American Journal of Perinatology, Table of Contents

Am J Perinatol 2021; 38(08): 804-809
DOI: 10.1055/s-0039-3402719

Original Article

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

Jocelyn Y. Ang

¹Division of Infectious Diseases, Children's Hospital of Michigan, Detroit, Michigan

²Department of Pediatrics, Wayne State University, Detroit, Michigan

,

Antonio Arrieta

³Division of Pediatric Infectious Disease, Children's Hospital of Orange County, Orange, California

,

John S. Bradley

⁴Division of Infectious Disease, Rady Children's Hospital, San Diego, California

⁵Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California

,

Zufei Zhang

⁶Merck & Co., Inc., Kenilworth, New Jersey

,

Brian Yu

⁶Merck & Co., Inc., Kenilworth, New Jersey

,

Matthew L. Rizk

⁶Merck & Co., Inc., Kenilworth, New Jersey

,

Matthew G. Johnson

⁶Merck & Co., Inc., Kenilworth, New Jersey

,

Elizabeth G. Rhee

⁶Merck & Co., Inc., Kenilworth, New Jersey

› Author Affiliations

Hebammen

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.

Keywords

Keywords

antibacterials - clinical trial - study design - special population - gram-negative infections

References
1 Kaye KS, Pogue JM. Infections caused by resistant gram-negative bacteria: epidemiology and management. Pharmacotherapy 2015; 35 (10) 949-962
2 Oliver A, Mulet X, López-Causapé C, Juan C. The increasing threat of Pseudomonas aeruginosa high-risk clones. Drug Resist Updat 2015; 21-22: 41-59
3 Adler A, Katz DE, Marchaim D. The continuing plague of extended-spectrum β-lactamase-producing Enterobacteriaceae infections. Infect Dis Clin North Am 2016; 30 (02) 347-375
4 Logan LK, Braykov NP, Weinstein RA, Laxminarayan R. CDC Epicenters Prevention Program. Extended-spectrum β-lactamase-producing and third-generation cephalosporin-resistant Enterobacteriaceae in children: trends in the United States, 1999-2011. J Pediatric Infect Dis Soc 2014; 3 (04) 320-328
5 Logan LK, Gandra S, Mandal S. et al; Prevention Epicenters Program, US Centers for Disease Control and Prevention. Multidrug- and carbapenem-resistant Pseudomonas aeruginosa in children, United States, 1999-2012. J Pediatric Infect Dis Soc 2017; 6 (04) 352-359
6 Stoll BJ. Early-onset neonatal sepsis: a continuing problem in need of novel prevention strategies. Pediatrics 2016; 138 (06) 138
7 Medernach RL, Logan LK. The growing threat of antibiotic resistance in children. Infect Dis Clin North Am 2018; 32 (01) 1-17
8 van Duin D, Bonomo RA. Ceftazidime/avibactam and ceftolozane/tazobactam: second-generation β-lactam/β-lactamase inhibitor combinations. Clin Infect Dis 2016; 63 (02) 234-241
9 ZERBAXA™ (ceftolozane and tazobactam) for injection. Full prescribing information. Last revised June 2019. Whitehouse Station, NJ: Merck Sharpe & Dohme Corp; 2014
10 Roberts JK, Stockmann C, Constance JE. et al. Pharmacokinetics and pharmacodynamics of antibacterials, antifungals, and antivirals used most frequently in neonates and infants. Clin Pharmacokinet 2014; 53 (07) 581-610
11 Coppini R, Simons SHP, Mugelli A, Allegaert K. Clinical research in neonates and infants: challenges and perspectives. Pharmacol Res 2016; 108: 80-87
12 Sachs AN, Avant D, Lee CS, Rodriguez W, Murphy MD. Pediatric information in drug product labeling. JAMA 2012; 307 (18) 1914-1915
13 Euteneuer JC, Kamatkar S, Fukuda T, Vinks AA, Akinbi HT. Suggestions for model-informed precision dosing to optimize neonatal drug therapy. J Clin Pharmacol 2019; 59 (02) 168-176
14 Bradley JS, Ang JY, Arrieta AC. et al. Pharmacokinetics and safety of single intravenous doses of ceftolozane/tazobactam in children with proven or suspected gram-negative infection. Pediatr Infect Dis J 2018; 37 (11) 1130-1136
15 Schwartz GJ, Muñoz A, Schneider MF. et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol 2009; 20 (03) 629-637
16 U.S. Food and Drug Administration. Anti-Infective Drug Development in Neonates. Silver Spring, MD: FDA; ; September 15, 2016. Accessed December 23, 2019 at: https://www.fda.gov/drugs/news-events-human-drugs/anti-infective-drug-development-neonates
17 European Medicines Agency. Workshop on the Development of Antimicrobial Medicinal Products for Paediatric Patients. London, UK: EMA; ; June 21, 2018. Accessed December 23, 2019 at: https://www.ema.europa.eu/en/events/workshop-development-antimicrobial-medicinal-products-paediatric-patients
18 European Medicines Agency. Concept Paper on the Need for Revision of the Guideline on the Investigation of Medicinal Products in the Term and Preterm Neonate. London, UK: EMA; ; May 29, 2019. Accessed December 23, 2019 at: https://www.ema.europa.eu/en/documents/scientific-guideline/adopted-concept-paper-need-revision-guideline-investigation-medicinal-products-term-preterm-neonate_en.pdf
19 Pfizer. Safety, tolerability and efficacy of ceftaroline in paediatrics with late-onset sepsis. 2015 . Accessed December 23, 2019 at: https://clinicaltrials.gov/ct2/show/NCT02424734
20 Bradley J, Leister-Tebbe H, Yan JL. et al. Ceftaroline Fosamil in Neonates and Very Young Infants with Late-Onset Sepsis: Safety and Efficacy Results from a Phase II Trial. Abstract O0301. Paper presented at: 29th ECCMID; April 13, 2019; Amsterdam, The Netherlands
21 Benjamin Jr DK, Kaufman DA, Hope WW. et al. A phase 3 study of micafungin versus amphotericin B deoxycholate in infants with invasive candidiasis. Pediatr Infect Dis J 2018; 37 (10) 992-998
22 European Medicines Agency. Ethical considerations for clinical trials on medicinal products conducted with minors. Brussels, Belgium: European Commission, September 18, 2017