Article Figures & Data
Figures
- FIG 1
Observed versus predicted ceftazidime (a) and amikacin (b) concentrations in the in vitro pharmacodynamic model.
- 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
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
- TABLE 1
Genotypes and MICs for amikacin and ceftazidime-avibactam for P. aeruginosa and K. pneumoniae isolates selected for the study
Isolate Genotype Amikacin MIC (μg/ml) Ceftazidime-avibactam MIC (μg/ml)a P. aeruginosa C42-72 Unknown 8 8/4 C42-45 Unknown 16 8/4 1504 aph(3′)-IIb blaOXA-50 catB4 fosA1; probable MexXY-OprM mutation(s) 64 4/4 K. pneumoniae 329b ant(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 sul3 32 1/4 375 ant(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 sul2 64 4/4 352 aac(6′)-Ib C aph(3′)-Ia fosA9 catA1 blaSHV-11 blaKPC-3 dfrA12 sul1 64 8/4 ↵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
Isolate Amikacin Ceftazidime Avibactam Target fAUC/MIC Observed fAUC/MIC Target fT>MIC (%) Observed fT>MIC (%) Target fT>1 μg/ml (%)c Calculated fT>1 μg/ml (%)d P. aeruginosa C42-72 4,482 3,379 ± 404 90.6 76.2 ± 22.3b 75.8 93.9 ± 8.6 C42-45 2,241 1,909 ± 111 90.6 96.7 ± 0.5 75.8 99.6 ± 0.8 1504 560 425 ± 17 100 99.4 ± 0.8 75.8 99.5 ± 0.7 K. pneumoniae 329b 1,120 881 ± 10 100 100.0 75.8 98.8 ± 2.2 375 560 492 ± 3 100 99.7 ± 0.3 75.8 99.8 ± 0.3 352 560 465 ± 10 90.6 96.3 ± 3.8 75.8 100.0 ↵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
Isolate CFU at 72 h (log10/ml)a P value (all groups) P value (CZA vs CZA-amikacin) Control CZA alone CZA-amikacin combination P. aeruginosa C42-72 7.44 ± 0.21 6.80 ± 0.97 2.65 ± 1.35 0.017 0.027 C42-45 6.60 ± 0.24 5.61 ± 0.70 4.19 ± 0.34 0.005 0.020 1504 7.20 ± 0.52 4.36 ± 0.15 3.96 ± 0.01 0.003 0.298 K. pneumoniae 329b 8.41 ± 0.14 5.52 ± 1.22b 5.56 ± 0.50 0.011 0.963 375 8.39 ± 0.29 6.04 ± 0.03 1.7 ± 0c <0.001 <0.001 352 8.38 ± 0.23 6.82 ± 0.93 4.48 ± 0.30d 0.003 0.021 ↵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
Isolate AUBC over 72 h (log10 · h/ml)a P value (all groups) P value (CZA vs CZA-amikacin) Control CZA alone CZA-amikacin combination P. aeruginosa C42-72 506 ± 12 394 ± 0.2 139 ± 21 <0.001 <0.001 C42-45 500 ± 7 359 ± 22 288 ± 3 0.001 0.013 1504 562 ± 34 301 ± 3 210 ± 8 <0.001 0.020 K. pneumoniae 329b 592 ± 4 324 ± 23b 236 ± 28 <0.001 <0.001 375 605 ± 2 323 ± 64 133 ± 11 0.002 0.015 352 567 ± 56 447 ± 46 165 ± 6c <0.001 0.001 ↵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.
