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In vivo studies on antibiotic combination for the treatment of carbapenem-resistant Gram-negative bacteria: a systematic review and meta-analysis protocol
  1. Elda Righi1,
  2. Luigia Scudeller2,
  3. Margherita Chiamenti1,
  4. Kamilia Abdelraouf3,
  5. Thomas Lodise4,
  6. Elena Carrara1,
  7. Alessia Savoldi1,
  8. Dario Menghin1,
  9. Gloria Pellizzari1,
  10. Sally Ellis5,
  11. Francois Franceschi5,
  12. Laura Piddock5,
  13. Chiara Rebuffi6,
  14. Maurizio Sanguinetti7,
  15. Evelina Tacconelli1
  1. 1Infectious Diseases, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
  2. 2Clinical Epidemiology and Biostatistics, IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano Foundation, Milan, Italy
  3. 3Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA
  4. 4Albany College of Pharmacy and Health Sciences, Albany, New York, USA
  5. 5Global Antibiotic Research & Development Partnership (GARDP), Geneva, Switzerland
  6. 6Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
  7. 7Microbiology, A. Gemelli Hospital, Catholic University of the Sacred Heart, Rome, Italy
  1. Correspondence to Professor Elda Righi; elda.righi{at}


Objective There is poor evidence to determine the superiority of combination regimens versus monotherapy against infections due to carbapenem-resistant (CR) Gram-negative bacteria. In vivo models can simulate the pathophysiology of infections in humans and assess antibiotic efficacy. We aim to investigate in vivo effects of antibiotic combination on mortality and disease burden for infections due to CR Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae and provide an unbiased overview of existing knowledge. The results of the study can help prioritising future research on the most promising therapies against CR bacteria.

Methods and analysis This protocol was formulated using the Systematic Review Protocol for Animal Intervention Studies (SYRCLE) Checklist. Publications will be collected from PubMed, Scopus, Embase and Web of Science. Quality checklists adapted by Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies and SYRCLE’s risk of bias tool will be used. If the meta-analysis seems feasible, the ES and the 95% CI will be analysed. The heterogeneity between studies will be assessed by I2 test. Subgroup meta-analysis will be performed when possible to assess the impact of the studies on efficacy of the treatments. Funnel plotting will be used to evaluate the risk of publication bias.

Dissemination This systematic review and meta-analysis is part of a wider research collaboration project, the COmbination tHErapy to treat sepsis due to carbapenem-Resistant bacteria in adult and paediatric population: EvideNCE and common practice (COHERENCE) study that includes also the analyses of in vitro and human studies. Data will be presented at international conferences and the results will be published in peer-reviewed journals.

PROSPERO registration number CRD42019128104(available at:

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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  • Funding This work was supported by Global Antibiotic Research and Development Partnership.

  • Competing interests None declared.

  • Ethics approval Not applicable

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Preregistration This systematic review and meta-analysis protocol reported in this article was formally preregistered on PROSPERO.

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