Antibiotic failure: Beyond antimicrobial resistance

Cesar de la Fuente-Nunez; Angela Cesaro; Robert E W Hancock

doi:10.1016/j.drup.2023.101012

Antibiotic failure: Beyond antimicrobial resistance

Drug Resist Updat. 2023 Nov:71:101012. doi: 10.1016/j.drup.2023.101012. Epub 2023 Oct 18.

Authors

Cesar de la Fuente-Nunez¹, Angela Cesaro², Robert E W Hancock³

Affiliations

¹ Machine Biology Group, Departments of Psychiatry and Microbiology, Institute for Biomedical Informatics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Departments of Bioengineering and Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA; Penn Institute for Computational Science, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: cfuente@upenn.edu.
² Machine Biology Group, Departments of Psychiatry and Microbiology, Institute for Biomedical Informatics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Departments of Bioengineering and Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA; Penn Institute for Computational Science, University of Pennsylvania, Philadelphia, PA, USA.
³ Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, Canada. Electronic address: bob@hancocklab.com.

PMID: 37924726
DOI: 10.1016/j.drup.2023.101012

Abstract

Despite significant progress in antibiotic discovery, millions of lives are lost annually to infections. Surprisingly, the failure of antimicrobial treatments to effectively eliminate pathogens frequently cannot be attributed to genetically-encoded antibiotic resistance. This review aims to shed light on the fundamental mechanisms contributing to clinical scenarios where antimicrobial therapies are ineffective (i.e., antibiotic failure), emphasizing critical factors impacting this under-recognized issue. Explored aspects include biofilm formation and sepsis, as well as the underlying microbiome. Therapeutic strategies beyond antibiotics, are examined to address the dimensions and resolution of antibiotic failure, actively contributing to this persistent but escalating crisis. We discuss the clinical relevance of antibiotic failure beyond resistance, limited availability of therapies, potential of new antibiotics to be ineffective, and the urgent need for novel anti-infectives or host-directed therapies directly addressing antibiotic failure. Particularly noteworthy is multidrug adaptive resistance in biofilms that represent 65 % of infections, due to the lack of approved therapies. Sepsis, responsible for 19.7 % of all deaths (as well as severe COVID-19 deaths), is a further manifestation of this issue, since antibiotics are the primary frontline therapy, and yet 23 % of patients succumb to this condition.

Keywords: Antibiotic resistance; Biofilm; Global health; Infectious Diseases; Sepsis.

Publication types

Review

MeSH terms

Anti-Bacterial Agents* / pharmacology
Anti-Bacterial Agents* / therapeutic use
Biofilms
Drug Resistance, Bacterial
Humans
Sepsis* / drug therapy

Substances

Anti-Bacterial Agents

Grants and funding

R35 GM138201/GM/NIGMS NIH HHS/United States