Rapid evolution and host immunity drive the rise and fall of antibiotic resistance during acute infection

Antibiotic resistance poses a serious threat to human health. Resistant infections now cause more than 750,000 deaths per year and are predicted to increase to 10 million deaths per year by 2050. It is known that treating patients with antibiotics is associated with the emergence of resistance - and worse outcomes for patients. But how resistance emerges during infections remains poorly understood.

A new study published today in Nature Communications reports that rapid bacterial evolution interacts with host immunity to shape both the rise, and fall, of resistance during infection. This study was performed by the University of Oxford in collaboration with the University of Antwerp, University Hospital Son Espases and AstraZeneca as part of the IMI COMBACTE-MAGNET consortium. The consortium is a collaboration between academia and industry professionals aiming to find new approaches to combat antibiotic resistance.

This study highlights the need to understand better how our immune system works with antibiotics to suppress bacterial infections.

The research described in this article is part of a larger ASPIRE-ICU study, which stands for Advanced understanding of Staphylococcus aureus and Pseudomonas aeruginosa Infections in EuRopE – Intensive Care Units. The ASPIRE-ICU trial was conducted by the COMBACTE consortium and brought together multiple collaborators from leading academic research labs along with AstraZeneca scientists.

The Europe-wide ASPIRE-ICU study observed the frequency of pneumonia in mechanically ventilated patients caused by Staphylococcus aureus or P. aeruginosa and followed patients during their ICU stay. One of these patients was found to harbour P. aeruginosa in multiple samples over time in both the respiratory and intestinal tract. The evolutionary responses of bacterial populations to antibiotic treatment during infections are not well studied, which was done in this study where the evolutionary response to treatment was mapped in high definition through genomic and phenotypic characterization of more than 100 isolates from this patient with P. aeruginosa pneumonia.

At the University of Antwerp, all samples from this patient were screened for the presence and abundance of P. aeruginosa that were also whole-genome sequenced (Professor Malhotra-Kumar/Professor H. Goossens). Also at the University of Antwerp, the host immune response was studied, not in serum as is routinely done but in the endotracheal aspirates from the patient, to screen for specific immune markers at the site of infection (Professor Kumar-Singh). Population genomics and bacterial fitness were studied at the University of Oxford (Professor Maclean) and were combined with accurate antibiotic susceptibility testing and resistance genomic profiling performed at the University Hospital Son Espases (Dr. Oliver).

Together these data showed that natural selection was a rapid drive for survival against multiple antibiotic agents including the last resort antibiotic colistin. Host immunity helped to suppress the infection, probably removing >90% of resistant mutants that were present at the start of antibiotic treatment. Host immunity also eventually eliminated the resistant populations that were present after treatment. In conclusion, this study highlights the importance and represents a perfect example of the increased collaboration and cross-talk within the WP3A academic, as well as with the industry, researchers of the COMBACTE MAGNET consortium.

Read the paper here