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

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 three age cohorts, received CAZ/AVI single dose (Part A) or multiple dose every 8 hours (Part B) by 2-hour 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% 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.