72 (CZA MIC, 8 μg/ml; AMK MIC, 8 μg/ml) (a), P. aeruginosa C42-45 (CZA MIC, 8 μg/ml; AMK MIC, 16 μg/ml) (b), and P. aeruginosa 1504 (CZA MIC, 4 μg/ml; AMK MIC, 64 μg/ml) (c). Dashed line, lower limit of detection.

  • FIG 3
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    FIG 3

    Mean bacterial densities over 72 h for ceftazidime-avibactam (CZA) alone and CZA plus amikacin (AMK) combination therapy against K. pneumoniae 329b (CZA MIC, 1 μg/ml; AMK MIC, 32 μg/ml) (a), K. pneumoniae 375 (CZA MIC, 4 μg/ml; AMK MIC, 64 μg/ml) (b), and K. pneumoniae 352 (CZA MIC, 8 μg/ml; AMK MIC, 64 μg/ml) (c). Dashed line, lower limit of detection.

Tables

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  • TABLE 1

    Genotypes and MICs for amikacin and ceftazidime-avibactam for P. aeruginosa and K. pneumoniae isolates selected for the study

    IsolateGenotypeAmikacin MIC (μg/ml)Ceftazidime-avibactam MIC (μg/ml)a
    P. aeruginosa
        C42-72Unknown88/4
        C42-45Unknown168/4
        1504aph(3′)-IIb blaOXA-50 catB4 fosA1; probable MexXY-OprM mutation(s)644/4
    K. pneumoniae
        329bant(3′)-Ia ant(2′)-Ia aadA1 aadA2 aac(6′)-Ib aph(3′)-Ia aph(4′)-Ia fosA9 catA1 blaSHV-11 blaSHV-5 blaOXA-9 blaTEM-1 blaKPC-2 mphA dfrA12 sul1 sul3321/4
        375ant(3′)-Ia ant(2′)-Ia aac(6′)-Ib (two copies) strA strB aadA1 aph(3′)-Ia fosA9 catA1 blaSHV-5 blaOXA-9 blaTEM-1A blaKPC-3 mphA dfrA12 dfrA14 sul1 sul2644/4
        352aac(6′)-Ib C aph(3′)-Ia fosA9 catA1 blaSHV-11 blaKPC-3 dfrA12 sul1648/4
    • ↵a Ceftazidime-avibactam MICs were determined in the presence of a fixed concentration of avibactam at 4 μg/ml.

  • TABLE 2

    Target versus observed pharmacodynamic parameters achieved in the in vitro pharmacodynamic modela

    IsolateAmikacinCeftazidimeAvibactam
    Target fAUC/MICObserved fAUC/MICTarget fT>MIC (%)Observed fT>MIC (%)Target fT>1 μg/ml (%)cCalculated fT>1 μg/ml (%)d
    P. aeruginosa
        C42-724,4823,379 ± 40490.676.2 ± 22.3b75.893.9 ± 8.6
        C42-452,2411,909 ± 11190.696.7 ± 0.575.899.6 ± 0.8
        1504560425 ± 1710099.4 ± 0.875.899.5 ± 0.7
    K. pneumoniae
        329b1,120881 ± 10100100.075.898.8 ± 2.2
        375560492 ± 310099.7 ± 0.375.899.8 ± 0.3
        352560465 ± 1090.696.3 ± 3.875.8100.0
    • ↵a Observed pharmacodynamic exposure reported as mean ± standard deviation of results from two to four observations.

    • ↵b One ceftazidime-avibactam experiment (when studied in combination with amikacin) resulted in less than the target ceftazidime fT>MIC due to low concentrations in one 8-h interval. The bacterial time-kill curve did not appear different from its duplicate run, and exposure was still above 50% fT>MIC and was observed only in the combination run, so this experiment was included.

    • ↵c Target fT>1 μg/ml values for avibactam were derived from the ELF concentration profile (13).

    • ↵d Avibactam concentrations were not measured in the experiment but were calculated as one-fourth of ceftazidime concentrations due to the use of a formulation with a 4:1 ceftazidime/avibactam concentration ratio. Note that the pharmacodynamic target exposure for avibactam is at least 50% fT>1 μg/ml, and therefore this exposure was achieved in all experiments.

