The in vitro activity of LY 146032, a cyclic lipopeptide antibiotic belonging to the class of agents designated A21978C, was compared with those of vancomycin, cefpirome, cefotaxime, and clindamycin against selected gram-positive bacteria. The new drug inhibited all staphylococcal isolates, including methicillin-resistant strains, at concentrations of less than or equal to 1.0 microgram/ml. The activity of LY 146032 was comparable to that of vancomycin against most streptococci, but the latter demonstrated greater potency against Streptococcus faecium and penicillin-resistant strains of pneumococci and viridans group streptococci. LY 146032 was markedly less active than vancomycin against Listeria monocytogenes (MICs for 90% of strains tested, 16 and 1.0 microgram/ml, respectively). The activity of LY 146032 was enhanced as the concentration of calcium in the test medium was increased. MBCs were within eightfold of the MIC for each of 12 strains tested. In a rat model of enterococcal endocarditis, the administration of LY 146032 resulted in increased survival and a reduction in the bacterial titer within cardiac vegetations compared with untreated control animals.
Intermittent administration of ampicillin alone has resulted in high failure rates in previously described animal models of enterococcal endocarditis. We developed a rat model of enterococcal endocarditis which permits comparison of continuous intravenous infusion of ampicillin with intramuscular therapy. Continuous low-dose ampicillin infusion (450 mg/kg [body weight] per day) was compared with the same dose given intramuscularly in three divided doses and with high-dose infusion (4.5 g/kg per day) of the drug. For the infecting strain of Streptococcus faecalis, the MIC and MBC were 1 ,ug/ml. Mean ampicillin levels in serum were 53.9 + 4.8 (peak) However, no statistically significant advantage was found for high-dose compared with low-dose ampicillin infusion in lowering bacterial titers in vegetations (P > 0.3).Aside from viridans group streptococci and Staphylococcus aureus, enterococci are the most common pathogens causing bacterial endocarditis, and enterococcal endocarditis represents a major therapeutic challenge (14). Streptococcus faecalis, the most common species of enterococcus to cause human infection, is typically susceptible to ampicillin, but the lack of consistent bactericidal activity of cellwall-active antibiotics against enterococci usually requires that they be combined with an aminoglycoside to obtain a synergistic bactericidal effect (17). However, under appropriate experimental circumstances, experimental enterococcal endocarditis may be successfully treated with ampicillin alone (21). Studies dealing with the effect of antibiotic administration modes on tissue penetration are limited in number and display contradictory results. However, in some situations, continuous infusion of 1-lactam antibiotics may be advantageous (1). The purpose of this study was to evaluate the efficacy of ampicillin administered in a standard fashion by intermittent injection compared with continuous intravenous infusion in experimental enterococcal endocarditis in rats and, further, to compare the effectiveness of low and high doses of ampicillin administered by continuous infusion. These studies assume particular relevance because the recent emergence of S. faecalis isolates containing multiple aminoglycoside-modifying enzymes (16; S. Kathpalia, V. Lorian, R. Levandowski, and G. G. Jackson, Clin. Res. 32:3724, 1984) has created a situation in which penicillin-aminoglycoside therapy is not more effective than penicillin alone and in which the clinician thus has little choice but to use the most active single-drug regimen available when treating endocarditis caused by such organisms. MATERIALS AND METHODS Test organism. S. faecalis 1310 used throughout the study was a clinical blood culture isolate recovered at the Massachusetts General Hospital, Boston, Mass. The MIC and MBC of ampicillin for this strain were 1 jig/ml, determined in dextrose-phosphate broth (GIBCO Diagnostics, Madison, Wis.) by using a macrobroth dilution technique (12).Killing curves. Evaluation of the bactericidal activity of ampicillin agai...
The in vitro activity of S-6123, a synthetic antimicrobial compound of the new oxazolidinone series, was compared with those of other orally administered agents against 328 clinical isolates. The (Fig. 1).In this study, we describe the in vitro antibacterial spectrum of S-6123 in comparison with currently available oral antibacterial agents and the in vivo activity of the compound in a lethal peritonitis model in the rat. The mechanism of antibacterial action of S-6123 was explored by examining its effects on the syntheses of DNA, RNA, and protein in whole cells and on polypeptide synthesis in isolated bacterial ribosomes.( Agar dilution susceptibility studies. Susceptibility testing was performed by a standard agar dilution technique (11), using Mueller-Hinton agar (BBL Microbiology Systems, Cockeysville, Md.), which was supplemented with 5% defibrinated sheep blood when nonenterococcal streptococci were tested or IsoVitaleX (BBL) and 5% chocolatized horse blood for testing Haemophilus influenzae. Inocula of approximately 104 CFU were applied to plates with a 32-prong inoculating device. Inocula were prepared by appropriate dilution of overnight broth cultures (gram-negative bacilli) or suspensions prepared from fresh plates (gram-positive organisms and H. influenzae) in fresh Mueller-Hinton broth (BBL). Suspensions were standardized to a 0.5 McFarland standard before dilution. Inoculated plates were examined for growth after 18 to 20 h of incubation at 37°C in room air. Campylobacter jejuni were tested on brucella agar (Difco Laboratories, Detroit, Mich.) with 10% sheep blood, and plates were read after 24 h of incubation in a microaerophilic atmosphere (BBL). To evaluate effects of different media and supplements on the in vitro activity of S-6123, susceptibility studies against selected isolates were performed with dextrose phosphate broth (GIBCO Laboratories, Grand Island, N.Y.) plus 1.5% Bacto-agar (Difco) and MuellerHinton agar supplemented with 5% defibrinated sheep blood, horse blood, pooled human serum, rat serum, or thymidine phosphorylase (Burroughs Wellcome). Thymidine phosphorylase was added to examine whether thymidine in the media affected the in vitro activity of the new compound.
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