Article Figures & Data
Figures
- FIG 1
Arithmetic mean (±SD) plasma concentration-time curves for ceftazidime for cohorts 1 to 4 following single-dose (day 1) administration of ceftazidime-avibactam (pharmacokinetic analysis population).
- FIG 2
Arithmetic mean (±SD) plasma concentration-time curves for avibactam for cohorts 1 to 4 following single-dose (day 1) administration of ceftazidime-avibactam (pharmacokinetic analysis population).
Tables
- TABLE 1
Summary of dose regimen used in the study
Drug Dose (all administered as a 2-h i.v. infusion) for cohort: 1 (≥12 yr to <18 yr) 2 (≥6 yr to <12 yr) 3 (≥2 yr to <6 yr) 4 (≥3 mo to <2 yr) ≥40 kg <40 kg Ceftazidime 2,000 mg 2,000 mg 50 mg/kg 50 mg/kg 50 mg/kg Avibactam 500 mg 500 mg 12.5 mg/kg 12.5 mg/kg 12.5 mg/kg - TABLE 2
Baseline patient characteristics (safety analysis population)
Parameter Value for cohort: 1 (≥12 to <18 yr) (n = 8) 2 (≥6 to <12 yr) (n = 8) 3 (≥2 to <6 yr) (n = 8) 4 (≥3 mo to <2 yr) (n = 8) Age, yr Mean (SD) 14.9 (1.6) 8.0 (1.4) 3.5 (1.0) 0.9 (0.5) Median (range) 14.9 (13.0–17.3) 7.7 (6.5–10.8) 3.8 (2.1–4.9) 0.9 (0.3–1.8) Female, n (%) 5 (62.5) 3 (37.5) 6 (75.0) 3 (37.5) Race, n (%) White 6 (75.0) 6 (75.0) 7 (87.5) 5 (62.5) Black or African American 1 (12.5) 2 (25.0) 0 3 (37.5) Othera 1 (12.5) 0 1 (12.5) 0 Weight, kg; mean (SD) 51.90 (7.15) 24.95 (3.03) 15.73 (2.39) 9.20 (2.51) BMI, kg/m2; mean (SD) 20.80 (3.21) 15.41 (0.78) 15.47 (0.95) NAd CrCL, ml/min/1.73 m2; mean (SD) 115.29 (18.14) 156.97b (42.92) 181.57 (100.99) 104.35 (26.20) Normal renal function, n (%) 8 (100) 8 (100) 8 (100) 8 (100) Any concomitant antibiotic,c n (%) 8 (100) 8 (100) 8 (100) 8 (100) Lincosamides 3 (37.5) 2 (25.0) 4 (50.0) 6 (75.0) 3rd-generation cephalosporins other than ceftazidime 1 (12.5) 3 (37.5) 1 (12.5) 1 (12.5) Penicillins plus β-lactamase inhibitors 1 (12.5) 0 2 (25.0) 2 (25.0) Vancomycin 1 (12.5) 1 (12.5) 0 2 (25.0) Metronidazole 2 (25.0) 2 (25.0) 0 0 Aminoglycosides 2 (25.0) 1 (12.5) 0 1 (12.5) 1st-generation cephalosporins 1 (12.5) 0 1 (12.5) 1 (12.5) Azithromycin 1 (12.5) 1 (12.5) 1 (12.5) 0 Extended-spectrum penicillin 1 (12.5) 1 (12.5) 1 (12.5) 0 Meropenem 0 2 (25.0) 0 0 Levofloxacin 0 0 2 (25.0) 0 ↵a Asian (n = 1 in cohort 3 [≥2 to <6 years]) and American Indian or Alaskan native (n = 1 in cohort 1 [≥12 to <18 years]).
↵b One patient in cohort 2 (≥6 to <12 years) had a value greater than the upper limit of normal and is not included in the mean (SD) calculation.
↵c Taken any time between the initiation of study therapy and the day 3 follow-up assessment. Most commonly used antibiotics/groups are shown.
↵d NA, not applicable.
