PHARMACODYNAMICS OF RP-59500 (QUINUPRISTIN-DALFOPRISTIN) ADMINISTEREDBY INTERMITTENT VERSUS CONTINUOUS-INFUSION AGAINST STAPHYLOCOCCUS-AUREUS-INFECTED FIBRIN-PLATELET CLOTS IN AN IN-VITRO INFECTION MODEL

We evaluated the bactericidal activity of RP 59500 (quinupristin-dalfo pristin) against fibrin-platelet clots (FPC) infected with two clinica l isolates of Staphylococcus aureus, one constitutively erythromycin a nd methicillin resistant (S, aureus AW7) and one erythromycin and meth icillin susceptible (S, aureus 1199), in an in vitro pharmacodynamic i nfection model, RP 59500 was administered by continuous infusion (peak steady-state concentration of 6 mu g/ml) or intermittent infusion (si mulated regimens of 7.5 mg/kg of body weight every 6 h (q6h) q8h, and q12h, FPCs were infected with S. aureus to achieve an initial bacteria l density of 10(9) CFU/g, Model experiments were run in duplicate over 72 h, Two FPCs were removed from each model at 0, 12, 24, 36, 48, and 72 h, and the bacterial densities (in CFU per gram) were determined a nd compared to those of growth control experiments, Additional samples were also removed from the model over the 72-h period for pharmacokin etic evaluation, All regimens significantly (P less than or equal to 0 .01) decreased bacterial densities in the infected FPCs for both isola tes compared to growth controls, This occurred even though MBCs were e qual to or greater than the RP 59500 concentrations achieved in the mo dels. There were no significant differences found between the dosing f requencies and levels of killing when examining each isolate separatel y. However, examination of the residual bacterial densities (CFU per g ram at 72 h) and visual inspection of the overall killing effect (kill ing curve plots over 72 h) clearly demonstrated a more favorable bacte ricidal activity against 1199 than against the AW7 isolate. This was m ost apparent when the q8h and the q12h AW7 regimens were compared to a ll 1199 treatment regimens by measuring the 72-h bacterial densities ( P less than or equal to 0.01), Killing (99.9%) was not achieved agains t the AW7 isolate, However, a 99.9% kill was demonstrated for all dosi ng regimens against the 1199 isolate, The area under the concentration -time curve from 0 to 24 h was found to be significantly correlated wi th reduction in bacterial density for the AW7 isolate (r = 0.74, P = 0 .04), No resistance was detected during any experiment for either isol ate, RP 59500 efficacy against constitutively erythromycin- and methic illin-resistant S. aureus may be improved by increasing organism expos ure to RP 59500 as a function of dosing frequency.