Y-688, a new quinolone active against quinolone-resistant Staphylococcus aureus: lack of in vivo efficacy in experimental endocarditis.

Abstract

Y-688 is a new fluoroquinolone with increased activity against ciprofloxacin-resistant staphylococci. The MICs of Y-688 and other quinolones were determined for 58 isolates of ciprofloxacin-resistant and methicillin-resistant Staphylococcus aureus (MRSA). The MICs at which 50% and 90% of bacteria were inhibited were >/=128 and >/=128 mg/liter, respectively, for ciprofloxacin, 16 and 32 mg/liter, respectively, for sparfloxacin, and 0.25 and 1 mg/liter, respectively, for Y-688. This new quinolone was further tested in rats with experimental endocarditis due to either of two isolates of ciprofloxacin-resistant MRSA (namely, P8/128 and CR1). Infected animals were treated for 3 days with ciprofloxacin, vancomycin, or Y-688. Antibiotics were administered through a computerized pump to simulate human-like pharmacokinetics in the serum of rats. The anticipated peak 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 organisms (P less, similar 0.05). In contrast, Y-688 only marginally decreased vegetation bacterial counts (P greater, similar 0.05). Moreover, several vegetation that failed Y-688 treatment grew staphylococci for which the MICs of the test antibiotic were increased two to eight times. Y-688 also selected for resistance in vitro, and isolates for which the MICs were increased eight times emerged at a frequency of ca. 10(-8). Thus, in spite of its low MIC for ciprofloxacin-resistant MRSA, Y-688 failed in vivo and its use carried the risk of resistance selection. The fact that ciprofloxacin-resistant staphylococci became rapidly resistant to this potent new drug suggests that the treatment of ciprofloxacin-resistant MRSA with new quinolones might be more problematic than expected.

• Authors: J M Entenza, O Marchetti, M P Glauser, P Moreillon
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 42 Issue 8 Pg. 1889-94 (Aug 1998) ISSN: 0066-4804 [Print] United States
• PMID: 9687379 (Publication Type: Journal Article)

Chemical References

• Anti-Infective Agents
• Fluoroquinolones
• Y 688
• Ciprofloxacin

Topics

• Animals
• Anti-Infective Agents (pharmacology, therapeutic use)
• Ciprofloxacin (pharmacology)
• Drug Resistance, Microbial
• Endocarditis, Bacterial (drug therapy)
• Fluoroquinolones
• Microbial Sensitivity Tests
• Rats
• Spleen (microbiology)
• Staphylococcal Infections (drug therapy)
• Staphylococcus aureus (drug effects)