Scientists have documented a notable case of antibiotic resistance evolving within a critically ill patient during treatment for an E. coli bloodstream infection, providing genomic evidence of how drug resistance can emerge in real time.
This new study, led by Liverpool School of Tropical Medicine (LSTM) and published in the Journal of Medical Microbiology, details the rapid evolution of resistance in an E. coli strain exposed to piperacillin/tazobactam (TZP), a first-line treatment for serious bacterial infections that pairs an antibiotic with a compound that inhibits beta-lactamase enzymes, a widespread antibiotic resistance gene.
While the initial infection appeared treatable, the bacteria quickly developed a mechanism to escape the drug’s effects, not by acquiring new resistance genes, but by amplifying one it already carried, overcoming the effects of the resistance inhibitor.
Dr Thomas Edwards, a researcher within the LSTM Centre for Drugs and Diagnostics and co-senior author of the study, said: “This is a striking example of resistance evolving under antibiotic pressure.
“We identified a tenfold increase in copies of a key resistance gene within the bacterial isolate, leading to a 32-fold increase in the level of antibiotic required to kill the bacteria, ultimately causing the treatment to fail, and all within the course of a single patient’s illness.”
The research team, which included genomic scientists, microbiologists and clinicians from Liverpool Clinical Laboratories, Liverpool University Hospital Foundation Trust and the University of Strathclyde, used high-resolution whole-genome sequencing to confirm the genetic changes.
The amplified resistance gene in E. coli, named blaTEM-1, produces a beta-lactamase enzyme that breaks down the antibiotic piperacillin. Although the TZP drug combination is meant to inhibit these enzymes, the sheer volume produced following gene duplication overwhelmed its protective effect, allowing the infection to persist. Further lab experiments confirmed that exposure to TZP led E. coli to generate even more copies of the gene.
Alice Fraser, an MRC DTP student in the Department of Tropical Disease Biology and the lead author of the study, said: “This case highlights just how adaptable bacteria can be. Not only did we see resistance develop rapidly, but we also observed duplications of other genes that could reflect broader adaptations, potentially affecting how the pathogen behaves inside the host.”
This form of ‘within-patient evolution’ presents a major diagnostic challenge. Routine resistance tests may underestimate the risk of treatment failure if they don’t detect bacteria capable of rapidly increasing enzyme production under antibiotic pressure.
The study also highlights that 40% of new antibiotic candidates in the pipeline are beta-lactamase inhibitor combinations like TZP, raising critical concerns for drug developers and frontline clinicians alike.
“This study underscores why relying on static resistance profiles can be misleading,” added Dr Edwards. “We need diagnostic tools that can detect emerging mechanisms like gene amplification, not just the presence or absence of resistance genes.”
The findings underscore the need for greater investment in diagnostics and surveillance tools that can detect dynamic, hard-to-spot resistance mechanisms before they undermine treatment.
Building on this work, Dr Edwards and colleagues are conducting a two-year project funded by the Academy of Medical Sciences to further investigate the mechanisms ofblaTEM-1 amplification in E. coli and whether the process can be effectively predicted.