Comparison of Inhibitory and Bactericidal Activities and Postantibiotic Effects of LY333328 and Ampicillin Used Singly and in Combination against Vancomycin-Resistant Enterococcus faecium

Abstract

One hundred ninety-five individual vancomycin-resistant Enterococcus faecium (VRE) isolates from five upstate New York hospitals were studied for antimicrobial susceptibilities to LY333328, quinupristin-dalfopristin, teicoplanin, ampicillin, and gentamicin. LY333328 was the most active antibiotic against VRE. The effect of media and methods on the antibacterial activity of LY333328, its synergy with ampicillin, and the postantibiotic effects (PAE) of LY333328 and ampicillin were evaluated. In microdilution tests, the MIC of LY333328 at which 90% of the isolates were inhibited (MIC 90 ) was 2 g/ml in Mueller-Hinton II (MH II) broth and 1 g/ ml in brain heart infusion (BHI) broth. In contrast, on MH II agar the MIC 90 was 4 g/ml and on BHI agar it was >16 g/ml. Bactericidal activity was observed for most strains at concentrations from 8 to >133 times the MIC of the tube macrodilution in MH II broth. A bactericidal effect of LY333328 plus ampicillin was demonstrated in time-kill studies, but there was great strain-to-strain variability. By the MH II agar dilution method, bacteristatic synergy (defined as a fractional inhibitory concentration of <0.5) with LY333328 and ampicillin was demonstrated for 61% of the strains tested. Under similar conditions, there was synergy with LY333328 and quinupristin-dalfopristin or gentamicin for 27 and 15% of the strains tested, respectively. The PAE of LY333328 was prolonged (23.0 h at 10 times the MIC). However, 50% normal pooled human serum decreased the PAE to 12.2 h at 10 times the MIC. Test conditions and media had a considerable effect on VRE susceptibilities to LY333328. The prolonged PAE of LY333328, a potent new bactericidal glycopeptide, and its synergy with ampicillin in a large proportion of strains suggest that further evaluation of this drug in pharmacokinetic studies and experimental infections, including those with VRE, is warranted.

Oritavancin: a new promising agent in the treatment of infections due to Gram-positive pathogens

“…Conflicting results are reported from several studies. Synergy with ampicillin, quinupristin dalfopristin and gentamicin was shown in an in vitro study against vancomycin-resistant E. faecium [119] . In another in vitro study, synergy with ciprofloxacin was also demonstrated against E. faecalis [121] .…”

“…The PAE of oritavancin is not fully investigated yet; recent data support that it is concentration dependent and seems to be longer in staphylococci and enterococci compared with other Gram-positive pathogens [119] . In an early in vitro study testing oritavancin against VRE isolates, the PAE of oritavancin was prolonged (23 h at 10-times the MIC).…”

“…In an early in vitro study testing oritavancin against VRE isolates, the PAE of oritavancin was prolonged (23 h at 10-times the MIC). However, 50% normal pooled human serum decreased the PAE to 12.2 h at 10-times the MIC [119] . [137] .…”

“…Oritavancin is also extremely active against Streptococcus spp. Data from earlier and recent in vitro studies are depicted in Table 2 , the shaded area representing assays performed with the inclusion of 0.002% of polysorbate-80 [56,57,[110][111][112][113][114][115][116][117][118][119][120][121][122][123] .…”

Oritavancin: a novel lipoglycopeptide active against Gram-positive pathogens including multiresistant strains

“…A synergistic effect against vancomycin-resistant Enterococcus faecalis is produced when oritavancin is added to gentamicin [21]. Combinations with ampicillin, quinupristin/dalfopristin and gentamicin are synergistic against vancomycin-resistant Enterococcus faecium [22].…”