Effectiveness and safety of ceftazidime-avibactam and ceftolozane-tazobactam in the pediatric population: Systematic review and meta-analysis protocol
DOI:
https://doi.org/10.30968/jhphs.2025.164.1401Abstract
Objectives: This protocol describes a systematic review with meta-analysis and evidence gap map to evaluate the efficacy, effectiveness, and safety of the antibiotic combinations ceftazidime-avibactam and ceftolozane-tazobactam in hospitalized children and adolescents with infections caused by multidrug-resistant organisms (MDROs). Pediatric patients are especially vulnerable to adverse outcomes due to limited pharmacological data, off-label drug use, and increasing antimicrobial resistance. Methods: The review is registered on PROSPERO (CRD420251025715) and follows Cochrane Collaboration. Eligible studies include randomized controlled trials, observational studies (cohort and case-control and case reports), involving children aged 0–18 years with complicated intra-abdominal infections, urinary tract infections, hospital-acquired or ventilator-associated pneumonia, or bacteremia. Comparators will include other intravenous antibiotics with similar indications. Searches will be conducted in MEDLINE, Embase, CENTRAL, LILACS, Scopus, Web of Science, Epistemonikos, and Scielo, with no language or date restrictions. Two reviewers will independently perform screening, data extraction, and risk-of-bias assessment using RoB 2, ROBINS-I, JBI, as appropriate. The quality of the studies included will be assessed according to GRADE. Meta-analyses will be performed using a random-effects model. Heterogeneity will be assessed through the I² statistics. In addition to the random-effects meta-analysis, an evidence gap map will be developed using RStudio. The visual matrix will cross interventions with outcomes, where colored bubbles will represent study designs and density of evidence. Expected Results: Identify the scope, quality, and gaps in the current literature regarding these antimicrobial combinations in pediatric populations. The visual mapping will support decision-making and help prioritize areas for future research.
Downloads
References
1. Lehane E, Leahy-Warren P, O’Riordan C, et al. Evidence-based practice education for healthcare professions: an expert view. BMJ Evid Based Med. 2019;24(3):103-108. doi:10.1136/bmjebm-2018-111019
2. Meng M, Zhou Q, Lei W, et al. Recommendations on Off-Label Drug Use in Pediatric Guidelines. Front Pharmacol. 2022;13:892574. doi:10.3389/fphar.2022.892574
3. Tang L, Zhao K, Hou N. Off-label use of antimicrobials among hospitalized children: a retrospective study of 3,406 patients. Front Microbiol. 2023;14:1173042. doi:10.3389/fmicb.2023.1173042
4. Romandini A, Pani A, Schenardi PA, et al. Antibiotic Resistance in Pediatric Infections: Global Emerging Threats, Predicting the Near Future. Antibiotics. 2021;10(4):393. doi:10.3390/antibiotics10040393
5. Fanelli U, Chiné V, Pappalardo M, et al. Improving the Quality of Hospital Antibiotic Use: Impact on Multidrug-Resistant Bacterial Infections in Children. Front Pharmacol. 2020;11:745. doi:10.3389/fphar.2020.00745
6. Rodriguez BA, Girotto JE, Nicolau DP. Ceftazidime/avibactam and ceftolozane/tazobactam: novel therapy for multidrugresistant gram-negative infections in children. Curr Pediatr Rev. 2018;14(2):97-109. doi:10.2174/157339631466618112-7124112
7. Tamma PD, Aitken SL, Bonomo RA, et al. Infectious Diseases Society of America Guidance on the Treatment of Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa). Clin Infect Dis. 2021;72(7):e169-e183. doi:10.1093/cid/ciaa1478
8. Olney KB, Thomas JK, Johnson WM. Review of novel β-lactams and β-lactam/β-lactamase inhibitor combinations with implications for pediatric use. Pharmacotherapy. 2023;43(7):713-731. doi:10.1002/phar.2782
9. Labé P, Husain M, Parize P, et al. Evaluation of Ceftazidimeavibactam and Ceftolozane-tazobactam Prescriptions in a Tertiary Hospital for Children in France: An Observational Study, 2017-2022. Pediatr Infect Dis J. 2025;44(7):630-636. doi:10.1097/INF.0000000000004768
10. Perruccio K, D’Amico MR, Baretta V, et al. Ceftolozane/Tazobactam and Ceftazidime/Avibactam: An Italian Multicenter Retrospective Analysis of Safety and Efficacy in Children With Hematologic Malignancies and Multi-drug Resistant Gram-negative Bacteria Infections. Pediatr Infect Dis J. 2022;41(12):994-996. doi:10.1097/INF.0000000000003716
11. Miake-Lye IM, Hempel S, Shanman R, et al. What is an evidence map? A systematic review of published evidence maps and their definitions, methods, and products. Syst Rev. 2016;5:28. doi:10.1186/s13643-016-0204-x
12. Higgins JPT, Thomas J, Chandler J, et al. Cochrane Handbook for Systematic Reviews of Interventions, version 6.5. Chichester : Cochrane; 2024.
13. Campbell F, Tricco AC, Munn Z, et al. Mapping reviews, scoping reviews, and evidence and gap maps (EGMs): the same but different—the “Big Picture” review family. Syst Rev. 2023;12:45. doi:10.1186/s13643-023-02178-5
14. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi:10.1136/bmj.n71
15. Hartling L, Featherstone R, Nuspl M, et al. Grey literature in systematic reviews: a cross-sectional study of the contribution of non-English reports, unpublished studies and dissertations to the results of meta-analyses in children-relevant reviews. BMC Med Res Methodol. 2017;17(1):64. doi:10.1186/s12874-017-0347-z.
16. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomized trials. BMJ. 2019;366:l4898. doi:10.1136/bmj.l4898
17. Sterne JAC, Hernán MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919. doi:10.1136/bmj.i4919
18. Joanna Briggs Institute. Checklist for Case Control Studies. Adelaide: JBI; 2020.
19. Joanna Briggs Institute. Critical Appraisal Checklist for Case Reports. Adelaide: JBI; 2020
20. Basu A. A tutorial on how to write evidence gap maps. Qeios. 2021; PPR622210. doi:10.32388/A58M1M
21. Wickham H. ggplot2: Elegant Graphics for Data Analysis. Cham. Bern: Springer;2016. doi:10.1007/978-3-319-24277-4
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Authors
This work is licensed under a Creative Commons Attribution 4.0 International License.
The authors hereby transfer, assign, or otherwise convey to JHPHS : (1) the right to grant permission to republish or reprint the stated material, in whole or in part, without a fee; (2) the right to print republish copies for free distribution or sale; and (3) the right to republish the stated material in any format (electronic or printed). In addition, the undersigned affirms that the article described above has not previously been published, in whole or part, is not subject to copyright or other rights except by the author(s), and has not been submitted for publication elsewhere, except as communicated in writing to JHPHS with this document.
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License (CC-BY) that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
Serlf-archiving policy
This journal permits and encourages authors to post and archive the final pdf of the articles submitted to the journal on personal websites or institutional repositories after publication, while providing bibliographic details that credit its publication in this journal.
