Biomedical subjects
Publications and source records attributed to B P Goldstein.
In a phase 2 open-label, dose-ranging study in patients with candidemia, anidulafungin was effective in eradicating Candida albicans and other species of Candida. The anidulafungin MIC distribution showed that Candida albicans and C. glabrata were the most susceptible species and C. parapsilosis was the least susceptible species.
Dalbavancin is a bactericidal dimethylaminopropyl amide glycopeptide derivative possessing an extended serum elimination half-life in humans that allows once-weekly dosing for the therapy of Gram-positive infections. Strains from this baseline surveillance protocol in North America (NA; USA and Canada) and Europe (EU, 14 countries) were sampled in 2003. A total of 7,765 Gram-positive isolates (3,695 from NA and 4,070 from EU) were tested by reference broth microdilution methods against dalbavancin and 10 comparator agents. Species were analyzed separately by resistance phenotypes such as methicillin- (oxacillin-) resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and penicillin-resistant Streptococcus pneumoniae. Dalbavancin and other glycopeptides were very active against staphylococci (n=4648) with dalbavancin being 16- to 32-fold more potent than vancomycin (MIC90, 0.06 versus 2 mg/L). MRSA rates were greater (31.6%) in NA than in EU (26.1%). Quinupristin/dalfopristin resistance (MIC, > or = 2 mg/L; 0.1-0.5%) was documented more often in EU compared to NA. Dalbavancin (MIC50, 0.03-0.06 mg/L) was active against enterococci, except VanA resistance phenotypes. VRE rates were lower in EU (8.3%) then in NA (35.9%) from this resistance-enhanced enterococcal collection. Streptococci (dalbavancin MIC90, 0.016-0.03 mg/L) were generally most susceptible to glycopeptides (100.0%), quinupristin/dalfopristin (98.6-100.0%) and linezolid (100.0%); but dalbavancin was 16-fold more active than comparators. All vancomycin-susceptible enterococci and > 90% of vanB VRE had dalbavancin MIC values at < or = 1 mg/L,but vanA VRE strains had dalbavancin MIC results ranging from 0.06 to > 8 mg/L (median MIC, > or = 8 mg/L). Dalbavancin MIC values were not adversely influenced by geographic region or resistance phenotype (except vanA VRE). Infrequently isolated Gram-positive organisms such as Bacillus spp. (MIC90, 0.12 mg/L), Corynebacterium spp. (MIC90, 0.12 mg/L), Listeria monocytogenes (MIC90, 0.25 mg/L) and Micrococcus spp. (MIC90, 0.03 mg/L) were very susceptible to dalbavancin. In conclusion, these 2003 baseline resistance surveillance findings confirm the potent dalbavancin activity compared to several comparator agents against important Gram-positive pathogens. This high volume international survey indicates potential therapeutic roles for dalbavancin against many troublesome resistant Gram-positive phenotypes.
Nisin is a cationic peptide produced by Lactococcus lactis. Its activity against clinical isolates of Clostridium difficile was compared to that of vancomycin and metronidazole by minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and time-kill studies. Nisin was more active than the other agents, with a MIC90 of 0.256 mg/L and strong bactericidal activity. Nisin may be a promising agent for the management of C. difficile associated diarrhea.
The rabbit model of endocarditis was used to test the effectiveness of vancomycin and two different lysostaphin dosing regimens for the treatment of infections caused by a Staphylococcus aureus strain with reduced susceptibility to vancomycin (glycopeptide-intermediate susceptible S. aureus [GISA]). Vancomycin was ineffective, with no evidence of sterilization of aortic valve vegetations. However, rates of sterilization of aortic valve vegetations were significantly better for animals treated with either a single dose of lysostaphin (43%) or lysostaphin given twice daily for 3 days (83%) than for animals treated with vancomycin. Rabbits given a single dose of lysostaphin followed by a 3-day drug-free period had mean reductions in aortic valve vegetation bacterial counts of 7.27 and 6.63 log10 CFU/g compared with those for untreated control rabbits and the vancomycin-treated group, respectively. We conclude that lysostaphin is an effective alternative for the treatment of experimental aortic valve endocarditis caused by a clinical VISA strain.
