Daptomycin in Combination with Ceftolozane-Tazobactam or Cefazolin against Daptomycin-Susceptible and -Nonsusceptible Staphylococcus aureus in an In Vitro, Hollow-Fiber Model

• Published in: Antimicrobial agents and chemotherapy Vol. 60; no. 7; pp. 3970 - 3975
• Main Authors: Smith, Jordan R, Arya, Anu, Yim, Juwon, Barber, Katie E, Hallesy, Jessica, Singh, Nivedita B, Rybak, Michael J
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.07.2016
• Subjects: Anti-Bacterial Agents; Anti-Bacterial Agents - pharmacology; Cefazolin; Cefazolin - pharmacology; Cephalosporins; Cephalosporins - pharmacology; Daptomycin; Daptomycin - pharmacology; Experimental Therapeutics; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests; Penicillanic Acid; Penicillanic Acid - analogs & derivatives; Penicillanic Acid - pharmacology; Staphylococcus aureus; Staphylococcus aureus - drug effects
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01666-15

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 μg/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.