Fluoroquinolone Resistance inStreptococcus pneumoniae: Evidence ThatgyrAMutations Arise at a Lower Rate and That Mutation ingyrAorparCPredisposes to Further Mutation

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Abstract
Fluoroquinolones are being increasingly used for acute lower respiratory tract infection where Streptococcus pneumoniae is the most important bacterial pathogen. S. pneumoniae becomes resistant to quinolone antibiotics by mutations in a small section of the parC and gyrA genes. In this study, we investigated the mutation rates and spectrum of resistance when ciprofloxacin and gemifloxacin were the selective agents. When ciprofloxacin was the selective agent, parC mutants arose at a rate of 1.1 × 10-9 mutations per cell division. There were two double mutants: parC + gyrA and parC + gyrB, and these mutations arose in as few as five generations. When gemifloxacin was the selective agent, all but one of the colonies growing on the × 2 MIC plate had no mutations in gyrA or parC. The only mutation identified was in gyrA, and it appeared at a rate of 1.6 × 10-11. When the gemifloxacin MIC of strains with mutations in parC was determined, there was no change from the susceptible parent. These data indicate that S. pneumoniae becomes resistant to gemifloxacin through mutation in gyrA rather than parC. Because gyrA mutations arise at a lower rate than parC mutations, it is likely that resistance to gemifloxacin will emerge more slowly than is seen with those quinolones that become resistant through an initial mutation in parC. The rate at which second-step mutants emerged was 1.3 × 10-8 for parC Serine 79 Tyrosine and 7.2 × 10-9 for gyrA Serine 81 Phenylalanine, 12 and 450 times higher, respectively, than for first-step rates, suggesting that mutation in either gene readies the genome for further mutation.