The emergence of clinical isolates of methicillin-resistant Staphylococcus aureus with reduced susceptibility to vancomycin has prompted a search for new and novel therapeutic agents active against S. aureus. Lysostaphin, a peptidase produced by Staphylococcus simulans, specifically cleaves the glycine-glycine bonds unique to the interpeptide cross-bridge of the S. aureus cell wall. The effectiveness of various regimens of dosing with intravenous lysostaphin was compared to that of vancomycin in the rabbit model of aortic valve endocarditis caused by a clinical methicillin-resistant S. aureus isolate. All animals were treated for a total of 3 days. The most active regimen, lysostaphin given three times daily, produced sterile vegetations in 10 of 11 treated rabbits, with a mean reduction in vegetation bacterial counts of 8.5 log10 CFU/g compared to the counts in the untreated controls. In contrast, vancomycin given twice daily sterilized no vegetations and reduced vegetation bacterial counts by only 4.8 log10 CFU/g. Lysostaphin given once daily was less effective, reducing mean vegetation bacterial counts by only 3.6 log10 CFU/g, but the combination of lysostaphin once daily and vancomycin twice daily reduced the mean vegetation bacterial density by 7.5 log10 CFU/g, a result that was significantly better than that for either regimen alone (P < 0.05). Lysostaphin was well tolerated by the rabbits, with no evidence of immunological reactions following up to 9 weeks of intravenous administration. We conclude that lysostaphin given alone or in combination with vancomycin is more effective in the treatment of experimental methicillin-resistant S. aureus aortic valve endocarditis than vancomycin alone.
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Purpuromycin (1) is an antibiotic with a broad spectrum of antimicrobial activity, encompassing bacteria, fungi, and protozoa, particularly those involved in vaginal infections. With the aim of enhancing the solubility and reducing the serum binding, a chemical program of modifications was undertaken on the natural compound, and a new interesting series of derivatives at the naphthoquinone system was synthesized and evaluated as potential topical agents for vaginal infections. In particular three semisynthetic derivatives, 7'-amino (8a), 7'-methylamino (8b), 7'-ethylamino (8c), of 7'-demethoxypurpuromycin seemed to be the most promising. They were tested for in vitro activity against three of the most important vaginal pathogens and showed activity similar to that of purpuromycin against Candida isolates while they were significantly more active against Trichomonas vaginalis and Gardnerella vaginalis, which are cultured in media containing blood or serum. This is probably due to the fact that the activity of the derivatives is less antagonized by these supplements than that of purpuromycin.
We investigated the effect of ramoplanin coating on Staphylococcus aureus colonization of catheter segments in mice. Segments (1 cm in length) were inserted subcutaneously, 10(7) cfu of S. aureus were inoculated nearby at different times and segments were removed 24 or 48 h later. Uncoated segments were colonized with 10(4) to >10(5) cfu, whereas ramoplanin-coated segments had mean counts of <10 to approximately 100 cfu. Ramoplanin coating may prevent colonization of catheters during the first few days after insertion.
MDL 62,879 (GE2270A) 1 is a new inhibitor of elongation factor-Tu (EF-Tu) and belongs to the class of thiazolyl peptide antibiotics. Controlled acid hydrolysis of 1 followed by treatment with base resulted in the lost of the two terminal amino acids and in the formation of water-soluble MDL 62,935 2. Although less active in vitro than its parent compound, 2 was able to inhibit by 50% an Escherichia coli cell-free protein synthesis system at roughly the same concentration of 1. MDL 62,935 2 was subjected to further modification at the beta-phenylserine residue. Derivatives obtained from 2 were less active in both antimicrobial (MIC) and enzymatic (IC50) assays. This suggests that beta-phenylserine plays an important role for the inhibition of EF-Tu by 1 and 2.
Purpuromycin, an antibiotic produced by Actinoplanes ianthinogenes, had been reported previously to inhibit protein synthesis. In the present report, we demonstrate that the mechanism of action of this antibiotic is quite novel in that it binds with fairly high affinity to all tRNAs, inhibiting their acceptor capacity. Although more than one molecule of purpuromycin is bound to each tRNA molecule, the inhibitory activity of this antibiotic was found to be selective for the tRNA acceptor function; in fact, after the aminoacylation step, purpuromycin was found to affect none of the other tested functions of tRNA (interaction with the ribosomal P- and A-sites and interaction with translation factors). Accordingly, purpuromycin was found to inhibit protein synthesis only when translation depended on the aminoacylation of tRNA and not when the system was supplemented with pre-formed aminoacyl-tRNAs. Because purpuromycin did not interfere with the ATP-PPi exchange reaction of the synthetase or with the initial interaction of the enzyme with its tRNA substrate, the basis for the inhibition of aminoacylation is presumably the formation of a nonproductive synthetase-tRNA complex in the presence of purpuromycin in which the tRNA is unable to be charged with the corresponding amino acid.
