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

410

323

The emergence and spread of multidrug-resistant gram-positive bacteria represent a serious clinical problem. Telavancin is a novel lipoglycopeptide antibiotic that possesses rapid in vitro bactericidal activity against a broad spectrum of clinically relevant gram-positive pathogens. Here we demonstrate that telavancin's antibacterial activity derives from at least two mechanisms. As observed with vancomycin, telavancin inhibited latestage peptidoglycan biosynthesis in a substrate-dependent fashion and bound the cell wall, as it did the lipid II surrogate tripeptide N,N-diacetyl-L-lysinyl-D-alanyl-D-alanine, with high affinity. Telavancin also perturbed bacterial cell membrane potential and permeability. In methicillin-resistant Staphylococcus aureus, telavancin caused rapid, concentration-dependent depolarization of the plasma membrane, increases in permeability, and leakage of cellular ATP and K ؉ . The timing of these changes correlated with rapid, concentration-dependent loss of bacterial viability, suggesting that the early bactericidal activity of telavancin results from dissipation of cell membrane potential and an increase in membrane permeability. Binding and cell fractionation studies provided direct evidence for an interaction of telavancin with the bacterial cell membrane; stronger binding interactions were observed with the bacterial cell wall and cell membrane relative to vancomycin. We suggest that this multifunctional mechanism of action confers advantageous antibacterial properties.The emergence and spread of bacterial resistance to vancomycin, an important antibiotic used to treat serious infections caused by gram-positive bacteria, has prompted active research to discover new glycopeptides and semisynthetic analogs with improved antimicrobial properties. Vancomycin and related glycopeptide antibiotics inhibit cell wall synthesis in susceptible bacteria by binding with high specificity to peptidoglycan precursors containing the C-terminal D-alanyl-D-alanine (D-Ala-DAla) motif (8). The peptide portion of glycopeptide antibiotics forms a carboxylate binding pocket that imparts, through a combination of five hydrogen bonds plus favorable hydrophobic interactions, strong affinity for the D-Ala-D-Ala-containing terminus of lipid II (8,46,54). Rational approaches toward the design of glycopeptides with improved antimicrobial activities have been described previously (for reviews, see references 35 and 36). One promising approach has been the discovery of lipoglycopeptides, analogs containing hydrophobic groups substituted at the amine position of the disaccharide moiety (20,39,40,45).Telavancin, a semisynthetic derivative of vancomycin possessing a hydrophobic (decylaminoethyl) side chain appended to the vancosamine sugar and a hydrophilic [(phosphonomethyl)aminomethyl] group on the resorcinol-like 4Ј position of amino acid 7 (33), is in late-stage clinical development for the treatment of serious gram-positive infections. Telavancin and other lipoglycopeptides exhibit superior in vitro activity compa...

Section: Discussioncontrasting

confidence: 54%

Telavancin, a Multifunctional Lipoglycopeptide, Disrupts both Cell Wall Synthesis and Cell Membrane Integrity in Methicillin-Resistant Staphylococcus aureus

Higgins

Chang

Debabov

et al. 2005

410

323

“…2C was 0.9693, whereas the RMSE was 0.9840 for the simple log-linear model in Fig. 2A Taken together, the data presented here are very consistent with those in several published reports suggesting that bacterial killing associated with daptomycin is concentration dependent and is therefore related to the absolute concentration or to the ratio of the daptomycin concentration to the MIC (6,(14)(15)(16). Discernible increases in the rate of S. aureus killing were observed over a range of free daptomycin concentrations in the peripheral compartment, ranging from approximately 0.12x to 27x the MIC and appeared to be consistent with a saturable process.…”

supporting

confidence: 81%

“…Several investigators have compared the activity of daptomycin at various concentrations in a timekill curve fashion and have reported concentration-dependent killing against gram-positive cocci (6,(14)(15)(16). Most of those investigations were done over a relatively narrow range of daptomycin concentrations in comparison with the MICs.…”

mentioning

confidence: 99%

“…These data confirm that daptomycin exhibits concentration-dependent g over a wide range of fee daptomycn concentrations relative to the MIC and suggest that this is a saturable process similar to the Michaelis-Menten pharmacokinetic elimination of certain drugs. Daptomycin (6,(14)(15)(16). Most of those investigations were done over a relatively narrow range of daptomycin concentrations in comparison with the MICs.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Investigation of the early killing of Staphylococcus aureus by daptomycin by using an in vitro pharmacodynamic model

