Daptomycin (LY146032) treatment of experimental enterococcal endocarditis

Abstract

This study compared daptomycin (LY146032) with penicillin G procaine and vancomycin without and with gentamicin for treatment of experimental enterococcal endocarditis. The strain of Streptococcus (Enterococcus) faecalis used in this study was killed by daptomycin in vitro in broth but not in serum. In rabbits treated for 3 days, daptomycin signfficantly reduced bacterial counts of vegetations compared with no therapy but was significantly less effective than penicillin G procaine or vancomycin. Daptomycin-gentamicin significantly reduced bacterial counts of vegetations compared with daptomycin alone but was significantly less effective than vancomycin plus gentamicin. The efficacy of daptomycin-gentamicin did not differ significantly from that of penicillin G procaine-gentamicin. The lack of enterococcal killing by daptomycin alone in serum and in experimental endocarditis is probably related to the high protein binding of the agent.Enterococci are the third most common cause of infective endocarditis and are responsible for about 10% of infective endocarditis cases (8). Unlike most other streptococcal species, enterococci demonstrate resistance to a wide range of antimicrobial agents, and rarely is a single agent bactericidal against the organisms in vitro (15). To achieve in vitro bactericidal activity against enterococci, an aminoglycoside must be added to penicillin G, ampicillin, or vancomycin (16, 21). Although controlled trials are lacking, the recommended treatment of serious enterococcal infections, e.g., endocarditis, involves a combination of penicillin G or vancomycin plus an aminoglycoside (9, 11).The emergence of clinical enterococcal isolates which demonstrate high-level streptomycin resistance (16) and, more recently, strains with high-level gentamicin resistance (12, 23) threatens our ability to provide bactericidal antimicrobial therapy in cases of enterococcal endocarditis. In vitro experiments (12) and animal studies (2) have shown a loss of bactericidal activity with penicillin G plus an aminoglycoside against enterococcal isolates which demonstrate high-level aminoglycoside resistance. These developments, together with the recent demonstration of ,B-lactamase production by isolates of Streptococcus (Enterococcus)faecalis (17), illustrate the need for alternative antimicrobial therapy for serious enterococcal infections.Daptomycin (LY146032) is a cyclic lipopeptide compound that belongs to a class of antibiotics produced by Streptomyces roseosporus (4). It has a spectrum of activity against aerobic, facultative, and anaerobic gram-positive bacteria. Although its spectrum of activity is similar to those of the glycopeptide antibiotics vancomycin and teicoplanin, daptomycin differs from these antibiotics in structure and mechanism of action. Another characteristic of daptomycin which distinguishes it from the glycopeptide antibiotics is the in vitro demonstration of bactericidal activity against enterococci at concentrations near the MIC (4, 19). These features suggest that daptomycin may be...

Comparative evaluation of daptomycin (LY146032) and vancomycin in the treatment of experimental methicillin-resistant Staphylococcus aureus osteomyelitis in rabbits

“…In contrast to our osteomyelitis results, daptomycin has been found marginally effective in the endocarditis animal model (2,3 …”

The life and times of the Enterococcus

“…To cast further doubt on the bacteriologic identification, all of the enterococci were said to be susceptible to cephalothin and one to clindamycin, unusual properties for enterococci (79). In vitro, vancomycin is usually not bactericidal, and it does no better in animal models than penicillin alone (27,99,104,135,205,217). Among other agents that have been evaluated, ciprofloxacin was less effective than procaine penicillin in controlling enterococcal endocarditis (75,104,195).…”

In Vitro Activities of Daptomycin, Vancomycin, Linezolid, and Quinupristin-Dalfopristin against Staphylococci and Enterococci, Including Vancomycin- Intermediate and -Resistant Strains

“…The spectrum of activity is similar to those of vancomycin and teicoplanin, with activity against a wide variety of aerobic and anaerobic gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Daptomycin is also active against vancomycin-resistant gram-positive bacteria, including enterococci (4,5,7). The mechanism of action differs from that of the glycopeptides, involving the disruption of amino acid transport by the cell membrane and alterations of the cytoplasmic membrane potential (1)(2)(3).…”