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PubMed2007

Bactericidal activity and resistance development profiling of dalbavancin.

Dalbavancin, a semisynthetic lipoglycopeptide being developed for the treatment of skin and skin structure infections (SSSIs), has a half-life of 5 to 7 days in humans and offers promise for a convenient weekly dosing regimen. We studied the in vitro bactericidal activity of dalbavancin against target organisms, using the concentrations that are maintained in human blood with the proposed dosage regimen. Dalbavancin minimal bactericidal concentrations (MBCs) were or=3-log10 decrease in their viable counts when they were exposed to>or=1 microg/ml of dalbavancin for 24 h. Resistance development studies by both direct selection (resistance frequency, <10(-10)) and serial passage failed to produce stable mutants with decreased susceptibility to dalbavancin. These observations suggest that dalbavancin will be an effective choice for the management of patients with SSSIs.

Anti-Bacterial Agents↗
PubMed1986

In vitro and in vivo activity of LY 146032, a new cyclic lipopeptide antibiotic.

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.

Animals↗
PubMed1986

In vitro activity of LY146032 against staphylococci, streptococci, and enterococci.

The in vitro activities of LY146032 and seven comparative antimicrobial agents against 14 species of staphylococci, streptococci, and enterococci were studied. MICs of LY146032 were less than or equal to 0.5 microgram/ml for all staphylococci, including oxacillin-resistant strains; less than or equal to 0.25 microgram/ml for all streptococci (except viridans group streptococci); and less than or equal to 4 micrograms/ml for all viridans group streptococci and enterococci. MICs were minimally affected by variations in inoculum size, and LY146032 was bactericidal against all species tested.

Anti-Bacterial Agents↗
PubMed1986

Antistaphylococcal activity of a cyclic peptide, LY146032, and vancomycin.

The inhibitory and bactericidal activities of a novel cyclic peptide antibiotic, LY146032, and vancomycin against oxacillin-susceptible and oxacillin-resistant staphylococci were compared. The MICs for 90% of strains were two- to fourfold higher for vancomycin than for LY146032. MBC/MIC ratios for all strains were less than or equal to 2. In killing rate studies with four strains of staphylococci, there was no detectable growth in the presence of 4X the MIC of either LY146032 or vancomycin after 24 h of incubation.

Anti-Bacterial Agents↗
PubMed1987

Activity of LY146032 against Enterococci with and without high-level aminoglycoside resistance, including two penicillinase-producing strains.

We tested the activity of LY146032 (LY) against 57 strains of enterococci collected from Chile, Thailand, and the United States. Some of the strains were resistant to high levels of gentamicin or streptomycin (or both), and two produced beta-lactamase (Bla+). MICs of LY ranged from 0.5 to 8 micrograms/ml, and MBCs ranged from 1 to 64 micrograms/ml. In time-kill assays, a 2 to 3 log10 killing effect was observed with LY against two Bla+ strains of Streptococcus (Enterococcus) faecalis and against three strains that were highly resistant to streptomycin and gentamicin. Synergism was demonstrated with LY and streptomycin against a Bla+ strain lacking high-level streptomycin resistance. These in vitro results suggest that LY should be studied further for possible use in treatment of enterococcal infections.

Aminoglycosides↗
PubMed1987

Effect of calcium on in vitro activity of LY146032 against Clostridium difficile.

The in vitro MICs of LY146032 against 63 isolates of Clostridium difficile tested in Wilkins-Chalgren broth ranged from 0.5 to greater than 32 micrograms/ml, with MICs of 4 and 8 micrograms/ml for 50 and 90% of the isolates, respectively. However, when the test medium was supplemented with physiologic concentrations of calcium, the MIC for 90% of the isolates was reduced to less than or equal to 0.12 microgram/ml.

Anti-Bacterial Agents↗
PubMed1987

Antimicrobial activity and spectrum of LY146032, a lipopeptide antibiotic, including susceptibility testing recommendations.

LY146032, a new lipopeptide, was found to have a spectrum of gram-positive antimicrobial activity that includes activity against staphylococci (methicillin susceptible and resistant), beta-hemolytic Streptococcus spp., pneumococci, viridans group Streptococcus spp., anaerobic gram-positive cocci, Clostridium spp., and enterococci. The new lipopeptide was generally bactericidal and showed more rapid killing of Listeria spp. (MIC, 1 to 2 micrograms/ml) and staphylococci than either vancomycin or teicoplanin. The 30-micrograms disk was preferred to the 15-micrograms disk on the basis of the preliminary interpretive criteria for susceptibility which indicated zone diameters of greater than or equal to 16 mm for susceptible strains (MIC, less than or equal to 2.0 micrograms/ml) and greater than or equal to 12 mm for resistant strains (MIC, greater than or equal to 8.0 micrograms/ml). These criteria are valid pending the testing of additional gram-positive strains which have LY146032 MICs of greater than or equal to 8 micrograms/ml.

