The effects of antibiotic combination treatments on Pseudomonas aeruginosa tolerance evolution and coexistence with Stenotrophomonas maltophilia

Pseudomonas aeruginosa bacterium is a common pathogen of Cystic Fibrosis
(CF) patients due to its ability to evolve resistance to antibiotics
during treatments. While P. aeruginosa resistance evolution is well
characterised in monocultures, it is less well understood in polymicrobial
CF infections. Here, we investigated how exposure to ciprofloxacin,
colistin, or tobramycin antibiotics, administered at sub-MIC doses alone
and in combination, shaped the tolerance evolution of P. aeruginosa (PAO1
lab and clinical CF LESB58 strains) in the absence and presence of a
commonly co-occurring species, Stenotrophomonas maltophilia. Increases in
antibiotic tolerances were primarily driven by the presence of that
antibiotic in the treatment. We observed a reciprocal cross-tolerance
between ciprofloxacin and tobramycin, and when combined these antibiotics
selected increased MICs for all antibiotics. Though the presence of S.
maltophilia did not affect the tolerance or the MIC evolution, it drove P.
aeruginosa into extinction more frequently in the presence of tobramycin
due to its relatively greater innate tobramycin tolerance. In contrast, P.
aeruginosa dominated and drove S. maltophilia extinct in most other
treatments. Together, our findings suggest that besides driving high-level
antibiotic tolerance evolution, sub-MIC antibiotic exposure can alter
competitive bacterial interactions, leading to target pathogen extinctions
in multi-species communities.