scholarly journals Comparative In Vitro Activities of AC98-6446, a Novel Semisynthetic Glycopeptide Derivative of the Natural Product Mannopeptimycin α, and Other Antimicrobial Agents against Gram-Positive Clinical Isolates

2004 ◽  
Vol 48 (3) ◽  
pp. 739-746 ◽  
Author(s):  
Peter J. Petersen ◽  
T. Z. Wang ◽  
Russell G. Dushin ◽  
Patricia A. Bradford
Keyword(s):  
Natural Product ◽  
Bactericidal Activity ◽  
Antimicrobial Agents ◽  
Marked Decrease ◽  
Gram Positive ◽  
Novel Structure ◽  
Resistant Strains ◽  
Vancomycin Resistant ◽  
Further Development

ABSTRACT AC98-6446 is a novel semisynthetic cyclic glycopeptide antibiotic related to the natural product mannopeptimycin α (AC98-1). In the present study the activity of AC98-6446 was evaluated against a variety of recent clinical gram-positive pathogens including multiply resistant strains. AC98-6446 demonstrated similar potent activities against methicillin-susceptible and methicillin-resistant staphylococci and glycopeptide-intermediate staphylococcal isolates (MICs at which 90% of isolates are inhibited [MIC90s], 0.03 to 0.06 μg/ml). AC98-6446 also demonstrated good activities against both vancomycin-resistant and -susceptible strains of enterococci (MIC90s, 0.12 and 0.25 μg/ml, respectively) as well as against streptococcal strains (MIC90s, ≤ 0.008 to 0.03 μg/ml). AC98-6446 demonstrated bactericidal activity in terms of the reduction in the viable counts (>3 log10 CFU/ml) of staphylococcal and streptococcal isolates and a marked decrease in the viable counts of most enterococcal strains (from 0.2 to 2.5 log10 CFU/ml). Unlike vancomycin, which demonstrates time-dependent killing, AC98-6446 demonstrated concentration-dependent killing. The potent activity, novel structure, and bactericidal activity demonstrated by AC98-6446 make it an attractive candidate for further development.

In vitro evaluation of a novel ketolide antimicrobial agent, RU-64004.

1997 ◽  
Vol 41 (2) ◽  
pp. 454-459 ◽  
Author(s):  
C Jamjian ◽  
D J Biedenbach ◽  
R N Jones
Keyword(s):  
Moraxella Catarrhalis ◽  
In Vitro Tests ◽  
In Vitro Activity ◽  
Gram Positive ◽  
Beta Hemolytic Streptococcus ◽  
Serious Infections ◽  
Resistant Strains ◽  
Vancomycin Resistant

Ketolides, a novel macrolide subclass, possess a mode of action that is similar to that of structurally related macrolide-lincosamide-streptogramin (MLS) compounds. By using reference in vitro tests, the in vitro activity of RU-64004 was compared to those of six other MLS compounds against more than 800 clinical pathogens, including 356 gram-positive organisms. The spectrum of activity of the ketolide was most similar to that of clindamycin versus staphylococci and streptococci and superior to those of all macrolides tested against oxacillin-resistant staphylococci and vancomycin-resistant (vanA, vanB, and vanC) enterococcal isolates. The activity of the ketolide was greater than those of the macrolides, azalides, or clindamycin tested against vancomycin-susceptible enterococci (MICs at which 90% of isolates are inhibited [MIC90S], 0.25 to 4 micrograms/ml), penicillin-resistant pneumococci (MIC90, 0.25 micrograms/ml), and most beta-hemolytic streptococci. All Streptococcus pneumoniae and beta-hemolytic streptococcus strain were inhibited by ketolide concentrations of < or = 0.25 micrograms/ml. Against 165 erythromycin-resistant strains, RU-64004 inhibited (MICs, < or = 0.5 micrograms/ml) approximately one-third of staphylococci, all streptococci, and slightly more than one-half of the enterococci. Quinupristin-dalfopristin (a streptogramin combination) was active against all tested isolates with the exception of non-Enterococcus faecium enterococci, against which the ketolide exhibited greater potency (MIC50S, 0.03 to 2 micrograms/ml). The ketolide was also active against Haemophilus influenzae (MIC90, 2 micrograms/ml), Moraxella catarrhalis (MIC90, 0.12 micrograms/ml), pathogenic Neisseria spp. (MIC90, 0.5 micrograms/ml), and many gram-positive anaerobes (MIC90, 0.5 micrograms/ml). RU-64004 may enhance the role of macrolide drugs in the treatment of some serious infections caused by MLS-resistant gram-positive organisms.

