Y-688, A NEW QUINOLONE ACTIVE AGAINST QUINOLONE-RESISTANT STAPHYLOCOCCUS-AUREUS - LACK OF IN-VIVO EFFICACY IN EXPERIMENTAL ENDOCARDITIS

Y-688 is a new fluoroquinolone with increased activity against ciprofl oxacin-resistant staphylococci. The MICs of Y-688 and other quinolones were determined for 58 isolates of ciprofloxacin-resistant and methic illin-resistant Staphylococcus aureus (MRSA). The MICs at which 50% an d 90% of bacteria were inhibited were greater than or equal to 128 and greater than or equal to 128 mg/liter, respectively, for ciprofloxaci n, 16 and 32 mg/liter, respectively, for sparfloxacin, and 0.25 and 1 mg/liter, respectively, for Y-688, This new quinolone was further test ed in rats with experimental endocarditis due to either of two isolate s of ciprofloxacin-resistant MRSA (namely, P8/128 and CR1), Infected a nimals were treated for 3 days with ciprofloxacin, vancomycin, or Y-68 8, Antibiotics were administered through a computerized pump to simula te human-like pharmacokinetics in the serum of rats. The anticipated p eak and trough levels of Y-688 were 4 and 1 mg/liter at 0.5 and 12 h, respectively, Treatment with ciprofloxacin was ineffective. Vancomycin significantly decreased vegetation bacterial counts for both organism s (P less than or equal to 0.05), In contrast, Y-688 only marginally d ecreased vegetation bacterial counts (P greater than or equal to 0.05) , Moreover, several vegetation that failed Y-688 treatment grew staphy lococci for which the MICs of the test antibiotic were increased two t o eight times. Y-688 also selected for resistance in vitro, and isolat es for which the MICs were increased eight times emerged at a frequenc y of ca, 10(-8). Thus, in spite of its low MIC for ciprofloxacin-resis tant MRSA, Y-688 failed in vivo and its use carried the risk of resist ance selection, The fact that ciprofloxacin-resistant staphylococci be came rapidly resistant to this potent new drug suggests that the treat ment of ciprofloxacin-resistant MRSA with new quinolones might be more problematic than expected.