Activity of 4-quinolones against Pseudomonas aeruginosa

The minimum inhibitory concentrations (MICs), bactericidal activities and mechanisms of action of ofloxacin (CAS 82419-36-1), levofloxacin (CAS 100986-85-4) and ciprofloxacin (CAS 86393-32-0) were investigated against Pseudomonas aeruginosa. All three 4-quinolones were found to possess higher MICs against Pseudomonas aeruginosa than against other Gram-negative bacteria. Despite this, however, all three drugs were more rapidly bactericidal and produced a greater level of kill against Pseudomonas aeruginosa than against any other bacterial species previously tested. Thus MIC tests cannot be used to predict the bactericidal activity of 4-quinolones. Furthermore, MIC tests showed ciprofloxacin to be more potent than ofloxacin or levofloxacin against Pseudomonas aeruginosa. However, bactericidal tests showed levofloxacin to be about 10 times more bactericidal than either ciprofloxacin or ofloxacin. Thus MIC tests cannot predict the relative bactericidal potency of 4-quinolones against Pseudomonas aeruginosa. Therefore, MIC tests should not be used as the sole measure for the efficacy of 4-quinolones, as is often the case. Surprisingly, the characteristic biphasic dose response curve, normally shown by 4-quinolones against other bacteria, was absent when Pseudomonas aeruginosa was tested. This unusual effect was explained by the presence of bactericidal mechanism B associated with the unique loss of bactericidal mechanism A at high 4-quinolone concentrations. This loss of bactericidal mechanism A may explain the recent high incidences of chromosomally-mediated 4-quinolone resistance with Pseudomonas aeruginosa because it may be easier for Pseudomonas aeruginosa to mutate to resist one mechanism of action than to mutate to resist two or more mechanisms of action.