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Beth P Goldstein

Publications and source records attributed to Beth P Goldstein.

12 recordsLinked to original sources
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↗
PubMed2006

Spectrum and potency of dalbavancin tested against 3322 Gram-positive cocci isolated in the United States Surveillance Program (2004).

Dalbavancin is an injectable, next generation lipoglycopeptide with an extended serum elimination half-life. Once-weekly dosing has been successful for treatment of skin and skin structure (SSSI) and catheter-related bloodstream infections (CR-BSI). Concurrent with clinical trails, dalbavancin resistance surveillance was initiated in 2003, and results are reported here for the 2004 United States (USA) component. A total of 3322 Gram-positive cocci were tested by reference broth microdilution methods. Organism species tested included: Staphylococcus aureus (2102; 49% oxacillin-resistant), coagulase-negative staphylococci (CoNS; 255, 82% oxacillin-resistant), beta-hemolytic streptococci (241), viridans group streptococci (46), and Streptococcus pneumoniae (678). Dalbavancin (MIC90,0.06-0.12 microg/mL) was comparable in spectrum, but superior in potency to vancomycin (MIC90,1-2 microg/mL) against staphylococci. Dalbavancin MIC90 values against the tested streptococci was 0.03 microg/mL. Dalbavancin was more active against tested SSTI pathogens than comparator agents having complete susceptibility rates (100.0%) similar to vancomycin. Vancomycin, (16- to 32-fold), linezolid (8- to 32-fold), daptomycin (4- to 32-fold), and quinupristin/dalfopristin (4- to 32-fold) were less active than dalbavancin. In conclusion, dalbavancin exhibited greater potency than comparison glycopeptides or lipopeptides, streptogramin combinations, and oxazolidinones against Gram-positive pathogens associated with SSSI or CR-BSI. Dalbavancin wild-type MIC distributions remain unchanged compared with prior sampled years (2002-2003) in the USA.

Anti-Bacterial Agents↗
PubMed2006

In vitro interactions of anidulafungin with azole antifungals, amphotericin B and 5-fluorocytosine against Candida species.

Anidulafungin, an echinocandin, is in late stage development for the treatment of fungal infections. We investigated the activity of anidulafungin in combination with other antifungal agents (fluconazole, itraconazole, ketoconazole, amphotericin B and 5-fluorocytosine) against four isolates each of Candida albicans, Candida glabrata, Candida parapsilosis and Candida tropicalis, and two isolates of Candida krusei using a macrobroth chequerboard method with interactions evaluated by fractional inhibitory concentration indices (FICIs). Additive activity (FICI > 0.5 to 1) or indifference (FICI > 1 to < 4) was observed in 85 of 90 interactions of anidulafungin with another antifungal agent. Synergy with itraconazole (FICI or=4), a drug rarely used systemically, was noted for four strains of C. tropicalis. The combination of anidulafungin and amphotericin B demonstrated additive activity for each of the 18 isolates of Candida tested. These results suggest additional studies are warranted, for example in animal models, to evaluate further the potential of combination antifungal therapy with anidulafungin for Candida infections.

Amphotericin B↗
PubMed2006

Microbiologic characterization of isolates from a dalbavancin clinical trial for catheter-related bloodstream infections.

Dalbavancin, a new-generation semisynthetic lipoglycopeptide in phase 3 clinical development, has been documented to be more active than vancomycin or teicoplanin against Gram-positive bacteria, including multidrug-resistant strains, by in vitro testing and in animal models. The human pharmacokinetics of dalbavancin predicts efficacy at weekly dosing intervals. In a phase 2 open-label clinical trial, dalbavancin exhibited superiority when compared with vancomycin against catheter-related bloodstream infection (CR-BSI). The majority of pathogens identified in this study as in clinical practice were coagulase-negative staphylococci (CoNS), necessitating rigorous characterization of duplicate isolates to rule out contaminants and to validate cases for study evaluations. At follow-up for the intent-to-treat population, overall pathogen eradication was 92.3% for dalbavancin and 75.9% for vancomycin. We describe the details of organisms isolated, their epidemiologic/genetic characterization, susceptibility patterns against glycopeptides, and the eradication rates by organism group. In conclusion, dalbavancin was active against all isolated pathogens associated with CR-BSI (CoNS, Staphylococcus aureus and Enterococcus faecalis; all MIC results, < or = 0.25 microg/mL) and achieved significant (P < 0.05) clinical success when compared with vancomycin.

