Safety and Efficacy of Ceftolozane/Tazobactam Plus Metronidazole Versus Meropenem From a Phase 2, Randomized Clinical Trial in Pediatric Participants With Complicated Intra-abdominal Infection.
Journal
The Pediatric infectious disease journal
ISSN: 1532-0987
Titre abrégé: Pediatr Infect Dis J
Pays: United States
ID NLM: 8701858
Informations de publication
Date de publication:
01 Jul 2023
01 Jul 2023
Historique:
medline:
12
6
2023
pubmed:
1
4
2023
entrez:
31
3
2023
Statut:
ppublish
Résumé
Ceftolozane/tazobactam, a cephalosporin-β-lactamase inhibitor combination, is approved for the treatment of complicated urinary tract infections and complicated intra-abdominal infections (cIAI). The safety and efficacy of ceftolozane/tazobactam in pediatric participants with cIAI were assessed. This phase 2 study (NCT03217136) randomized participants to either ceftolozane/tazobactam+metronidazole or meropenem for treatment of cIAI in pediatric participants (<18 years). The primary objective was to assess the safety and tolerability of intravenous ceftolozane/tazobactam+metronidazole. Clinical cure at end of treatment (EOT) and test of cure (TOC) visits were secondary end points. The modified intent-to-treat (MITT) population included 91 participants (ceftolozane/tazobactam+metronidazole, n = 70; meropenem, n = 21). Complicated appendicitis was the most common diagnosis (93.4%); Escherichia coli was the most common pathogen (65.9%). Adverse events (AEs) occurred in 80.0% and 61.9% of participants receiving ceftolozane/tazobactam+metronidazole and meropenem, drug-related AEs occurred in 18.6% and 14.3% and serious AEs occurred in 11.4% and 0% of participants receiving ceftolozane/tazobactam+metronidazole and meropenem, respectively. No drug-related serious AEs or discontinuations due to drug-related AEs occurred. Rates of the clinical cure for ceftolozane/tazobactam+metronidazole and meropenem at EOT were 80.0% and 95.2% (difference: -14.3; 95% confidence interval: -26.67 to 4.93) and at TOC were 80.0% and 100.0% (difference: -19.1; 95% confidence interval: -30.18 to -2.89), respectively; 6 of the 14 clinical failures for ceftolozane/tazobactam+metronidazole at TOC were indeterminate responses imputed as failures per protocol. Ceftolozane/tazobactam+metronidazole was well tolerated in pediatric participants with cIAI and had a safety profile similar to the established safety profile in adults. In this descriptive efficacy analysis, ceftolozane/tazobactam+metronidazole appeared efficacious.
Sections du résumé
BACKGROUND
BACKGROUND
Ceftolozane/tazobactam, a cephalosporin-β-lactamase inhibitor combination, is approved for the treatment of complicated urinary tract infections and complicated intra-abdominal infections (cIAI). The safety and efficacy of ceftolozane/tazobactam in pediatric participants with cIAI were assessed.
METHODS
METHODS
This phase 2 study (NCT03217136) randomized participants to either ceftolozane/tazobactam+metronidazole or meropenem for treatment of cIAI in pediatric participants (<18 years). The primary objective was to assess the safety and tolerability of intravenous ceftolozane/tazobactam+metronidazole. Clinical cure at end of treatment (EOT) and test of cure (TOC) visits were secondary end points.
RESULTS
RESULTS
The modified intent-to-treat (MITT) population included 91 participants (ceftolozane/tazobactam+metronidazole, n = 70; meropenem, n = 21). Complicated appendicitis was the most common diagnosis (93.4%); Escherichia coli was the most common pathogen (65.9%). Adverse events (AEs) occurred in 80.0% and 61.9% of participants receiving ceftolozane/tazobactam+metronidazole and meropenem, drug-related AEs occurred in 18.6% and 14.3% and serious AEs occurred in 11.4% and 0% of participants receiving ceftolozane/tazobactam+metronidazole and meropenem, respectively. No drug-related serious AEs or discontinuations due to drug-related AEs occurred. Rates of the clinical cure for ceftolozane/tazobactam+metronidazole and meropenem at EOT were 80.0% and 95.2% (difference: -14.3; 95% confidence interval: -26.67 to 4.93) and at TOC were 80.0% and 100.0% (difference: -19.1; 95% confidence interval: -30.18 to -2.89), respectively; 6 of the 14 clinical failures for ceftolozane/tazobactam+metronidazole at TOC were indeterminate responses imputed as failures per protocol.
CONCLUSION
CONCLUSIONS
Ceftolozane/tazobactam+metronidazole was well tolerated in pediatric participants with cIAI and had a safety profile similar to the established safety profile in adults. In this descriptive efficacy analysis, ceftolozane/tazobactam+metronidazole appeared efficacious.
