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.

FIG. 1

Results of in vitro time-kill experiments performed with test compounds against the ciprofloxacin-resistant strains MRSA P8/128 (laboratory mutant) (A) and MRSA CR1 (clinical isolate) (B). Y-668 was added to the cultures at final concentrations which approximated the peak (4 mg/liter) and trough (1 mg/liter) antibiotic concentrations in the serum of rats. Vancomycin and ciprofloxacin concentrations (40 and 4 mg/liter, respectively) simulated the peak serum levels obtained in both the serum of humans and rats during antibiotic therapy (see Materials and Methods). •, control; •, Y-688 (4.0 mg/liter); ⧫, Y-688 (1.0 mg/liter); ▵, vancomycin (40 mg/liter); □, ciprofloxacin (4 mg/liter).

FIG. 2

Results of Y-688 therapy for experimental endocarditis due to ciprofloxacin-resistant isolates MRSA P8/128 (laboratory mutant) (A) and MRSA CR1 (clinical isolate) (B). Each dot in the columns represents the vegetation bacterial density (log₁₀ CFU per gram of vegetation) in a single rat. Open dots indicate the vegetations which grew staphylococcal derivatives for which the Y-688 MICs had increased two- to eightfold after 3 days of therapy. Vancomycin treatment significantly (P < 0.05) decreased the vegetation bacterial titers of both test organisms compared to those for untreated controls. In contrast, Y-688 did not significantly affect the vegetation infection caused by either of these bacteria (P > 0.05). Ciprofloxacin-treated animals, which were used as negative controls, were not considered in the statistical evaluation.

FIG. 3

Population analysis profile of the ciprofloxacin-resistant laboratory mutant P8/128 (closed squares) and the ciprofloxacin-resistant clinical isolate CR1 (closed triangles) grown on agar plates containing increasing concentrations of Y-688. Large bacteria numbers (up to 10¹⁰ CFU) were spread on plates containing twofold increasing concentrations of the drug. Resistant variants able to grow in the presence of increased concentrations of Y-688 were counted after 48 h of incubation at 35°C.