title: Vancomycin and piperacillin-tazobactam against methicillin-resistant Staphylococcus aureus and vancomycin-intermediate Staphylococcus aureus in an in vitro pharmacokinetic/pharmacodynamic model.
abstract: OBJECTIVE
  Synergy between β-lactams and vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate Staphylococcus aureus (VISA) has been observed in vitro and in vivo. However, studies investigating piperacillin-tazobactam with vancomycin against MRSA and VISA are limited despite broad clinical use of these antibiotics in combination. This study evaluated vancomycin and piperacillin-tazobactam against MRSA and VISA by using an in vitro pharmacokinetic/pharmacodynamic model.
  
  
  METHODS
  Two clinical MRSA strains (M3425 and M494) and one VISA strain (Mu50) were tested in duplicate by using a 72-hour, 1-compartment pharmacokinetic/pharmacodynamic model with the following exposures: growth control, vancomycin only, piperacillin-tazobactam only, and vancomycin with piperacillin-tazobactam. Vancomycin 1 g every 12 hours (free trough concentration, 8.75 mg/L; Cmin, 17.5 mg/L) and piperacillin-tazobactam 13.5 g per 24 hours' continuous infusion (free steady-state concentration, 27 mg/L) were simulated. Time-kill curves were constructed, and reductions in log10 CFU/mL at all time points were compared between regimens tested.
  
  
  RESULTS
  Vancomycin and piperacillin-tazobactam MICs for M494, M3425, and Mu50 were 1, 1, and 4 and 1.5, 32, and >256 mg/L, respectively. All isolates had an oxacillin MIC ≥ 4 mg/L. Against all 3 isolates, vancomycin with piperacillin-tazobactam achieved a significant reduction in inoculum at 72 hours compared with vancomycin alone (all, P ≤ 0.015). The superiority of vancomycin with piperacillin-tazobactam compared with vancomycin alone became detectable at 8 hours for M3425 (P < 0.001) and at 24 hours for M494 and Mu50 (both, P ≤ 0.008). Although vancomycin with piperacillin-tazobactam achieved enhanced antibacterial activity at 72 hours against M3425 compared with vancomycin alone, bacterial regrowth occurred. Reduced susceptibility to vancomycin at 72 hours for M3425 was confirmed by using population analysis profile/AUC analysis. At 72 hours, M3425 had a PAP/AUC ratio of 0.77 compared to 0.51 at baseline.
  
  
  CONCLUSIONS
  Vancomycin with piperacillin-tazobactam demonstrated enhanced antimicrobial activity against MRSA and VISA compared with vancomycin alone. These results further enhance existing data that support using vancomycin in combination with a β-lactam for invasive MRSA infections. Combination therapy with vancomycin and a β-lactam against MRSA warrants clinical consideration.
authors: University of New Mexico College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico; Department of Pharmacy, Wheaton Franciscan Healthcare-St. Francis Hospital, Milwaukee, Wisconsin.
authors: Thomas J
authors: TJ
authors: Dilworth
authors: Northeastern University, Bouvé College of Health Sciences, School of Pharmacy, Boston, Massachusetts.
authors: Steve N
authors: SN
authors: Leonard
authors: University of New Mexico College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
authors: A Mary
authors: AM
authors: Vilay
authors: University of New Mexico College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. Electronic address: rmercier@salud.unm.edu.
authors: Renée-Claude
authors: RC
authors: Mercier
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D004357:Drug Synergism; D016106:Methicillin Resistance / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D010878:Piperacillin / Q000493:pharmacokinetics / Q000494:pharmacology; D000077725:Piperacillin, Tazobactam Drug Combination; D013211:Staphylococcus aureus / Q000187:drug effects*; D014640:Vancomycin / Q000493:pharmacokinetics / Q000494:pharmacology*; D020713:Vancomycin Resistance / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D000077725:Piperacillin, Tazobactam Drug Combination; D014640:Vancomycin; D010397:Penicillanic Acid; D010878:Piperacillin
keywords: combination therapy; methicillin-resistant Staphylococcus aureus; piperacillin-tazobactam; vancomycin; vancomycin-intermediate Staphylococcus aureus