Anti-Bacterial Agents↗
PubMed2006

Comparison of dalbavancin MIC values determined by Etest (AB BIODISK) and reference dilution methods using gram-positive organisms.

While standardized microdilution testing methodologies and quality control ranges exist for the novel glycolipopeptide dalbavancin, no testing methods have been described that are immediately available for routine use in clinical laboratories. In this study, we found that the dalbavancin Etest (AB BIODISK, Solna, Sweden) procedure demonstrated a high degree of agreement (100% within +/-2 log(2) dilution steps) with the standardized broth microdilution method, validating the use of the Etest as an alternative test for investigational or clinical purposes following regulatory approval.

Anti-Bacterial Agents↗
PubMed2005

Origin, structure, and activity in vitro and in vivo of dalbavancin.

Dalbavancin is a novel semi-synthetic lipoglycopeptide that was designed to improve upon the natural glycopeptides currently available, vancomycin and teicoplanin. Chemical modification of natural glycopeptides has produced compounds with more potent antimicrobial activity and longer t(1/2), while maintaining an excellent safety profile. Dalbavancin, prepared from a teicoplanin-like glycopeptide, has better activity, in vitro and in animal infection models, than vancomycin and teicoplanin. In particular, dalbavancin has excellent activity against staphylococci, including coagulase-negatives. A unique feature of dalbavancin is its pharmacokinetics, characterized by a long elimination t(1/2) in humans which makes a once-weekly dosing regimen feasible. Dalbavancin recently completed Phase 3 clinical trials in skin and skin structure infection.

Animals↗
PubMed2005

In vitro antistaphylococcal activity of dalbavancin, a novel glycopeptide.

OBJECTIVES: Dalbavancin is a novel, semi-synthetic glycopeptide antibiotic. The aim of this study was to further explore its activity against staphylococci. METHODS: The bactericidal activity of dalbavancin was studied using MBC and time-kill methods. The potential for resistance to dalbavancin was examined using single-step and serial-passage experiments. RESULTS: Dalbavancin was bactericidal against methicillin-susceptible and -resistant Staphylococcus aureus, in both the presence and absence of human serum. No resistance was seen with any isolate tested. After serial passage, bacterial populations were more homogeneous in their susceptibility to dalbavancin than to vancomycin or teicoplanin. CONCLUSION: Dalbavancin is bactericidal for staphylococci. Resistance to this semi-synthetic glycopeptide is not readily developed in vitro.

Anti-Bacterial Agents↗
PubMed2005

Cross-resistance of Escherichia coli RNA polymerases conferring rifampin resistance to different antibiotics.

In this study we further defined the rifampin-binding sites in Escherichia coli RNA polymerase (RNAP) and determined the relationship between rifampin-binding sites and the binding sites of other antibiotics, including two rifamycin derivatives, rifabutin and rifapentine, and streptolydigin and sorangicin A, which are unrelated to rifampin, using a purified in vitro system. We found that there is almost a complete correlation between resistance to rifampin (Rif(r)) and reduced rifampin binding to 12 RNAPs purified from different rpoB Rif(r) mutants and a complete cross-resistance among the different rifamycin derivatives. Most Rif(r) RNAPs were sensitive to streptolydigin, although some exhibited weak resistance to this antibiotic. However, 5 out of the 12 Rif(r) RNAPs were partially resistant to sorangicin A, and one was completely cross-resistant to sorangicin A, indicating that the binding site(s) for these two antibiotics overlaps. Both rifampin and sorangicin A inhibited the transition step between transcription initiation and elongation; however, longer abortive initiation products were produced in the presence of the latter, indicating that the binding site for sorangicin A is within the rifampin-binding site. Competition experiments of different antibiotics with (3)H-labeled rifampin for binding to wild-type RNAP further confirmed that the binding sites for rifampin, rifabutin, rifapentine, and sorangicin A are shared, whereas the binding sites for rifampin and streptolydigin are distinct. Because Rif(r) mutations are highly conserved in eubacteria, our results indicate that this set of Rif(r) mutant RNAPs can be used to screen for new antibiotics that will inhibit the growth of Rif(r) pathogenic bacteria.