scholarly journals In vitro properties of antimicrobial bromotyrosine alkaloids

2006 ◽  
Vol 55 (4) ◽  
pp. 407-415 ◽  
Author(s):  
Neora Pick ◽  
Mamta Rawat ◽  
Dorit Arad ◽  
Jiong Lan ◽  
Junfa Fan ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Agents ◽  
Lead Compound ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Monocytes And Macrophages ◽  
Natural Inhibitor ◽  
Low Toxicity ◽  
Vancomycin Resistant

A bromotyrosine alkaloid family of antimicrobial agents was synthesized using the known structure of a natural inhibitor of the mycobacterial mycothiol S-conjugate amidase (MCA) as a template. This series of compounds represents a novel class of anti-infective agents against Gram-positive pathogens, including mycobacteria and meticillin- and vancomycin-resistant Staphylococcus aureus. The fact that these compounds are active against mycobacterial strains in which the MCA gene is deleted and against Gram-positive bacteria lacking mycothiol suggests the existence of an alternative target for these compounds. One member of this family, EXEG1706, was identified as the lead compound possessing low MICs (2·5–25 μg ml−1) for several clinical isolates, whilst having low toxicity for THP-1 monocytes and macrophages.

scholarly journals Pharmacodynamics of Telavancin (TD-6424), a Novel Bactericidal Agent, against Gram-Positive Bacteria

2004 ◽  
Vol 48 (8) ◽  
pp. 3043-3050 ◽  
Author(s):  
Sharath S. Hegde ◽  
Noe Reyes ◽  
Tania Wiens ◽  
Nicole Vanasse ◽  
Robert Skinner ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Gram Positive ◽  
Time Curve ◽  
Once Daily ◽  
Gram Positive Bacteria ◽  
Resistant Strains ◽  
Vancomycin Resistant ◽  
Dose Dependent

ABSTRACT Telavancin (TD-6424) is a novel lipoglycopeptide that produces rapid and concentration-dependent killing of clinically relevant gram-positive organisms in vitro. The present studies evaluated the in vivo pharmacodynamics of telavancin in the mouse neutropenic thigh (MNT) and mouse subcutaneous infection (MSI) animal models. Pharmacokinetic-pharmacodynamic studies in the MNT model demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio was the best predictor of efficacy. Telavancin produced dose-dependent reduction of thigh titers of several organisms, including methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), penicillin-susceptible and -resistant strains of Streptococcus pneumoniae, and vancomycin-resistant Enterococcus faecalis. The 50% effective dose (ED50) estimates for telavancin ranged from 0.5 to 6.6 mg/kg of body weight (administered intravenously), and titers were reduced by up to 3 log10 CFU/g from pretreatment values. Against MRSA ATCC 33591, telavancin was 4- and 30-fold more potent (on an ED50 basis) than vancomycin and linezolid, respectively. Against MSSA ATCC 13709, telavancin was 16- and 40-fold more potent than vancomycin and nafcillin, respectively. Telavancin, vancomycin, and linezolid were all efficacious and more potent against MRSA ATCC 33591 in the MSI model compared to the MNT model. This deviation in potency was, however, disproportionately greater for vancomycin and linezolid than for telavancin, suggesting that activity of telavancin is less affected by the immune status. The findings of these studies collectively suggest that once-daily dosing of telavancin may provide an effective approach for the treatment of clinically relevant infections with gram-positive organisms.

scholarly journals Comparative in vitro activities of trovafloxacin (CP-99,219) against 445 gram-positive isolates from patients with endocarditis and those with other bloodstream infections.