Starting from the antibiotic A-40926 and the aglycone of A-40926 a series of compounds were prepared by modifying the free functionalities. Their antimicrobial activity was determined, particularly against Neisseria gonorrhoeae, against which A-40926, unlike other natural glycopeptides, is active. Improved in vivo activity was displayed by the monomethyl ester of A-40926 esterified at the carboxyl group of the N-acylamino-glucuronyl moiety.
Novel cyclic peptide antibiotics A21459 A and B are produced by a member of the genus Actinoplanes sp. These antibiotics inhibit bacterial protein synthesis and have selective antimicrobial activity against clostridia, mycoplasma and some Gram-negative bacteria.
Carboxamides and hydrazide of glycopeptide antibiotic eremomycin were obtained by a direct reaction of the carboxy group of eremomycin with an appropriate amine or hydrazine using diphenyl phosphorazidate as a condencing agent. Eremomycin hydrazide was also obtained by hydrazinolysis of the eremomycin methyl ester. Use of dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide for amidation led to the corresponding eremomycin ureides. The ESI-MS data indicate that eremomycin and its amides exist as dimers. The carboxamide, methylamide and benzylamide of eremomycin were as active against Gram-positive bacteria as the parent antibiotic, and the methylamide, benzylamide and hydrazide were almost an order of magnitude more active than eremomycin against Staphylococcus epidermidis clinical isolates in vitro. Amide of eremomycin as well as ureides were devoid of histamine liberating properties, which demonstrates that protection of the carboxyl group leads to a decrease in the allergenic properties.
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The new thiazolyl peptide antibiotic MDL 62,879 (GE2270 A) showed excellent in vitro activity in testing against staphylococci and streptococci, with MIC90s ranging from 0.23 to 0.9 mg/l. It was very active against Clostridium difficile and Propionibacterium acnes (MIC90 0.06 mg/l in each case) and had variable activity against Bacteroides spp. MDL 62,879 had exceptionally good activity against Enterococcus faecalis, including against a collection of high-level aminoglycoside-resistant isolates where it had an MIC90 of 0.047. The antibiotic was bacteriostatic for enterococcal isolates but bactericidal for a methicillin-resistant isolate of Staphylococcus aureus.
Purpuromycin and its semi-synthetic derivative MDL 63,604 had in-vitro activity similar to that of amphotericin B against isolates of Candida albicans. MDL 63,604 had activity similar to that of metronidazole against Trichomonas vaginalis. Both compounds were very active against most species of Gram-positive and Gram-negative anaerobes and against Gardnerella vaginalis. MDL 63,604 had significantly lower MICs than purpuromycin against T. vaginalis and most of the bacteria, probably due to antagonism of purpuromycin's activity by medium supplements (blood or serum). Purpuromycin or related compounds may have a potential role in the topical treatment of vaginitis and vaginosis.
MDL 63,246 is a semisynthetic derivative of the naturally occurring glycopeptide antibiotic MDL 62,476 (A40926). It was more active in vitro against Staphylococcus aureus and coagulase-negative staphylococci than MDL 62,476, teicoplanin, and vancomycin and was more active than mideplanin (MDL 62,873) against some isolates. MDL 63,246 had excellent activity against streptococci and teicoplanin-susceptible enterococci, and it also had in vitro activity against some VanA enterococcal isolates. It was more active than teicoplanin and vancomycin against acute staphylococcal, streptococcal, and enterococcal septicemia in immunocompetent and neutropenic mice. It was highly efficacious in reducing the bacterial load in the hearts of rats in staphylococcal endocarditis experiments and the bacterial load of Staphylococcus epidermis in a high infection model in neutropenic mice. The excellent in vivo activity of MDL 63,246 appears to correlate both with its in vitro antibacterial activity and with its long half-life in rodents.
Vancomycin resistance in enterococci is an emerging therapeutic problem. Resistance is not always detected by standard microbiological methods. Oligonucleotide primers for PCR were designed to target amplification of defined regions of genes of the vanA cluster, as well as vanB and vanC1. These primers correctly identified 30 vancomycin-resistant isolates tested (17 VanA, 7 VanB, and 6 Enterococcus gallinarum). No amplification was observed with Enterococcus casseliflavus or vancomycin-susceptible strains. Using PCR and Southern blotting, we found that all 17 VanA isolates had orf-1, orf-2, vanR, vanS, vanH, vanA, and vanY genes in the same sequence and that the intergenic distances in the vanR-vanA segments were the same. The described methods should be applicable to the rapid detection of the different vancomycin resistance genotypes in enterococci.