Pharmacokinetics, Tissue Distribution, and Efficacy of VIO-001 (Meropenem/Piperacillin/Tazobactam) for Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia in Immunocompetent Rabbits with Chronic Indwelling Vascular Catheters.

MRSA infections of surgically implanted subcutaneous vascular catheters (SISVCs) cause serious morbidity in patients with chronic illnesses. Previous in vitro and murine models demonstrated synergistic interaction of equimolar concentrations of meropenem/piperacillin/tazobactam (M/P/T; VIO-001) against MRSA infection. We investigated the pharmacokinetics (PK) and efficacy of VIO-001 for treatment of MRSA bacteremia in immunocompetent rabbits with SISVCs. In PK studies, we determined that optimal dosing to achieve T/4×MIC T/MIC for the duration of 3-3.30h required 1h-infusion with Q4h dosing. Study groups in efficacy experiments consisted of M/P/T combination of 100/150/100 (MPT100), 200/300/200 (MPT200), 400/600/400 (MPT400) mg/kg, vancomycin (VAN) at 15 mg/kg, and untreated controls (UC). The inoculum of MRSA isolate USA300-TCH1516 (1×103) was administered via the SISCV on Day-1 and locked for 24h. The 8-day therapy started 24h post-inoculation. There was significant reduction of MRSA in blood cultures from the SISVCs in all treatment groups with full clearance on Day-4 vs UC (p<0.05). Consistent with clearance of SISVC-related infection, full eradication of MRSA was achieved in lungs, heart, liver, spleen, and kidneys at end of study vs UC (p <0.01). These results strongly correlated with time-kill data, where MPT in the range of 4/6/4 to 32/48/32 μg/mL demonstrated significant six-log decrease in bacterial burden vs UC (p<0.01). In summary, VIO-001 demonstrated a favorable PK/PD profile and activity against SISCV MRSA infection, bacteremia, and disseminated infection. This rabbit model provides a new system for understanding new antimicrobial agents against MRSA SISVC-related infection and these data provide a basis for future clinical investigation.