Within lung interspecies plasmid transfer causes sudden and extreme antibiotic resistance in human infections

Many human infections are caused by antibiotic-sensitive bacteria and resistance develops inside the host after treatment is initiated. Previous work indicates that resistance emerging in vivo is generally due to the step-wise accumulation of mutations in pathogen genomes. Here we show an alternative mechanism wherein bacteria capable of growth in the environment and within human lungs transferred resistance genes to established lung pathogens after high-dose tobramycin treatment had been initiated. The bacteria transferring resistance were only transiently detected in clinical cultures, but the genes they transferred produced instantaneous ~10,000-fold increases in resistance. Resistance was durable even when antibiotics were absent, and it imposed no apparent fitness costs in >1000 tested growth conditions. Most cases we identified were caused by a previously undescribed transposon likely generated when an insertion sequence mobilized a novel resistance gene from environmental bacteria. While not previously recognized as a cause of clinical resistance, we found the transposon sequence in data deposited from sites worldwide. These results show that transiently-infecting bacteria can transfer resistance genes to pathogens inside humans after antibiotics are started and transform their ability to resist treatment.