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c Ceftolozane-tazobactam (TOL-TAZ) is a novel cephalosporin/beta-lactamase inhibitor with activity against several Gram-negative pathogens. Daptomycin (DAP) has demonstrated synergistic activity with beta-lactams against methicillin-resistant Staphylococcus aureus (MRSA) isolates with reduced lipopeptide and glycopeptide susceptibilities. Our objective was to determine if DAP and TOL-TAZ possess synergy in hollow-fiber pharmacokinetic/pharmacodynamic (PK/PD) models. One isogenic pair of daptomycin-susceptible and daptomycin-nonsusceptible MRSA strains was evaluated. DAP, TOL-TAZ, and cefazolin (CFZ) MIC determinations were performed. DAP MIC determinations were also performed in the presence of subinhibitory concentrations of TOL-TAZ and CFZ. Ninety-six-hour in vitro models were run, simulating DAP at 10 mg/kg of body weight/day; TOL-TAZ at 1,500 mg every 8 h; TOL at 1,000 mg every 8 h; and DAP combined with TOL-TAZ (DAP؉TOL-TAZ), DAP؉TOL, DAP؉TAZ, and DAP؉CFZ at 2,000 mg every 8 h. DAP MICs were 0.5 and 4 g/ml for strains R8845 and R8846, respectively. In the presence of CFZ, R8845 and R8846 DAP MICs were reduced 8-fold and 16-fold, respectively. TOL and TAZ had no effect on DAP MICs. PK/PD models demonstrated bactericidal activity with DAP؉CFZ against both strains. The combination of DAP؉TOL-TAZ was bactericidal against R8845 but was not bactericidal against daptomycin-nonsusceptible strain R8846. DAP؉TOL and DAP؉TAZ were not bactericidal. No other regimens were bactericidal. DAP؉TOL-TAZ did not demonstrate synergistic activity against daptomycin-nonsusceptible S. aureus but prevented daptomycin-nonsusceptible MRSA emergence. Because DAP؉TOL or TAZ alone did not prevent daptomycin-nonsusceptible MRSA emergence, the combination TOL-TAZ may be necessary for synergy with DAP. DAP؉CFZ demonstrated enhancement against both strains. The combination of DAP؉CFZ warrants further clinical study. Staphylococcus aureus is the leading cause of hospital-associated infections in the United States, and methicillin-resistant S. aureus (MRSA) strains comprise up to 50% of isolates (1). More problematic is the emergence of MRSA isolates with reduced susceptibility to vancomycin, a drug which has been a mainstay of MRSA therapy for more than 40 years (2). Treatment options against such isolates are limited. Among them is daptomycin (DAP), a lipopeptide antibiotic with bactericidal activity against Gram-positive pathogens (3). Daptomycin maintains activity against MRSA isolates with reduced vancomycin susceptibility, and nonsusceptibility to daptomycin is rare, occurring in Ͻ0.05% of a sampling of Ͼ9,000 S. aureus isolates (4). Daptomycin nonsusceptibility has been reported, however, and creative therapies are needed to combat this problem (5-10). Recent data have demonstrated that beta-lactam antibiotics in combination with daptomycin are efficacious in both preventing daptomycin nonsusceptibility and providing bactericidal activity (6,8,(10)(11)(12)(13).Because antibiotic resistance among Gram-negative bacteria is as much, if no...