LY146032, alone and in combination with gentamicin, for the treatment of enterococcal pyelonephritis in the rat model

Abstract

The in vivo and in vitro activity of LY146032 against Streptococcusfaecalis GK was examined. The following MICs and MBCs in micrograms per milliliter were obtained: ampicillin, 0.8 and 1.5; vancomycin, 0.8 and 50; gentamicin, 12 and 25; and LY146032, 0.8 and 6. A time-kill-curve study involving approximately 106 organisms per ml showed a drop in the number of organisms of almost 2 loglo in the tube containing LY146032 (2 ,ug/ml) plus gentamicin (4 ,ug/ml) compared with bacterial numbers for the control at 4 h of incubation.However, regrowth was observed at 24 and 48 h, and no in vitro synergism was observed with the combination.A sample (1 ml) of overnight growth of this enterococcal strain at a concentration of 107 was then injected intravenously into 184 maie Wistar rats weighing about 100 g each. After 12 days, 10 rats were sacrificed and the renmaining ones were randomized into four treatment groups: (i) untreated control, (ii) LY146032 (3 mg) given subcutaneously, (iii) gentamicin (0.8 mg) given intramuscularly, and (iv) LY146032 plus gentamicin at the same dosages as when the drugs were used singly. The rats received antibiotics for 4 weeks twice daily, and approximately 10 rats in each group were sacrificed for quantitative kidney cultures at 1, 2, 4, and 6 weeks after the start of therapy. At the end of the 4-and 6-week periods, significantly better results were obtained with the combination of LY146032 plus gentamicin than with no treatment or treatment with single antibiotics.

Treatment of experimental endocarditis caused by a beta-lactamase-producing strain of Enterococcus faecalis with high-level resistance to gentamicin

“…The relative success of daptomycin in this study stands in contrast to results of previous studies using this drug in the treatment of enterococcal pyelonephritis (17) [.g/ml) were within the range of levels in serum attained in the other study (peak level, 44 p.g/ml; serum half-life, 5.8 h).…”

Treatment of Resistant Enterococcal Urinary Tract Infections

“…In vitro synergism has been noted against multidrug-resistant E. faecium and E. faecalis with gentamicin, rifampin, and fosfomycin [53••]. Daptomycin was shown to be effective in combination with gentamicin in a rat model of enterococcal pyelonephritis [60]. Case reports exist of its successful use in combination with other agents (rifampin with gentamicin, and ampicillin with gentamicin) in the treatment of VRE endocarditis [61,62].…”

Therapy of enterococcal infections

“…Enterococcus faecium isolates are generally more resistant (Table 1). Although the drug appears to be bactericidal against enterococci based on determination of MBCs, timekill studies indicate that the rate and extent of killing by this drug (of strains not highly resistant to aminoglycosides), like that of other cell wall-active agents, is enhanced in combination with an aminoglycoside (78,79). In two animal studies in which the drug was administered by intermittent injection, daptomycin was relatively ineffective in the treatment of enterococcal pyelonephritis (79) and endocarditis (80).…”