Vance‐Bryan

Larson

Rotschafer

et al. 1992

The purpose of this study was to develop a pharmacodynamic model to describe the dependency of the rate of Staphykooccus aureus killing upon the concentration of daptomycin. A range of fee (unbound) daptomycin concentrations ranging from 0.12 to 27 times the MIC were simulated in the peripheral ptment of a two-compartment pharmacoldnetic model. ILg-linear regression of fee daptomycin concentraions versus growth or kill rate constants showed a significant correlation (r = -0.90; P < 0.0001). A Uineweaver-Burk plot of the reciprocal transformation of these data yielded a poor fit (r = -0.38; P > 0.05). When a Lineweaver-Burk-type regression analysis was performed on the reciprocal of the change in the rate constant rather than the rate constant itself, the result demonstrated good correlation (r = 0.90; P < 0.0001). The observations were also well described by a sigmoidal maximum plateau phamnacologic effect model, in which the pharmacologic effect of daptomycin is a reduction in the bacterial exponential growth rate constant from the baseline in the absence of antibiotic to a lower (positive) growth or (negative) death rate constant observed in the presence ofantibiotic. These data confirm that daptomycin exhibits concentration-dependent g over a wide range of fee daptomycn concentrations relative to the MIC and suggest that this is a saturable process similar to the Michaelis-Menten pharmacokinetic elimination of certain drugs.Daptomycin (LY146032) is a semisynthetic lipopeptide antibiotic with excellent in vitro activity against a variety of gram-positive bacteria including methicillin-susceptible and methicillin-resistant strains of Staphylococcus aureus (2, 3, 5, 8-10, 12, 17). Several investigators have compared the activity of daptomycin at various concentrations in a timekill curve fashion and have reported concentration-dependent killing against gram-positive cocci (6,(14)(15)(16). Most of those investigations were done over a relatively narrow range of daptomycin concentrations in comparison with the MICs. Those studies generally also incorporated study designs which would not easily allow mathematical modeling of pharmacodynamic data. Most of those investigations were also conducted under static in vitro environmental conditions in which antibiotic concentrations were held constant for various lengths of time. Unfortunately, the relationship between antibiotic concentration and time for most infectious disease processes cannot be accurately described as static.Previous investigations have failed to quantitate the concentration-versus-kill rate relationship in a fashion that would enable the prediction of a concentration-time proffile of drug delivery that would produce superior killing efficiency. Without a mathematical model to depict the interaction of drug concentration and pharmacologic effects, clinicians are in the same position that they were in at the infancy of the science of pharmacokinetics. One could measure drug concentrations in body fluids and relate a high or low concentration to toxici...

“…Kill-kinetic studies were performed using log-phase cultures adjusted to approximately 106 CFU/ml in supplemented Mueller-Hinton broth. The concentrations tested were 4x the MIC for daptomycin, a concentration previously shown to be maximally bactericidal for most enterococci (20); 1 x, 2 x, and 4 x the MIC for ramoplanin; 20 ,ug/ml for vancomycin; 40 ,ug/ml for ampicillin; and 3 ,ug/ml for ciprofloxacin. The concentrations of the currently available antibiotics were chosen because they reflected medium to maximal clinically achievable blood concentrations.…”

mentioning

confidence: 99%

Bactericidal activities of peptide antibiotics against multidrug-resistant Enterococcus faecium

Mobarakai¹,

Quale²,

Landman³

1994

Multidrug-resistant Enterococcus faecium has emerged as a serious pathogen for which no effective therapy has been established. In this report, we describe the activities of two peptide antibiotics, ramoplanin and daptomycin, against 15 isolates of E. faecium resistant to vancomycin, ampicillin, and aminoglycosides using time-kill experiments. Both antibiotics were rapidly bactericidal when tested in broth; however, the addition of 50% serum resulted in significant regrowth. The combination of ampicillin with either ramoplanin or daptomycin largely prevented this regrowth. These peptide antibiotics showed good activity against these pathogens. While the development of daptomycin has been halted, ramoplanin may hold promise for the therapy of multidrug-resistant E. faecium, especially when combined with ampicillin.