Pharmacodynamics of RP 59500 alone and in combination with vancomycin against Staphylococcus aureus in an in vitro-infected fibrin clot model

Abstract

The bactericidal activity and emergence of resistance to RP 59500 (quinupristin/dalfopristin) when it was administered alone and in combination with vancomycin against fibrin clots that have been infected with methicillin-susceptible Staphylococcus aureus ATCC 25923 or methicillin-resistant S. aureus (MRSA) 67 were evaluated in an in vitro pharmacodynamic infected fibrin clot model. Fibrin clots were infected with S. aureus to achieve an inoculum of approximately 10 9 CFU/g. Antibiotics were administered to simulate pharmacokinetics in humans: RP 59500 (7.5 mg/kg of body weight) every 8 h and vancomycin (15 mg/kg) every 12 h over 72 h. Preliminary test tube time-kill experiments with an inoculum of ϳ10 5 CFU/ml suggested that RP 59500 was more rapid in achieving a 99.9% reduction in the number of CFU per milliliter than vancomycin against ATCC 25923 (6.94 versus 24 h; P ‫؍‬ 0.0003) and MRSA 67 (6.77 versus 17.03 h; P ‫؍‬ 0.004). At a higher inoculum (ϳ10 8 CFU/ml), 99.9% kill was achieved only with the combination regimen against ATCC 25923 and MRSA 67 (10.9 and 10.5 h, respectively), with total reductions of 6.35 and 6.33 log 10 CFU/ml over 24 h, respectively. In the fibrin clot model, RP 59500 was more effective than vancomycin in reducing organism titers over 72 h. However, the combination regimen was the most effective therapy, with a total reduction of colony count against ATCC 25923 (total reduction of 1.24 log 10 CFU/g for RP 59500, 0.56 log 10 CFU/g for vancomycin, and 3.3 log 10 CFU/g for the combination; P < 0.002) and MRSA 67 (total reduction of 1.66 log 10 CFU/g for RP 59500, 0.50 log 10 CFU/g for vancomycin, and 2.48 log 10 CFU/g for the combination; P < 0.04). Resistance of both strains of S. aureus was noted in the model only after exposure to RP 59500 (32-fold increase in the MIC), as was a simultaneous increase in the erythromycin MIC (32-fold) for ATCC 25923, but no changes in the lincomycin MIC were noted. Overall, RP 59500 demonstrated more potent bactericidal activity than vancomycin against S. aureus over 72 h. In the fibrin clot model, the most optimal therapy was the combination regimen.

Efficacies of Vancomycin, Arbekacin, and GentamicinAlone or in Combination against Methicillin-Resistant Staphylococcus aureus in an In Vitro InfectiveEndocarditisModel

“…The IVIEM prepared was a one-compartment model and was equipped with a tube with a cap where the fibrin clot could be attached as previously described (13,20). After 700 ml of CAMHB medium was placed inside the model by using 6 sets in 2 fibrin clots, the study was conducted by eliminating each set during 72 h. The temperature was maintained at 37°C for 72 h, and the medium within the model was stirred well with a stir bar.…”

“…The MIC at which 90% of the isolates tested are inhibited was 1.56 g/ml (15), and some synergistic effect was demonstrated in in vitro studies if it was combined with vancomycin (17,33). However, in vitro study results could not be applied directly to the clinical setting, so many studies with an in vitro infection model have been attempted in recent years (6,13). We used the in vitro infective endocarditis model (IVIEM) to confirm the efficacies of each antibiotic, including vancomycin, arbekacin, and gentamicin, against MRSA and to compare these efficacies to those of vancomycin and gentamicin in combination and vancomycin and arbekacin in combination.…”

Vancomycin-Resistant Enterococci

“…It does not exhibit crossresistance with any existing antibiotics (131,250). In vitro studies have demonstrated increased activity of RP 59500 when combined with vancomycin against MRSA (136). However, no synergy was found against VRE when the drug was combined with ampicillin, ciprofloxacin, gentamicin, rifampin, streptomycin, teicoplanin, or vancomycin (L. B.…”

Influence of Platelets and Platelet Microbicidal Protein Susceptibility on the Fate of Staphylococcus aureus in an In Vitro Model of Infective Endocarditis

“…Recently, an in vitro pharmacokinetic and pharmacodynamic model has been developed to simulate IE (4,6,15,17,20,22 25,1997). Like the in vivo model, the in vitro model poses a rigorous challenge to antimicrobial agent efficacy, due to the presence of high organism densities in the setting of a complex biomatrix comprising the simulated vegetation.…”