evernimicin and Bacterial-Infections

The increasing resistance among Gram-positive cocci have been accompanied by their increasing frequency as cause of severe infection. Thus new antimicrobial agents, TAZ/PIPC, synercid and linezolid, are in various stages of development. TAZ/PIPC, a combination drug of a new beta-lactamase inhibitor tazobactam and piperacillin at ratio in 1 to 4 has a broad spectrum of antimicrobial activity. Evidence from randomized clinical trials in adults in Japan has shown that TAZ/PIPC is superior to PIPC as a drug for complicated urinary tract infection. Synercid is a streptogramin antibiotic. The spectrum of activity of synercid is similar to vancomycin. Furthermore, most of E. faecium were susceptible. The efficacy of synercid in clinical trials in patients infected with VREF was 65-70%. Linezolid is a member of the oxazolidinones. The antimicrobial spectrum of linezolid is similar to that of vancomycin. In the US, patients with significant infection caused by resistant Gram-positive organisms(mostly VREF) were treated with linezolid. The efficacy of linezolid was about 75%. The clinical trials for everninomicin had been discontinued because of insufficient clinical data supporting its efficacy and safety.

Topics: Acetamides; Adult; Aminoglycosides; Anti-Bacterial Agents; Anti-Infective Agents; Bacterial Infections; Drug Combinations; Drug Therapy, Combination; Enzyme Inhibitors; Humans; Linezolid; Oxazolidinones; Penicillanic Acid; Penicillins; Piperacillin; Protein Synthesis Inhibitors; Tazobactam; Virginiamycin

Topics: Aminoglycosides; Anti-Bacterial Agents; Anti-Infective Agents; Bacterial Infections; Daptomycin; Drug Resistance, Bacterial; Drug Therapy, Combination; Fluoroquinolones; Humans; Oxazolidinones; Protein Synthesis Inhibitors; Vancomycin; Virginiamycin

One of the most challenging issues in the design of phase II/III clinical trials of antimicrobial agents is dose selection. The choice is often based on preclinical data from pharmacokinetic (PK) studies with animals and healthy volunteers but is rarely linked directly to the target organisms except by the MIC, an in vitro measure of antimicrobial activity with many limitations. It is the thesis of this paper that rational dose-selection decisions can be made on the basis of the pharmacodynamics (PDs) of the test agent predicted by a mathematical model which uses four data sets: (i) the distribution of MICs for clinical isolates, (ii) the distribution of the values of the PK parameters for the test drug in the population, (iii) the PD target(s) developed from animal models of infection, and (iv) the protein binding characteristics of the test drug. In performing this study with the new anti-infective agent evernimicin, we collected a large number (n = 4,543) of recent clinical isolates of gram-positive pathogens (Streptococcus pneumoniae, Enterococcus faecalis and Enterococcus faecium, and Staphylococcus aureus) and determined the MICs using E-test methods (AB Biodisk, Stockholm, Sweden) for susceptibility to evernimicin. Population PK data were collected from healthy volunteers (n = 40) and patients with hypoalbuminemia (n = 12), and the data were analyzed by using NPEM III. PD targets were developed with a neutropenic murine thigh infection model with three target pathogens: S. pneumoniae (n = 5), E. faecalis (n = 2), and S. aureus (n = 4). Drug exposure or the ratio of the area under the concentration-time curve/MIC (AUC/MIC) was found to be the best predictor of microbiological efficacy. There were three possible microbiological results: stasis of the initial inoculum at 24 h (10(7) CFU), log killing (pathogen dependent, ranging from 1 to 3 log(10)), or 90% maximal killing effect (90% E(max)). The levels of protein binding in humans and mice were similar. The PK and PD of 6 and 9 mg of evernimicin per kg of body weight were compared; the population values for the model parameters and population covariance matrix were used to generate five Monte Carlo simulations with 200 subjects each. The fractional probability of attaining the three PD targets was calculated for each dose and for each of the three pathogens. All differences in the fractional probability of attaining the target AUC/MIC in this PD model were significant. For S. pneumoniae, the probabi

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Area Under Curve; Bacterial Infections; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Gram-Positive Bacteria; Methicillin Resistance; Mice; Microbial Sensitivity Tests; Monte Carlo Method; Oligosaccharides; Protein Binding; Staphylococcus aureus

Novel antibiotic everninomicin D is chemically transformed into new biologically active derivatives. Reactions of a nitro group attached to a tertiary carbon center have been investigated. Synthesis and reactions of hydroxylaminoeverninomicin D, aminoeverninomicin D and their derivatives have been discussed.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Chemical Phenomena; Chemistry; Drug Stability; Glycosides; Rats