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In search for a synergistic combination against pandrug-resistant A. baumannii; methodological considerations

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Abstract

Purpose

Pending approval of new antimicrobials, synergistic combinations are the only treatment option against pandrug-resistant A. baumannii (PDRAB). Considering the lack of a standardized methodology, the aim of this manuscript is to systematically review the methodology and discuss unique considerations for assessing antimicrobial combinations against PDRAB.

Methods

Post-hoc analysis of a systematic review (conducted in PubMed and Scopus from inception to April 2021) of studies evaluating antimicrobial combination against A. baumannii, based on antimicrobials that are inactive in vitro alone.

Results

Eighty-four publications were reviewed, using a variety of synergy testing methods, including; gradient-based methods (n = 11), disk-based methods (n = 6), agar dilution (n = 2), checkerboard assay (n = 44), time-kill assay (n = 50), dynamic in vitro PK/PD models (n = 6), semi-mechanistic PK/PD models (n = 5), and in vivo animal models (n = 11). Several variations in definitions of synergy and interpretation of each method were observed and are discussed. Challenges related to testing combinations of antimicrobials that are inactive alone (with regards to concentrations at which the combinations are assessed), as well as other considerations (assessment of stasis vs killing, clinical relevance of re-growth in vitro after initial killing, role of in vitro vs in vivo conditions, challenges of clinical testing of antimicrobial combinations against PDRAB infections) are discussed.

Conclusion

This review demonstrates the need for consensus on a standardized methodology and clinically relevant definitions for synergy. Modifications in the methodology and definitions of synergy as well as a roadmap for further development of antimicrobial combinations against PDRAB are proposed.

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Acknowledgements

We thank Professor Georgios Chamilos (Department of Clinical Microbiology and Microbial Pathogenesis, University Hospital of Heraklion, Heraklion, Greece) for his critical input.

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  1. Department of Internal Medicine and Infectious Diseases, University Hospital of Heraklion, Heraklion, Greece

    Stamatis Karakonstantis, Petros Ioannou & Diamantis D. Kofteridis

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  1. Stamatis Karakonstantis
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  3. Diamantis D. Kofteridis
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Karakonstantis, S., Ioannou, P. & Kofteridis, D.D. In search for a synergistic combination against pandrug-resistant A. baumannii; methodological considerations. Infection 50, 569–581 (2022). https://doi.org/10.1007/s15010-021-01748-w

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