1997 ◽  
Vol 41 (5) ◽  
pp. 1146-1149 ◽  
Author(s):  
H P Endtz ◽  
J W Mouton ◽  
J G den Hollander ◽  
N van den Braak ◽  
H A Verbrugh
Keyword(s):  
Antimicrobial Agents ◽  
Rank Order ◽  
Bloodstream Infections ◽  
In Vivo Studies ◽  
Gram Positive ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant ◽  
Viridans Group Streptococci

The in vitro activity of trovafloxacin (CP-99,219), a new fluoroquinolone, was compared with the in vitro activities of other commonly used quinolones and other antimicrobial agents against 445 gram-positive microorganisms isolated between 1986 and 1995 from patients with endocarditis and those with other bloodstream infections. The MICs at which 90% of the isolates are inhibited (MIC90) of trovafloxacin for methicillin-susceptible staphylococci, viridans group streptococci, and enterococci were 0.06, 0.25, and 0.5 mg/liter, respectively. The MIC90 of trovafloxacin for vancomycin-resistant enterococci as well as for methicillin-resistant Staphylococcus aureus and methicillin-susceptible and ciprofloxacin-resistant S. aureus, isolated from sources other than blood, was 1 mg/liter. For the quinolones the rank order of activity was trovafloxacin > sparfloxacin > ciprofloxacin = ofloxacin > pefloxacin. Depending on the species tested, trovafloxacin was 4- to 64-fold more active than ciprofloxacin. Further experimental and in vivo studies are warranted to evaluate the efficacy of trovafloxacin in the treatment of bacterial endocarditis and other infections caused by gram-positive organisms.

scholarly journals Quinupristin-Dalfopristin Resistance among Gram-Positive Bacteria in Taiwan

2000 ◽  
Vol 44 (12) ◽  
pp. 3374-3380 ◽  
Author(s):  
Kwen-Tay Luh ◽  
Po-Ren Hsueh ◽  
Lee-Jene Teng ◽  
Hui-Ju Pan ◽  
Yu-Chi Chen ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Animal Husbandry ◽  
Coagulase Negative Staphylococci ◽  
Gram Positive ◽  
In Vitro Susceptibility ◽  
Methicillin Resistant ◽  
Gram Positive Bacteria ◽  
Vancomycin Resistant ◽  
Viridans Group Streptococci

ABSTRACT To understand quinupristin-dalfopristin resistance among clinical isolates of gram-positive bacteria in Taiwan, where this agent is not yet available for clinical use, we evaluated 1,287 nonduplicate isolates recovered from January 1996 to December 1999 for in vitro susceptibility to quinupristin-dalfopristin and other newer antimicrobial agents. All methicillin-susceptible Staphylococcus aureus (MSSA) isolates were susceptible to quinupristin-dalfopristin. High rates of nonsusceptibility to quinupristin-dalfopristin (MICs, ≥2 μg/ml) were demonstrated for the following organisms: methicillin-resistant S. aureus (MRSA) (31%), coagulase-negative staphylococci (CoNS) (16%),Streptococcus pneumoniae (8%), viridans group streptococci (51%), vancomycin-susceptible enterococci (85%), vancomycin-resistantEnterococcus faecalis (100%), vancomycin-resistantEnterococcus faecium (66%), Leuconostoc spp. (100%), Lactobacillus spp. (50%), andPediococcus spp. (87%). All isolates of MSSA, MRSA,S. pneumoniae, and viridans group streptococci were susceptible to vancomycin and teicoplanin. The rates of nonsusceptibility to vancomycin and teicoplanin were 5 and 7%, respectively, for CoNS, ranging from 12 and 18% for S. simulans to 0 and 0% for S. cohnii and S. auricularis. Moxifloxacin and trovafloxacin had good activities against these isolates except for ciprofloxacin-resistant vancomycin-resistant enterococci and methicillin-resistant staphylococci. In Taiwan, virginiamycin has been used in animal husbandry for more than 20 years, which may contribute to the high rates of quinupristin-dalfopristin resistance.

scholarly journals In Vitro Evaluation of CBR-2092, a Novel Rifamycin-Quinolone Hybrid Antibiotic: Microbiology Profiling Studies with Staphylococci and Streptococci

2008 ◽  
Vol 52 (7) ◽  
pp. 2324-2334 ◽  
Author(s):  
Gregory T. Robertson ◽  
Eric J. Bonventre ◽  
Timothy B. Doyle ◽  
Qun Du ◽  
Leonard Duncan ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Minimal Bactericidal Concentration ◽  
Gram Positive ◽  
Mutant Prevention Concentration ◽  
Balanced Contributions ◽  
Resistant Strains ◽  
Hybrid Antibiotic ◽  
Time Kill ◽  
Gram Positive Cocci