Anti-Bacterial Agents↗
PubMed1987

Bactericidal activity of deptomycin (LY146032) compared with those of ciprofloxacin, vancomycin, and ampicillin against enterococci as determined by kill-kinetic studies.

This study used kill-kinetic methods to provide data on the bactericidal activity of subinhibitory (1/2 X MIC), inhibitory (1 x MIC), and suprainhibitory (4X, 6X, and 8X MIC) concentrations of deptomycin (LY146032) against strains of enterococci compared with those of ciprofloxacin, vancomycin, and ampicillin. Deptomycin was the most active agent tested, as determined by broth microdilution methods, with all strains being inhibited at concentrations less than or equal to 2 micrograms/ml. The kill-kinetic demonstrated that deptomycin had greater activity at all concentrations tested than the other cell wall-active agents; regrowth was seen, however, at lower concentrations. At higher concentrations (6X and 8X MIC), all agents tested demonstrated the same or less bactericidal activity than at 4X MIC, presumably due to the Eagle effect. Nevertheless, these results suggest that further evaluation of deptomycin as a therapeutic agent for serious enterococcal infections is warranted.

Ampicillin↗
PubMed1987

Inhibition of peptidoglycan biosynthesis in gram-positive bacteria by LY146032.

LY146032, a cyclic lipopeptide antibiotic, is an inhibitor of cell wall peptidoglycan biosynthesis in gram-positive bacteria. Although LY146032 at relatively high concentrations inhibited the in vitro polymerization of UDP-linked sugar precursors, inhibition of cell wall formation in intact Staphylococcus aureus and Bacillus megaterium cells did not lead to the accumulation of UDP-N-acetyl-muramyl (MurNAc)-peptide(s). Experiments that measured formation of UDP-MurNAc-peptides revealed that LY146032 inhibited the formation of these nucleotide-linked intermediates. This antibiotic had a disruptive effect on membrane permeability as evidenced by the loss of intracellular potassium immediately after exposure to the drug. The lack of any major disruption of the phosphoenolpyruvate:sugar phosphotransferase system indicated that the membrane is not likely a lethal target for this antibiotic. The findings are consistent with a mechanism by which LY146032 inhibits the formation of precursor molecules utilized in peptidoglycan biosynthesis. The observed membrane effects likely result from transit of the inhibitor to its lethal target site.

Anti-Bacterial Agents↗
PubMed1987

Activity of LY146032 in vitro and in experimental enterococcal pyelonephritis.

The efficacy of LY146032 (LY), a new lipopeptide antibiotic, was compared with that of vancomycin, ciprofloxacin, ceftriaxone, imipenem, and gentamicin and combinations of LY-ceftriaxone, LY-imipenem, and LY-gentamicin against 15 strains of Streptococcus (Enterococcus) faecalis by microtiter dilution and checkerboard techniques. LY was effective within a very narrow range of drug concentrations (from 0.125 to 2.0 micrograms/ml) and was more active than other agents tested against S. faecalis. Enhanced inhibition of S. faecalis was seen more frequently with combinations of either penicillin or ampicillin and an aminoglycoside than with combinations of LY and gentamicin, imipenem, or ceftriaxone. The in vivo efficacy of LY was compared with that of vancomycin and ampicillin alone and combinations of vancomycin-gentamicin, ampicillin-gentamicin, and LY-gentamicin in a rat model of chronic enterococcal pyelonephritis. At a dose of 10 mg/kg given twice daily, LY reduced the number of organisms per kidney significantly compared with that in infected untreated controls within 48 h after the initiation of therapy. At 20 mg/kg given once a day, LY was less effective but reduced colony counts significantly after 4 days of therapy, and its activity was comparable to that of vancomycin or vancomycin-gentamicin given twice daily. LY may be a promising agent for the treatment of enterococcal infections.

Animals↗
PubMed1987

Activity of LY146032 compared with that of methicillin, cefazolin, cefamandole, cefuroxime, ciprofloxacin, and vancomycin against staphylococci as determined by kill-kinetic studies.