- TABLE 3
Summary of ceftazidime and avibactam pharmacokinetic parameters measured in pediatric patients (pharmacokinetic population)
Drug and parametera Value for cohort: 1 (n = 8) (≥12 to <18 yr) 2 (n = 8) (≥6 to <12 yr) 3 (n = 8) (≥2 to <6 yr) 4 (n = 8) (≥3 mo to <2 yr) Ceftazidime Cmax (mg/liter) 79.8 (41.8) 81.3 (17.8) 80.1b (14.7) 91.7b (19.6) tmaxc (h) 2.0 (1.9–2.6) 2.1 (1.9–2.4) AUC0–t (h · mg/liter) 229.2 (30.9) 217.8 (18.4) AUC0–∞ (h · mg/liter) 230.6 (30.7) 221.2 (17.4) t1/2c (h) 1.7 (0.9–2.8) 1.6 (0.9–1.8) Vss (liters) 22.2 (42.0) 13.0 (17.8) CL (liter/h) 8.7 (45.5) 5.6 (16.0) CL/W (liter/kg/h) 0.169 (37.9) 0.226 (20.0) Avibactam Cmax (mg/liter) 15.1 (52.4) 14.1 (23.0) 13.7b (22.4) 16.3b (22.6) tmax (h) 2.0 (1.9–2.6) 2.1 (1.9–2.4) AUC0–t (h · mg/liter) 36.3 (33.7) 34.4 (23.4) AUC0–∞ (h · mg/liter) 36.4 (33.6) 34.8 (22.6) t1/2 (h) 1.6 (0.9–2.8) 1.7 (0.9–2.0) Vss (liters) 31.0 (53.3) 19.3 (27.0) CL (liter/h) 13.7 (52.6) 8.9 (30.2) CL/W (liter/kg/h) 0.267 (44.2) 0.359 (35.8) - TABLE 4
Summary of ceftazidime and avibactam observed and population pharmacokinetic model-predicted exposures in pediatric patients (pharmacokinetic population)
Drug AUC0-∞ (h · mg/liter) Observed value for cohorta: Predicted value for cohortb: Value for adult reference populationc (n = 16) 1 (≥12 to <18 yr) 2 (≥6 to <12 yr) 3 (≥2 to <6 yr) 4 (≥3 mo to <2 yr) Ceftazidime 230.6 (30.7) 221.2 (17.4) 255.32 (43.95) 286.27 (37.13) 289.0d (15.4) Avibactam 36.4 (33.6) 34.8 (22.6) 43.25 (12.14) 48.99 (10.64) 42.1e (16.0) ↵a Data for cohorts 1 and 2 are geometric means (percent coefficients of variation).
↵b Data for cohorts 3 and 4 are means (SD) based on population pharmacokinetic model predictions (42).
↵c Values are geometric means (percent coefficients of variation) for observed exposures from a phase I study in healthy adult volunteers on day 1 after receiving a single dose of ceftazidime-avibactam (2,000 to 500 mg) (44).
↵d n = 15.
↵e n = 13.
- TABLE 5
Summary of AEs in cohorts 3 and 4 (safety analysis population)c
System organ class/preferred term No. (%) of patients with AE for cohortb: 3 (≥2 to <6 yr)(n = 8) 4 (≥3 mo to <2 yr)(n = 8) Totala (n = 32) Any 4 (50.0) 2 (25.0) 6 (18.8) Cardiac disorders 0 1 (12.5) 1 (3.1) Sinus tachycardia 0 1 (12.5) 1 (3.1) Gastrointestinal disorders 3 (37.5) 0 3 (9.4) Constipation 1 (12.5) 0 1 (3.1) Diarrhea 1 (12.5) 0 1 (3.1) Vomiting 1 (12.5) 0 1 (3.1) Investigations 1 (12.5) 0 1 (3.1) Increased alanine aminotransferase 1 (12.5) 0 1 (3.1) Increased aspartate aminotransferase 1 (12.5) 0 1 (3.1) Increased blood triglycerides 1 (12.5) 0 1 (3.1) Increased gamma-glutamyltransferase 1 (12.5) 0 1 (3.1) Injury, poisoning, and procedural complications 0 1 (12.5) 1 (3.1) Procedural site reaction 0 1 (12.5) 1 (3.1)
