The Effects of Antibiotic Combination Treatments on Pseudomonas aeruginosa Tolerance Evolution and Coexistence with Stenotrophomonas maltophilia

The 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-characterized 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-minimum inhibitory concentration (MIC) doses, both 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. The 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, the selected antibiotics increased the MICs for all of the 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 multispecies communities.

Automated summary

This study investigated the impact of sub-minimum inhibitory concentration (MIC) antibiotic exposure on the tolerance evolution of Pseudomonas aeruginosa in polymicrobial cystic fibrosis (CF) infections. The presence of antibiotics drove the evolution of antibiotic tolerance, with reciprocal cross-tolerance observed between ciprofloxacin and tobramycin. The presence of Stenotrophomonas maltophilia did not affect tolerance or MIC evolution, but increased the likelihood of P. aeruginosa extinction in the presence of tobramycin.