The role of tumor necrosis factor alpha (TNF-a) in host defense against systemic Candida albicans infection was evaluated in a murine model of systemic candidiasis in which uniform death occurred between 5 and 6 days after infection. TNF-a was first detected at 16 h postinfection and progressively increased thereafter. Peak levels (700 to 900 pg/ml) were measured in mice near death. Administration of 0.5 to 1.0 mg of polyclonal immunoglobulin G (IgG) TNF-oa antibody (TNF-ax Ab) to mice 2 h preinfection neutralized serum TNF-a for up to 30 h. However, this regimen shortened survival from a mean of 5.5 days for IgG controls to 3.4 days (P = 1.9 x 10-12). Semiquantitative cultures of spleen, lung, liver, and kidney conducted at 1, 2, and 3 days postinfection found colony counts of spleen and kidney to be significantly higher for TNF-aL Ab recipients but only for the first 48 h. Administration of 1.5 and 1.0 mg of TNF-ea Ab at 2 h before and 48 h after fungal injection, respectively, shortened the mean survival from 4.9 to 2.3 days (P = 5.2 x 10-8). This regimen neutralized serum TNF-a throughout infection. With this regimen, colony counts of all organs were significantly higher in TNF-a Ab recipients at 1, 2, and 3 days postinfection. Histopathologic studies showed an increase in the number and size of C. albicans foci in tissues. Peripheral leukocyte counts and inflammatory response in tissue were similar for TNF-a Ab and IgG sham recipients. In vitro, incubation of C. albicans with four to eight times the peak serum levels of TNF-c for up to 24 h did not inhibit the rate of germ tube or pseudohypha formation. Thus, TNF-aL that was produced during infection with C. albicans augmented host resistance against this organism and prolonged survival. The protective effect of TNF-a was not mediated by increased leukocytes in blood or tissues nor by a direct anticandidal effect of TNF-ai. This study suggests that the administration of exogenous TNF-a may enhance host resistance against systemic C. albicans infection and may improve host survival.
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.
We investigated the antistaphylococcal activity of daptomycin, vancomycin, oxacillin, gentamicin, and rifampin in human monocyte-derived macrophages. Compared with vancomycin and oxacillin, daptomycin had the most rapid and greatest antibacterial activity, but that of oxacillin was most sustained. The combination of daptomycin, gentamicin, and rifampin was most effective intracellularly, while daptomycin plus gentamicin and the three-drug combination were most effective extracellularly, completely eliminating viable Staphylococcus aureus.
Killing curves were used to characterize Staphylococcus haemolyticus isolates previously reported to contain subpopulations showing increased resistance to vancomycin. Results suggested that vancomycin and teicoplanin were ineffective at a concentration of 8 micrograms/ml and growth was seen between 24 and 48 h. Conversely, the lipopeptide antibiotic daptomycin at the same concentration rapidly killed tested strains by 6 h. Various staphylococcal strains were examined to determine if vancomycin resistance could be selected in all strains of staphylococci, was specie(s) restricted, or was unique to this patient's clinical isolates. About 1 x 10(8) colony-forming units were added to melted brain-heart infusion agar plates containing 12 micrograms/ml of vancomycin. Plates were examined after 48 h for presence of resistant clones. Results indicated that selection for vancomycin resistance was restricted to S. haemolyticus strains. Further, all S. haemolyticus isolates that displayed a double zone of growth around imipenem agar diffusion discs (Impdz) contained stably resistant subpopulations. Vancomycin resistance could not be selected in imipenem-sensitive derivative clones. Impdz isolates that were recovered from geographically distinct locations displayed nearly identical SDS-PAGE protein profiles. It appears that a characteristic susceptibility pattern displayed by clinical isolates of S. haemolyticus may provide a marker for those strains that contain subpopulations having increased resistance to vancomycin.
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