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Use of Monte Carlo Simulations To Select Therapeutic Doses and Provisional Breakpoints of BAL9141. Johan W. Mouton, 2004.BAL9141, a new antimicrobial agent belonging to the class of parenteral pyrrolidinone-3-ylidenemethyl cephalosporins, is active against most gram-positive microorganisms, including methicillin-resistant variants (methicillin-resistant Staphylococcus aureus [MRSA] and methicillin-resistant Staphylococcus epidermidis [MRSE]), as well as against penicillin-resistant pneumococci (PRP) and many gram-negative microorganisms . BAL9141 is administered as the prodrug BAL5788, which is rapidly converted to BAL9141 by plasma esterases . Pharmacokinetic (PK) data obtained in a previous multiple ascending dose study were used to fit a population PK model to using the NPEM2 program, yielding PK parameter estimates and its covariance matrix for BAL9141 . These estimates and matrix were used to perform Monte Carlo simulations (MCSs) and obtain unbiased target attainment rates (TARs) for various time periods during which the concentration remains above the MIC (T>MIC) . Assuming a T>MIC of 40%, TARs of 100% were reached with a dose of 500 mg/liter every 12 h for pathogens with MICs of 2 mg/liter and with a dose of 750 mg/liter every 12 h for pathogens with MICs of 4 mg/liter . Because MICs are  2 mg/liter for most strains of MRSA, MRSE, and PRP (with some strains showing an MIC of 4 mg/liter), a dosing regimen of 750 mg every 12 h is proposed for clinical studies . The corresponding provisional breakpoint is S (susceptible)
4 mg/liter .
Combined Use of Cultivation-Dependent and Cultivation-Independent Methods Indicates that Members of Most Haloarchaeal Groups in an Australian Crystallizer Pond Are Cultivable. D. G. Burns, 2004.Haloarchaea are the dominant microbial flora in hypersaline waters with near-saturating salt levels . The haloarchaeal diversity of an Australian saltern crystallizer pond was examined by use of a library of PCR-amplified 16S rRNA genes and by cultivation . High viable counts (106 CFU/ml) were obtained on solid media . Long incubation times (  8 weeks) appeared to be more important than the medium composition for maximizing viable counts and diversity . Of 66 isolates examined, all belonged to the family Halobacteriaceae, including members related to species of the genera Haloferax, Halorubrum, and Natronomonas . In addition, isolates belonging to a novel group (the ADL group), previously detected only as 16S rRNA genes in an Antarctic hypersaline lake (Deep Lake), were cultivated for the first time . The 16S rRNA gene library identified the following five main groups: Halorubrum groups 1 and 2 (49%), the SHOW (square haloarchaea of Walsby) group (33%), the ADL group (16%), and the Natronomonas group (2%) . There were two significant differences between the organisms detected in cultivation and 16S rRNA sequence results . Firstly, Haloferax spp . were frequently isolated on plates (15% of all isolates) but were not detected in the 16S rRNA sequences . Control experiments indicated that a bias against Haloferax sequences in the generation of the 16S rRNA gene library was unlikely, suggesting that Haloferax spp . readily form colonies, even though they were not a dominant group . Secondly, while the 16S rRNA gene library identified the SHOW group as a major component of the microbial community, no isolates of this group were obtained . This inability to culture members of the SHOW group remains an outstanding problem in studying the ecology of hypersaline environments .
Characterization of Streptococcus suis Genes Encoding Proteins Homologous to Sortase of Gram-Positive Bacteria. Makoto Osaki, 2002. Two Nucleoside Uptake Systems in Lactococcus lactis: Competition between Purine Nucleosides and Cytidine Allows for Modulation of Intracellular Nucleotide Pools. Jan Martinussen, 2003.A method for measuring internal nucleoside triphosphate pools of lactococci was optimized and validated . This method is based on extraction of 33P-labeled nucleotides with formic acid and evaluation by two-dimensional chromatography with a phosphate buffer system for the first dimension and with an H3BO3-LiOH buffer for separation in the second dimension . We report here the sizes of the ribo- and deoxyribonucleotide pools in laboratory strain MG1363 during growth in a defined medium . We found that purine- and pyrimidine-requiring strains may be used to establish physiological conditions in batch fermentations with altered nucleotide pools and growth rates by addition of nucleosides in different combinations . Addition of cytidine together with inosine to a purine-requiring strain leads to a reduction in the internal purine nucleotide pools and a decreased growth rate . This effect was not seen if cytidine was replaced by uridine . A similar effect was observed if cytidine and inosine were added to a pyrimidine-requiring strain; the UTP pool size was significantly decreased, and the growth rate was reduced . To explain the observed inhibition, the nucleoside transport systems in Lactococcus lactis were investigated by measuring the uptake of radioactively labeled nucleosides . The Km for for inosine, cytidine, and uridine was determined to be in the micromolar range . Furthermore, it was found that cytidine and inosine are competitive inhibitors of each other, whereas no competition was found between uridine and either cytidine or inosine . These findings suggest that there are two different high-affinity nucleoside transporters, one system responsible for uridine uptake and another system responsible for the uptake of all purine nucleosides and cytidine .
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