Identifiants
pubmed: 37000942
doi: 10.1097/INF.0000000000003911
pii: 00006454-202307000-00006
pmc: PMC10259210
doi:
Substances chimiques
ceftolozane
37A4IES95Q
Meropenem
FV9J3JU8B1
Metronidazole
140QMO216E
Anti-Bacterial Agents
0
Penicillanic Acid
87-53-6
Cephalosporins
0
ceftolozane, tazobactam drug combination
0
Tazobactam
SE10G96M8W
Types de publication
Randomized Controlled Trial
Clinical Trial, Phase II
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
557-563Informations de copyright
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.
Déclaration de conflit d'intérêts
J.L., F.-H.S, J.A.H., M.B., M.G.J., C.D.A., E.G.R., and C.J.B. are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD), who may own stock and/or hold stock options in Merck & Co., Inc., Rahway, NJ, USA. M.W.P. was an employee of MSD at the time of the study conduct. C.-C.A.J. received consulting fees from MSD and holds stock in Merck & Co., Inc., Rahway, NJ, USA. J.N. reports funding to conduct the study from MSD to his institution. N.D. has no potential conflicts of interest to disclose.
Références
Menichetti F, Sganga G. Definition and classification of intra-abdominal infections. J Chemother. 2009;21(suppl 1):3–4.
Newman N, Wattad E, Greenberg D, et al. Community-acquired complicated intra-abdominal infections in children hospitalized during 1995-2004 at a paediatric surgery department. Scand J Infect Dis. 2009;41:720–726.
Sartelli M, Catena F, Ansaloni L, et al. Complicated intra-abdominal infections in Europe: a comprehensive review of the CIAO study. World J Emerg Surg. 2012;7:36.
Lob SH, Badal RE, Hackel MA, et al. Epidemiology and antimicrobial susceptibility of gram-negative pathogens causing intra-abdominal infections in pediatric patients in Europe-SMART 2011-2014. J Pediatric Infect Dis Soc. 2017;6:72–79.
Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. 2010;50:133–164.
Sartelli M, Chichom-Mefire A, Labricciosa FM, et al. The management of intra-abdominal infections from a global perspective: 2017 WSES guidelines for management of intra-abdominal infections. World J Emerg Surg. 2017;12:29.
Badal RE, Bouchillon SK, Lob SH, et al. Etiology, extended-spectrum β-lactamase rates and antimicrobial susceptibility of gram-negative bacilli causing intra-abdominal infections in patients in general pediatric and pediatric intensive care units--global data from the Study for Monitoring Antimicrobial Resistance Trends 2008 to 2010. Pediatr Infect Dis J. 2013;32:636–640.
Blot S, Antonelli M, Arvaniti K, et al.; Abdominal Sepsis Study (AbSeS) group on behalf of the Trials Group of the European Society of Intensive Care Medicine. Epidemiology of intra-abdominal infection and sepsis in critically ill patients: “AbSeS,” a multinational observational cohort study and ESICM Trials Group Project. Intensive Care Med. 2019;45:1703–1717.
Bassetti M, Poulakou G, Ruppe E, et al. Antimicrobial resistance in the next 30 years, humankind, bugs and drugs: a visionary approach. Intensive Care Med. 2017;43:1464–1475.
Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis [Published online January 18, 2022]. Lancet. 2022;399:629–655.
Zerbaxa ® (ceftolozane and tazobactam). US Prescribing information. Merck Sharp & Dohme LLC;2022.
Solomkin J, Hershberger E, Miller B, et al. Ceftolozane/tazobactam plus metronidazole for complicated intra-abdominal infections in an era of multidrug resistance: results from a randomized, double-blind, phase 3 trial (ASPECT-cIAI). Clin Infect Dis. 2015;60:1462–1471.
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;37:1130–1136.
Larson KB, Patel YT, Willavize S, et al. Ceftolozane-tazobactam population pharmacokinetics and dose selection for further clinical evaluation in pediatric patients with complicated urinary tract or complicated intra-abdominal infections. Antimicrob Agents Chemother. 2019;63:e02578-e025718.
Lob S, Hackel M, Andrew DeRyke C, et al. 1273. Activity of ceftolozane/tazobactam and comparators against Enterobacterales and P. aeruginosa isolates from pediatric patients—SMART United States 2017-2019. Open Forum Infect Dis. 2021;8(Suppl 1):725–725.
Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial susceptibility testing. 30th ed. Available at: https://www.nih.org.pk/wp-content/uploads/2021/02/CLSI-2020.pdf . Accessed November 30, 2021.
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med. 1985;4:213–226.
Roilides E, Ashouri N, Bradley JS, et al. Safety and efficacy of ceftolozane/tazobactam versus meropenem in neonatal and pediatric participants with complicated urinary tract infection, including pyelonephritis: a phase 2, randomized, clinical trial. Pediatr Infect Dis J. 2022;42:292–298.
Thompson AE, Marshall JC, Opal SM. Intraabdominal infections in infants and children: descriptions and definitions. Pediatr Crit Care Med. 2005;6(3 Suppl):S30–S35.
Sethaphanich N, Santanirand P, Rattanasiri S, et al. Pediatric extended spectrum β-lactamase infection: community-acquired infection and treatment options. Pediatr Int. 2016;58:338–346.