  • TABLE 3

    CFU at 72 h for control, ceftazidime-avibactam alone, and ceftazidime-avibactam plus amikacin combination therapy

    IsolateCFU at 72 h (log10/ml)aP value (all groups)P value (CZA vs CZA-amikacin)
    ControlCZA aloneCZA-amikacin combination
    P. aeruginosa
        C42-727.44 ± 0.216.80 ± 0.972.65 ± 1.350.0170.027
        C42-456.60 ± 0.245.61 ± 0.704.19 ± 0.340.0050.020
        15047.20 ± 0.524.36 ± 0.153.96 ± 0.010.0030.298
    K. pneumoniae
        329b8.41 ± 0.145.52 ± 1.22b5.56 ± 0.500.0110.963
        3758.39 ± 0.296.04 ± 0.031.7 ± 0c<0.001<0.001
        3528.38 ± 0.236.82 ± 0.934.48 ± 0.30d0.0030.021
    • ↵a Data are mean ± standard deviation of results from experiments in duplicate, unless otherwise noted. CZA, ceftazidime-avibactam.

    • ↵b Mean ± standard deviation from four experiments with CZA alone against K. pneumoniae 329b.

    • ↵c Both experiments reached the lower limit of detection (1.7 log10/ml), so the standard deviation is zero.

    • ↵d Mean ± standard deviation of results from three experiments with CZA-amikacin against K. pneumoniae 352.

  • TABLE 4

    AUBC over 72 h for control, ceftazidime-avibactam alone, and ceftazidime-avibactam plus amikacin combination therapy

    IsolateAUBC over 72 h (log10 · h/ml)aP value (all groups)P value (CZA vs CZA-amikacin)
    ControlCZA aloneCZA-amikacin combination
    P. aeruginosa
        C42-72506 ± 12394 ± 0.2139 ± 21<0.001<0.001
        C42-45500 ± 7359 ± 22288 ± 30.0010.013
        1504562 ± 34301 ± 3210 ± 8<0.0010.020
    K. pneumoniae
        329b592 ± 4324 ± 23b236 ± 28<0.001<0.001
        375605 ± 2323 ± 64133 ± 110.0020.015
        352567 ± 56447 ± 46165 ± 6c<0.0010.001
    • ↵a Data are mean ± standard deviation of results from experiments in duplicate, unless otherwise noted. AUBC, area under the bacterial growth curve; CZA, ceftazidime-avibactam.

    • ↵b Mean ± standard deviation from four experiments with CZA alone against K. pneumoniae 329b.

    • ↵c Mean ± standard deviation from three experiments with CZA-amikacin against K. pneumoniae 352.

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Antibacterial Activity of Human Simulated Epithelial Lining Fluid Concentrations of Ceftazidime-Avibactam Alone or in Combination with Amikacin Inhale (BAY41-6551) against Carbapenem-Resistant Pseudomonas aeruginosa and Klebsiella pneumoniae
Safa S. Almarzoky Abuhussain, Joseph L. Kuti, David P. Nicolau
Antimicrobial Agents and Chemotherapy Jun 2018, 62 (7) e00113-18; DOI: 10.1128/AAC.00113-18

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Antibacterial Activity of Human Simulated Epithelial Lining Fluid Concentrations of Ceftazidime-Avibactam Alone or in Combination with Amikacin Inhale (BAY41-6551) against Carbapenem-Resistant Pseudomonas aeruginosa and Klebsiella pneumoniae
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Antibacterial Activity of Human Simulated Epithelial Lining Fluid Concentrations of Ceftazidime-Avibactam Alone or in Combination with Amikacin Inhale (BAY41-6551) against Carbapenem-Resistant Pseudomonas aeruginosa and Klebsiella pneumoniae
Safa S. Almarzoky Abuhussain, Joseph L. Kuti, David P. Nicolau
Antimicrobial Agents and Chemotherapy Jun 2018, 62 (7) e00113-18; DOI: 10.1128/AAC.00113-18
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KEYWORDS

aminoglycoside
cephalosporin
pharmacodynamics

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