Activity of simulated serum concentrations of daptomycin versus vancomycin during the first 24h of treatment in the presence of physiological albumin concentrations against vancomycin-susceptible, -tolerant or -intermediate-resistant Staphylococcus aureus.

In order to determine whether reduced susceptibility or tolerance to vancomycin in Staphylococcus aureus influences the activity of daptomycin by simulating serum concentrations in the first 24h of treatment in the presence of physiological concentrations of human albumin, a computerised pharmacodynamic simulation was performed using Mueller-Hinton broth with 4 g/dL human albumin concentrations. For daptomycin, the media was adjusted to physiological ionised calcium concentrations by adding 100 µg/mL Ca(2+). Protein binding was measured. Six S. aureus isolates were used, comprising one vancomycin-susceptible S. aureus (VSSA), three vancomycin-tolerant strains, one heteroresistant vancomycin-intermediate S. aureus (hVISA) and one homogeneous vancomycin-intermediate S. aureus (VISA). Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of daptomycin increased eight times when determined in the presence of albumin (MIC(ALB) and MBC(ALB), respectively). Measured protein binding was 86.6% (C(max)) and 86.5% (C(min)) for daptomycin and 51.6% (C(max)) and 42.2% (C(min)) for vancomycin. Similar values were obtained for fAUC/MIC (where fAUC is the area under the concentration-time curve obtained with extrapolated concentrations using the highest protein binding rate experimentally obtained) and AUC/MIC(ALB) for each antibiotic. Daptomycin showed early (≤ 6 h) bactericidal activity [maximal effect (E(max)) >4 log(10) reductions in initial inocula] against all strains. Vancomycin produced an E(max) of 2.3 log(10) reductions at 8h against the VSSA and reductions ≤1.8 log(10) for the other strains in the 8-24h period. Pharmacodynamic parameters were fAUC/MBC from 8.0 to 15.6 (vancomycin) and from 56.0 to 111.6 (daptomycin) for tolerant strains, and fAUC/MIC of 126.8 and 63.3 for vancomycin and 222.6 and 113.2 for daptomycin against hVISA and VISA strains, respectively. Against the study strains (vancomycin-susceptible, -tolerant, heteroresistant or intermediate), daptomycin, in contrast to vancomycin, exhibited early bactericidal activity despite its high protein binding.

Comparative antimicrobial characterization of LBM415 (NVP PDF-713), a new peptide deformylase inhibitor of clinical importance.

LBM415 (NVP PDF-713) is the first member of the peptide deformylase (PDF) inhibitor class being developed for clinical trials as a parenteral and oral agent for treatment of community-acquired respiratory tract disease and serious infections caused by antimicrobial-resistant gram-positive cocci. In this study susceptibility testing results from 1,306 recent clinical isolates selected to over-represent resistance trends among the species were summarized. All staphylococci (153 strains; MIC at which 90% of isolates were inhibited [MIC90], 2 microg/ml), Streptococcus pneumoniae (170 strains; MIC90, 1 microg/ml), other streptococci (150 strains; MIC90, 1 microg/ml), enterococci (104 strains; MIC90, 4 microg/ml), Moraxella catarrhalis (103 strains; MIC90, 0.5 microg/ml), and Legionella pneumophila (50 strains; MIC90, 0.12 microg/ml) were inhibited at < or = 8 microg of LBM415/ml, as were 97% of Haemophilus influenzae isolates (300 strains; MIC90, 4 to 8 microg/ml). Among other bacterial groups, 100% of gram-positive and -negative anaerobes, including 22 Bacteroides spp. strains (31 strains total; MIC90, 1 microg/ml), were inhibited by < or = 4 microg/ml, whereas Enterobacteriaceae (112 strains) and most nonfermentative bacilli (107 strains) were not inhibited at readily achievable concentrations. The compound was found to have a dominantly bacteriostatic action, and spontaneous single-step mutational rates occurred at low levels (10(-6) to <10(-8)). Drug interaction studies failed to identify any class-specific synergistic interactions, nor were antagonistic interactions observed. Variations in broth and agar MIC test conditions demonstrated that, whereas the agar-based method trended towards a 1-log2 dilution-higher MIC than the broth method and was inoculum dependent, other variations in incubation environment, medium supplements, pH, or calcium concentration had little influence on LBM415 MIC results. Use of the efflux inhibitor phe-arg-beta-naphthylamide showed an average of 1 log2 dilution decrease in H. influenzae MICs, demonstrating the contribution of efflux pumps in influencing susceptibility to PDF inhibitors. The in vitro activity of LBM415 against targeted bacterial species, including resistant subsets, and other laboratory characteristics of this novel compound demonstrate the potential of PDF inhibitors as a new class of antimicrobial agents.