Pharmacokinetics and Safety of Ceftazidime-Avibactam in Neonates and Young Infants: A Phase 2a, Multicenter Prospective Trial

Abstract

Background: This phase 2a study evaluated pharmacokinetics and safety of ceftazidime-avibactam (CAZ/AVI; combination dosed as fixed 4:1 ratio) in neonates and young infants with suspected/confirmed infections due to Gram-negative pathogens requiring intravenous antibiotics.

Methods: Hospitalized neonates and infants (gestational age ≥ 26 weeks to < 3 months), enrolled sequentially into 3 age cohorts, received CAZ/AVI single dose (Part A) or multiple dose every 8 h (Part B) by 2-h intravenous infusions. Infants > 28 days (Cohort 1) received CAZ/AVI 37.5 mg/kg/dose (CAZ 30 mg/kg and AVI 7.5 mg/kg). Full-term neonates ≤ 28 days (Cohort 2) and preterm neonates ≤ 28 days (Cohort 3) received 25 mg/kg/dose (CAZ 20 mg/kg and AVI 5 mg/kg). Pharmacokinetics, safety, and clinical and microbiological outcomes (Part B only) were assessed descriptively.

Results: Forty-six patients received CAZ/AVI, 25 in Part A and 21 in Part B. Sepsis (39.1%) and urinary tract infection (15.2%) were the predominant diagnoses. Observed drug plasma-concentration time profiles were generally similar across cohorts. Overall, 23 patients (50%) had ≥ 1 adverse event (AE), 8 patients (17.4%) had ≥ 1 serious AE (SAE), and 2 patients (4.3%) died; no SAE or death was treatment related. In Part B, ≥ 80% of patients had favorable clinical and microbiological responses.

Conclusions: Plasma exposures after single and multiple CAZ/AVI doses in neonates and young infants < 3 months old (37.5 [30/7.5] mg/kg/dose for > 28 days; 25 [20/5] mg/kg/dose for ≤ 28 days) were similar to approved doses for older children. The safety profile of CAZ/AVI was as expected based on previous observations. Study funded by Pfizer. Trial registration: NCT04126031.

Keywords: Gram-negative bacteria; antibiotic therapy; antimicrobial resistance; neonatal infection; sepsis.

Figure 1.

Patient Disposition. In Part A, 2 enrolled patients discontinued from the screening phase prior to receiving study treatment: 1 patient due to withdrawal by parent/guardian and 1 patient due to “other” (parents wished to discontinue because the vein catheter was not working). In Part B, 1 patient (Cohort 2) was discontinued from the treatment phase after receiving 1 dose of study treatment due to sudden onset hypertransaminasemia which was attributed to a previous surgical procedure (of note, the blood sample that indicated hypertransaminasemia was taken prior to administration of the first dose of CAZ/AVI). The investigator decided to continue treatment with commercial CAZ/AVI at the protocol-specified dose, but with the patient excluded from any pharmacokinetic assessments or analysis of efficacy. Cohort 1: Full-term infants with chronological age > 28 days to < 3 months or preterm infants with corrected age > 28 days to < 3 months. Cohort 2: Full-term neonates with chronological age from birth to ≤ 28 days. Cohort 3: Preterm neonates from birth to chronological age ≤ 28 days. AE, adverse event; CAZ/AVI, ceftazidime-avibactam.

Figure 2.

Median Plasma Concentrations of Ceftazidime and Avibactam (Pharmacokinetic Analysis Set, Excludes a Patient with a Medication Error in Part A) Median plasma concentration of (A) ceftazidime and (B) avibactam. Error bars represent % coefficient of variation. Data for Part A and Part B offset around each nominal time point for improved visualization. Cohort 1: Full-term infants with chronological age > 28 days to < 3 months or preterm infants with corrected age > 28 days to < 3 months. Cohort 2: Full-term neonates with chronological age from birth to ≤ 28 days. Cohort 3: Preterm neonates from birth to chronological age ≤ 28 days.