Kill-kinetic methods were used to provide data on the bactericidal activity of subinhibitory (0.5x MIC), inhibitory (1x MIC), and suprainhibitory (4x MIC) concentrations of LY146032 against methicillin-susceptible and -resistant Staphylococcus aureus and Staphylococcus epidermidis. These bactericidal activities were compared with those of methicillin, cefazolin, cefamandole, cefuroxime, ciprofloxacin, and vancomycin. LY146032 was among the most active of the antistaphylococcal agents tested, as determined by broth microdilution methods, with all strains being inhibited at concentrations of less than or equal to 1 microgram/ml. Time kill-kinetic studies demonstrated that at 4x MIC, LY146032 was rapidly bactericidal against all strains of staphylococci. Our data show that LY146032 has significant bactericidal activity against staphylococci in comparison with other antistaphylococcal agents. Further evaluation of LY146032 against serious staphylococcal infections is warranted.

Anti-Bacterial Agents↗
PubMed1988

LY146032 compared with penicillin G in experimental aortic valve endocarditis caused by group G streptococci.

Rabbits with group G streptococcal aortic endocarditis received no therapy (controls); repeated doses of procaine penicillin G, 300 mg/kg (body weight) per day, administered intramuscularly; or LY146032, a new peptolide antibiotic, 20 mg/kg per day, administered intravenously. Penicillin G and LY146032 reduced mean intravegetation group G streptococcal densities significantly below those observed in controls at both day 3 and day 6 of therapy. Penicillin G effected a more rapid clearance of intravegetation streptococci than LY146032 by day 3, but not by day 6, of therapy.

Animals↗
PubMed1988

In vitro selection of bacteria resistant to LY146032, a new cyclic lipopeptide.

Isolates of Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus faecium, and coagulase-positive and -negative staphylococci were investigated for their abilities, in vitro, to develop resistance to LY146032. Exposure of the organisms to incremental concentrations of LY146032 resulted in MICs 8- to 32-fold higher than those for the original isolates. After three passages on antibiotic-free medium, the high MICs were maintained for the coagulase-negative staphylococci and pneumococci, with a twofold decrease observed for the enterococci and a fourfold decrease observed for Staphylococcus aureus. The frequency of spontaneous emergence of resistance was highest with S. pneumoniae (1.2 X 10(-6) at 16 times the original MIC) and lowest with S. aureus (7.0 X 10(-10) at 8 times the original MIC). For bacteria For bacteria surviving time-kill studies MICs were also higher than were those for the original isolates. Exposure to LY146032 in vitro selected for strains with decreased susceptibilities to the antimicrobial agent. However, the emergence of resistance in vivo is unpredictable and can be evaluated only after prolonged clinical use of the drug.

Anti-Bacterial Agents↗
PubMed1988

Comparison of cefazolin, cefamandole, vancomycin, and LY146032 for prophylaxis of experimental Staphylococcus epidermidis endocarditis.

We evaluated antibiotic prophylaxis in the rabbit model of experimental endocarditis with three strains of Staphylococcus epidermidis of differing susceptibility patterns. For the first strain, which was highly susceptible to methicillin and cephalosporins, vegetations grew S. epidermidis for all 15 untreated rabbits compared with 1 of 20 rabbits receiving cefazolin, 3 of 20 receiving cefamandole, none of 20 receiving vancomycin, and none of 20 receiving LY146032. For the second strain, which was methicillin resistant but cephalosporin susceptible, vegetations were positive for 14 of 15 untreated controls, 4 of 20 receiving cefazolin, 5 of 22 receiving cefamandole, none of 20 receiving vancomycin, and none of 20 receiving LY146032. For the third strain, which was methicillin resistant and only intermediately susceptible to cephalosporin antibiotics, vegetation cultures were positive for 15 of 17 untreated controls, 14 of 21 receiving cefazolin, 11 of 20 receiving cefamandole, 5 of 20 receiving vancomycin, and 0 of 22 receiving LY146032. In conclusion, these studies in the endocarditis model indicate that cefazolin and cefamandole have some protective value against certain strains of S. epidermidis. Vancomycin and LY146032, however, were more active than cephalosporins for all three strains included in this analysis. These findings support the need for trials of vancomycin and LY146032 prophylaxis in patients undergoing placement of prosthetic heart valves.

Animals↗
PubMed1988

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

The in vivo and in vitro activity of LY146032 against Streptococcus faecalis 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 10(6) organisms per ml showed a drop in the number of organisms of almost 2 log10 in the tube containing LY146032 (2 micrograms/ml) plus gentamicin (4 micrograms/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 10(7) was then injected intravenously into 184 male Wistar rats weighing about 100 g each. After 12 days, 10 rats were sacrificed and the remaining 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.

Ampicillin↗