ABSTRACT We present data from antimicrobial assays performed in vitro that pertain to the potential clinical utility of a novel rifamycin-quinolone hybrid antibiotic, CBR-2092, for the treatment of infections mediated by gram-positive cocci. The MIC90s for CBR-2092 against 300 clinical isolates of staphylococci and streptococci ranged from 0.008 to 0.5 μg/ml. Against Staphylococcus aureus, CBR-2092 exhibited prolonged postantibiotic effects (PAEs) and sub-MIC effects (SMEs), with values of 3.2, 6.5, and >8.5 h determined for the PAE (3× MIC), SME (0.12× MIC), and PAE-SME (3× MIC/0.12× MIC) periods, respectively. Studies of genetically defined mutants of S. aureus indicate that CBR-2092 is not a substrate for the NorA or MepA efflux pumps. In minimal bactericidal concentration and time-kill studies, CBR-2092 exhibited bactericidal activity against staphylococci that was retained against rifampin- or intermediate quinolone-resistant strains, with apparent paradoxical cidal characteristics against rifampin-resistant strains. In spontaneous resistance studies, CBR-2092 exhibited activity consistent with balanced contributions from its composite pharmacophores, with a mutant prevention concentration of 0.12 μg/ml and a resistance frequency of <10−12 determined at 1 μg/ml in agar for S. aureus. Similarly, CBR-2092 suppressed the emergence of preexisting rifamycin resistance in time-kill studies undertaken at a high cell density. In studies of the intracellular killing of S. aureus, CBR-2092 exhibited prolonged bactericidal activity that was superior to the activities of moxifloxacin, rifampin, and a cocktail of moxifloxacin and rifampin. Overall, CBR-2092 exhibited promising activity in a range of antimicrobial assays performed in vitro that pertain to properties relevant to the effective treatment of serious infections mediated by gram-positive cocci.

scholarly journals In Vitro Activities of Daptomycin, Vancomycin, Linezolid, and Quinupristin-Dalfopristin against Staphylococci and Enterococci, Including Vancomycin- Intermediate and -Resistant Strains

2000 ◽  
Vol 44 (4) ◽  
pp. 1062-1066 ◽  
Author(s):  
Michael J. Rybak ◽  
Ellie Hershberger ◽  
Tabitha Moldovan ◽  
Richard G. Grucz
Keyword(s):  
Multidrug Resistant ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Vancomycin Resistant Enterococci ◽  
Alternative Drug ◽  
Potential Alternative ◽  
Resistant Strains ◽  
Vancomycin Resistant ◽  
Time Kill

ABSTRACT The in vitro activity of daptomycin was compared with those of vancomycin, linezolid, and quinupristin-dalfopristin against a variety (n = 203) of gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and S. epidermidis (MRSA and MRSE, respectively), vancomycin-resistant enterococci (VRE), and vancomycin-intermediate S. aureus(VISA). Overall, daptomycin was more active against all organisms tested, except Enterococcus faecium and VISA, against which its activity was similar to that of quinupristin-dalfopristin. In time-kill studies with MRSA, MRSE, VRE, and VISA, daptomycin demonstrated greater bactericidal activity than all other drugs tested, killing ≥3 log CFU/ml by 8 h. Daptomycin may be a potential alternative drug therapy for multidrug-resistant gram-positive organisms and warrants further investigation.

scholarly journals In Vitro Activities of Linezolid against Important Gram-Positive Bacterial Pathogens Including Vancomycin-Resistant Enterococci

1999 ◽  
Vol 43 (8) ◽  
pp. 2059-2062 ◽  
Author(s):  
Gary A. Noskin ◽  
Farida Siddiqui ◽  
Valentina Stosor ◽  
Donna Hacek ◽  
Lance R. Peterson
Keyword(s):  
Antibacterial Agents ◽  
Antimicrobial Agents ◽  
Active Agent ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
New Class ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant ◽  
Emergence Of Resistance

ABSTRACT The emergence of resistance in gram-positive bacteria has necessitated a search for new antimicrobial agents. Linezolid is an oxazolidinone, a new class of antibacterial agents with enhanced activity against pathogens. We compared the activity of linezolid to those of other antimicrobial agents against 3,945 clinical isolates. Linezolid demonstrated potent activity against all isolates tested. For all vancomycin-susceptible enterococci, staphylococci, and streptococci, the activity of linezolid was comparable to that of vancomycin. Against oxacillin-resistant staphylococci and vancomycin-resistant enterococci, linezolid was the most active agent tested. In summary, linezolid appears to be a promising new antimicrobial agent for the treatment of gram-positive infections.

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