Analysis of daptomycin efficacy and breakpoint standards in a murine model of Enterococcus faecalis and Enterococcus faecium renal infection.
Daptomycin efficacy against clinical isolates of Enterococcus faecalis, Enterococcus faecium, and a lab-derived daptomycin-resistant isolate of E. faecalis was investigated in a mouse model of renal infection. The daptomycin MICs against these enterococci ranged from 0.5 to 50 micro g/ml. The objective of this study was to determine the relationship between the MICs of drugs against E. faecalis and E. faecium and the level of daptomycin exposure needed to evaluate the drug's efficacy. Correlating the required therapeutic exposures of mice with the exposures achieved clinically allowed us to project enterococcal breakpoint values. Mice pretreated with carrageenan were infected intravenously with 3 x 10(8) to 4 x 10(8) CFU of E. faecalis or E. faecium. Daptomycin (5 to 50 mg of drug/kg of body weight) or saline control was administered 4 h postinfection and continued once daily for 2 days (three total doses). On day 4, infected kidneys were harvested, homogenized, and dilution plated. Efficacy was defined as a > or = 2-log(10) (99%) reduction in bacterial burden in infected kidneys. At clinically relevant dosages and exposures (area under the curve, 400 to 600 microg.hr/ml), daptomycin demonstrated similar and marked efficacy against all clinical enterococcal isolates tested. Daptomycin achieved efficacy with comparable doses against both vancomycin-sensitive (MIC, < or = 4 microg/ml) and -resistant enterococcal strains tested. Efficacy was also established against the lab-derived daptomycin-resistant E. faecalis isolate. In this murine renal infection model, clinically relevant exposures of daptomycin were effective against E. faecalis and E. faecium strains for which MICs were < or = 8 microg/ml. These murine efficacy data for daptomycin, along with surveillance data and human pharmacokinetic exposures achieved, suggest a breakpoint concentration value of < or = 8 microg/ml (susceptible) and > or = 16 microg/ml (resistant) for daptomycin against E. faecium and E. faecalis.
Department of Microbiology and Pharmacology, Cubist Pharmaceuticals, Inc., Lexington, Massachusetts 02421, USA. jadler@cubist.com
Jeff
J
Alder
Tongchaun
T
Li
Donghui
D
Yu
Larry
L
Morton
Jared
J
Silverman
Xi-Xian
XX
Zhang
Ian
I
Critchley
Grace
G
Thorne
D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D019540:Area Under Curve; D017576:Daptomycin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D013293:Enterococcus faecalis / Q000187:drug effects; D016984:Enterococcus faecium / Q000187:drug effects; D005260:Female; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D007668:Kidney / Q000382:microbiology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests
D000900:Anti-Bacterial Agents; D017576:Daptomycin