title: Cefazolin and Ertapenem, a Synergistic Combination Used To Clear Persistent Staphylococcus aureus Bacteremia.
abstract: Ertapenem and cefazolin were used in combination to successfully clear refractory methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. In addition, recent work has demonstrated activity of combination therapy with beta-lactams from different classes against methicillin-resistant S. aureus (MRSA). The ertapenem-plus-cefazolin combination was evaluated for synergy in vitro and in vivo in a murine skin infection model using an index MSSA bloodstream isolate from a patient in whom persistent bacteremia was cleared with this combination and against a cadre of well-described research strains and clinical strains of MSSA and MRSA. Against the index MSSA bloodstream isolate, ertapenem and cefazolin showed synergy using both checkerboard (fractional inhibitory concentration [FIC] index = 0.375) and time-kill assays. Using a disk diffusion ertapenem potentiation assay, the MSSA isolate showed a cefazolin disk zone increased from 34 to 40 mm. In vitro pharmacokinetic/pharmacodynamic modeling at clinically relevant drug concentrations demonstrated bactericidal activity (>3 log10-CFU/ml reduction) of the combination but bacteriostatic activity of ether drug alone at 48 h. A disk diffusion potentiation assay showed that ertapenem increased the cefazolin zone of inhibition by >3 mm for 34/35 (97%) MSSA and 10/15 (67%) MRSA strains. A murine skin infection model of MSSA showed enhanced activity of cefazolin plus ertapenem compared to monotherapy with these agents. After successful use in clearance of MSSA bacteremia, the combination of ertapenem and cefazolin showed synergy against MSSA in vitro and in vivo This combination may warrant consideration for future clinical study in MSSA bacteremia.
authors: University of California San Diego School of Medicine, La Jolla, California, USA gsakoulas@ucsd.edu.|Sharp Healthcare System, San Diego, California, USA.
authors: George
authors: G
authors: Sakoulas
authors: University of California San Diego School of Medicine, La Jolla, California, USA.
authors: Joshua
authors: J
authors: Olson
authors: Eugene Appelbaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA.
authors: Juwon
authors: J
authors: Yim
authors: Eugene Appelbaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA.
authors: Niedita B
authors: NB
authors: Singh
authors: University of California San Diego School of Medicine, La Jolla, California, USA.
authors: Monika
authors: M
authors: Kumaraswamy
authors: Department of Biological Sciences, University of California San Diego, La Jolla, California, USA.
authors: Diana T
authors: DT
authors: Quach
authors: Eugene Appelbaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA.
authors: Michael J
authors: MJ
authors: Rybak
authors: Department of Biological Sciences, University of California San Diego, La Jolla, California, USA.
authors: Joseph
authors: J
authors: Pogliano
authors: University of California San Diego School of Medicine, La Jolla, California, USA.|Skaggs School of Pharmacy, University of California San Diego, La Jolla, California, USA.
authors: Victor
authors: V
authors: Nizet
mesh_terms: D000369:Aged, 80 and over; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016470:Bacteremia / Q000188:drug therapy* / Q000382:microbiology; D002437:Cefazolin / Q000494:pharmacology*; D004195:Disease Models, Animal; D052978:Disk Diffusion Antimicrobial Tests; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000077727:Ertapenem; D005260:Female; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development / Q000302:isolation & purification; D051379:Mice; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013207:Staphylococcal Skin Infections / Q000188:drug therapy* / Q000382:microbiology; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D000077727:Ertapenem; D002437:Cefazolin