Anti-Bacterial Agents↗
PubMed2004

A randomized, double-blind trial of anidulafungin versus fluconazole for the treatment of esophageal candidiasis.

Anidulafungin is a novel antifungal agent of the echinocandin class. This randomized, double-blind, double-dummy study compared the efficacy and safety of intravenous anidulafungin to that of oral fluconazole in 601 patients with endoscopically and microbiologically documented esophageal candidiasis. Patients received intravenous anidulafungin (100 mg on day 1, followed by 50 mg per day) or oral fluconazole (200 mg on day 1, followed by 100 mg per day) for 7 days beyond resolution of symptoms (range, 14-21 days). At the end of therapy, the rate of endoscopic success for anidulafungin (242 [97.2%] of 249 treated patients) was found to be statistically noninferior to that for fluconazole (252 [98.8%] of 255 treated patients; treatment difference, -1.6%; 95% confidence interval, -4.1 to 0.8). The safety profile of anidulafungin was similar to that of fluconazole; treatment-related adverse events occurred in 9.3% and 12.0% of patients, respectively. Laboratory parameters were similar between treatment arms. Anidulafungin is as safe and effective as oral fluconazole for the treatment of esophageal candidiasis, when assessed at the completion of therapy.

Administration, Oral↗
PubMed2004

Phase 2, randomized, dose-ranging study evaluating the safety and efficacy of anidulafungin in invasive candidiasis and candidemia.

This study evaluated the safety and efficacy of anidulafungin, a novel echinocandin, in patients with invasive candidiasis, including candidemia. A total of 123 eligible patients were randomized to one of three intravenous regimens, 50, 75, or 100 mg once daily. Treatment continued for 2 weeks beyond resolution or improvement of signs and symptoms. The primary efficacy criterion was a successful global response rate (i.e., clinical and microbiological success) in the evaluable population at the follow-up (FU) visit, 2 weeks after end of therapy (EOT). One hundred twenty (120) patients received at least one dose of anidulafungin; 68 were evaluable. Review of adverse events and laboratory data indicated no dose response for safety parameters. Non-albicans Candida species accounted for approximately one-half of all isolates. Success rates at EOT were 84, 90, and 89% in the 50-, 75-, and 100-mg groups, respectively. At FU, the success rates were 72, 85, and 83%. Phase 3 studies of anidulafungin for the treatment of invasive candidiasis and candidemia are warranted.

APACHE↗
PubMed2003

Once-weekly dalbavancin versus standard-of-care antimicrobial regimens for treatment of skin and soft-tissue infections.

Dalbavancin, a novel glycopeptide with a long elimination half-life ( approximately 9-12 days), was compared to standard antimicrobial therapy for skin and soft-tissue infections (SSTIs). In a randomized, controlled, open-label, phase 2 proof-of-concept trial, adults received 1100 mg of dalbavancin (as a single intravenous infusion), 1000 mg of dalbavancin intravenously and then 500 mg intravenously 1 week later, or a prospectively defined standard-of-care regimen. A gram-positive pathogen was isolated from samples obtained from 41 (66%) of 62 patients at baseline; Staphylococcus aureus was the most prevalent species (83% of pathogens). Clinical success rates at a follow-up visit (test of cure) were 94.1% among patients treated with 2 doses of dalbavancin, 61.5% among patients treated with 1 dose of dalbavancin, and 76.2% among patients treated with a standard-of-care regimen. All treatment regimens were well tolerated; drug-related adverse reaction rates were similar across the 3 groups. These findings suggest that a regimen of 2 doses of dalbavancin administered 1 week apart is effective in the treatment of complicated, gram-positive bacterial SSTIs and warrants further study.

Adult↗