Antimicrobial resistance (AMR) represents one of the most pressing global threats to human health, undermining decades of progress in infectious disease management. In this influential Lancet Series paper, Holmes and colleagues provide a wide-ranging analysis of the biological mechanisms and societal drivers that underpin the emergence, persistence, and global spread of antimicrobial resistance.
The authors first frame resistance as a natural evolutionary phenomenon, deeply rooted in microbial ecology. Many resistance mechanisms, such as enzymatic drug inactivation, target modification, efflux systems, and reduced permeability, long predate modern medicine. However, the unprecedented scale and intensity of antimicrobial use in humans, animals, and agriculture have dramatically accelerated the selection and dissemination of resistant microorganisms. The paper highlights the critical role of horizontal gene transfer, particularly plasmid-mediated transmission, in enabling rapid spread of resistance across bacterial species and geographic boundaries.
At the individual level, antimicrobial exposure profoundly alters the human microbiome, promoting the selection of resistant organisms even during short treatment courses. At the population level, the authors dissect the complex relationship between antimicrobial consumption and resistance, showing that misuse and overuse, both in hospitals and in the community, remain key drivers, while acknowledging that reductions in use do not always result in predictable declines in resistance.
A defining strength of this review is its integrated “One Health” perspective. The contribution of veterinary medicine, food production, and environmental contamination is examined in depth, supported by evidence linking antimicrobial use in livestock, pharmaceutical pollution, and inadequate sanitation to resistance transmission. Global travel, migration, and disparities in access to clean water, diagnostics, and effective antimicrobials are also identified as critical amplifiers of resistance spread.
Importantly, the article challenges the assumption that antimicrobial resistance necessarily imposes a fitness cost on bacteria. The persistence and global success of resistant clones demonstrate that resistance can be stable and durable, even in the absence of ongoing selective pressure. This has major implications for policy, highlighting the limits of strategies based solely on reducing antimicrobial use.
In conclusion, the authors argue convincingly that tackling antimicrobial resistance requires coordinated, multidisciplinary, and sustained action. Advances in diagnostics, therapeutics, surveillance, infection prevention, and policy must be pursued in parallel to preserve the effectiveness of existing and future antimicrobials. This paper remains a cornerstone reference for understanding why AMR has emerged as a global crisis and how it must be addressed.
Reference
Holmes AH, Moore LSP, Sundsfjord A, et al. Understanding the mechanisms and drivers of antimicrobial resistance. Lancet, 2016.
