title: Pharmacodynamics of Ceftaroline plus Ampicillin against Enterococcus faecalis in anIn VitroPharmacokinetic/Pharmacodynamic Model of Simulated Endocardial Vegetations.
abstract: The combination of ampicillin plus ceftaroline has been suggested to be more reliably synergistic againstEnterococcus faecalisthan ampicillin plus ceftriaxone using time-kill methods. The purpose of this study was to determine if this trend persists in a two-compartment model of simulated endocardial vegetations (SEV) using clinically relevant pharmacokinetic exposures of these antimicrobials. Three clinically derivedE. faecalisstrains were included in the study. The MICs of study antimicrobials were determined by broth microdilution. Simulations of ampicillin (2 g every 4 h [q4h]; maximum concentration of drug in serum [Cmax], 72.4 mg/liter; half-life [t1/2], 1.9 h), ceftaroline-fosamil (600 mg q8h;Cmax, 21.3 mg/liter;t1/2, 2.66 h), ceftriaxone (Cmax, 257 mg/liter;t1/2, 8 h), and ampicillin plus ceftaroline and ampicillin plus ceftriaxone were evaluated against 3 strains ofE. faecalisisolated from patients with endocarditis in anin vitroPK/PD SEV model over 72 h, with a starting inoculum of ∼9 log10CFU/g. All strains were susceptible to ampicillin (MIC, ≤2 mg/liter). Ceftaroline MICs varied from 2 to 16 mg/liter. All strains had ceftriaxone MICs of 256 mg/liter. W04 and W151 exhibited high-level aminoglycoside resistance but W07 did not. Ampicillin plus ceftaroline resulted in significantly greater reductions in CFU per gram by 72 h than ampicillin for all strains (P≤ 0.025) than ampicillin plus ceftriaxone for W04 (P= 0.019) but not W07 or W151 (P≥ 0.15). A 4-fold increase in ampicillin MIC was observed for W07 at 72 h, but this was prevented by the addition of ceftaroline or ceftriaxone. The combination of ampicillin plus ceftaroline appears to be at least as efficacious as ampicillin plus ceftriaxone and may lead to improved activity against some strains ofE. faecalis, but these differences may be small and the clinical significance should not be overestimated.
authors.affiliation: Department of Pharmacy University of Washington School of Pharmacy, Seattle, Washington, USA bwerth@uw.edu.
authors.forename: Brian J
authors.identifier: 0000-0001-6751-4098
authors.initials: BJ
authors.lastname: Werth
authors.affiliation: Department of Pharmacy University of Washington School of Pharmacy, Seattle, Washington, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Shireman
mesh_terms: D000667:Ampicillin / Q000493:pharmacokinetics* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D002443:Ceftriaxone / Q000493:pharmacokinetics* / Q000494:pharmacology; D002511:Cephalosporins / Q000493:pharmacokinetics* / Q000494:pharmacology; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004697:Endocarditis, Bacterial / Q000188:drug therapy / Q000382:microbiology; D013293:Enterococcus faecalis / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D010477:Perfusion; D012212:Rheology; D000097583:Ceftaroline
chemical_list: D000667:Ampicillin; D000900:Anti-Bacterial Agents; D002443:Ceftriaxone; D002511:Cephalosporins; D000097583:Ceftaroline
keywords: HLAR; PK/PD; ceftriaxone; dual β-lactam; endocarditis; infective endocarditis; synergy