Treating multi-drug resistance is not straightforward, and finding new antibiotics is not easy. Bacteria evolve rapidly to survive aggressive antibiotic treatments, but during these evolutions some trade-offs may occur. Those may become weaknesses that could be exploited and used as new drug targets.
A standard practice when people are extremely sick and fighting multi-drug resistant infections in hospital is to change antibiotic regimens. If one antibiotic isn’t working, then doctors and nurses replace it with another. This can be done either by antibiotic cycling – which involves the scheduled, sequential use of different antibiotic classes; or antibiotic mixing, which is the random allocation of diverse, appropriate antibiotics to individual patients. Clinicians change antibiotic regimens dynamically, making switches in response to undesired clinical outcomes.
COMBACTE-MAGNET realised that investigating antibiotic mixing in ICUs could be the perfect environment to test whether trade-offs made by multi-drug resistant bacteria are happening, and whether they make these bacteria more susceptible to other antibiotics. The study was the first to provide real-world evidence that mixing antibiotics in ICU patients is effective because of these evolutionary trade-offs.
“Because tracking how bacteria adapt in real-time is incredibly difficult, scientists have historically lacked data on collateral effects. Uncovering these evolutionary trade-offs provides a powerful new layer of insight to support clinicians and optimize future stewardship strategies,” says Surbhi Malhotra-Kumar, one of the leading authors of the study.
Exposing vulnerabilities of multi-drug resistant bacteria
Samples of microorganisms were taken periodically from 25 patients across several days so that the evolution of the bacteria could be observed. On average, those patients were receiving 2.24 different antibiotic classes over 27.5 days.
The researchers’ results showed that the minimum amount of an antibiotic needed to have an effect significantly increased the longer the patient was exposed to that antibiotic.
However, the researchers also showed that the minimum amount of antibiotic needed to have an effect actually dropped for those antibiotics which were not administered initially, indicating that the bacteria, while developing resistance to the administered antibiotic, could become more susceptible to other antibiotics.
This is one of the first studies to provide real-world evidence showing how the vulnerabilities of multi-drug resistant bacteria shifts when exposed to different antibiotics in real-world settings.
According to Malhotra-Kumar, this could mean a more tailored and personalised approach to treatment for multi-drug resistant infections in the future.
“For years, combating multi-drug resistant bacteria has felt like a losing battle. Now, instead of just fighting antibiotic resistance, we’ve found a way to let the bacteria’s own evolutionary adaptations work against them. By strategically changing antibiotics, we turn their main strength—their rapid ability to adapt—into a weakness that allows us to clear the infection,” she says.