Ceftolozane/Tazobactam in Neonates and Young Infants: The Challenges of Collecting Pharmacokinetics and Safety Data in This Vulnerable Patient Population

Abstract

Objective New treatments are needed for multidrug-resistant (MDR) gram-negative infections in neonates. Ceftolozane/tazobactam is a β-lactam/β-lactamase inhibitor combination that has broad-spectrum activity against most common gram-negative bacteria, including MDR strains. We evaluated pharmacokinetics (PK) and safety of ceftolozane/tazobactam in term and premature neonates and young infants. Study Design This is a subgroup analysis of a phase 1, noncomparative, open-label, multicenter study that characterized the PK, safety, and tolerability of a single intravenous (IV) dose of ceftolozane/tazobactam in pediatric patients with proven/suspected gram-negative infection or receiving perioperative prophylaxis. Results Seven patients were enrolled in Group A (birth [7 days postnatal] to < 3 months, > 32 weeks gestation) and six patients were enrolled in Group B (birth [7 days postnatal] to < 3 months, ≤ 32 weeks gestation). PK profiles in neonates and young infants were generally comparable to those of older children receiving a single IV dose of ceftolozane/tazobactam. No serious adverse events (AEs), treatment-related AEs, severe AEs, or clinically significant laboratory abnormalities were reported. Conclusion Among term and premature neonates and young infants, PK was comparable to older children and ceftolozane/tazobactam was generally well tolerated. An adaptable and flexible study design is necessary for enrollment in neonatal PK trials.

Microbiological, Clinical, and PK/PD Features of the New Anti-Gram-Negative Antibiotics: β-Lactam/β-Lactamase Inhibitors in Combination and Cefiderocol—An All-Inclusive Guide for Clinicians

“…Similarly, in critically ill, mechanically ventilated patients, lung penetration was 50% and 62%, respectively [102]. Ceftolozane Vd is about 13.5 L, while tazobactam is 18.2 L; these parameters are increased in patients with pneumonia compared with healthy subjects [103] and in neonates, consistent with age-related physiologic changes [104,105]. The combination has been employed off-label in skin and soft-tissue, bone and joint, bloodstream and multiple infections, suggesting good tissue penetration also in these tissues [100].…”

Finding the Dose for Ceftolozane-Tazobactam in Critically Ill Children with and without Acute Kidney Injury

“…Currently, data regarding ceftolozane-tazobactam PK in children and adolescents are scarce [ 9 , 10 , 20 ]. A recent phase I clinical study evaluating the PK, safety, and tolerability of single i.v.…”

Use of Antibiotics in Preterm Newborns

“…Ceftolozane/tazobactam is a combination of the β-lactam/β-lactamase inhibitors that has a broad-spectrum activity against the most common Gram-negative bacteria, including MDR strains. The PK and safety profile of this combination was evaluated in a phase I, noncomparative, open-label, multicenter study on pediatric patients with proven/suspected Gram-negative infections or perioperative prophylaxis receiving a single intravenous (iv) dose of ceftolozane/tazobactam [ 157 ]. In particular, patients were divided into two groups: Group A (GA > 32 weeks) and Group B (GA ≤ 32 weeks).…”

“…Therefore, the authors conclude that, among term and premature neonates and young infants, PK was comparable to older children, and that ceftolozane/tazobactam was generally well tolerated. However, they highlight the necessity of proper neonatal PK trials [ 157 ].…”